(BQ) Part 2 boook “A clinical approach to medicine” has contents: Medical oncology, neurology, pediatrics, obstetrics and gynecology, renal medicine, respiratory medicine, rehabilitative medicine, rheumatology.
Medical Oncology This page intentionally left blank 50 Pathogenesis of Cancer Richard Epstein GENERAL CONCEPTS Is cancer most accurately regarded as a disease, a group of different diseases, or a “normal” degenerative condition similar to aging? To gain insight into this key question, we need to consider what is already wellestablished about the natural history of human cancer First, malignancy is remarkably uncommon in individuals younger than 40 years old, suggesting a Darwinian predilection for the postreproductive age group Consistent with this, human cells are more difficult to transform in vitro than are cells of more short-lived mammalian species Hence, genetic stability is an intrinsic property of cells which appears to vary inversely with cancer susceptibility in vivo Second, tumor types which can be cured in their advanced stages tend to be rare, whereas common cancers in their advanced stages are usually incurable This is not simply a matter of bad luck for the human race Rather, it reflects the fact that rare neoplasms arise due to rare genetic events (which in turn are often flagged by characteristic chromosomal translocations), whereas common cancers arise via the progressive 869 870 A Clinical Approach to Medicine accumulation of common genetic mutations This latter process results not only in loss of growth control, but also in profound genetic instability similar to that which normally confers an adaptive survival advantage on bacterial cells Conversely, the sustained clinical remissions that famously accompany the treatment of certain advanced malignancies are likely to be related to the relatively normal composition (and hence stability) of the genome in those tumor cells The main problem that most cancer patients face today is not rapid tumor cell growth as such, but rather the presence of genetic instability that transforms the disease into a therapeutic “moving target” Not surprisingly, then, the distinction between rare and common cancers has implications for pathogenesis at the molecular level For a single chromosomal translocation event to trigger cell transformation, a critical mutation (including gain-of-function mutations) must be induced to drive or permit the necessary growth advantage In contrast, the pathogenesis of common cancers depends mainly on the incremental accumulation of loss-of-function mutations This dichotomy gives rise to the contemporary model of two broad groups of “cancer genes”: oncogenes and tumor suppressor genes Oncogenes (or proto-oncogenes, which term designates the normal cellular homologue) are genes involved in cell growth A gain-of-function mutation affecting one of these genes can have profound consequences on cell growth, and as few as two oncogene mutations can fully transform an otherwise normal cell line in vitro On the other hand, the sudden acquisition of an activated oncogene by a completely normal cell can result not in cell growth but in cell death, indicating the existence of intact molecular “checkpoints” to cell growth Tumor suppressor genes are most commonly cell cycle control genes, though not invariably A single cell line or tumor can accumulate numerous mutations of tumor suppressor genes, each one of which may contribute independently to the transformed phenotype The acquisition of these control defects plays a permissive role in cell growth by conferring resistance to normal cell death (apoptosis) Tumor suppressor gene defects can also permit the viable retention of oncogene mutations, further driving uncontrolled growth It is this combined genetic picture of suppressor gene loss and oncogene activation that characterizes most common advanced human cancers Examples of tumor suppressor genes which often incur disabling mutations in human tumors include p53, Pathogenesis of Cancer 871 p21Cip1, p16Ink4, and pRb (the retinoblastoma susceptibility gene product), whereas dominant oncogenes may undergo constitutive activation by mutations (e.g the codon 12 mutation implicated in K-Ras activation in colon carcinogenesis) PROCESSES AND PATHWAYS How and why mutations occur in the genes of normal cells? Normal DNA is subject to numerous damaging events, with many thousands of such events occurring in each cell every day That these damaging lesions are so efficiently removed is evidence of a highly efficient repair enzyme network within cell nuclei This process of DNA damage and repair is an entirely normal one in all living organisms and environments There are several different possible outcomes from this interaction between DNA damage and repair First, the cell can repair the damage and continue to grow This is by far the most common outcome, and the timing of the cell cycle makes allowance for such repair prior to both DNA synthesis and mitotic cell division (i.e during the gap — G1 and G2 — phases of the cell cycle) Second, if the amount of damage induced is sufficiently high, extra time will be required for these cells to repair; this is made evident by the occurrence of cell cycle delay A third possible outcome is that the cell is so overwhelmed by damage that it is unable to repair, resulting in cell death With respect to cancer pathogenesis, DNA damage plays a critical role insofar as it increases the probability of gene mutations, some of which may not be repaired The latter will be clonally preserved if they confer a short-term growth advantage Such growth-promoting mutations can accumulate progressively within the clonal cell outgrowth, leading to progressive dominance of the abnormal cell clone that may form a tumor Such tumors may be benign or malignant, depending upon whether the uncontrolled growth is also associated with tissue invasion or distant metastasis The pathogenesis of these manifestations of tumor progression may well involve positive-feedback growth loops between normal stromal cells and tumor cells mediated via a complex cross-talk between secreted proteases and cytokines It is important to note that not all steps in cancer progression are mediated via genetic mutations So-called epigenetic events may also contribute to tumorigenesis: an instructive example is that of methylase-dependent 872 A Clinical Approach to Medicine cytosine methylation, whereby methylcytosine-binding proteins recruit histone deacetylases to induce heritable transcriptional repression via chromatin condensation Non-mutated tumor suppressor genes are frequently inactivated via promoter methylation occurring within tumors, just as wild-type proto-oncogenes may become hyperactivated via regional DNA hypomethylation ENVIRONMENT VERSUS GENES To most people cancer is a bewildering phenomenon; understandably, then, many attempts have been made to explain its occurrence One of the most popular models for experimental human cancer has involved the application of chemical carcinogens to animals This early work led to the distinction between two qualitatively different cancer-causing chemical categories: genotoxic carcinogens, which directly damage the genetic material, and non-genotoxic carcinogens, which promote the growth of established tumors but not interact directly with DNA The distinction between these two classes of cancer-causing chemicals led to the modeling of tumor growth into two phases: initiation and promotion The relevance of this model to human cancer growth is debatable It is certainly possible that tumors can be initiated by genotoxic stimuli, as was evident following the Hiroshima atomic bomb If the background level of tumor incidence in the human population is related to genotoxic stimuli, however, then for many cancers the risk appears to be distributed so evenly as to suggest that such exposure is ubiquitous Of course, there are several important exceptions to this The most obvious is cigarette smoking, an exposure now notorious for the high concentration of carcinogens associated with it Similarly, ultraviolet irradiation of pale skin is associated with the efficient accumulation of DNA-damaging events, some of which are capable of causing cell transformation Prolonged viral infections, such as those causing chronic hepatitis or papillomavirus infection of the cervix, are also associated with cancer induction, albeit via uncertain pathways An intriguing aspect of human carcinogenesis involves the rising incidence of certain tumors following the putative “Westernization” of lifestyle This was illustrated by migration studies and longitudinal studies in developing countries, particularly with respect to cancers of the breast, colon and prostate The most obvious lifestyle variable implicated Pathogenesis of Cancer 873 in this process is diet, though whether the culprit will turn out to be total calories or a qualitative component (e.g saturated fat) remains controversial Certainly, it appears unlikely that any directly genotoxic ingredient will be centrally implicated In recent years a number of environmental etiologies have been identified in relation to certain malignancies Chronic infection with the acidresistant bacterium, Helicobacter pylori, has been linked to both gastric cancer and to the rare gastric MALToma lymphoid neoplasm A role for chronic injury in predisposing to cancer is supported by the finding of a 45-fold increase in the incidence of esophageal adenocarcinoma in individuals with prolonged severe gastroesophageal influx Yet another association of interest has been that between bladder cancer and ingestion of a diet low in water content IMPLICATIONS FOR CANCER PREVENTION Approximately 50% of human cancers can be prevented — at least in theory Such preventive measures include the cessation of cigarette smoking; prevention of cervical papillomavirus infection via the routine use of barrier prophylaxis; vaccination against infections such as hepatitis B; detection of pre-invasive neoplastic change in accessible organs such as the breast (via radiology) and cervix (via cytology); and avoidance of over-exposure to sunlight In practice, however, it has not proven easy to upgrade the efficacy of existing preventive efforts For individuals known to be at high risk of tumor development, recent advances have created new opportunities for prevention An example is the recognition of breast and ovarian cancer predisposition in those individuals whose families are characterized by BRCA1 mutations Such individuals can be offered early intensive mammographic and clinical screening; the use of prophylactic tamoxifen to prevent breast cancer in other “high-risk” individuals is also being evaluated The ultimate status of these interventions, with respect to both high-risk and standard-risk patients, is still being evaluated Conversely, the popularity of hormone replacement therapy (HRT) for postmenopausal women has recently been dented by its association with increased breast cancer risk The relative contribution of environment and genes to cancer pathogenesis seems likely to remain a subject of intense debate Relatively few cancer patients come from families with a strong history of cancer, 874 A Clinical Approach to Medicine suggesting that inherited genetic predispositions are not responsible for the majority of cancers On the other hand, striking geographical clustering of cancer has been noted in the context of many occupational and environmental conditions A complex probabilistic (stochastic) interaction between normal endogeneous and microenvironmental processes thus seems likely to be implicated in the development of most human tumors Newer high-throughput diagnostic technologies such as DNA microarray and phosphoproteomics seem likely to help accelerate this exciting process of discovery 51 Population Cancer Screening Soh Lay Tin Cancer is currently the top-killer in Singapore, claiming 3881.6 lives annually during the period, 1993–1997.1 Generally, for most cancers, detection of earlier stage disease leads to improved prognosis Hence, it is the hope of many people that screening will contribute to early detection of cancerous conditions and improved outcome Screening refers to tests that are performed to identify asymptomatic individuals in the general population who are likely to have a particular type of cancer Like all tests, screening has both advantages and disadvantages One of the advantages is improved outcome if the disease is detected at an early stage Detection of earlier stage disease will lead to less radical treatment There will be reassurance for the ones with negative results There is also the possibility of lower treatment cost for earlier stage disease as the treatment is less radical However, screening has a longer list of disadvantages It can lead to over-treatment of borderline abnormalities that might never have any clinical significance Those with false-negative results will have a false sense of reassurance and might ignore subsequent development of symptoms resulting in delayed diagnosis and poorer prognosis For those with 875 876 A Clinical Approach to Medicine false-positive results, unnecessary anxiety might result In addition, falsepositive result might lead to additional diagnostic tests, which together with the over-treatment of borderline abnormalities, will lead to additional cost There is also the potential hazard of the test itself if the screening test is invasive Hence, for a screening test to be advocated for a cancerous condition, it needs to have adequate sensitivity (i.e proportion of those with the disease who are tested positive) and adequate specificity (i.e proportion of those without the disease who are tested negative) In addition, it should preferably be non-invasive, easily carried out and acceptable to those who need to be screened Cancers likely to benefit from screening, usually have the following characteristics Firstly, there should be a definable high-risk population Secondly, the condition should have a long natural history with preferably, a pre-malignant phase Thirdly, the pre-malignant condition should be treatable With the current data, screening of the general population can be advocated for only cancerous conditions This article aims to discuss the role of screening of the average risk population CERVICAL CANCER Cervical cancer is an ideal disease for screening because it has a long treatable pre-malignant phase Furthermore, the screening test is simple and cheap It is the Papanicolaou test or PAP smear In this test, exfoliated or desquamated cells are brushed from the cervical surface for cytologic examination This test enables the detection of the invasive and preinvasive cervical cancer There is no randomized trial on the benefit of screening in cervical cancer However, there are evidence to support the use of screening in cervical cancer to improve the incidence and mortality In the Nordic countries, marked reduction in the incidence and mortality from cervical cancer followed the introduction of screening programs.2 Organized screening started in most of the Nordic countries soon after 1960 Up to 1985, the screening was most intense in Iceland followed by Finland, Sweden and Denmark In Norway, screening was only spontaneous in late 1994 During the period 1986–1995, the reduction in mortality and incidence rate was highest in Iceland (mortality: 76% and incidence: 67%) Population Cancer Screening 877 and Finland (73% and 75% respectively), intermediate in Sweden (60% and 55% respectively) and Denmark (55% and 54% respectively) and lowest in Norway (43% and 34% respectively) Similarly, in Canada3 and in Scotland,4 intense screening was also associated with reduction in mortality from the disease Case-control studies5,6 also showed that screening improves prognosis in cervical cancer In contrast, in North America, much of Europe and in Singapore,1 where organized screening is absent and screening is mainly opportunistic, reductions in incidence and mortality from cervical cancer have not been dramatic In Singapore, PAP smear is only carried out for pre- and post-natal patients and those who turn up at the gynecological clinic with a gynecological complaint There is no figure for the PAP smear rate for asymptomatic women The estimates are that 60% of all Singapore women undergo regular PAP smears The target of the Gynecology Cancer Workgroup is for 80% of all women to have regular PAP smear screening and achieve a crude incidence rate of 13 and a crude death rate of 6.16, which represents a reduction of 15% It is recommended that all women who ever had sex are advised to have their first PAP smear by the age of 25 years The second smear is taken one year after the first smear and subsequent smears are taken at yearly interval A woman can be discharged from screening at age 65 years if the smear taken at 65 years is negative and there was a previous negative smear within the last years Women who have never had sexual intercourse need not have PAP smear screening unless they have symptoms As the sensitivity of the PAP smear is dependent on sampling technique and the interpretation of the findings, several new techniques were promoted to improve the sensitivity One of these commonly used innovations in cervical cancer screening is liquid-based cytologic collection and analysis However, reviews7,8 of the studies using this technique have concluded that the accuracy of the analysis is uncertain Other ways to improve the sensitivity include reevaluation of conventional smears initially interpreted as negative; either manually or with the assistance of a computerized technique These methods are only more cost effective when used in the laboratories where the PAP smear has relatively poor sensitivity In laboratories that can interpret the PAP smear with a high degree of accuracy, these additional tests merely increase the cost of screening.9 As human papillomavirus (HPV) is a predisposing factor for 878 A Clinical Approach to Medicine the development of cervical cancer, other newer methods of screening tried to incorporate HPV testing in the screening However, the role of HPV testing either as an adjunct to or substitute for cytologic screening needs to be evaluated BREAST CANCER The second cancer for which screening has an impact is breast cancer In contrast to the situation in cervical cancer, there are reported randomized trials10–18 on breast cancer screening Most trials used mammography either alone or in combination with physical examination These trials showed that in the 50- to 69-year-old woman, early detection of breast cancer by regular mammography, with or without breast examination, reduces breast cancer mortality by one-third However, for women aged 40–49, the result is less clear There is no reduction in mortality from breast cancer within years after the initiation of screening There is a trend toward reduced breast cancer mortality only after a follow-up of 10 or more years and the decrease is estimated to be 18% The first randomized breast cancer screening trial was conducted by the Health Insurance Plan (HIP)10 of greater New York About 62 000 women between the age of 40 and 64 years were randomized in the early 1960s to Table Characteristics of the Randomized Trials on Breast Cancer Screening Study Year Age at Screen Screening Modality Entry Round Interval (Yr) HIP Two-county 1963 1977 40–64 40–74 Malmo Gothenburg Stockholm Edinburgh 1976 1983 1981 1976 45–69 39–49 40–64 45–64 Canada Canada 1980 1980 40–49 50–59 4 2-MM ϩ PE (Ͻ 50) 1-MM 2.8 (Ͼ 50) 1.8 2-MM 1.5 2-MM 2.3 1-MM PE 2-MM 2-MM ϩ PE 2-MM ϩ PE Study (n) Control (n) 30 239 78 085 30 756 56 782 21 088 11 724 39 164 23 226 21 195 14 217 19 943 21 904 25 214 19 711 25 216 19 694 From Screening Sensitivity and Sojourn Time From Breast Cancer, Early Detection Clinical Trials: Mammograms and Physical Exainations Yu Shen and Marvin Zelen, J Clin Oncol 19(15):3490–3499, 2001 Population Cancer Screening 879 screening using annual 2-view mammography and breast clinical examination to a total of screens or to a control group Seventy-five percent of the women were older than 50 years old As the trial was conducted in the early years of mammography, only 33% of breast cancers were detected by mammography alone The majority of the breast cancers were detected by physical examination In the trial, the reduction in breast cancer mortality was 30% and was restricted to women between the ages of 50 and 64 years The Edinburgh randomized breast cancer screening trial11 recruited women aged 45–64 years from 1978–1981 (cohort 1) and those aged 45–49 years during 1982–1985 (cohorts and 3) and they were clusterrandomized to either screening or to a control group The women were screened by mammography every years and annual clinical examination Results were based on 14 years of follow-up and 270 000 womanyears of observation 28 628 women were offered screening and 26 026 women were not screened After adjustment for socioeconomic status and censoring for deaths due to diagnosis more than years after the end of the study, the breast cancer mortality rate in the screened group was 0.71 of the unscreened group However, no breast cancer mortality benefit was observed for women whose breast cancer was diagnosed when they were younger than 50 years As in the HIP trial, the benefit in women who entered the trial before the age of 50 years was limited to diagnosis of breast cancer after the age of 50 years In the Swedish Two-county trial,12 the women in Kopparberg and Ostergotland were also cluster-randomized to either single-view mammogram at 24-month interval for women aged 40–49 and 33-month interval for women aged 50–70 In this trial, 133 000 women were randomized between 1977 and 1979 to regular screening or to control The initial results,12 published in 1985, showed a significant 30% reduction in breast cancer mortality in the screened group and was primarily for women aged 50 years or older Subsequently, the control group was also invited for screening After 15 years of follow-up,13 the 32% reduction in breast cancer mortality was maintained [relative risk (RR) ϭ 0.68, 95% confidence interval (CI) ϭ 0.59–0.80, p Ͻ 0.001] The largest effect on mortality (39% reduction) can be seen at ages 50 to 69 The reduction in mortality (5%) for women aged 40 to 49 years are significant only for the Kopparberg county but not the Ostergotland county In this study, the mean sojourn time (MST), sensitivity and the positive predictive value (PPV) were most favorable for women aged 50 to 69 years 880 A Clinical Approach to Medicine The Stockholm trial14 was initiated in Mar 1981 and 40 318 women aged 40 to 64 years were clustered-randomized to single-view mammography screening alone while 20 000 women were randomized to no intervention Two rounds of screening were done at 28 months interval In 1986, the control group was invited once to screening After a mean follow-up of 11.4 years, a non-significant mortality reduction of 26% was observed for the whole study group, with a RR of death in breast cancer of 0.74 (95% CI ϭ 0.5–1.1) For women aged 50–64 years, a significant 38% mortality reduction was observed with a RR of 0.62 (CI ϭ 0.38–1.0) For women aged 40–49 years, no effect on mortality was found, with a RR of death in breast cancer of 1.08 (CI ϭ 0.54–2.17) after 11.4 years of follow-up In the Malmo mammographic15 screening trial, women aged 45–79 years were randomized to rounds of 2-view mammographic screening at 18–24 months intervals In women Ͻ 55 years, more women died of breast cancer [RR ϭ 1.29 (CI 0.74–2.25)] in the first years but the trend reversed after that As for the women aged Ͼ 55 years, there is a 20% reduction in mortality from breast cancer [RR ϭ 0.79 (CI 0.51–1.24)] The Gothenburg breast screening trial16 studied only women aged 39 to 49 years Between September 1983 and April 1984, 11 724 women aged 39–49 years were cluster-randomized to two-view mammographic screening at 18 months interval and 14 217 women were not invited to undergo screening until the 5th screen of the study group (6 to years after randomization) A 45% reduction in mortality from breast cancer was observed in the study group compared with the control (RR ϭ 0.55, p ϭ 0.035, 95% CI, 0.31–0.99) However, the mortality of the two groups only began to separate to years after randomization and the gap continued to widen thereafter In the Canadian Study 2,17 women aged 50–59 years were randomized to annual screening consisting of two-view mammography and physical examination or a control where they were screened with annual physical examination alone This study involved 39 405 women recruited between 1980 through 1985 Although yearly mammography in addition to physical examination detected considerably more lymph node-negative and small breast cancers than screening with physical examination alone, it had no impact on mortality It suggests that screening by mammography does not further reduce breast cancer mortality above and beyond the benefit of screening by clinical breast examination alone Population Cancer Screening 881 In the Canadian Study I (CNBSS I)18 involving women aged 40–49 years, 25 214 women were randomized to to rounds of screening at 12 months interval These women were screened with 2-view mammography and clinical examination Another 25 216 women were randomized to a control group who had a clinical examination at the initiation of the trial followed by the usual health care At a follow-up of 8.5 to 13 years, the RR in the screened group appears to be worse at 1.14 compared to the control group Other authors19,20 have criticized this trial in view of the excess advanced cancer in the screened arm and questioned whether there was non-random allocation of the women Analysis revealed that a quarter of the women in the control received one or more mammograms in the course of the trial as in the “usual medical care” Of note is the Malmo trial that also showed an excess mortality in the Ͻ 50 years old women in the first years and it reversed with subsequent follow-up At 11.4 years of follow-up, the Stockholm trial also showed a RR of breast cancer deaths of 1.08 in the younger women Whether this excessive breast cancer death in the screened group in the CNBSS I will reverse with longer follow-up remains to be seen In the Swedish overview including all randomized trials in Sweden, with a follow-up of to 14 years, the mortality reduction in the group aged 50 to 69 was 29% However, in the group aged 40 through 49 years, it was a non-significant 13%.21 An updated meta-analysis (after an additional to years of follow-up), presented at the Falun meeting in 1996,22 showed a relative mortality of 0.77 (95% CI 0.59–1.01) in the age group 40–49 years Combining all trials gave a figure of 0.85 (CI 0.71–1.01) The conclusion was that there was a mortality benefit, albeit a smaller and more variable one than that observed in the older women and the mortality takes longer to appear in the younger women In a meta-analysis by Kerlikowske,23 for women between ages 50 to 74 at entry into these studies, breast cancer mortality in the screened group was significantly less than in the control group after to years of followup with a relative risk of 0.74 (95% CI 0.66–0.83) The magnitude of the benefit is not affected by further follow-up However, for women aged 40 to 49 at entry, the duration of follow-up did affect the risk of death The relative risk of death in the screened group was 1.02 (95% CI 0.73–1.27) after to years of follow-up but 0.83 (95% CI 0.65–1.06) after 10 to 12 years of follow-up The same result was also reported by Hendrick et al.24 882 A Clinical Approach to Medicine However, the design of these trials not allow an adequate estimation of the extra benefit obtained by starting screening at age 40 instead of at age 50 A possible explanation for the delayed benefit in the younger women is that screening mammogram is probably not effective in the younger women The delayed effect of screening women below the age of 50 at entry into the clinical trials may be the results of these women undergoing screening beyond the age 50 This “age creep” effect was studied and suggested by De Konig et al.25 Why should age 50 affect the effectiveness of mammographic screening? This is because age 50 corresponds approximately to the time of the menopause It is a well-known fact that menopausal status26 has an impact on the biology of breast cancer and premenopausal breast cancer grows faster than postmenopausal breast cancer This explains the higher incidence of interval cancer (diagnosed between screening) in premenopausal than in postmenopausal women.27 Therefore, theoretically, reducing the screening interval to less than 18 months in premenopausal women may reduce breast cancer mortality Furthermore, the sensitivity of mammography is lower in the premenopausal women.28 Rosenberg reported that in women younger than 40 years, the sensitivity is 54% In the 40- to 49-year-olds, up to one-fourth of all invasive breast cancers are not detected by mammography compared with one-tenth of cancers in the 50- to 69-year-olds Kerlikowske et al.29 showed that the sensitivity of first screening mammogram increases with age: 77.3% for age 30 to 39 years, 86.7% for age 40 to 49 years, 93.6% for age 50 to 59 and 94.1% for age 60 to 69 years Despite these controversies, the proponents of screening mammogram in women aged 40 to 49 feels that it should be advocated However, one has to consider the risk of radiation-induced breast cancer Radiation has been shown to cause breast cancer The risk is related to the dose and the younger the exposure, the greater the life-time risk as it occurs at least 10 years after the exposure Beemsterboer et al.30 developed a computer stimulation model to calculate the breast cancer deaths induced by exposure to low-dose radiation in mammographic screening and the number of lives saved With a 2year screening interval and a mean dose of mGy to each breast from a 2-view mammogram, for women aged 50 to 69, the ratio of breast cancer death prevented to those induced as a result of the screening is 242 : This ratio decreases to 97 : in women aged 40 to 49 years This risk is theoretical as there has been no report of mammogram-induced breast cancer Population Cancer Screening 883 Screening appears to have no impact on diagnoses made after the end of the screening period In the HIP trial,10 diagnoses of breast cancer made 3.0–3.5 years after the end of the study are not impacted by the screening In the Edinburgh study,11 the estimated benefit of screening was slightly larger when deaths from diagnoses more than years after the end of the study was censored The Swedish study21 also showed similar findings The role of clinical breast examination (CBE) and breast selfexamination alone as screening is not as clear as screening mammography In most trials, CBE is part of the screening carried out together with mammography In only one trial was CBE carried out in the absence of mammography It is the Canadian National Breast Screening Studies II (CNBSS II16) CNBSS II recruited women aged 50 to 59 In women aged 50 to 59 years, the two-modalities screening (mammography + CBE) appears to be better as the detection rate for two-modalities was 7.2 per 1000 screening examinations versus 3.45 for CBE alone.31 This compared with a detection rate of 4.67 and 4.84 in women aged 50 to 59 years in the Swedish Two-county and Stockholm trials that used only mammography alone The sensitivities of the two modalities versus single modality were 88% versus 63% respectively.31 Despite the higher detection rate, the difference in mortality rate between single and two-modalities screening in CNBSS II did not appear significantly different at 10 years However, this does not exclude the possibility of a difference with longer follow-up In the CNBSS I that recruited women aged 40 to 49 years, both modalities were used in the screening The detection rate was 3.89 per 1000 screening examinations31 that is lower than in the older women in CNBSS II However, it is still higher than the detection rate of 2.09 and 2.06 in the 40 to 49 years old women in the Two-county and Stockholm trials that used mammography alone.31 The sensitivity in the CNBSS I was 81% compared to 62% and 53% in the Swedish Two-county and Stockholm studies respectively The efficacy of breast self-examination (BSE) is even less clear Metaanalysis32 suggests a benefit Two randomized controlled trials33,34 on BSE have been completed Preliminary results are not encouraging although they not rule out the possibility of benefit with longer follow-up An important point in BSE is that it has to be performed well and this will require good health education 884 A Clinical Approach to Medicine In Singapore, a screening project was undertaken in 199435 and it spanned over years In this project, 166 600 women aged 50–64 years were randomized to either 2-view mammography without physical examination (67 656) or observation (97 294, control) 28 231 (41.7%) responded and were screened Comparing to the general population, the responders were more likely to be married, have more formal education, be working, Chinese and be in a higher socioeconomic group In the responders, 4.8 cancers were detected per 1000 women screened per year The incidence of cancer in the control group was 1.3 per 1000 women per year However, the incidence of cancers in the non-respondents was 1.0 per 1000 women per year and was significantly less than in the control group This study revealed an interesting social aspect of the population It suggests that further health education needs to be targeted at the lower socioeconomic group before any organized screening program can succeed Besides limited knowledge of breast cancer, the poorer women have more urgent competing priorities COLORECTAL CANCER Like cervical cancer, colorectal cancer has a long natural history Detection of early disease is associated with improved outcome Hence, screening may reduce the mortality from this disease In this condition, there are three screening tests, which can be used either singly or in combination Among the three tests, guaiac-based fecal occult blood testing (FOBT) is the cheapest and has the most evidence as a screening tool There are large randomized trials on FOBT, which showed that colorectal cancer could be detected at an earlier stage leading to improved prognosis The Minnesota Colon Cancer36 Control Study randomized 46 551 participants’ ages 50 to 80 years to screening annually, once every years or to a control The participants submitted six guaiac-impregnated paper slides with smears from each of three consecutive stools Participants with positive FOBT were subjected to further evaluation including a colonoscopy At 13 years of follow-up, the cumulative colorectal cancer mortality ratio were 0.67 (95% CI 0.50–0.87) and 0.94 (95% CI ϭ 0.68–1.31) in the annually and biennially screened participants compared to the control In an update report at 18 years of follow-up, the cumulative colorectal cancer mortality ratio in the annually and biennially screened participants were 0.67 (95% CI ϭ 0.51–0.83) and 0.79 (95% CI ϭ 0.62–0.97) respectively compared to Population Cancer Screening 885 the control.37 Hence, biennial screening also results in a statistically significant reduction in colorectal cancer mortality The Danish group38 randomized 30 967 people aged 45 to 75 years to biennial screening and another 30 966 people as control There were screening rounds during a 5-year period followed by years of followup The test was carried out with dietary restriction during the days before the stools were collected People with positive FOBT will undergo further evaluation, including a colonoscopy Sixty-seven percent of those invited to be screened had completed the first screening round and were invited for further screening More than 90% accepted repeated screening During the 10-year period, 481 people in the screened group were diagnosed to have colorectal cancer compared to 483 people in the control group In the screened group, 205 people died compared to 249 deaths in the control group Therefore the mortality in the screened group compared to the control was 0.82 In an updated report, after seven rounds of biennial screening, the mortality in the screened group was reduced to Ͻ 0.7 compared to the unscreened ones.39 The UK40 group randomized people aged 45 to 74 years who lived in the Nottingham area, to biennial screening (76 466) using FOBT or no screening (76 384) As in the Danish study, the stools are not rehydrated Positive FOBT is followed-up by a colonoscopy At a median follow-up of 7.8 years, the cumulative colorectal cancer mortality in the screened group is 15% lower than in the control group Hence, FOBT reduces the mortality from colorectal cancer by 15–33% The magnitude is dependent on the frequency of the FOBT and whether the stool sample is rehydrated.41 Rehydration increases the sensitivity of the test but also increases the false-positive rate from 2% to 10% in older persons.36 With positive FOBT, the probability of finding a colorectal cancer or large adenoma in colonoscopy ranges from 17 to 46%.41 Sigmoidoscopy as a screening test is supported only by case-controlled studies Selby et al.42 and Newcomb et al.43 reported reduced recto-sigmoid mortality with screening sigmoidoscopy Ongoing randomized trials by the National Cancer Institute and United Kingdom on screening sigmoidoscopy will be able to provide further answers in future There are no controlled trials of screening double-contrast barium enema and colonoscopy As colorectal cancer develops in benign adenomatous polyps which are amenable to endoscopic resection, it is reasonable to believe that colonoscopy will complement FOBT in reducing the 886 A Clinical Approach to Medicine incidence and mortality from colorectal cancer Furthermore, a proportion of early colorectal cancer not bleed and FOBT is relatively ineffective in detecting polyps However, colonoscopy has a risk of perforation of about 1/1000 and if colonoscopy is the routine screening test, this risk can be significant CONCLUSION In conclusion, there are evidence to screen the average-risk individuals for the three cancers; cervical, breast and colorectal cancers Despite the benefits of screening, there is no organized screening program for either of these cancers Organizing such program is not easy Ethics and economics are important factors to consider This will determine the population to be screened, the screening test and the frequency of re-screening Another obstacle to the success of such program is the poor compliance of those at risk Health education and overcoming the economic barrier in such individuals are also essential before any screening program can succeed REFERENCES Chia KS, Lee HP, Seow A, Shanmugaratnam, Cancer Incidence in Singapore 1993–1997 Sigurdsson K, The Icelandic and Nordic cervical screening programs: trends in incidence and mortality rates through 1995, Acta Obstet Gynecol Scand 78(6):478–485, 1999 Miller AB, Lindsay J, Hill GB, Mortality from cancer of the uterus in Canada and its relationship to screening for cancer of the cervix, Int J Cancer 17:602–612, 1976 Walker JJ, Brewster D, Gould A, Raab GM, Trends in incidence of and mortality from invasive cancer of the uterine cervix in Scotland (1975–1994), Public Health 112(6):373–378, 1998 Hakama M, Chamberlain J, Day NE, et al., Evaluation of screening programmes for gynecological cancers, Br J Cancer 52:669–673, 1985 Sato S, Makino H, Yajima A, Fukao A, Cervical screening in Japan A case-control study, Acta Cytol 41(4):1103–1106, 1997 Nanda K, McCrory DC, Myers ER, et al., Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review, Ann Intern Med 132:810–819, 2000 Payne N, Chilcott J, McGoogan E, Liquid-based cytology in cervical screening Sheffield, England: University of Sheffield School of Health and Related Research, 2002 Population Cancer Screening 887 Brown AD, Garber AM, Cost-effectiveness of methods to enhance the sensitivity of Papanicolaou testing, JAMA 281:347–353, 1999 10 Shapiro S, Venet W, Strax P, Venet L, Periodic screening for breast cancer The Health Insurance Plan Project and its sequelae, 1963–1986, Baltimore: Johns Hopkins University Press, 1988 11 Alexander FE, Anderson TJ, Brown HK, et al., 14 years of follow-up from the Edinburgh randomized trial of breast-cancer screening, Lancet 353:1903–1908, 1999 12 Tabar L, Fagerberg CJG, Gad A, et al., Reduction in mortality from breast cancer after mass screening with mammography, Lancet I:829–832, 1985 13 Tabar L, Vitak B, Chen HH, Duffy SW, Yen MF, Chiang CF, et al., The Swedish TwoCounty Trial twenty years later — Updated mortality results and new insights from long-term follow-up, Radiol Clin North Am 38(4):625–651, 2000 14 Frisell J, Lidbrink E, Hellstrom L, Rutqvist LE, Followup after 11 years - update of mortality results in the Stockholm mammographic screening trial, Breast Cancer Res Treat 45:263–270, 1997 15 Andersson I, Aspergren K, Janzon L, Landberg T, Lindholm K, Linell F, Ljungberg O, et al., Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial, BMJ 297:943–948, 1988 16 Bjurstam N, Bjorneld L, Duffy SW, Smith TC, Cahlin E, Eriksson O, Hafstrom LO, et al., The Gothenburg Breast Screening Trial — first results on mortality, incidence and mode of detection for women ages 39–49 years at randomization, Cancer 80:2091–2099, 1997 17 Miller AB, To T, Baines CJ, Wall C, Canadian National Breast Screening Study-2: 13year results of a randomized trial in women aged 50–59 years, J Natl Cancer Inst 92(18):1490–1499, 2000 18 Miller AB, To T, Baines CJ, Wall C, The Canadian National Breast Screening Study: update on breast cancer mortality, J Natl Cancer Inst 22:37–41, 1977 19 Tarone RE, The excess of patients with advanced breast cancer in young women screened with mammography in the Canadian National Breast Screening Study, Cancer 75:997–1003, 1995 20 Boyd NF, The review of randomization in the Canadian National Breast Screening Study Is the debate over? Can Med Ass J 156:207–209, 1997 21 Nystrom L, Rutqvist LE, Wall S, et al., Breast cancer screening with mammography: overview of Swedish randomized trials, Lancet 341: 973–978, 1993 22 Breast cancer screening with mammography in women aged 40–49 years Report of the Organising Committee and Collaborators, Falun Meeting, Falun, Sweden (21 and 22 March 1996), Int J Cancer 68: 693–699, 1996 23 Kerlikowske K, Grady D, Rubin SM, et al., Efficacy of screening mammography A meta-analysis, JAMA 273:149–154, 1995 888 A Clinical Approach to Medicine 24 Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR, Benefit of screening mammography in women aged 40–49: a new meta-anlaysis of randomized controlled trials, J Natl Cancer Inst Monogr 22:87–92, 1997 25 De Konig HJ, Boer R, Warmerdam PG, et al., Quantitative interpretations of age-specific mortality reductions from the Swedish breast cancer screening trials, J Natl Cancer Inst 87:1217–1223, 1995 26 Harria JR, Morrow M, Bonadonna, Cancer of the Breast, in Cancer: Principles & Practice of Oncology, Vol 1, Devita VT, Hellman S, Rosenberg SA (eds.), JB Lippincott Co, pp 1264–1332, 1993 27 Tabar L, Fagerberg G, Day NE, Holmberg L, What is the optimum interval between mammographic screening examinations? An analysis based on the latest results of the Swedish two-county breast cancer screening trial, Br J Cancer 55:547–551, 1987 28 Rosenberg RD, Hunt WC, Williamson MR, et al., Effects of age, breast density, ethnicity and estrogen replacement therapy on screening mammographic senstivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico, Radiology 209(2):511–518, 1998 29 Kerlikowske K, Gady D, Barclay J, Sickles E, Ernster V, Likelihood ratios for moderen screening mammogaphy: risk of breast cancer based on age and mammographic interpretation, JAMA 276:39–43, 1996 30 Beemsterboer PM, Warmerdam PG, Boer R, de Konig HJ, Radiation risk of mammography related to benefit in screening programmes: a favourable balance? J Med Screen 5:81–87, 1998 31 Fletcher SW, Black W, Harria R, Rimer BK, Shapiro S, Report of the International Workshop on screening for breast cancer, J Natl Cancer Inst 85:1644–1656, 1993 32 Hill D, White V, Jolley D, et al., Self-examinations of the breast: is it beneficical? Metaanalysis of studies investigating breast self-examination and extent of disease in patients with breast cancer, BMJ 297:271–275, 1988 33 Thomas DB, Gao DL, Self SG, et al., A randomized trial of breast self-examination in Shanghai: methodology and preliminary results, J Natl Cancer Inst 89:355–365, 1997 34 Semiglazov VF, Moiseyenko VM, Breast self-examination for the early detection of breast cancer: a USSR/WHO controlled trial in Leningrad, Bull WHO 65:391–396, 1987 35 Ng EH, Ng FC, Tan PH, Low SC, Chiang G, Seow A, et al., Results of intermediate measures from a population-based, randomized trial of mammographic screening prevalence and detection of breast carcinoma among Asian women — The Singapore breast screening project, Cancer 82:1521–1528, 1998 36 Mandel JS, Bond JH, Church T, et al., Reducing mortality from colorectal cancer by screening for rectal cancer for fecal occult blood, N Engl J Med 328:1365–1371, 1993 37 Mandel JS, Church T, Ederer F, Bond JH, Colorectal Cancer mortality: effectiveness of biennial sreening for fecal occult blood, J Natl Cancer Inst 91(5):434–437, 1999 38 Kronborg O, Fenger C, Olsen, et al., Randomized study of screening for colorectal cancer with faecal occult blood test, Lancet 348: 1467–1471, 1996 Population Cancer Screening 889 39 Jorgensen OD, Kronborg O, et al., A randomized study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds, Gut 50:29–32, 2002 40 Hardcastle JD, Chamberlain JO, Robinson MH, et al., Randomized controlled trial of faecal occult blood screening for colorectal cancer, Lancet 348:1472–1477, 1996 41 Lang CA, Ransohoff DF, What can we conclude from the randomized controlled trials of fecal occult blood test screening? Eur J Gastroenterol Hepatol 10:199–204, 1998 42 Selby JV, Freedman GD, Quesenberry CP, et al., A case-control study of screening sigmoidoscopy and mortality from colorectal cancer, N Engl J Med 326:653–657, 1992 43 Newcomb PA, Northfleet RG, Storer BE, et al., Screening sigmoidoscopy and colorectal cancer mortality, J Natl Cancer Inst 84: 1572–1575, 1992 This page intentionally left blank 52 Malignant Lymphoma Lim Soon Thye and Miriam Tao INTRODUCTION Malignant lymphomas are fascinating and challenging to diagnose and treat because of the diversity of the clinical presentation and tumor behaviour This diversity is due to the malignant transformation occuring at different stages of lymphocyte maturation and somatic hypermutation.1 Lymphomas should always be excluded when a patient presents with metastatic disease, as potentially curative treatment can be given to patients with even very advanced stages of lymphoma Some of the major advances in the last three decades are: 1) an international consensus on the pathological classification of lymphoid neoplasms; 2) validation of prognostic scores separating patients into different relapse risk categories; 3) identification of specific viral- or bacterial-associated lymphomas; 4) publications of mature multicenterd comparative trials that have established standard therapy that are evidence-based; and 5) development of targeted therapy 891 892 A Clinical Approach to Medicine NON-HODGKIN’S LYMPHOMA Incidence The overall incidence of NHL in Singapore has increased over the last 30 years, similar to trends in Western countries.2,3 The ASR (age-standardized rate per 100 000 per year) for males were 7.0 (1993–1997) and 3.2 (1968–1972) This is almost 50% higher than the ASR for females, which were 4.1 (1993–1997) and 1.8 (1968–1972) Age The median age at diagnosis is 50ϩ years for all subtypes except for lymphoblastic lymphomas and Burkitt’s lymphoma (which are more commonly seen in children and young adults) Primary mediastinal large B-cell lymphomas and anaplastic large T/null-cell are more commonly seen in 30ϩ years old Clinical Presentation Nodal Non-Hodgkin’s lymphoma frequently presents with painless generalized or localized peripheral lymph node enlargement There may be waxing and waning of the lymph nodes for months to years (indolent or low-grade lymphomas) or rapid growth over several weeks (aggressive or high-grade lymphomas) Intra-cavitary lymph node enlargement may be massive before causing symptoms (e.g mediastinal adenopathy can cause breathlessness, retroperitoneal masses can cause back pain) Extranodal Lymphoma can involve any site in the body but the most common sites are the stomach, oropharynx, small intestine and the skin Patient may present with just fever, weight loss and night sweats, “B symptoms”, that can be associated in any stage or subtype of lymphoma Evaluation of Suspected Lymphoma: History 1) Is the swelling/lymph node painful? (Tenderness is usually associated with infection) Malignant Lymphoma 893 2) Is the swelling localized or generalized? Localized swelling may be due to infection whereas disseminated adenopathy are more likely due to malignancy although infections like HIV infection may also cause this 3) Has there been any weight loss, night sweats and fever (B symptoms)? 4) Any travel history or high risk behavior like multiple sex partners and sharing of needles? 5) Certain situations must always alert the clinician to the possibility of lymphoma: e.g painless testicular mass in an elderly male Examination 1) Examine all lymph node regions, oral cavity for tonsillar involvement and the abdomen for mesenteric or retroperitoneal masses and hepatosplenomegaly Also look for testicular or ovarian masses, focal neurological signs and skin involvement 2) Look for infection or malignancy in the areas drained by the enlarged lymph nodes Diagnosis 1) Excision biopsy: The most representative enlarged lymph node or extranodal site should be biopsied and sufficient material obtained 2) Core needle biopsy: If the only enlarged nodes are retroperitoneal and open biopsy is not possible, CT-guided core needle biopsy is acceptable 3) Fine needle biopsy is not adequate for diagnosis of lymphoma Careful examination for peripheral lymph node enlargement may save a patient an unnecessary mediastinal biopsy or exploratomy laparatomy If a high-grade or very aggressive lymphoma is suspected, it is ideal to expedite all investigations as urgent treatment may be needed Histology should always be reviewed by a hemato-pathologist Histopathological Classification Prior to 1982 there were many different classifications, which caused confusion and difficulty in comparing treatment outcomes at different institutions 894 A Clinical Approach to Medicine Working formulation4 This classification was based on only morphology (cellular feature and tissue architecture) and biological aggressiveness Only 10 subtypes of NHL were recognized and no distinction was made between B- and T-cell lymphomas Although this classification is still referred to, it is no longer adequate for current practice Revised European-American classification of lymphoid neoplasms (REAL) This was based on immunological and genetic tests in addition to morphology It recognized 12 types of B-cell and 11 types of T-cell lymphoid malignancies World Health Organization (WHO) classification5 This is based on the same principles and similar to the REAL classification with some modifications (Table 1) Table World Health Organization Classification of Neoplastic Diseases of the Lymphoid Tissues B-Cell Neoplasms T-Cell Neoplasms Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/lymphoma Precursor T-cell neoplasm: Precursor T-lymphoblastic leukemia/lymphoma Peripheral B-cell neoplasms B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) variant: with monoclonal gammopathy/plasmacytoid differentiation B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma (immunocytoma) Mantle cell lymphoma (MCL) variant: blastic Follicular lymphoma (FL) Peripheral T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia variants: small cell cerebriform cell T-cell large granular lymphocyte leukemia (LGL): T-cell type, NK-cell type Aggressive NK leukemia NK/T-cell lymphoma, nasal and nasal-type (angiocentric) Sezary syndrome Mycosis fungoides Malignant Lymphoma 895 Table Continued B-Cell Neoplasms T-Cell Neoplasms variants: grade I (Ͻ 15% centroblasts) grade II (Ͼ 15% to 50% centroblasts ) grade III (Ͼ 50% centroblasts) cutaneous Marginal zone B-cell lymphoma (MZL) of Mucosa-associated lymphoid tissue (MALT-type) Nodal MZL ϩ/Ϫ monocytoid B cells Splenic MZL ϩ/Ϫ villous lymphocytes Hairy cell leukemia (HCL) Diffuse large B-cell lymphoma (DLCL) variants: centroblastic immunoblastic T-cell or histiocyte-rich anaplastic large B cell Diffuse large B-cell lymphoma subtypes Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma in HIV patients/serous lymphoma Burkitt’s lymphoma variants: endemic sporadic atypical (pleomorphic) atypical, with plasmacytoid differentiation (AIDS-associated) variants: pagetoid reticulosis MF-associated follicular mucinosis granulomatous slack skin disease Angioimmunoblastic T-cell lymphoma (AILD) Peripheral T-cell lymphomas, unspecified variants: lymphoepithelioid (Lennert’s) T-zone Adult T-cell leukemia/lymphoma HTLV-1 ϩ (ATL/L) variants: acute lymphomatous chronic smouldering Hodgkin-like Anaplastic large cell lymphoma (ALCL), CD 30ϩ, T- and null-cell types variants: lymphohistiocytic small cell Primary cutaneous CD-30 positive T-cell Lymphoproliferative disorders variants: lymphomatoid papulosis (type A and B) primary cutaneous anaplastic large cell lymphoma Borderline lesions Subcutaneous panniculitis-like T-cell lymphoma Enteropathy-type intestinal T-cell lymphoma Hepatosplenic ϩ “␥/␦” T-cell lymphoma 896 A Clinical Approach to Medicine Staging Ann Arbor and Cotswold staging system6,7 This system is applicable both NHL and HL Table Cotswold Staging Classification for Hodgkin’s Disease Stage Description I Involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer’s ring) Involvement of or more lymph node regions on the same side of the diaphragm Involvement of lymph node regions or structures on both sides of the diaphragm: III1: With involvement of splenic, hilar, celiac or portal nodes III2: With involvement of para-aortic, iliac or mesenteric nodes Involvement of one or more than extranodal sites in addition to a site for which designation E has been used II III IV Designation Applicable to any Disease Stage A B X X CS PS No symptoms Fever (temperature Ͼ 38ЊC, drenching night sweats, unexplained weight loss Ͼ 10% body weight in preceding months Bulky disease (mediastinal mass Ͼ 1/3 the maximum thoracic diameter or nodal mass Ͼ 10 cm) Involvement of a single extranodal site contiguous or proximal to a known nodal site Clinical stage Pathological stage Mandatory staging investigations: 1) Careful history for “B” symptoms and examination as described above 2) Bone marrow aspirate and trephine biopsy from posterior iliac crest It remained controversial whether bilateral bone marrow biopsies is more sensitive in detecting bone marrow involvement A change in disease stage by performing a second biopsy occurred in only 6% of patients with indolent histology and in 2.5% of patients with aggressive NHL.8 Flow cytometry and cytogenetics studies of marrow aspirate are indicated for prognostic purposes if marrow involvement is suspected and for selected cases such as lymphoblastic lymphoma, follicular, mantle or Burkitt’s lymphoma Malignant Lymphoma 897 3) CT scan of the thorax, abdomen and pelvis CT scan of postnasal space and neck if there are symptoms from the upper aerodigestive tract CT brain scan if there are neurological symptoms or focal neurological signs 4) CSF examination and cytology is indicated for: (a) lymphoblastic or Burkitt’s lymphoma; (b) aggressive lymphoma involving testes, paranasal sinus, extensive marrow or extranodal involvement; (c) HIV positive patients; and (d) primary CNS lymphoma 5) Upper gastrointestinal and small bowel follow through contrast radiographs only if patient has gastrointestinal primary or Waldeyer’s ring involvement 6) Ultrasound of the contralateral testis in testicular lymphoma Pre-treatment investigations: 1) Blood tests — full blood count, erythrocyte sedimentation rate, coagulation profile, electrolytes, renal and liver function tests, lactate dehydrogenase (LDH), serum calcium 2) Other investigations to assesss patient’s ability to undergo therapy: (a) serology for Hepatitis B, Hepatitis C and HIV; and (b) 2D echocardiogram or MUGA scan for cardiac function prior to any anthracycline drugs Prognosis The histologic type and patient characteristics as defined in the International Prognostic Index (IPI) can give an estimate of the prognosis.9 The prognostic factors are listed below (Table 3) The IPI score is Table International Prognostic Index and 2- and 5-year Survival for Aggressive Lymphomas Parameter Score “1” if Risk Group Adverse Factor Present Age Ͼ 60 LDH Ͼ ϫ normal ECOG status у Stage III, IV Extranodal Ͼ site involvement Low Low-intermediate High-intermediate High IPI Score 2-year 5-year Survival Survival (%) (%) or or 84 66 54 34 73 51 43 26 898 A Clinical Approach to Medicine Table Survival by Histologic Type and the International Prognostic Index Consensus Diagnosis Follicular, all grades Mantle cell Marginal zone B-cell MALT Marginal zone B-cell, nodal Small lymphocytic (CLL) Diffuse large B-cell Primary mediastinal large B-cell High grade B-cell, Burkitt-like Precursor T-lymphoblastic Peripheral T-cell all types Anaplastic large T/null-cell % 5-yr Overall Survival % 5-yr Failure-free Survival Index 0/1 Index 4/5 Index 0/1 Index 4/5 84 57 89 76 76 73 77 71 29 36 81 17 40 50 38 22 0 40 15 83 55 27 83 30 35 63 69 71 29 27 49 0 13 19 0 40 10 83 defined as the total number of adverse factors present and identifies groups that correlate with survival outcome in aggressive lymphomas The clinical relevance of REAL/WHO classification and IPI for all NHL histologic types was confirmed by the Non-Hodgkin’s Lymphoma Classification Project (Table 4).10 Treatment Treatment recommendations are determined mainly by the subtype of lymphoma, stage and IPI score Lymphomas may be divided into lowgrade and aggressive lymphomas Low-grade lymphomas (E.g Follicular grades I and II, small lymphocytic lymphoma, lymphoplasmacytic lymphoma) Only 10–20% have localized disease The majority present with disseminated disease and about 40% with marrow involvement Median survival is to 10 years • Asymptomatic patients may be observed (watch and wait strategy) without treatment.11 Malignant Lymphoma • • 899 Indications to start therapy are: (a) B symptoms; (b) progression of disease; (c) lymphomatous involvement of vital organs or structures resulting in obstruction or organ dysfunction; (d) marrow involvement; (e) bulky disease; or (f) transformation to a more aggressive lymphoma The therapeutic options are extensive but no treatment has been shown to be curative12 or clearly superior The median duration of 1st remission is between 1.5 to years Recurrence is inevitable but multiple treatment options are available Median duration of 2nd remission is about 13 months and median survival after recurrence was 4.5 years in one series Stage IA and IIA: Radiotherapy potentially curative with 10-year freedom from relapse of 40–50% with involved field (IF)RT and 85% with total lymphoid irradiation (TLI) Stage IIIA and IVA: 1) Watch and wait strategy.13 2) Alkylating chemotherapy agents, single or combination, e.g chlorambucil or CVP (cyclophosphamide, vincristine, prednisolone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) 3) Nucleoside analogues, single or combination, e.g fludarabine or FMP (fludarabine, mitoxantrone, dexamethasone) 4) Monoclonal antibodies, e.g Rituximab 5) Radioimmunotherapy, e.g Tositumomab (iodine-131 conjugated with anti-B1 antibody) Marginal zone lymphoma MALT (mucosa-associated lymphoid tissue) Gastric MALT lymphoma is a low grade lymphoma and frequently presents with non-specific GI symptoms and diagnosis requires endoscopy Helicobacter pylori is present in over 90% of gastric MALT lymphomas Anti-Helicobacter therapy as sole initial treatment for disease confined to mucosa and submucosa has shown 70% complete histological remission 900 A Clinical Approach to Medicine of gastric MALT It may take up to months to achieve regression Relapses may be treated with a second course of antibiotics, single agent chemotherapy, irradiation or surgery Aggressive lymphomas (E.g Diffuse large B cell lymphoma, follicular lymphoma grade 3, peripheral T-cell lymphoma, anaplastic large T/Null-cell lymphoma, and nasal NK/T-cell lymphomas) • • • • • They are primarily treated with combination chemotherapy CHOP remains the standard chemotherapy and showed complete response rates of 45–55%, with cure rates of 30–35% A phase III comparison of CHOP with more dose intensive chemotherapy regimens (m-BACOP, ProMACE-CytaBOM, and MACOP-B) for the treatment of patients with aggressive NHL showed that CHOP was just as effective but much less toxic.14 Patients with stage III and IV disease are usually treated with to cycles of chemotherapy In localized aggressive NHL, a short course of CHOP (3–4 cycles) combined with radiotherapy to regions involved by lymphoma is an option Although this approach was initially shown to be superior to cycles of CHOP alone, excess late relapses and deaths from lymphoma are now reported with longer follow up Consequently, patients are now treated with a short course of CHOP followed by radiation only if they have a very low risk of relapse.15,16 Recently, a phase III trial in elderly patients with previously untreated advanced aggressive B-cell NHL compared cycles of standard dose CHOP to the same regimen plus rituximab (CHOP-R) This trial showed a significant advantage with the addition of rituximab, an anti-CD20 antibody, CHOP in terms of complete remission rate (76% vs 63%) and overall survival 3-year survival (62% vs 51%).17 Currently, up-front, high dose therapy followed by autologous stem cell transplant cannot be recommended outside of a clinical trial, even for patients at high risk of relapse Ongoing studies may ultimately define which patients could benefit from these aggressive approaches.18 Stage I and II non-bulky: CHOP ϫ ϩ IFRT or CHOP 6–8 cycles bulky у 10cm or large mediastinal mass: CHOP ϫ 6–8 ϩ IFRT Malignant Lymphoma 901 Stage III and IV CHOP ϫ 6-8 cycles or CHOP ϫ 6-8 ϩ anti-CD20 monoclonal antibody Relapse aggressive lymphoma A number of second-line regimens have been developed using non-cross resistant drugs at higher doses for patients with relapsed aggressive lymphomas Although response rates of up to 60–70% may be achieved with some of these regimens, they are seldom lasting and long-term disease-free survival is rare Currently, high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) is the treatment of choice for these patients An important factor in determining outcome with HDC followed by ASCT is the demonstration of chemosensitivity at relapse The advantage of this approach was confirmed in a multicenter trial known as the PARMA trial.19 In this study, patients with relapsed aggressive NHL first received cycles of a second-line chemotherapy (DHAP) and those who responded were randomly assigned to receive either additional cycles of DHAP or HDC followed by ASCT With median follow up of more than years, patients assigned to the high dose arm has a better overall survival (53%) compared to patients receiving conventional chemotherapy (32%) In a subsequent analysis of prognostic factors for the patients in this study, superior overall survival was seen in patients with at least on poor prognostic factor For favorable patients with no adverse prognostic factor (i.e IPI socre of zero), the outcome between HDC followed by ASCT was similar to DHAP alone.20 New treatment for NHL 1) Monoclonal antibody E.g Rituximab is a chimeric mouse-human anti-CD20 monoclonal antibody It attaches to the CD20 receptor, an antigen that is expressed only on B-lineage cells and is important for cell cycle initiation and differentiation Rituximab is approved for use in relapsed follicular lymphoma 2) Radioimmunotherapy In this approach, radioisotopes are chemically attached to antibodies An example of a radioactive antibody is Bexxar, which is a mouse monoclonal anti-CD20 antibody tagged with the radioisotope I-131 Zevalin is another radioactive anti-CD20 antibody It is tagged with ytrrium-90 (Y-90) The challenge for the future is to learn how best to incorporate these new options into the care of NHL 902 A Clinical Approach to Medicine 3) Biological therapy In this approach, biological response modifiers are used to stimulate the patient’s own immune system to attack and destroy the lymphoma cells Examples include interferons and interleukins 4) Myeloablative and non-myeloablative transplant Myeloablative allogenic transplant has been tested with some success in relapse and refractory NHL but is associated with a high rate of treatment related mortality and is therefore not routinely recommended Non-myeloablative transplant is a newer approach and uses much lower doses of chemotherapy than in standard transplant Immunosuppressive agents are given to allow donor cells to engraft and partly take over the patient’s immune system The donor cells then begin reacting against the lymphoma cells and killing them 5) Gene chip Recently, a new molecular technology that has enabled clinicians to genetically distinguish lymphomas This involves what is called a “lymphochip”, which is essentially a small piece of glass that contains thousands of genes expressed by normal B cells in a grid-like pattern Through this technique, it is discovered that diffuse large B-cell lymphomas (DLBCL) are actually two different diseases One subgroup is termed germinal center B-like DLBCL and expresses genes that are hallmarks of the germinal center stage of B cell development The other subgroup is termed activated B-like DLBCL and resembles activated peripheral blood B cells in gene expression More than 75% of patients with germinal center B-like DLBCL were alive years after treatment compared with fewer than 25% of patients with activated B-like DLBCL It is hoped that such information would help physicians understand the molecular basis for the differences in treatment outcomes, and also in identifying patients who are not likely to be effectively treated by current treatment so that more specific or experimental treatment may be offered HODGKIN’S LYMPHOMA Incidence The ratio of NHL to HL is about 10:1 The rate for HL in 1993–1997 was considerably ASR 0.6 and 0.3 for males and females respectively Malignant Lymphoma 903 Age Common age range is 15 to 30 years Classification The WHO classification of Hodgkin’s lymphoma is as follows: • • Nodular lymphocyte predominance HD Classical HD: Nodular sclerosis (Grades I and II) Classical HD, lymphocyte-rich HD, mixed cellularity HD, lymphocyte depletion Staging The staging investigations required are essentially similar to that for NHL In the 1970s, when radiation was primary treatment for HL, staging laparotomy to detect occult intra-abdominal disease was an essential component in staging Patients who were found to have occult intraabdominal disease would require more extensive radiation fields that include the para-aortic lymph nodes and spleen However, the current approach to early stage patients is combination of brief chemotherapy with limited radiation therapy The inclusion of systemic chemotherapy allows a patient to be treated wiht a smaller radiation field and eliminates the need for staging laparotomy as chemotherapy is able to eradicate occult intra-abdominal disease Moreover, staging laparotomy was associated with complications such as infections from splenectomy and operative risks Thus, with combined modality treatment, staging laparotomy and splenectomy are no longer required in the management of HL Prognosis The overall survival for patients with HL is 81% with current treatments There are prognostic factors that identify those patients who would benefit from less toxic treatment and those in whom standard therapy may fail Localized HL (Stage I and II) may be separated into very favorable, favorable and unfavorable prognostic groups based on specific criteria 904 A Clinical Approach to Medicine Table IPI for Advanced HD and 5-yr Progression-free Survival and Overall Survival Combined Score Grouped # Pts (%) Rate of FFP (%) Rate of OS (%) or у2 0–2 у3 0–3 у4 459 (29) 114 (371) 939 (58) 679 (42) 1317 (81) 301 (19) 79 60 74 55 70 47 90 74 86 70 83 59 These vary across institutions but include presence or absence of B symptoms, large mediastinal mass, bulky adenopathy, elevated ESR, extranodal involvement and number of nodal sites involved A prognostic scoring system is also developed for advanced stage HL Based on data collected from more than 5000 patients with advanced HL, seven unfavorable factors were identified and were used to create a prognostic index These seven factors are: serum albumin less than 40 g/L, hemoglobin less than 10.5 g/dL, male gender, age over 45 years, stage IV, while blood cell count Ն 15000/L, and lymphocyte count less than 600/L and/or less than percent of the while blood cell count Each factor has the same weight in increasing the likelihood of relapse The prognositc index is thus simply calculated by adding the number of unfavorable factors present Table showed the spread in the progression free and overall survival at five years associated with the various risk groups Treatment Early stage HL (stage I & II) Total lymphoid irradiation was shown to be curative in localized HL almost 30 decades ago However, the complications in long-term survivors and death from causes other than HD became the driving force to redefine the optimal treatment for HD Randomized studies in early stage Hodgkin’s disease showed that combining various short courses of chemotherapy with total nodal irradiation resulted in better freedom from disease progression compared to raidation alone The high cure rates with combination chemotherapy in advanced stage HD paved the way for combined modality therapy (CMT) with chemotherapy and Malignant Lymphoma 905 smaller volumes and doses of radiotherapy.21 The goals of current treatment recommendations in early stage HD is to maintain high cure rates while minimizing long-term pulmonary, cardiac complications and second neoplasms 1) Very Favorable Criteria: Female with IA or IIA nodular sclerosis HL, р nodal sites and Ͻ 26 years Treatment: Extended Field (EF) RT Alternatively Mantle RT after negative laparotomy or ABVD (adriamycin, bleomycin, vinblastine, tacarbazine) ϫ cycles Note: Mantle RT without staging laparotomy has been associated with 6-year relapse-free survival of only 68%.22 Criteria: Male with IA lymphocyte predominant HL unilateral high neck (above the thyroid notch) or epitrochlear Treatment: Involved Field (IF) RT only 2) Favorable Criteria: No B symptoms, no bulky adenopathy or mediastinal mass to thoracic ratio (MTR) Ͻ 0.35, ESR Ͻ 50 mm/hr, Age Ͻ 50 years, less than separate sites of nodal involvement Treatment: ABVD ϫ followed by involved field radiotherapy (IFRT) 36–40 Gy Alternatively ABVD ϫ in smokers or females Ͻ 27 years 3) Unfavorable Criteria — Any of the following: ESR Ͼ 50, Age Ͼ 50 years, у4 separate sites of nodal involvement, mediastinal mass to thoracic ratio (MTR) Ͼ0.35, bulky adenopathy у10cm, B symptoms Treatment: ABVD ϫ followed by involved field radiotherapy (IFRT) 36–40 Gy Advanced stage HL (stage III or IV) 1) Combination chemotherapy ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) to cycles is currently standard treatment Patients with advanced stage HL are treated with multiagent chemotherapy The first chemotherapy regimen used was MOPP, which was developed in the 1960s However, toxicity has been an important limitation to MOPP It is replaced by ABVD, which has 906 A Clinical Approach to Medicine been shown to be as active as MOPP without the associated toxicities, especially secondary malignancies and sterility Side-effects with ABVD are mainly transient although irreversible toxicities such as pulmonary or cardiac toxicity may occur in less than 5% of patients The approximate complete remission rate and 5-year survival rate with ABVD were 70 and 60%, respectively 2) Escalated BEACOPP • BEACOPP is a complex chemotherapy regimen containing seven drugs The German Hodgkin Study Group did a study to compare dose-escalated BEACOPP with standard BEACOPP and a ABVDlike regimen This study involved 1195 patients and showed that dose-escalated BEACOPP is associated with a higher rate of freedom from treatment failure at five years compared to the other regimens Overall, five-year survivals were 91% for escalated BEACOPP, 88% for standard BEACOPP and 83% for the ABVDlike regimen However, escalated-BEACOPP was also associated with greater hematologic toxicity and secondary malignancies Further follow up will be necessary to determine the safety of this new aggressive approach Relapsed HL 1) Patients relapsing after being treated with radiation alone for early stage HL may be treated with systemic chemotherapy such as ABVD for 6–8 recycles 2) Patients relapsing after having received chemotherapy are still potentially curable and therapy depends on the duration of remission after the initial chemotherapy as well as the presence of other prognostic factors If the relapse occurs more than 12 months after the first complete remission, the patient may be treated with combination chemotherapy At five years, about 40–50% of them will remain disease free Relapses after MOPP may be treated with ABVD Relapses after ABVD may be treated with MOPP or one of the salvage regimens Patients relapsing within 12 months, patients relapsing at multiple sites or patients with constitutional symptoms at relapse have much poorer outcomes They are candidates for high dose chemotherapy followed by stem cell transplant Malignant Lymphoma 907 Follow-up Patients with lymphoma are re-evaluated during and after completion of treatment to determine their response and subsequent management If they are in complete remission, they are monitored every months for the first years as relapses of aggressive lymphomas are most likely to occur during this period They should remain under lifelong follow-up for late relapses as well as for long-term pulmonary or cardiac complications and secondary malignancies REFERENCES Kuppers R, Klein U, Hansmann ML, Rajewsky K, Cellular origin of human B-cell lymphomas, N Engl J Med 341(20):1520–1529, 1999 Chia KS, Seow A, Lee HP, Shanmugaratnam K, Cancer Incidence in Singapore 1993–1997 Singapore Cancer Registry, Report No 5, pp 116–118, 2000 Chia KS, Lee HP, Seow A, Shanmugaratnam K, Trends in Cancer Incidence in Singapore 1968–1992 Singapore Cancer Registry, Report No 5, pp 176, 181, 1996 National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage The Non-Hodgkin’s Lymphoma Pathologic Classification Project, Cancer 49(10):2112–2135, 1982 Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller–Hermelink HK, Vardiman J, Lister TA, Bloomfield CD, World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997, J Clin Oncol 17(12):3835–3849, 1999 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M, Report of the Committee on Hodgkin’s Disease Staging Classification, Cancer Res 31(11):1860–1861, 1971 Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M, Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting, J Clin Oncol 7(11): 1630– 1636, 1989 Wang J, Weiss LM, Chang KL, Slovak ML, Gaal K, Forman SJ, Arber DA, Diagnostic utility of bilateral bone marrow examination: significance of morphologic and ancillary technique study in malignant, Cancer 94(5):1522–1531, 2002 The International Non-Hodgkin’s Lymphoma Prognostic Factors Project, A Predictive Model for Aggressive Non-Hodgkin’s Lymphoma, N Engl J Med 329:987–994, 1993 908 A Clinical Approach to Medicine 10 A clinical evaluation of the International Lymphoma Study Group classification of nonHodgkin’s lymphoma The Non-Hodgkin’s Lymphoma Classification Project, Blood 89(11):3909–3918, 1997 11 Horning SJ, Rosenberg SA, The natural history of initially untreated low-grade nonHodgkin’s lymphomas, N Engl J Med 311(23): 1471–1475, 1984 12 Peterson BA, Current treatment of follicular, low grade lymphomas, Semin Oncol 26(Suppl 14):2–11, 1999 13 Young RC, Longo DL, Glatstein E, et al., The treatment of indolent lymphomas Watchful waiting Vs aggressive combined modality treatment, Semin Hematol 25:11–26, 1988 14 Fisher RI, Gaynor ER, Dahlberg S, et al., Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma, N Engl J Med 328:1002–1006, 1993 15 Miller TP, Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma, N Engl J Med 339(1):21–26, 1998 16 Miller TP, Leblanc M, Spier C, Chase E, Fischer RI, CHOP Alone Compared to CHOP Plus Radiotherapy for Early Stage, Aggressive Non-Hodgkin’s Lymphomas: Update of the Southwest Oncology Group (SWOG) Randomized Trial, ASH 2001 (abstr 3024) 17 Coiffier B, CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma, N Engl J Med 346(4):235–242, 2002 18 Shipp MA, Abeloff MD, Antman KH, et al., International Consensus Conference on High Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive NonHodgkin’s Lymphoma: report of the jury, J Clin Oncol 423–429, 1999 19 Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, et al., Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma, N Engl J Med 333(23):1540–1545, 1995 20 Blay J, Gomez F, Sebban C, Bachelot T, Biron P, Guglielmi C, Hagenbeek A, Somers R, Chauvin F, Philip T, The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial, Parma Group, Blood 92(10):3562–3568, 1998 21 Santoro A, Bonfante V, Viviani S, Devizzi L, Zanini M, Soncini F, Gasparini M, Valagussa P, Bonadonna G, Subtotal nodal (STNI) vs involved field (IFRT) irradiation after cycles of ABVD in early stage Hodgkin’s disease, Proc Amer Soc Clin Oncol 15:415, 1996 (abstr) 22 Hagenbeek A, Carde P, Noordijk EM, Thomas J, Tirelli U, Monconduit M, Eghbali H, Mandard AM, Henry Amar, Prognostic factor tailored treatment of early-stage Hodgkin’s disease Results of a prospective randomized stage III clinical trial in 762 patients (H7 study), Blood 90:565a, 1997 (abstr, suppl 1) 53 Rational Use of Tumor Markers Wong Nan Soon and Khoo Kei Siong INTRODUCTION Tumor markers are substances that are produced by normal tissues in minute quantities, but are secreted in excess by malignantly transformed tissues and in other pathological states In recent years, the definition of tumor markers has expanded to include not only circulating products in the blood, urine and cerebral spinal fluid, but also the assay of genes and oncogene products The ideal tumor marker is specific to the type of malignancy and can be detected with sufficient sensitivity even in the early stages of disease To date, no such tumor marker exists The use of tumor markers has become increasingly popular among clinicians Potential applications include screening, diagnosis, prognostication, treatment monitoring, localization and therapy The common clinically useful tumor markers in wide usage include carcinoembryonic antigen (CEA), prostatic specific antigen (PSA), alpha fetoprotein (AFP), beta human chorionic gonadotropin (b-hCG), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) 909 910 A Clinical Approach to Medicine CEA Biology CEA is a glycoprotein with a molecular mass of 180 kDa It is an oncodevelopmental human tumor marker, found in minute quantities on the luminal aspect of adult colonic epithelial cells but in large amounts on the basolateral membranes of embryonic intestine and colonic tumors It is postulated to function as an intercellular adhesion molecue The CEA gene family has been cloned and is located on chromosome 19 CEA is elevated in colorectal carcinoma The incidence of positive CEA assays ranges from 20% in patients with Duke’s A to 90% in patients with metastatic disease.1 In addition, elevated CEA levels are seen in other malignancies such as carcinomas of the lung, breast, stomach and pancreas CEA is elevated in 30% of small cell lung cancer and 60–70% of non-small cell lung cancer Elevated CEA levels can be seen in a number of benign conditions These include smoking, bronchitis, emphysema, hepatitis, cirrhosis, cholangitis, pancreatitis, renal disease, inflammatory bowel disease and colonic polyps Elevated levels are also seen in diabetes and collagen vascular disease CEA has a half-life of 1–5 days and clearance is hepatic Clinical Utility Screening CEA has limited utility in screening for colorectal carcinoma as elevated plasma levels are encountered in a number of benign conditions CEA has a sensitivity for the detection of early colorectal carcinoma of 40% and a specificity of 90% Studies in which asymptomatic individuals with elevated CEA were investigated have shown a low cancer detection rate ranging from 0.1 to 4%.2,3 Diagnosis Due to lack of specificity, elevated CEA cannot replace histologic diagnosis in the diagnosis of colorectal and other malignancies Rational Use of Tumor Markers 911 In a patient with metastatic carcinoma of unknown origin, CEA has not been found to be useful in identifying the primary site and origin However, a markedly elevated CEA is highly suggestive of a malignancy of epithelial origin Prognosis Pre-operative CEA is a prognostic marker in colorectal carcinoma independent of stage and tumor grade In one series, the risk of recurrence is increased by 1.62-fold if the preoperative CEA was Ͼ 2.5 ng/mL and by 3.25-fold if the CEA was Ͼ 10 ng/L A study has also found a shorter disease free survival of 13 months in patients with pre-operative CEA Ͼ ng/mL compared to 23 months with CEA Ͻ ng/mL Stage specific survival is higher in patients with CEA Ͻ ng/mL In breast cancer, the prognostic significance of elevated CEA is controversial Treatment monitoring After successful resection of colorectal cancer the CEA level should decline to normal levels within to weeks A persistently elevated CEA indicates incomplete resection or metastatic disease, and is an adverse prognostic indicator CEA is currently not recommended as the sole test for monitoring response to chemotherapy in patients with metastatic colorectal carcinoma However if no other simple test is available to indicate response to treatment CEA monitoring every to months may be used In this scenario, two values above baseline are adequate to document progressive disease even in the absence of radiological corroboration.2,4 Detection of recurrence In colorectal carcinoma, serial CEA monitoring is presently regarded as the most cost-effective non-invasive method for the detection of resectable recurrences Two consecutive elevations in CEA yielded a sensitivity of 84% and a specificity of 100% in the detection of recurrent disease according to one study However other studies have found false-positive rates of 30% 912 A Clinical Approach to Medicine CEA monitoring enables detection of recurrences at an earlier stage, which would enable resection of isolated liver metastasis with curative intent It is thus recommended that CEA is monitored every to months for years after primary treatment for stage II and III colorectal carcinoma in individuals who are medically fit to undergo resection of detected liver metastases In breast cancer, CEA monitoring has limited utility in the monitoring of recurrent disease The sensitivity of CEA for this purpose is 50% with a false-positive rate of 12% The lead time gained ranges from 2.5 to months before the onset of clinical disease Due to the lack of curative treatment options early detection of disease recurrence does not translate into improved patient survival or quality of life AFP Biology Alpha fetoprotein is an oncodevelopmental glycoprotein with a molecular weight of 70 kDa produced in high amounts in fetal life and is homologous to albumin Levels remain high in infancy until months to year of age In adulthood AFP is elevated in 85% of hepatocellular carcinoma and 40–60% of patients with non-seminomatous germ cell tumor depending on stage Other malignancies associated with elevated levels include gastric, pancreatic and lung carcinoma as well as hepatoblastoma Benign conditions such as pregnancy, alcoholic disease, hepatitis, cirrhosis, biliary tract obstruction, ataxia telangiectasia and hereditary tyrosinemia can also cause elevated AFP but levels are generally between 20–400 g/L The half-life of AFP is days Clinical Utility Screening Screening for hepatocellular carcinoma in the high-risk population of chronic hepatitis B carriers is currently the standard of care It is pertinent to note however that no study exists to date that documents improved disease specific survival with screening AFP Ͼ 20 g/L has approximate sensitivity of 60% and specificity of 90% in this setting.5 Rational Use of Tumor Markers 913 Diagnosis In the presence of liver lesions on imaging, AFP of Ͼ 500 g/L is diagnostic of hepatocellular carcinoma In germ cell tumors, elevated AFP is found in non-seminomatous germ cell tumors but not in pure seminomas, hence enabling the two to be distinguished Prognosis AFP is a prognostic marker in patients with non-seminomatous germ cell tumors A study by the International Germ Cell Cancer Collaborative Group found that patients with advanced non-seminomatous germ cell tumor with AFP Ͻ 1000 g/L had a 5-year survival of 83% By comparison the 5-year survival was 57% for patients with AFP Ͼ 10 000 g/L Elevated AFP is also associated with poor prognosis in hepatocellular carcinoma In one study the relative risk of death was 1.8 for AFP positive patients compared to AFP negative ones and median survival was significantly shorter.6 Treatment monitoring In advanced non-seminomatous germ cell tumors the level of AFP should decline at half-life during chemotherapy Failure of marker decline is indicative of poor response and should prompt a switch in therapy Persistently elevated AFP after orchidectomy in patients with stage I nonseminomatous germ cell tumor is indicative of disease outside the peritoneum and should prompt systemic chemotherapy Detection of recurrent disease AFP is useful in the early detection of recurrent disease in patients with germ cell tumors In patients with non-seminomatous germ cell tumor with disease confined to the testis (T1) who opt for observation rather than retroperitoneal lymph node dissection the risk of relapse is 20% In this setting serial monitoring with AFP and b-HCG is recommended monthly for the first year, 2-monthly for the second year and quarterly for the third year and less frequently thereafter Monitoring of AFP is also recommended in patients who have had curative resection for hepatocellular carcinoma 914 A Clinical Approach to Medicine bHCG Biology HCG is a glycoprotein hormone with a molecular weight of 50 kDa composed of an alpha and a beta subunit The beta subunit is specific to HCG and is detected in current radioimmunoassays (beta-HCG), while the alpha subunit is structurally common to LH, FSH and TSH HCG is secreted by placental syncytiotrophoblast cells and functions to facilitate implantation of the embryo and maintenance of the corpus luteum Elevated levels of HCG are seen in all patients with trophoblastic disease, in 20–40% of non-seminomatous germ cell tumors depending on stage and 20% of advanced pure seminomas Elevated levels are also seen in other malignancies including melanomas, breast, gastrointestinal, lung and ovarian cancers Benign conditions associated with elevated hCG include pregnancy, cirrhosis, duodenal ulcer and inflammatory bowel disease Excretion of hCG is via the renal route and the half-life is approximately 24 hours Clinical Utility Screening HCG is not indicated as a screening test for germ cell tumors or gestational trophoblastic disease in the asymptomatic population due to low disease prevalence Diagnosis In the setting of gestational trophoblastic disease, persistently elevated HCG after evacuation of molar pregnancy in the presence of metastatic lesions on chest XR or CT scan is sufficient to make the diagnosis of choriocarcinoma and prompt chemotherapy without obtaining histology In germ cell tumors elevated HCG is useful to distinguish germ cell tumor from other causes of mediastinal masses Prognosis A HCG level greater than 100 000 mIU/L is associated with a high risk of persistent gestational trophoblastic disease after evacuation of a complete Rational Use of Tumor Markers 915 mole Although controversial short courses of chemoprophylaxis have been used in this situation In patients with choriocarcinomas, the extent of elevation of hCG is used as part of a prognostic scoring system to identify patients who require more intensive chemotherapy Similarly hCG is also used to stratify patients with non-seminomatous germ cell tumors into good, intermediate and poor risk groups Treatment monitoring In patients with gestational trophoblastic disease, the level of HCG should become undetectable after to 10 weeks after evacuation of a molar pregnancy Weekly determinations of HCG until consecutive readings are undetectable followed by monthly tests for months is used in the follow-up of patients post evacuation In choriocarcinoma monitoring with HCG to document a log decline in levels within 18 days of starting chemotherapy followed by monthly determinations is recommended In advanced germ cell tumors b-HCG should decline at half-life with appropriate chemotherapy Failure to so should prompt a switch in therapy Persistently elevated b-HCG after orchidectomy in patients with stage I non-seminomatous germ cell tumor is indicative of disease outside the peritoneum and should prompt systemic chemotherapy Detection of recurrence HCG is indicated for the detection of recurrent disease in patients with treated germ cell tumors and gestational trophoblastic disease CA19-9 Biology CA19-9 is a glycoprotein mucin first discovered in 1979 using a monoclonal antibody raised against the human colon adenocarcinoma cell line designated SW1116 It has a molecular mass of 36 kDa and is structurally related to the human Lewis, a blood group determinant It is postulated to function in cell adhesion Elevated levels of CA19-9 are seen in the majority of cases of pancreatic cancer, cholangiocarcinomas, stomach and colorectal carcinomas and 916 A Clinical Approach to Medicine mucinous ovarian carcinomas Less commonly, elevated levels are also found in lung, breast, uterine and non-mucinous ovarian carcinomas Benign conditions associated with elevated CA19-9 include pancreatitis, cirrhosis, cholecystitis, biliary obstruction, gastric ulcer disease and pulmonary diseases CA19-9 has a serum half-life of 1–3 days Clinical Utility Screening In the detection of pancreatic cancer, CA19-9 has a sensitivity of 78–90% and a specificity of 95% However due to the low prevalence of pancreatic carcinoma in the general population, the positive predictive value of CA19-9 is approximately 2%, making it unsuitable for screening.7 An exception to this is the use of CA19-9 for early detection of cholangiocarcinoma in the highrisk population of patients with sclerosing cholangitis Diagnosis Numerous conditions mentioned above can cause elevation of CA19-9 Hence marker elevation alone is not sufficient for making the diagnosis of pancreatic carcinoma and tissue diagnosis is required Prognosis Both pre-operative and post-operative elevation of CA19-9 levels have been found to correlate inversely with survival in small retrospective studies.8 CA19-9 is not routinely used for prognostic purposes in pancreatic carcinoma Treatment monitoring Despite limited data, this is the most common application of CA19-9 A rising value of CA19-9 during palliative chemotherapy should prompt imaging procedures to assess disease response with a view towards changing treatment A downward trend of CA19-9 has been associated with improved survival in one study.9 Rational Use of Tumor Markers 917 Detection of recurrence CA19-9 detects recurrent disease with sensitivity of 88% and a lead time of up to months However due to the lack of curative treatment modalities for recurrent disease monitoring of CA19-9 after surgical resection has limited impact on patient survival PSA Biology First identified in 1971, PSA is a glycoprotein enzyme with a molecular weight of 30 kDa It is produced predominantly by epithelial cells lining the acinii and ducts of the prostate gland While initially thought to be tissue specific, PSA has since been found in female periurethral tissue, breast cancer tissue, primary ovarian cancer and in breast milk In the serum it exists as both free form as well as a complexed form bound to alpha-1-chymotrypsin and alpha-2-marcoglobulin PSA functions as a kallikrein-like serine-protease, and its physiologic role is that of degradation of proteins in semen, leading to semen liquefaction To date, prostate cancer is the only malignancy giving rise to elevated serum PSA Other benign conditions that may lead to elevated PSA include benign prostatic hypertrophy, prostatitis, urinary retention, rigid cystoscopy, transurethral resection of the prostate, prostate biopsy, prostate massage and ejaculation Prostatic intraepithelial neoplasia, digital rectal examination and flexible cystoscopy not appear to cause clinically significant elevations of PSA Drugs can cause a decline in PSA levels leading to false-negative studies These include LHRH analogues such as goserelin, antiandrogens such as flutamide, the 5-alpha reductase inhibitor finasteride and herbal remedies such as PC SPES and serenoa repens The PSA gene is located on 13q of chromosome 19 The half-life of PSA is to days after radical prostatectomy Following radiotherapy decline of PSA to nadir levels is reached within a median of 17 months 918 A Clinical Approach to Medicine Clinical Utility Screening PSA Ͼ 4.0 ng/mL has a sensitivity of 75% while a PSA Ͻ 4.0 ng/mL has a negative predictive value of 67.5–80% Hence 20–30% of tumors will be missed when PSA alone is used as a screening test Digital rectal examination is complementary to PSA and increases the sensitivity of screening Various measures have been undertaken to improve the sensitivity of PSA testing One such method is the age-adjusted PSA For example a lower cut-off of 2.5 ng/mL is used to define normal PSA levels in younger patients below the age of 40 Another method to improve sensitivity involves PSA velocity, which follows serum PSA values over time Some investigators feel that an increase of 0.75 ng/mL per year warrants further work-up While both age-adjusted PSA and PSA velocity improve sensitivity the trade-off is an increased number of unnecessary prostate biopsies An elevated PSA ( Ͼ 4.0 ng/mL) has a specificity of 60–70% The positive predictive value of elevated PSA above 4.0 ng/mL in a patient age over 50 is 20–30% Modifications to PSA testing have been attempted to improve specificity but at the expense that some cancers will be missed One method is age-adjusted PSA using a higher normal PSA cut-off value for older patients Another method involves the free-to-total PSA ratio For reasons that are unclear a lower free-total ratio is seen in prostate cancer while a higher free-total ratio is seen in benign conditions A free-total ratio of less than 14–28% is taken by various investigators to warrant a prostate biopsy PSA density is defined as the ratio of PSA to gland volume and is another method of improving specificity based on the fact that a larger prostate produces more PSA No consensus has been reached to date regarding the optimal use of these maneuvers in view of the various trade-offs in sensitivity and specificity The use of PSA in screening for prostate cancer remains controversial at this point in time Given the long natural history in most cases of prostate cancer and the older patient population for this malignancy, many patients will die from other causes with microscopic clinically insignificant prostate cancer even if early disease is detected through screening Rational Use of Tumor Markers 919 At present, if early detection is offered, it should be limited to men age over 50 with a life expectancy of more than 10 years Two randomized controlled trials are underway in the United States and Europe to address the question of whether PSA screening for prostate cancer will lead to significant reduction in disease morbidity and mortality to justify the cost and significant morbidity associated with treatment Diagnosis PSA has limited utility as a sole diagnostic marker of prostate cancer due to the lack of specificity However it has a place in the evaluation of metastatic cancer to bone of unknown primary in the male patient to exclude prostatic cancer which is potentially amenable to hormonal therapy Pre-treatment staging Serum PSA is proportional to the extent of prostate cancer In one series 5% of patients with pre-operative PSA greater between 4.0–10 ng/mL had extraprostatic disease compared with 15% of patients with PSA between 20–30 ng/mL Pre-operative PSA is useful for determining the need for staging bone scan and CT scan In one series the incidence of positive bone scan was 0.8% in patients with PSA Ͻ 10 ng/mL and 2.6% in patients with PSA between 15–20 ng/mL Hence routine bone scan is not indicated in the asymptomatic patient with PSA Ͻ 20 ng/mL Similarly CT scan to detect pelvic lymphadenopathy is rarely positive in patients with PSA Ͻ 25 ng/mL and is not indicated Pre-treatment PSA Ͻ 10 ng/mL can also help to identify a subset of patients in whom the risk of pelvic lymph node metastasis is very low making lymph node dissection unnecessary Pre-treatment PSA is a predictive factor with a level of Ͻ 10 ng/mL predicting good response to local therapy Treatment monitoring PSA is used in periodic monitoring after primary local therapy to detect early recurrence The time to elevation (Ͻ 12 months) and doubling time (Ͻ 6months) of PSA help to point towards distant rather than local recurrence 920 A Clinical Approach to Medicine In addition it is used to assess response to treatment in the metastatic setting The nadir PSA and percent PSA decline while on treatment predict for progression free survival and overall survival CA125 Biology CA125 is a carbohydrate epitope discovered in the 1970s as a result of efforts to develop monoclonal antibodies active against ovarian cancer While the antibody developed (termed OC125) possessed specificity against ovarian cancer it failed to interact with human effector cells to have value as a therapeutic agent and found application as a diagnostic agent CA125 is associated with a family of glycoproteins with variable molecular weights ranging from 200 kDa to 1000 kDa The precise chemical composition and physiological function of CA125 is as yet undefined, nor has the gene been isolated The major forms in serum have molecular weights ranging from 200 kDa to 400 kDa Elevated levels of CA125 are seen in 80–85% of epithelial ovarian cancers as a group, with a lower proportion of patients with early stage ovarian cancer and mucinous subtypes showing elevated levels In addition, levels are elevated in a wide variety of malignancies including colorectal, gastric, pancreatic, liver, endometrial and cervical cancer Benign disorders such as endometriosis, menstruation, pelvic inflammatory disease, acute pancreatitis, cirrhosis, peritonitis and ascites also lead to elevated CA125 levels The serum half-life of CA125 is 4.5 days Clinical Utility Screening CA125 determination is not useful in screening for ovarian carcinoma The sensitivity of a single determination of CA125 is 78% in one study and the positive predictive value is under 10% Diagnosis CA125 measurement is useful in the differential diagnosis of ovarian cysts In the post-menopausal population, ovarian cysts under cm Rational Use of Tumor Markers 921 which are unilocular with normal doppler flow studies and normal CA125 are benign and can be followed up In the pre-menopausal population ovarian cysts associated with rising CA125 during serial follow-up or a single reading greater than 65 to 200 U/mL is indicative of malignancy Prognosis Pre-operative level of CA125 is related to disease bulk and has not been found to have independent prognostic value on multivariate analysis Post-operative CA125 however has been found to have independent prognostic value Treatment monitoring CA125 is useful for monitoring response to chemotherapy in ovarian carcinoma A rising level of CA125 is associated with progression of disease in 90% of cases Similarly a falling CA125 is associated with disease response to treatment CA125 is however less useful in determining the presence of residual disease in that 50% of patients will still have residual disease on second look laparotomy despite return of CA125 to less than 35 U/mL Detection of recurrence CA125 is a useful tool for the detection of recurrent disease in patients who have an intially elevated pre-treatment CA125 level Coupled with physical examination the sensitivity of this test is 90% While a rising level of CA125 predicts recurrence a normal CA125 does not exclude the diagnosis CA15-3 Biology MUC1 (CD227) is a transmembrane mucinous glycoprotein expressed by most glandular and ductal epithelial cells It functions in cell protection, lubrication and reduction of cell-cell and cell-matrix adhesion Synonyms for this molecule include polymorphic epithelial mucin (PEM), epithelial membrane antigen (EMA) and episalin The gene for MUC1 is located on chromosome 1q21 922 A Clinical Approach to Medicine MUC1 gene is frequently overexpressed in malignant breast tumors CA15-3 assay detects an epitope on MUC1 using two monoclonal antibodies DF3 and 115D8 using a double determinant immunoassay CA27.29 assay using monoclonal antibody BR27.29 detects an epitope on MUC1 which overlaps that recognized by DF3 antibody used in the CA15-3 assay CA15-3 is not specific to breast cancer It is elevated in benign breast diseases in addition to hepatitis and cirrhosis Elevated levels are also seen in colorectal, lung, ovarian and pancreatic carcinoma Clinical Utility Screening CA15-3 has a sensitivity of 9% for detection of stage I breast cancer and 19% for detection of stage II disease The sensitivity increase to 38% for stage III disease and 75% for stage IV disease The false-positive rate is 5–6% for healthy subjects, increasing to 30% for patients with benign breast disorders Hence CA15-3 is not a useful screening test for breast cancer Diagnosis Similarly CA15-3 cannot be relied upon as the sole diagnostic test to confirm the presence of breast cancer due to its low positive predictive value Prognosis Studies have shown that pre-operative CA15-3 does not correlate with prognosis In addition, a low level of CA15-3 does not exclude the presence of metastatic disease and a given CA15-3 level cannot be used to determine the stage of disease Treatment monitoring CA15-3 cannot be used alone as a definitive assessment of response to treatment of metastatic disease Studies suggest that up to 34% of patients with disease responding to treatment will show a rising CA15-3 trend while 20% will have stable CA15-3 in the face of progressive disease.14 Rational Use of Tumor Markers 923 A portion of false elevations may be the result of transient marker rise in response to effective treatment Hence, levels of CA15-3 should only be drawn several weeks after the initiation of chemotherapy and decision to stop therapy should be made after radiological confirmation of disease progression Detection of recurrence The low sensitivity of CA15-3 for detection of early breast cancer suggests that the marker lacks the necessary sensitivity to detect early recurrence Several studies have shown that 30% of patients with recurrent disease will not have an elevated CA15-3 level while 6% of patients without recurrence will show a false marker elevation.15 The lead time from marker elevation to clinically apparent recurrent disease ranges from to months but at present no curative salvage therapy exists for recurrent breast cancer hence negating any clinical benefit from early detection of recurrence CONCLUSION AND FUTURE DIRECTIONS The advent of tumor markers was initially hailed as a major breakthrough in cancer research amidst great enthusiasm and hope that they will serve as the perfect tool in cancer screening, diagnosis and treatment monitoring However subsequent research has shown that the ideal tumor marker remains an elusive goal Current tumor markers have no role in disease screening of low-risk populations at this point in time As diagnostic tests they have limited utility and not replace tissue diagnosis Exceptions to this rule include AFP in the context of hepatocellular carcinoma, and b-HCG in choriocarcinoma and gestational trophoblastic disease In the work-up of metastatic cancer of unknown primary, tumor markers have limited utility due to lack of specificity Exceptions to this include PSA in the setting of a male patient with bone metastasis of unknown primary and the use of AFP and b-HCG in the work-up of a patient with mediastinal or retroperitoneal lymphadenopathy The mainstay of application of currently available tumor markers is in monitoring of disease response to treatment and the detection of recurrent disease after successful completion of treatment 924 A Clinical Approach to Medicine Research is underway to develop algorithms using combination of tumor markers to enhance sensitivity and specificity, and new tumor markers are continuously being developed and tested SUMMARY TABLE Tumor Marker CEA AFP bHCG PSA Classification Oncofetal Protein Oncofetal Protein Hormone Enzyme Utility Colon Breast Liver Germ Cell Germ Gestational Prostate Cell Trophoblastic Disease Screening Diagnosis Prognosis Monitoring Response Detection of Recurrence — — X X — — — X — X X — — — X X — — X X — X X X X — — X X — X X X X X Tumor Marker CA19-9 CA125 CA15-3 VMA Classification Carbohydrate Epitope Carbohydrate Epitope Carbohydrate Catecholamine Epitope Utility Pancreas, Cholangiocarcinoma Ovary Breast Carcinoids Screening Diagnosis Prognosis Monitoring Response Detection of Recurrence — — — X — — — X — — — X — X — — X X — — Rational Use of Tumor Markers 925 REFERENCES Phil G, Goldenberg NA, The carcinoembryonic antigen: past, present and future, McGill J Medicine 3:46–66, 1997 Bast RC Jr, Ravdin P, Hayes DF, et al., 2000 Update of Recommendations for the Use of Tumour Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American society of Clinical Oncology, J Clin Oncol 19:1865–1878, 2001 Fletcher RH, Carcinoembryonic Antigen, Ann Intern Med, 104:66–73, 1986 Ward U, Primrose JN, Firian PJ et al., The use of tumour markers CEA, CA-195, CA-242 in evaluating response to chemotherapy in patients with advanced colorectal carcinoma, Br J Cancer 67:1132–1135, 1993 Chalasani N, Horlander JC Sr, Said A, et al., Screening for hepatocellular carcinoma in patients with advanced cirrhosis Am J Gastroenterol 94:2988–2993, 1999 Stillwagon GB, Order SE, Guse C, et al., Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01, Int J Radiat Oncol Biol Phys 20:65–71, 1991 Roulston JE, Novel tumour markers: A diagnostic role in pancreatic cancer? Br J Cancer 70:389–390, 1994 Nakao A, Oshima K, Nomoto S, et al., Clinical usefulness of CA19-9 in pancreatic carcinoma, Semin Surg Oncol 15:15–22, 1998 Ziske C, Schlie C, Gorschlutter M, et al., Prognostic value of CA19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine, B J Cancer 89:1413–1417, 2003 10 American Urological Association: Prostate-Specific Antigen (PSA) Best Practice Policy, Oncology 14:267–286, 2000 11 Seregni E, Botti C, Ballabio G, et al., Biochemical characteristics and recent biological knowledge on prostate-specific antigen, Tumori 82:72–77, 1996 12 Bast RC Jr, Knapp RCL, CA125: History, Current Status, and Future Prospects, McGill J Med 3:67–71, 1997 13 NIH Consensus Statement, Ovarian Cancer Screening, Treatment, And Follow-up, 12(3) 1994 14 American Society of Clinical Oncologists, Clinical Practice Guidelines for the Use of Tumour Markers in Breast and Colorectal Cancer, J Clin Oncol 14:2843–2877, 1996 15 Safi F, Kohler I, Rottinger E, et al., Comparison of CA 15-3 and CEA in diagnosis and monitoring of breast cancer, Intl J Biol Markers 4:207–214, 1989 This page intentionally left blank 54 Metastatic Cancer of Unknown Primary See Hui Ti and Sandeep Kumar Rajan BACKGROUND Metastatic cancer of unknown primary is defined as metastatic solid tumors at one or more sites for which the site of origin is not known after clinical and pathological evaluation.1 The incidence of metastatic malignant disease of undetermined origin in Singapore is approximately 3.1% It is ranked 9th most commonly diagnosed cancer for male residents in Singapore, and 10th most commonly diagnosed cancer for female residents in Singapore.2 In other parts of the world, the incidence ranges from 0.5% and 7.0% depending on the scope and the duration of the diagnostic investigation This entity is a persistent and perplexing problem as it is difficult to define the limits of test in search for the primary tumor Most international series concur on the median survival to be less than months for this group of patients as a whole Despite this dismal overall survival statistics, there are subsets of patients with distinct clinical and pathological details who carry a better prognosis These patients 927 928 A Clinical Approach to Medicine could be considered for potentially curative management The focus is therefore in identifying these patients PRESENTATION OF CARCINOMA OF UNKNOWN PRIMARY AND GENERAL PRINCIPLES OF MANAGEMENT Most solid tumor cancers are described as arising from an organ and then have spread to lymph nodes or distant organs Hence patients may present as carcinoma of unknown primary as lymph-node enlargements, bone metastases, or with malignant cells in various body fluids If presenting complaints, physical exam and a cost-effective management strategy not localize the primary site of cancer, the neoplasm may be called that of unknown primary An optimum work-up would exclude a neoplasm for which curative treatment is possible or which better fits as a locally advanced site cancer rather than a metastatic one of unknown primary or a tumor amenable to hormonal palliative treatment A simple algorithm for this work-up is described in Fig Suspect carcinoma of unknown primary Could it be a tumor with curative potentialexclude germ cell and hematologic malignancies No Yes Confirm and treat accordingly Is it locally advanced tumor rather than metastatic-rule out • head and neck squamous cell carcinoma, • nasopharyngeal carcinoma, • axillary lymph nodes with occult breast cancer No Yes Does further work up alter treatment? Confirm and treat accordingly Yes No Identify a tumor responsive to hormonal therapy Classify as carcinoma of unknown primary • breast cancer or and administer palliative treatment • prostate cancer Identify a tumor where effective site specific chemotherapy exists Fig Approach to carcinoma with unknown primary Metastatic Cancer of Unknown Primary 929 PATHOLOGIC SUBSETS OF CARCINOMA OF UNKNOWN PRIMARY Pathological review separates various subtypes of carcinoma of unknown origin These subtypes include adenocarcinoma, undifferentiated or poorly differentiated cancer, squamous cell carcinoma, and neuroendocrine or small cell carcinoma The frequency of the histology is consistent from one series to another The most common subtype being adenocarcinoma followed by undifferentiated carcinoma and squamous cell carcinoma Direct communication with a pathologist is essential in the management of these patients Fine needle aspiration biopsies are often inadequate for appropriate pathologic examination Indeed, the commonest cause of reason for non-specific pathologic diagnosis is a small, inadequate biopsy For the undifferentiated or poorly differentiated neoplasm, meticulous pathological work-up is essential to exclude better prognosis tumors like lymphoma and germ cell cancers This may require special immunohistochemical testing as well as sometimes FISH probes Such studies can help to distinguish the more poorly differentiated tumors.3–4 Usually it is important to distinguish between a poorly differentiated tumor of epithelial, hematopoietic, or neuroectodermal origin (i.e melanoma) Key immuno-stains used for this distinction include cytokeratins (for carcinoma), leukocyte common antigen (for lymphomas), vimentin (for sarcoma) and S-100, a neuroectodermal antigen expressed in melanomas.5 Distinguishing the origin of an adenocarcinoma may be aided by staining for milk protein, PSA, surfactant protein, thyroglobulin These may help direct an adenocarcinoma respectively to a specific site such as breast, prostate, lung or thyroid Prostate specific antigen (PSA) analysis can accurately differentiate tumors of prostatic origin from other types of cancer Immunohistochemical stains are also available for human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) analysis Although neither is absolutely specific for germ cell tumors (HCG and AFP) or hepatoma (AFP), they are important because germ cell tumors are effectively treated with combination chemotherapy Undifferentiated tumors presenting as carcinoma of unknown primary can be germ cell tumor, the recognition of which would lead to a substantial clinical response or even to cure.6 930 A Clinical Approach to Medicine Although currently not routinely available in Singapore, polymerase chain reaction analysis can also allow DNA amplification of Epstein–Barr virus (EBV) genomes to support the diagnosis of nasopharyngeal carcinoma in tissue provided by fine-needle aspiration biopsy The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma.7 A single study has also shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.8 EVALUATING A PATIENT WITH CARCINOMA OF UNKNOWN PRIMARY First and foremost is in obtaining histological diagnosis Common sense tells us that probably the best way of getting a diagnosis is from the most accessible tumor; either the lymph node or the actual tumor itself After that, one can then embark on the search for the primary from whence the tumor evolved Inability to identify a primary site for metastatic cancer often generates anxiety for patients and relatives They may believe that the physician’s evaluation has been substandard or that the prognosis would be improved if a primary site could be definitely established However, we know now that that is not the case As a result, patients are often subjected to a battery of investigations that yield distressingly little valuable information Routine clinical evaluation should include a complete history taking, focusing on identifying risk factors such as smoking, or a family history of cancer A complete physical examination is mandatory, paying close attention to thyroid gland, integument, mucous membranes, breast, testicles, rectum, prostate and gynecological breast exam in females Blood tests should include liver function tests, full blood count, urinalysis, and stool occult blood IMAGING STUDIES IN EVALUATION OF CARCINOMA OF UNKNOWN PRIMARY A computed tomography of the thorax and abdomen must be done in all patients detected with a carcinoma of unknown primary These imaging studies help rule out a primary in lungs or pancreas When a female Metastatic Cancer of Unknown Primary 931 patient presents with an axillary or supraclavicular lymph-node or with bone metastases, a bilateral mammogram should also be considered to exclude a breast primary Similarly pelvic imaging with an ultrasound or CT-Scan must be considered in a patient with symptoms localizing to this area or when presentation is with malignant ascites In addition, further imaging must become essential with emergence of abnormalities of primary work-up Any imaging study, however, would be futile if the overall performance status of a patient is very poor and no oncologic therapy is planned ENDOSCOPY IN MANAGEMENT OF CARCINOMA OF UNKNOWN PRIMARY For a patient presenting with squamous cell or undifferentiated carcinoma in the neck region, it is imperative to perform endoscopic evaluation (often under general anesthesia) to exclude a primary in head and neck, or nasopharynx These tumors may be curatively treated with combination of surgery and radiation therapy, radiation alone or with combined chemotherapy and radiation Upper and lower gastrointestinal endoscopy and bronchoscopy are not generally recommended unless symptoms or signs like microcytic anemia or fecal occult blood positivity indicate a gastrointestinal neoplasm Even when widely metastatic, it may be important to localize the primary in such cases as identification and arrest of bleeding may be mandatory for optimum management or a specific diagnosis such as colon cancer may allow a specific chemotherapy, which may be more efficacious Routine endoscopies all cases of carcinoma of unknown primary are not indicated, except for age-appropriate screening, which may pick up a synchronous premalignancy or malignancy THE USE OF TUMOR MARKERS A variety of tumor markers are available, including carcinoembryonic antigen (CEA), Ca 125, Ca 153, Ca 19.9, PSA alpha-fetoprotein, and human chorionic gonadotropin Marker may be helpful in suggesting a primary tumor, but because of the diagnostic uncertainty posed by patients with metastatic carcinoma of unknown origin, determinants are often ordered indiscriminately Studies have shown a significant overlap among markers With the exception of PSA, they are seldom helpful in 932 A Clinical Approach to Medicine Table Tumor Markers in Carcinoma of Unknown Primary Subgroup Condition to be Excluded Appropriate Tumor Markers Patients with mediastinal or retroperitoneal masses Extragonadal primary germ cell tumors Alpha-fetoprotein, beta-hCG Liver mass or principal liver mass with diffuse metastases Hepatocellular carcinoma Alpha-fetoprotein Pancreatic mass alone or with liver metastasis Pancreatic cancer Ca 19-9 Men with diffuse Prostate cancer metastatic disease to bone and/or lungs PSA making specific diagnosis unless patients fall into one of the favorable subgroup as shown in Table DEFINING PATIENTS WITH CARCINOMA OF UNKNOWN PRIMARY WITH BETTER PROGNOSIS In 1994, a large series of more than 900 patients identified a possible better prognosis for patients with lymph node only involvement, and of neuroendocrine pathology.9 Since then, researchers have been trying to define models to prognosticate patients The following sections discuss management of a subgroup of patients with unidentified primary tumors These patients may have a better prognosis than other patients with metastatic disease of unknown origin, and specific therapeutic approaches may be justified Patients with Midline Anaplastic Carcinoma All patients who have midline tumors, which have histology of undifferentiated cancer or anaplastic cancer, should have their alpha-fetoprotein and beta-hCG checked Even if they are not raised, the diagnosis of Metastatic Cancer of Unknown Primary 933 extragonadal germ cell carcinoma may be entertained The supporting characteristics of the patient include that of young age at presentation (Ͻ50 years old), presence of a midline tumor, short duration of onset with rapid tumor growth, negative smoking history Patients may be offered treatment with combination cisplatin containing chemotherapy regime These patients tend to well, and may have long-term survival [nccn guidelines] Patients with Neuroendocrine Tumors A subset of patients with poorly differentiated neuroendocrine tumors has been described Patients have rapidly growing tumors in multiple sites and involvement of mediastinal and retroperitoneal lymph nodes They may present with diffuse hepatic or bone metastases Results of immunocytochemical studies are positive for neuron-specific enolase Neuroendocrine tumors have a response rate of over 50% to combination chemotherapy Patients may therefore attain good palliation from such regimes Patients with Squamous Cell Carcinoma of the Cervical Lymph Nodes Patients who present with metastatic cancer in the high cervical lymph nodes require imaging of the head and neck and chest Even if the result of initial imaging is negative, examination using general anesthesia should include nasopharyngoscopy, laryngoscopy, bronchoscopy, and esophagoscopy should be performed With this examination, a primary head and neck cancer is identified in 20–50% of patients.10 Even if no primary tumor is found, blind biopsies should still be performed of the postnasal space, tonsillar fossa, and base of the tongue Even when the primary site remains occult, oncological management strategies similar to that used for head and neck can still result in a 20–30% cure rate.11 Patients who present with metastatic cancer in the low cervical lymph nodes tend to have a worst prognosis as the primary site is more likely to be an occult lung or gastrointestinal tumor These patients would require a bronchoscopy and/or a gastroscopy If the primary remains occult, involved field radiation can be offered 934 A Clinical Approach to Medicine Women with Axillary Node Metastases In this subgroup of patients, breast cancer should be suspected until proven otherwise Following a thorough breast examination, a mammogram should be performed, and should it prove negative, an ultrasound Even in the absence of a palpable mass in the breast or mammographic abnormality, subsequent mastectomy still reveals occult primary tumor in 65–75% of these women.12–14 In the absence of any primary tumor identified in the breast, axillary lymph node dissection and measurement of estrogen and progesterone receptors are performed This not only provides information regarding the identity of the primary lesion but also allows treatment to be instituted Patients are treated for stage II breast cancer.15 Women with Peritoneal Carcinomatosis In women who have peritoneal cancer with an unidentified primary site, pathologic and diagnostic considerations are similar to those patients with ovarian cancer Even if an oncological Whethim’s surgery fails to identify a primary lesion, patients should be offered treated as primary peritoneal carcinoma or as stage III ovarian cancer.16 Patients with Inguinal Lymph Node Disease Cancer found in the inguinal lymph node usually indicates a primary site in the genital or anorectal area Women should have careful examination of the vulva, vagina and cervix; men need careful inspection of the penis In both sexes, the anorectal area should be examined for any suspicious lesions Patients may be treated with surgery (radical resection), chemoradiation, chemotherapy, or radiation alone Half of the complete responders have a prolonged survival.17 Patients with Skeletal Metastases Skeletal metastases, especially if osteoblastic, should raise the suspicion of metastatic prostate cancer in male An elevated serum PSA level or a prostate biopsy specimen that stains positive for PSA by immunochemical technique confirms the diagnosis Patients would then be treated as for metastatic prostate carcinoma The availability of relatively non-toxic Metastatic Cancer of Unknown Primary 935 hormonal approaches emphasize the need to evaluate this diagnostic possibility in the setting of unknown primary.18 Skeletal metastases in women should raise the suspicion of metastatic breast cancer The histology specimen should be send for estrogen and progesterone receptor staining to assist in the diagnosis, and to guide in the management of such patients MANAGEMENT OF PATIENTS WHO DO NOT FIT INTO THE FAVORABLE GROUP In 1995, a large study involving more than 900 patients was published It identified diagnoses, which were associated with male sex, increased tumor load and sites of involvement, liver and adrenal metastases, and histology of adenocarcinoma, which carries a far worse prognosis Despite their prognosis, patients may still benefit from treatment with palliative chemotherapy However, there are no randomized phase III studies that can prove that treatment with combination or single agent chemotherapy can result in any prolongation of survival A truthful discussion with the patient and his or her family should be undertaken to discuss the role of any treatment with or without chemotherapy The aim of any treatment is to maintain function, and improve quality of life CONCLUSION Unfocused radiological and endoscopic evaluation of asymptomatic areas is not productive and should be avoided Clinical and pathological evaluation should be directed at identifying the specific subgroups of patients who could potentially benefit from curative treatment REFERENCES Leonard RJ, Nystrom JS, Diagnostic evaluation of patients with carcinoma of unknown primary tumour site, Semin Oncol 20(3):244–250, 1993 Chia KS, Seow A, Lee HP, Shanmugaratnam K, Cancer Incidence in Singapore 1993–1997, Singapore Cancer Registry Report, No 5, 2000 Ruddon RW, Norton SE, Use of biological markers in the diagnosis of cancers of unknown primary tumour, Semin Oncol 20(3):251–260, 1993 936 A Clinical Approach to Medicine Mackay B, Ordonez NG, Pathological evaluation of neoplasms with unknown primary tumour site, Semin Oncol 20(3):206–228, 1993 Battifora H, Recent progress in the immunohistochemistry of solid tumours, Semin Diagn Pathol 1(4):251–271, 1984 Greco FA, Hainsworth JD, Cancer of unknown primary site, in: DeVita VT JR, Hellman S, Rosenberg SA, (eds.), Cancer: Principles and Practice of Oncology, Philadelphia, Pa, Lippincott–Raven Publishers, 5th ed., pp 2423–2443, 1997 Feinmesser R, Miyazaki I, Cheung R, Freeman JL, Noyek AM, Dosch HM, Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration, N Eng J Med 326(1):17–21, 1992 Bosl GJ, Ilson DH, Rodriguez E, Motzer RJ, Reuter VE, Chaganti RS, Clinical relevance of the i(12p) marker chromosome in germ cell tumours, J Natl Cancer Inst 86(5):349–355, 1994 Abbruzzese JL, Abbruzzese M, Hess K, Raber M, Lenzi R, Frost P, Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients, J Clin Oncol 12(6):1272–1280, 1994 10 Kirsten F, Chi CH, Leary JA, Ng AB, Hedley DW, Tattersall MH, Metastatic adeno or undifferentiated carcinoma from an unknown primary site: natural history and guidelines for the identification of treatable subsets, Q J Med 62(238):143–161, 1987 11 De Braud F, Al-Sarraf M, Diagnosis and management of squamous cell carcinoma of unknown primary tumour site of the head and neck, Semin Oncol 20(3):273–278, 1993 12 Baron PL, Moore MP, Kinne DW, Candela FC, Osborne MP, Petrek JA, Occult breast cancer presenting with axillary nodal metastases: updated management, Arch Surg 125(2):210–214, 1990 13 Bhatia SK, Saclarides TJ, Witt TR, Bonomi PD, Anderson KM, Economou SG, Hormone receptor studies in axillary metastases from occult breast cancers, Cancer 59(6):1170–1172, 1987 14 Ellerbroek N, Holmes F, Singletary E, Evans H, Oswald M, McNeese M, Treatment of patients with isolated axillary nodal metastases from occult primary carcinoma consistent with breast origin, Cancer 66(7):1461–1467, 1990 15 Ellerbroek N, Holmes F, Singletary E, Evans H, Oswald M, McNesse M, Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin, Cancer 66(7):1461–1467, 1990 16 Guarischi A, Keane TJ, Elhakim T, Metastatic inguinal nodes from an unknown primary neoplasm; a review of 56 cases, Cancer 59(3): 572–577, 1987 17 Yam LT, Winkler CF, Janckila AJ, Li CY, Lam KW, Prostatic cancer presenting as metastatic adenocarcinoma of undetermined origin: immunodiagnosis by prostatic acid phosphatase, Cancer 51(2): 283–287, 1983 55 Chemoprevention Sandeep K Rajan Malignant tumors generally take many years to emerge, through multiple steps of carcinogenesis This lengthy period of development provides an opportunity to interrupt a pre-cancerous condition during its march towards malignancy Chemoprevention is defined as the use of specific natural or synthetic chemical agents to reverse, prevent or suppress the carcinogenic process to invasive cancer It is hoped that using this strategy against pre-cancerous lesions will reduce cancer deaths; just as treatment of early cardiovascular disease process has prevented deaths from heart disease Only few chemopreventive agents have been approved for clinical use Many were developed for other indications and their chemoprevention property has recently been recognized This chapter will describe briefly how chemoprevention works and discuss the tumor types where chemoprevention has firm basis supported by current literature HOW CHEMOPREVENTION WORKS Carcinogenesis is a multi-step process Initiation stage is characterized by the conversion of a normal cell into a cell altered by DNA damaging 937 938 A Clinical Approach to Medicine agents The promotion stage is marked by the transformation of an initiated cell into a population of pre-neoplastic cells, as a result of alterations in gene expression and cell proliferation The progression stage involves the transformation of the pre-neoplastic cells to a neoplastic cell cluster with additional genetic alterations In some tumors, an early manifestation of such neoplastic cells may be an intra-epithelial neoplasia (IEN) Ductal carcinoma in situ, oral pre-malignancy, cervical carcinoma in situ are such examples Surveillance for these and surgical excision is one way of preventing cancer and has existed for long However, not only does this modality cause major morbidity but also it does not treat the entire epithelial field at risk (Field cancerization) Chemoprevention is a more comprehensive approach that works at a molecular level to modify cancer risk Such agents may bind to carcinogens, which minimizes their exposure to normal cells, hence preventing tumor initiation Such example would be calcium, which binds bile salts that may prove to be carcinogenic for colonic epithelium Alternatively these may act on targets that overexpress in the promotion and progression stages Many such targets are currently poorly understood Figure briefly describes this multi-step carcinogenesis and activity of various chemopreventive compounds at various levels These agents may eventually diminish the pre-malignant cells by either diminishing their growth, causing them to differentiate, or cause cell death (apoptosis) The multiple genetic and molecular events Fig Sites of action for chemoprevention strategies Chemoprevention 939 Fig Spectrum of colorectal carcinogenesis and Targets for chemoprevention have been best studied in colon cancer and the steps of carcinogenesis and chemoprevention are shown in Fig Hence chemoprevention agents may work at various levels: at clinical level, by reduction of cancer development, at the tissue level by reversal of pre-malignant lesions and at the cellular level by re-regulation of growth and differentiation WHO SHOULD RECEIVE CHEMOPREVENTION? Chemoprevention can be offered in many settings One is primary prevention, when no malignant or pre-malignant lesion exists At least servings of fresh fruits and vegetables, and regular exercise are some methods recommended to the population at standard risk for minimizing development of cancer However, no chemoprevention drug has to date been proven in randomized controlled studies to prevent the risk of cancer for all standard risk groups Evidence-based medicine for such drug interventions have mainly focused at high-risk group by way of inherited or demographic conditions; or with pre-malignant conditions (in this case, intervention would be secondary prevention); or in patients who have been diagnosed with a curable cancer, but have risk of developing a second cancer due to associated risk (second primary) In the latter it is called tertiary prevention Some examples of secondary prevention 940 A Clinical Approach to Medicine would be interventions in patients detected with pre-malignant lesions like dysplasia, or leukoplakia in the oro-digestive tract, colonic polyps or intra-epithelial neoplasm of breast, cervix or prostate Other groups would be subjects with a high-risk behavior like smoking or a demographic risk like the people of Linxian province in China, who have a high incidence of esophao-gastric cancers due to paucity of essential micronutrients in the soil and deficiency of key vitamins in the diet Early intervention with nutrients like Selenium and antioxidant vitamins in a large population intervention study in over 3000 people showed a 16% reduction in pre-cancerous lesions on endoscopy in patients with chemoprevention.1 Most subjects receiving chemoprevention are usually healthy and without cancer Hence the agents must have no appreciable toxicity, especially since carcinogenesis is a slow process, thus duration of use would be lengthy and often life-long WHAT ARE THE CHEMOPREVENTION AGENTS? Certain infections like hepatitis B and C, and Helicobacter pylori are associated with certain cancers like hepatoma, gastric cancer, MALT lymphoma, etc Though anti-viral and antibiotic therapies directed at eradicating these infections could also be considered chemopreventive for cancer, in the ensuing paragraphs, agents with a direct role will be presented Among the agents that have been extensively studied in laboratory and clinic as chemoprevention agents are non-steroidal anti-inflammatory drugs (NSAIDs), retinoids and its analogues, and estrogen hormone antagonists like tamoxifen and raloxifen Most elaborate studies with chemoprevention are available in efforts in preventing colon cancer, head and neck squamous cell carcinoma, and breast cancer These will be discussed below CHEMOPREVENTION IN COLON CANCER Epidemiologic, experimental (animal), and clinical investigations suggest that diets high in total fat, protein, calories, alcohol, and meat (both red and white) and low in calcium and folate are associated with an increased incidence of colorectal cancer But cereal fibre supplementation and diets low in fat and high in fibre, fruits, and vegetables, however, did not reduce the rate of adenoma recurrence over a 3-year to 4-year period.2 The most substantial advancements in the development of Chemoprevention 941 chemopreventive regimens for colorectal cancer to date have been made using NSAIDs that are effective inhibitors of prostaglandin synthesis Enthusiasm for this approach is based on the presence of high levels of prostaglandin E2 in colon cancers NSAIDS, including piroxicam, sulindac and aspirin, may prevent adenoma formation or cause adenomatous polyps to regress in the setting of familial adenomatous polyposis Hence it can be said that “an aspirin a day keeps colon adenoma away” Most, but not all, epidemiological studies have reported a reduction in colon cancer incidence associated with the use of aspirin In large group of over 600 000 adults enrolled in an American Cancer Society study, mortality in regular users of aspirin was about 40% lower for cancers of the colon and rectum.3 In a report from the Health Professionals Follow-up Study of 47 000 males, regular use of aspirin (at least times per week) was associated with a 30% reduction in colorectal cancer.4 A population-based retrospective cohort study of non-aspirin NSAID use among individuals aged 65 and older was also associated with lower risk, particularly with increasing durations of use.5 However in another study, 22 000 men aged 40 to 84 were randomized to placebo or aspirin (325 mg every other day) for years There was no reduction in invasive cancers or adenomas at a median follow-up of 4.5 years.6 In a subsequent analysis over a 12-year period, both randomized and observational analyses indicated that there was no association between the use of aspirin and the incidence of colorectal cancer The low dose of aspirin and the short treatment period may account for the negative findings.7 Many studies have demonstrated the efficacy of sulindac in reducing the size and number of adenomas in familial polyposis as well.8,9 Another NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.10 The cyclooxygenase (COX) enzymes are either continuously expressed (COX-1) or induced by inflammatory processes (COX-2) They have been associated with cancer at various sites, including the colon, gastrointestinal tract, lung, and skin.11 Increased prostaglandin and thromboxane production in tumor cells has been linked to increased angiogenesis and proliferation, and decreased differentiation and apoptosis.12,13 Epidemiologic, experimental, and intervention research on inhibition of COX-1 and COX-2 by NSAIDs indicate that NSAIDs may prevent tumor growth and increase differentiation and apoptosis through this 942 A Clinical Approach to Medicine mechanism.14,15 For example, in patients with familial adenomatous polyposis, celecoxib (a COX-2 inhibitor) significantly reduced the number of colorectal polyps by 28% and the polyp burden (sum of polyp diameters) by almost 31% after months of treatment, compared with patients administered placebos.16 Though NSAIDs are proving to be effective in reducing adenomatous polyps, there are several unresolved issues before making general recommendations for their use These include uncertainty about the proper dose and duration for these agents, and concern whether the potential preventive benefits would balance against longterm risks such as gastrointestinal ulceration and hemorrhage.17 Studies in Europe and the United States are under way to assess the efficacy of aspirin, rofecoxib, and celecoxib in preventing the recurrence of sporadic adenomatous polyps after polypectomy, with a planned recruitment of more than 1000 subjects A randomized French study of two doses of aspirin (160 mg and 300 mg) in a similar setting has finished recruiting subjects Combination therapy with NSAIDs and folate, eflornithine, angiotensin-converting enzyme inhibitors, statins or calcium, is also under investigation Cyclooxygenase-2 inhibitors may become the preferred chemopreventive agent owing to their favorable gastrointestinal safety profile A randomized placebo-controlled trial tested the effect of calcium supplementation [3 g calcium carbonate daily (1200 mg elemental calcium)] on the risk of recurrent adenoma.18 In this study with majority male patients (72%), risk of detecting recurrent adenoma on follow up for endoscopies had an adjusted risk ratio of 0.81 (a 19% risk reduction) The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fibre The study was limited to individuals with a recent history of colorectal adenomas and so could not determine the effect of calcium on risk of first adenoma, nor was it large enough or of sufficient duration to examine risk of invasive colorectal cancer Epidemiologic studies have found a lower incidence of colorectal cancer among those with the highest dietary folate intake,19 whereas those with diets low in folate (and often with high alcohol intake) appear to have an increased risk of colorectal adenomas and carcinomas.19,20 Although large amounts of folate in the diet appear to be protective against the development of colorectal adenomas (relative risk, 0.91 in women and 0.78 in men), the degree of benefit is greater among those Chemoprevention 943 who take folate supplements (relative risk, 0.66 for women and 0.63 for men).20,21 In the Nurses’ Health Study, supplementation with folate (usually as part of multivitamin supplementation) was protective against colorectal cancer, with the greatest risk reduction among women taking high daily doses of folate (more than 400 g); this reduction (relative risk, 0.25) became statistically significant only after 15 years of use.21 The long time needed for a clinical benefit to become evident suggests that folate acts early in colon carcinogenesis These recent observations suggest that aspirin and other NSAIDs, supplemental folate and calcium, have a chemopreventive benefit Since the value of such prophylactic strategies has not yet been confirmed in double-blind, placebo-controlled, randomized studies in the general population, chemoprevention cannot yet be accepted as standard medical practice Chemoprevention should not replace periodic fecal occult-blood tests and endoscopic screening, as well as modification in known risk factors for colorectal cancer, such as reduction in the intake of red meat, appropriate exercise, smoking cessation, and weight control CHEMOPREVENTION IN BREAST CANCER The risk of breast cancer is related to levels of endogenous and exogenous estrogenic hormones.22 Tamoxifen and raloxifene are selective estrogenreceptor modulators, hence as estrogen antagonists, they can reduce the risk of breast cancer Tamoxifen is active against advanced breast cancer In the analysis of trials of adjuvant therapy conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), treatment with tamoxifen for five years reduced the annual odds of contralateral breast cancer by 47%, regardless of the receptor status of the initial tumor.23 This led to National Surgical Adjuvant Breast and Bowel Project (NSABP) Tamoxifen Prevention Trial, a randomized, placebo-controlled study, evaluating if 20 mg of tamoxifen daily for five years could reduce the incidence of breast cancer in women at increased risk.24 Subjects with a predicted five-year risk of breast cancer that was equivalent to that of a 60-year-old woman (greater/equal 1.66%) were enrolled Among 13 388 women followed for about four years, tamoxifen reduced the overall odds of invasive and non-invasive breast cancer by nearly 50% (P Ͻ 0.001) The effect of tamoxifen was exerted exclusively against receptor-positive tumors The reduction occurred among women in all age groups, those 944 A Clinical Approach to Medicine with a history of lobular carcinoma in situ (56% reduction), and those with atypical hyperplasia (86% reduction) Two smaller European trials failed to show this beneficial effect of tamoxifen, probably due to their smaller sample size and inclusion of lower risk patients or those with very high genetic risk that is not modified by tamoxifen This reduction in invasive breast cancer does come at a higher incidence of uterine cancer, thromboembolic phenomenon and other side effects of tamoxifen like climacteric and depression Hence raloxifene, which has no incremental risk of uterine carcinoma, was evaluated The risk of breast cancer, have been monitored in several ongoing placebo-controlled trials of raloxifene directed at osteoporosis and other endpoints The Multiple Outcomes of Raloxifene Evaluation (MORE) trial randomly assigned 7705 postmenopausal women with existing osteoporosis to receive 60 or 120 mg of raloxifene per day, or a placebo After 40 months of follow-up, raloxifene was found to have reduced the annual odds of breast cancer by 65% (on the basis of 58 events) and reduced the risk of invasive breast cancer by 76% (P Ͻ 0.001).25 A partially overlapping meta-analysis of nine randomized trials of raloxifene (including the MORE trial), which involved 10 575 patients, found a somewhat smaller (54%) reduction in the risk of invasive and non-invasive breast cancer Like tamoxifen, raloxifene influences only receptor-positive cancers and there is less evidence supporting the use of raloxifene to reduce the risk of breast cancer than there is supporting the use of tamoxifen Hence use of raloxifene for this indication remains investigational Furthermore none of these trials have been directed to show any improvement in survival with this risk reduction of invasive breast cancer Nevertheless in a recent report by the American Society of Clinical Oncology the use of tamoxifen and raloxifene to reduce the risk of breast cancer was reviewed 26 It was summarized that women at increased risk for breast cancer (defined as a risk of at least 1.7% over five years) may be offered tamoxifen (20 mg/day) to reduce their risk after an informed decision-making process, with careful consideration of risks and benefits Since the overall benefits to health and survival have not been established, the decision to use tamoxifen for risk reduction depends on an individual woman’s perception of her breast-cancer risk and her reaction to this risk On the basis of current information, the routine use of raloxifene should be reserved for treatment of bone loss in postmenopausal women Chemoprevention 945 CHEMOPREVENTION IN HEAD & NECK SQUAMOUS CELL CARCINOMA (HNSCC) Pre-malignant lesions like leukoplakia, erythroplakia, and dysplasia often precede head and neck squamous cell carcinoma These provide an ideal target for testing of chemoprevention principles Retinoids have established efficacy in reversal of early pre-malignant lesions27,28,30 but is associated with considerable mucocutaneous toxicity Initial reports in 1986 by Hong et al.27 using high-dose 13-cis retinoic acid for months versus a placebo had resolution of lesions in 2/3 of treated patients versus 10% of placebo arm (P ϭ 0.002) Several other trials confirmed retinoid activity in oral pre-malignant lesions However relapses after treatment-cessation were frequent, which indicated the need for maintenance Also, even though the high dose was tolerated for short periods, it was unlikely that it could be tolerated for long periods of maintenance To address these questions a follow-up trial was done to evaluate long-term maintenance of retinoid response in oral pre-malignancy Maintenance consisted of months of either low-dose 13cRA (0.5 mg/kg/day) or beta-carotene following induction with months of high-dose 13cRA (1.5 mg/kg/day) Low-dose retinoid was more effective in maintaining the initial response to induction 13cRA than was beta-carotene (92% versus 45%; P ϭ 0.001).35 Another retinoid, retinamide (40 mg/day orally and 40 mg/day topically) with major response in lesions occurring in 27 of the 31 patients on treatment (87%), but only of the 30 patients on placebo (16.7%) had major responses, and none were complete.30 Toxicity was minimal, consisting of minor elevations of serum transaminase in two patients No data on skin toxicity was reported Stich et al.28 evaluated the effects of vitamin A in 65 patients (tobacco users or betel nut chewers) with oral leukoplakia; 30 subjects received 100 000 IU of vitamin A twice weekly, and 34 were assigned to placebos Among the 21 evaluable vitamin A patients, 12 (57.1%) had complete remissions and no patient progressed during treatment Among the 33 subjects on placebos, only (3.0%) had a complete remission, and (21.2%) progressed Another randomized maintenance trial, conducted by Chiesa et al.,30 was reported with 170 evaluable patients randomized to receive either fenretinide (200 mg/day) or no intervention (control) for year following laser resection of oral leukoplakia The failure rate in terms of local relapses or new lesions was 29% in the placebo-control arm, versus an 946 A Clinical Approach to Medicine 18% failure rate in the fenretinide group (P ϭ 0.01) Other agents have also been tested in this setting, most notably beta-carotene and vitamin E Advanced pre-malignant lesions of the upper aero digestive tract like moderate to severe dysplasia are associated with a 36–50% risk of progression into invasive cancer Such lesions are resistant to single agent retinoid chemoprevention, and, to provide a chemoprevention strategy for this high-risk group, a combination of ␣-interferon, ␣-tocopherol, and 13-cis-retinoic acid were evaluated.31 The study showed that the treatment combination was active in preventing progression of laryngeal lesions but not oral lesions After 12 months of treatment, laryngeal sites showed no complete responses Based on these findings, a new study addressing exclusively laryngeal dysplasia incorporating a year of induction with the same regimen and years of maintenance with fenretinide or placebo, has been designed and the results are eagerly awaited The same combination for year has been highly effective as a bioadjuvant approach in patients previously treated for a locally advanced head and neck cancer The Phase II trial by Shin et al.29 showed that 84% of patients were disease-free and alive at years after the completion of definitive treatment for their primary tumor In head and neck squamous cell carcinoma (HNSCC), the overall annual second primary tumor (SPT) rates range from 1.2% to 4.7% in retrospective studies In prospective studies, however, these rates have been reported as ranging from 4% to 7% Based on positive retinoid data in oral leukoplakia and the lack of effective adjuvant therapy in preventing primary recurrence or SPTs, Hong et al.32 conducted an adjuvant randomized, double-blinded, placebo-controlled, chemoprevention trial of high-dose 13-cRA for year in 103 patients curatively treated for cancer of the head and neck The major trial endpoints were recurrence of the primary disease, development of an SPT (different histological type or at a site more than cm from the previous disease or occurring more than years after initial diagnosis), and survival With a median follow-up of 32 months, SPTs developed in significantly fewer 13-cRA treated patients (4%) than in patients receiving placebo (24%) (P ϭ 0.005) As with retinoids in other preclinical and clinical carcinogenesis systems, the retinoid’s impact on annual overall SPT incidence has decreased over time since completing the 12 months’ intervention A subset analysis of SPT only within the high-risk tobacco-exposed field of the head and neck, Chemoprevention 947 lung, and esophagus showed chemopreventive activity persisting at the same level of significance as earlier overall results This long-lasting retinoid activity is unprecedented in previously reported clinical or preclinical retinoid carcinogenesis studies The synthetic retinoid etretinate was tested in 1994 in a French trial33 designed to prevent SPT following definitive treatment of squamous cell carcinoma of the oral cavity or oropharynx Patients randomly received either a placebo or etretinate (50 mg/day for month followed by 25 mg/day for 24 months) SPT and primary recurrence rates were equivalent in both study arms The French report provided few details regarding tobacco and alcohol usage, study adherence, or toxicity, making interpretation difficult Based on the positive findings of the trial by Hong et al.,32 the National Cancer Institute sponsored the largest chemoprevention trial in head and neck cancer, NCI C91–002, in which patients were prospectively randomized to low-dose 13-cRA for years versus placebo This trial was closed to accrual in June 1999 with more than 1200 participants An interim analysis shows that the annual SPT rate in active, former, and never smokers was 5.1%, 4.1%, and 3%, respectively (P ϭ 0.06 for active smokers vs nonsmokers).34 More mature treatment results are eagerly awaited Future agents for use in preventing cancer of the head and neck most likely will be selected from new-agent studies in the oral pre-malignancy system Current study in these two areas involves intervention targeted toward p53 abnormalities, selective cyclooxygenase-2 inhibitors, epidermal growth factor receptor kinase inhibitors, and farnesyl transferase inhibitors CHEMOPREVENTION IN LUNG CANCER All over the world, lung cancer is soon becoming the leading cause of cancer and mortality from it Staying away from smoking is the best strategy for its prevention Individuals who are at risk for lung cancer and were treated with beta-carotene, retinol, isotretinoin, or N-acetyl-cysteine for lung cancer prevention did not experience clinical benefits There is also evidence that the use of beta-carotene and isotretinoin for lung cancer chemoprevention in high-risk individuals may increase the risk for lung cancer, especially in individuals who continue to smoke.36,37 These agents should not be used outside of a clinical trial for primary, secondary, or tertiary lung cancer prevention 948 A Clinical Approach to Medicine SUMMARY Chemoprevention is a useful strategy to reduce cancer incidence Prospective studies have identified success of chemoprevention strategy in limited clinical scenario, like ladies with high risk of breast cancer (with tamoxifen), patients with familial polyposis (with COX-2 inhibitors and other NSAIDs), those with pre-malignant lesions of head and neck area and in curatively treated patients with HNSCC, for prevention of second primary tumor (retinoids) Though a reduction cancer risk is noted, it comes with definite side effects, and long-term mortality benefit and adequate length of intervention are controversial Epidemiological studies and large observational studies have suggested benefit of some such agents in lower risk general population as well and prospective randomized studies to this effect are ongoing Also, the same agents used for preventing some other cancer type may also paradoxically raise the risk of cancer Hence a physician experienced with their use should recommend chemoprevention after careful discussion of pros and cons with the patient, and wherever possible eligible subjects should participate in a clinical trial when available REFERENCES Dawsey SM, Wang GQ, Taylor PR, Li JY, Blot WJ, Li B, Lewin KJ, Liu FS, Weinstein WM, Wiggett S, et al., Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the Dysplasia Trial in Linxian, China, Cancer Epidemiology, Biomarkers & Prevention 3(2):167–172, 1994 Reddy B, Engle A, Katsifis S, et al., Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects, Cancer Research 49(16): 4629–4635, 1989 Thun MJ, Namboodiri MM, Health CW, Aspirin use and reduced risk of fatal colon cancer, N Engl J Med 325(23):1593–1596, 1991 Giovannucci E, Rimm EB, Stampfer MJ, et al., Aspirin use and the risk for colorectal cancer and adenoma in male health professionals, Ann Internal Med 121(4):241–246, 1994 Smalley W, Ray WA, Daugherty J, et al., Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study, Arch Internal Med 159(2):161–166, 1999 Chemoprevention 949 Gann PH, Manson JE, Glynn RJ, et al., Low-dose aspirin and incidence of colorectal tumors in a randomized trial, J Natl Cancer Inst 85(15): 1220–1224, 1993 Sturmer T, Glynn RJ, Lee IM, et al., Aspirin use and colorectal cancer: post-trial followup data from the Physicians’ Health Study, Ann Internal Med 128(9):713–720, 1998 Labayle D, Fischer D, Vielh P, et al., Sulindac causes regression of rectal polyps in familial adenomatous polyposis, Gastroenterology 101(3): 635–639, 1991 Giardiello FM, Hamilton SR, Krush AJ, et al., Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis, N Engl J Med 328(18):1313–1316, 1993 10 Earnest DL, Hixson LJ, Fennerty MB, et al., Inhibition of prostaglandin synthesis: potential for chemoprevention of human colon cancer, Cancer Bull 43(6):561–568, 1991 11 Fosslien E, Molecular pathology of cyclooxygenase-2 in neoplasia, Ann Clin Lab Sci 30:3–21, 2000 12 Wolf LA, Laster SM, Characterization of arachidonic acid-induced apoptosis, Cell Biochem Biophys 30:353–368, 1999 13 Attiga FA, Fernandez PM, Weeraratna AT, et al., Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases, Cancer Res 60:4629–4637, 2000 14 Kelloff GJ, Crowell JA, Steele VE, et al., Progress in cancer chemoprevention, Ann N Y Acad Sci 889:1–13, 1999 15 Giovannucci E, The prevention of colorectal cancer by aspirin use, Biomed Pharmacother 53:303–308, 1999 16 Steinbach G, Lynch PM, Phillips RKS, et al., The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis, N Engl J Med 342:1946–1952, 2000 17 Sandler RS, Aspirin and other nonsteroidal anti-inflammatory agents in the prevention of colorectal cancer, Cancer: Principles and Practice of Oncol Updates 11(6):1–14, 1997 18 Baron JA, Beach M, et al., for the Calcium Polyp Prevention Study Group: Calcium supplements for the prevention of colorectal adenomas, N Engl J Med 340(2):101–107, 1999 19 Ferraroni M, La Vecchia C, D’Avanzo B, Negri E, Franceschi S, Decarli A, Selected micronutrient intake and the risk of colorectal cancer, Br J Cancer 70:1150–1155, 1994 20 Baron JA, Sandler RS, Haile RW, Mandel JS, Mott LA, Greenberg ER, Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas, J Natl Cancer Inst 90:57–62, 1998 21 Giovannucci E, Stampfer MJ, Colditz GA, et al., Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study, Ann Intern Med 129:517–524, 1998 22 Lacassagne A, Hormonal pathogenesis of adenocarcinoma of the breast, Am J Cancer 27:217–228, 1936 23 Early Breast Cancer Trialists’ Collaborative Group, Tamoxifen for early breast cancer: an overview of the randomised trials, Lancet 351:1451–1467, 1998 950 A Clinical Approach to Medicine 24 Fisher B, Costantino JP, Wickerham DL, et al., Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study, J Natl Cancer Inst 90:1371–1388, 1998 25 Cummings SR, Eckert S, Krueger KA, et al., The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial, JAMA 281:2189–2197, 1999 26 Chlebowski RT, Collyar DE, Somerfield MR, Pfister DG, American Society of Clinical Oncology technology assessment of breast cancer risk reduction strategies: tamoxifen and raloxifene, J Clin Oncol 17:1939–1955, 1999 27 Hong WK, Endicott J, Itri LM, et al., 13-cis-retinoic acid in the treatment of oral leukoplakia, N Engl J Med 315:1501–1505, 1986 28 Stich HF, Hornby AP, Mathew B, et al., Response of oral leukoplakias to the administration of vitamin A, Cancer Lett 40:93–101, 1988 29 Shin DM, Khuri FR, Murphy B, et al., Combined interferon-alpha, 13-cis-retinoic acid, and alpha-tocopheral in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial, J Clin Oncol 19:3010–3017, 2001 30 Chiesa F, Tradati N, Marazza M, et al., Fenretinide (4-HPR) in chemoprevention of oral leukoplakia, J Cell Biochem Suppl 17F:255–261, 1993 31 Papadimitrakopoulou VA, Clayman GL, Shin DM, et al., Biochemoprevention for dysplastic lesions of the upper aerodigestive tract, Arch Otolaryngol Head Neck Surg 125:1083–1089, 1999 32 Hong WK, Lippman SM, Itri LM, et al., Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck, N Engl J Med 323:795–801, 1990 33 Bolla M, Lefur R, Ton Van J, et al., Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx Results of a multicentric double-blind randomised study, Eur J Cancer 30A:767–772, 1994 34 Khuri FR, Kim ES, Lee JJ, et al., The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial, Cancer Epidemiol Biomark Prev 10:823–829, 2001 35 Lippman SM, Batsakis JG, Toth BB, et al., Comparision of low dose isotretinoin with beta-carotene to prevent oral carcinogenesis, N Engl J Med 328:795, 1993 36 The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers, N Engl J Med 330:1029–1035, 1994 37 Omenn GS, Goodman GE, Thornquist MD, et al., Effects of a combination of betacarotene and vitamin A on lung cancer and cardiovascular disease, N Engl J Med 334:1150–1155, 1996 Neurology This page intentionally left blank 56 Approach to the Patient with Neurological Disease K Puvanendran and Udaya Seneviratne In no field of medicine is a good basic knowledge of anatomy and physiology along with clinical examination more necessary than in the diagnosis of neurological diseases because the nervous system is the most logically predictable There are two essential questions when approaching a neurological diagnosis 1) What is the site of lesion? This is usually determined by the physical signs 2) What is the likely pathology? Usually the patient’s history answers this Many consultations are also to prove the absence of pathology in the brain for reassurance that the patient’s headache is not caused by a brain tumor or internal bleeding If time is limited, it is prudent to be selective with the examination HISTORY Details of history taking are not in the scope of this chapter but it is emphasized that the history should be a chronology of events and should 953 954 A Clinical Approach to Medicine tell the story of the disease It should tell the onset, evolution to and period of maximum deficit, continuing progression or recovery to the present state If the condition came on acutely with dramatic suddenness, reaching the maximum in a few hours, and if it improved subsequently, though not completely, the likely pathology is vascular Disease that comes on gradually and worsens is a neoplasm or degeneration Spontaneous remission occurs in multiple sclerosis Periodic weakness of limbs with recovery can occur in periodic paralysis or a vascular malformation of the cord In transient ischemic attacks, the symptom improve within 24 hours Epilepsy, migraine, trigeminal neuralgia all cause a series of discrete events but the patient might only be interested in describing the most recent event, which might be the worst and the reason for consultation Often one recognizes a characteristic clustering of symptoms and signs, constituting a syndrome This helps to localize and gives the nature of the disease and progress The clinical picture of Parkinson’s disease for example is so characteristic that the diagnosis becomes apparent at once At the end of the history taking the neurologist would have conceptualized the anatomic localization of the lesion and the mechanism of the disease His disease hypothesis could be confirmed or revised after the neurological examination, and laboratory investigation On many occasions history can make the diagnosis Take for example the history of a young woman who had been getting throbbing hemicranial headaches for years, usually associated with her menses The facts that her mother too had similar headaches and that the patient experiences flashes of light and vomiting during the attack confirm the diagnosis of migraine A previous history of mitral valve disease in a young stroke leads us to an embolic etiology for the stroke Correlation with other symptoms of the nervous system and with other organs is often useful For example, headache in a case of paraplegia leads to a diagnosis of a parasaggital meningioma rather than a lesion in the spinal cord Multiorgan affection leads us to suspect a storage disease, mitochondrial disorder, or connective tissue diseases Information from an eyewitness rather than an EEG is more useful in diagnosing a seizure A patient who complains of every symptom probably has a somatiform disorder The examiner should, at the onset, assess the reliability of the history from the patient’s intelligence and whether there could be any financial Approach to the Patient with Neurological Disease 955 gain from the symptoms This occurs often in pain symptoms after an accident, for example, a whiplash injury in a motor car accident Exposure to toxins and work environment is relevant in neurological diseases The many cases of glue sniffing presenting like the Guillain Barre syndrome in Singapore in the previous decade is a good example to note Sexual history should be inquired discretely now, because sexually transmitted disease is reaching greater proportions Family history of a similar disease or consanguinity is very relevant In dystrophia myotonica the first generation member of the family tree can be affected with a mere cataract The subsequent generation could have profound muscle weakness (because of DNA amplification, gene expression may become more severe in each successive generation) Ethnicity is rarely important in diagnosis, though we know that some neurological disorders are common in some races Thyrotoxic periodic paralysis is a consideration for a young Chinese male in our population NEUROLOGICAL EXAMINATION A complete neurological examination checking every muscle, every modality of sensation as taught in the clinical examination books is hardly performed in practice However, the resident should know how to go into details as appropriate The purpose of the examination is to demonstrate functional aberrations that can localize in a part of the nervous system The presence of some signs or absence of other signs can be as diagnostic We learned to perform a focused examination to confirm the initial hypothesis of disease that we guessed from the history When a right-handed person presents with a right-sided hemiparesis, and if a left cerebral lesion is suspected, we should look for dysphasia, right hemianopsia, and right-sided pyramidal signs A patient presenting acutely with a unilatered foot drop, amongst other diagnosis, could have either a common peroneal nerve palsy (trauma over neck of fibula) or a L5 radiculopathy (lumbar disc protrusion) To differentiate, check another muscle (far apart) supplied by L5 root but through a different nerve Turn the patient on his face and check the gluteus maximus muscle (supplied by the inferior gluteal nerve) by asking him to lift the knee off the bed Another cause of an acute unilateral foot drop is motor neurone disease It is sometimes difficult to decide if a physical sign is abnormal An examiner will interpret a tuning fork vibration sensation on a patient as 956 A Clinical Approach to Medicine abnormal by comparing to himself Loss of ankle jerks or vibration sensation in the toe could be an expected finding for a patient aged over 60 years Soft signs like an asymmetric face or an inverted supinator jerk may be sufficient for an expert to place a diagnosis It was on a lock of white hair that a diagnosis of pernicious anemia as a cause of paraparesis was made, in spite of it being a rarity in Singapore This is a rare presentation of an uncommon disease where clinical acumen has to be sharp When the patients’ complaint is headache, a focused examination is not possible A screening examination testing the function of limbs, gait, cranial nerves, mental status and reflexes would be helpful If the patient can walk tandem, eyes closed, one can safely assume there is no affection of the peripheral nerves, spinal cord or cerebellum If the patient can a push up, arise from the floor without hand support, walk on heels and toes — one can assume normal muscle strength A general physical examination of other systems is always necessary Storage disorders, mitochondrial disorders and connective tissue disease affect many systems including the nervous system The lesion in the brain could be a secondary deposit if the patient has, for example, carcinoma of the lung Cerebellar signs in this patient with carcinoma of the lung would indicate a paraneoplastic syndrome A heart murmur (for example, mitral valve disease) with a cerebral lesion points to an embolic pathology CONCEPTUALIZING THE DIAGNOSIS The findings from the history and clinical examination should be dovetailed to come out with a hypothesis to explain the disease The other diseases that are to be considered, even if they are unlikely, form the basis of the differential diagnosis Anatomical localization comes before finding the cause One should first localize the disease to the muscle, peripheral nerve, spinal cord or brain Next, the physician has to decide if the disease occurs in one area or more than one area of the nervous system The diagnosis will be more likely if all the findings can be explained by one lesion For example, foot drop and gluteus maximus weakness on the same side (though the muscles are far apart in location) is explained on the basis of an L5 root innervation (common to both), rather than affection of separate nerves, namely the common peroneal nerve and inferior gluteal nerves Lesions that cannot be explained by one anatomical site or blood Approach to the Patient with Neurological Disease 957 supply could be from multiple metastasis, embolic infarct or multiple sclerosis A central scotoma (from optic neuritis) associated with paraparesis must have two lesions — optic nerve and spinal cord probably from multiple sclerosis (Devics disease) This is the grand over riding law of parsimony of nature, which says that entities must not be multiplied beyond what is necessary This is done by shaving an argument to its simplest form as in Occam’s Razor (after the English philosopher William of Occam who devised this principle) When a patient presents with acute vertigo, a peripheral vestibular end organ cause is usually suspected This cause is excluded if there are brainstem symptoms and signs These signs are dysphagia, dysphonia, (9th and 10th nucleus), cerebellar ataxia (inferior cerebellar peduncle) and Horners syndrome Dissociated sensory loss where the laterally placed spinothalamic tracts (pain and temperature) are involved but the medial lemiscus is spared, places the lesion in the lateral medulla where the vestibular nucleus is also situated This cluster of symptoms jigsaws into the lateral medullary syndrome of Wallenberg with a reputation of a benign outcome Patients who present with thalamic pain syndrome, rubral tremor, ataxia of limbs and homonymous hemianopsia, all on one side, have only one thing in common The thalamus, red nucleus, cerebellar connections and the occipital cortex are all supplied by branches of the posterior cerebral artery (thalamogeniculate, interpeduncular and cortical), thus one lesion explains all of the symptoms A good knowledge of neuro-anatomy comes in handy to tie up the signs After localizing the lesion anatomically we think of the likely pathology A hemiparesis coming on suddenly is probably a stroke If it came on slowly over weeks or months, it could be a tumour Multifocal affection can be progressive as in metastases or can be relapsing and remitting as in multiple sclerosis Degenerative disease and disease due to vitamin deficiency can be progressive Febrile history with multiple cranial nerve palsy suggests meningitis A patient who presents initially with wasting of small muscle of the hands and develops a bulbar palsy a few months later most probably has amyotrophic lateral sclerosis (ALS) Again the principle of parsimony makes a diagnosis of bilateral ulnar nerve palsy and stroke an unlikely possibility While considering the diagnostic possibilities, it would well to remember that an unusual presentation of a common disease is more 958 A Clinical Approach to Medicine common than a common presentation of a rare disease Syphilis though less frequently seen is a great mimic of diseases in the nervous system Tuberculosis and HIV infection presenting in an unusual fashion should always be thought of now in the differential diagnosis Treatable conditions, though unlikely, should be considered and even a trial of treatment tried, even when they mimic untreatable conditions like Alzheimer’s disease Memory loss, for example, is the basis for diagnosing dementia like Alzheimer’s disease If one goes that extra effort of getting a history of snoring, obstructive sleep apnea could be considered and a trial of CPAP (continuous positive airway pressure) can give occasional success LABORATORY INVESTIGATION These should be ordered with a clear objective Cost and risk to the patient should be kept in mind A routine investigation is not justified One should begin with hematological and biochemical bloods tests, and then proceed with neuroimaging and neurophysiological testing before considering biopsy A blood count, urea electrolytes is appropriate for a patient admitted for stroke This may not be justified in a patient with migraine A macrocytosis and low B12 level in blood could avoid expensive imaging in subacute combined degeneration The skilled diagnostician arrives at the final diagnosis by artful analysis of clinical data aided by the least number of essential laboratory tests Strategy of laboratory study should be based on therapeutic and prognostic consideration and not on the physicians curiosity or presumed medico legal exigencies It should be remembered that diagnostic tests comprise a large part of health care expense LUMBAR PUNCTURE CSF examination by lumbar puncture (LP) is necessary for diagnosing meningitis and starting the appropriate antibiotics without delay A delay clearly worsens the outcome Other indication for ordering an LP is meningeal malignancies, CNS vasculitis, sarcoidosis, multiple sclerosis (MS) and pseudotumor cerebri In subarachnoid hemorrhage however LP could establish the diagnosis when a CT Scan brain is falsely negative When raised intracranial pressure is suspected (evidenced by headache and papilloedema) a CT Scan brain should be done before the LP in order to exclude a mass lesion or edema Approach to the Patient with Neurological Disease 959 IMAGING CT Scan and magnetic resonance imaging are the core imaging method used For reasons of cost, speed and availability, CT Scan brain is still widely used for screening in the acute evaluation of stroke, head injury or acute infection CT is useful in showing the normal outline of the brain, ventricles and CSF spaces In daily clinical practice CT remains the choice (compared to MRI) for detecting acute hemorrhage Some early cerebral infarcts (in the first 24 hours) and subdural hematomas will be missed on CT CT is less useful for visualization of brainstem, cerebellum and spinal cord MRI is the gold standard and is the investigation of choice for demonstrating lesions in multiple sclerosis (in brain and spinal cord), brain stem pathology (tumors and infarct), and intrinsic lesions in spinal cord specially syringomyelia Gadolinium enhanced MRI (Gd-MRI) is most useful in increasing sensitivity to neoplastic and inflammatory lesions of the brain and spinal cord Gd-MRI is very useful in detecting meningitis, encephalitis (Herpes Simplex) and myelitis In AIDS, Gd-MRI is useful to differentiate between cerebral lymphomas, toxoplasmosis, or fungal lesions In temporal lobe epilepsy, high-resolution imaging can show hippocampal atrophy or sclerosis Diffusion weighted imaging (DWI) is a useful part of acute stroke imaging which can identify cerebral infarction within minutes of onset DWI can be combined with perfusion imaging to identify the penumbra zone of potentially salvageable tissue within the area of reduced perfusion but outside the unrecoverable infarct represented by DWI high signal Being non-invasive, MR angiography (MRA) is often used to study intracerebral arteries in strokes Conventional angiography is still the most sensitive examination for intracranial aneurysms and AVM, though MRA can be useful Duplex ultrasonography of carotid arteries is routinely used to evaluate carotid artery stenosis in strokes Though not asked for routinely, transcranial doppler is useful in detecting intracerebral artery occlusive disease EEG EEG is useful in aiding diagnosis and classification of epilepsy Characteristic interictal epileptiform discharge supports diagnosis of 960 A Clinical Approach to Medicine epilepsy but its absence does not rule this out The distinction between the generalized Hz spike and wave EEG discharge in childhood absence epilepsy and the temporal lobe spikes in complex partial seizures is important for prognosis and the choice of antiepileptic drug EEG has come to play a less important role in diagnosing structural lesions as neuroimaging is widely available Virtually diagnostic EEG changes (periodic complexes) are seen in subacute sclerosing panencephalitis and Creutzfeld–Jacob disease Cortical evoked potentials are of great value in demonstrating clinically unsuspected lesions in diagnosis of multiple sclerosis These potentials in the brain are evoked by stimulating the visual, auditory and somato sensory pathway peripherally ELECTROPHYSIOLOGIC STUDIES EMG and nerve conduction studies are well established as an essential part in the workup for neuromuscular disorders It is also essential for us to understand the pathophysiology of such diseases Recently, many new neuromuscular disorders have been identified by their characteristic electrophysiologic picture Such examples include Lambert–Eaton myasthenic syndrome (LEMS), multifocal motor neuropathy and acute axonal neuropathy There is no standard or routine testing but rather the test depends on the clinical evaluation The physician has to decide which studies to do, which muscles or nerves to examine It is good to recognize the limitations of electrophysiology testing and to interpret these results in the context of clinical findings Nerve conduction study (NCS) is a useful test in diffuse peripheral neuritis (like GBS, diabetic neuritis) or focal pressure neuropathy like carpal tunnel syndrome (median compression) or meralgia paresthetica (lateral cutaneous nerve of thigh compression) One occasionally recognizes a disorder, multifocal motor neuropathy with conduction block on NCS This closely resembles clinically motor neurone disease (ALS) but is treatable with immunosuppressive medication and intravenous immunoglobulin Peripheral neuropathy could be predominantly demyelinating or axonal, depending on the etiology This can be characterized by nerve conduction study and needle EMG of the muscle supplied Demyelination slows or blocks conduction where as axonal affection Approach to the Patient with Neurological Disease 961 causes low amplitude response on stimulating proximally and distally and causes denervation changes in EMG of that muscle The usefulness of electrophysiological studies is illustrated by this common clinical problem of numbness and paresthesia of the little finger with associated wasting of the intrinsic hand muscle This could result from a spinal cord lesion, C8T1 radiculopathy, brachial plexus (lower trunk or medial cord) or a lesion of the ulnar nerve If sensory nerve action potential can be recorded normally at the wrist following stimulation of digital nerve in the affected finger, the pathology is probably proximal to the dorsal root ganglion (DRG), i.e there is a radiculopathy or more central lesion Absence of sensory potential by contrast suggests distal pathology (distal to DRG) EMG will indicate whether pattern of affected muscles conforms to radiculopathy or ulna nerve territory or is more extensive (plexopathy) Ulna motor conduction study will distinguish between radiculopathy (normal conduction) and ulna neuropathy (abnormal conduction) and will identify site of ulna nerve lesion Late responses (H reflex or F waves) are able to study the proximal part of the nerve segments Stimulating a motor nerve causes impulses to travel orthodromically (towards nerve terminal) as well as antidromically (towards spinal cord) Such anti-dromic impulses go to the Anterior Horn Cell (AHC) through the anterior root and causes the AHC to discharge producing a small motor response that occurs considerably later (late response) than the direct response elicited by nerve stimulation This is the F wave and is delayed in proximal lesion like radiculopathies in GBS, and is useful in early diagnosis Needle EMG is helpful in detecting myotonia and in differentiating between denervating process and myopathy It helps to distinguish axonal neuropathy from demyelinating neuropathy It is useful in anterior horn cell disease like motor neurone disease The interpretations of EMG depend a lot on the electromyographer unlike nerve conduction studies which are well standardized Though MRI has became the first choice in workup for cervical or lumbar radiculopathy it cannot confirm radiculopathy in all cases (such as diabetes) Judicious use of needle EMG is needed even in the era of MRI Repetitive Nerve Stimulation (RNS) test is useful in diagnosing neuromuscular transmission disorders like myasthenia gravis (MG) or LEMS A decrement of the compound muscle action potential (CMAP) at Hz stimulation occurs in both An incremental response of the CMAP at 962 A Clinical Approach to Medicine a fast rate of stimulation (50 Hz) or after exercise is characteristic of LEMS and differentiates this from MG Tensilon test done clinically or during RNS is more dramatically positive in MG than in LEMS Single fiber EMG (SFEMG) is an extremely sensitive test for myasthenia gravis (MG) and other neuromuscular transmission (NMT) disorders (thus, it is non-specific for MG) A normal SFEMG study in a weak muscle rules out NMT disorder When recording single fiber muscle action potential (SFMAP) from two single muscle fibers belonging to the same motor unit by inserting the electrode between the two, there is always a slight variability in the time interval between the two potential in such pairs This variability is called the jitter that is measured ANTIBODY TESTS IN NEUROLOGICAL DISORDER Ach R antibodies in myasthenia gravis is a fairly routine testing Antivoltage gated calcium channel antibodies of muscle are found in LEMS Anti-Hu associated with small cell lung cancer and anti-Yo associated with cerebellar disorder are found in paraneoplastic syndrome These are not routinely tested Anti-GM1 antibodies are often seen in axonal type of GBS In GBS, antibodies to gangliosides is not a recommended test because many GBS patient not have this However most patients with Miller–Fisher Syndrome (a variant of GBS) have serum GQ1b antibodies and this antibody appears specific This assay is now commercially available and is useful in supporting the clinical diagnosis of Miller–Fisher Syndrome We will now consider how to approach two of the common neurological complaint that we often see in clinical practice This is the patient whose presenting complaint is either weakness or a sensory complaint The third is Nystagmus, which has anguished those just initiated and those more experienced in neurology SENSORY COMPLAINT AND SENSORY LOSS Ask patient to delineate the area of pain or sensory loss Patient normally can map it as well or better than the examiner and much more quickly The sensory impairment or pain can be of a dermatomal pattern A good example is a sacral saddle shaped loss of sensation around the anus in a cauda equina lesion or a forefinger paresthesia of a cervical disc disease causing C6 root lesion Approach to the Patient with Neurological Disease 963 Neuralgic facial pain is distributed along a branch of the trigeminal nerve and is paroxysmal In trigeminal neuralgia, the patient suffers severe paroxysmal bouts of pain distributed crisply over the distribution of a branch of the trigeminal nerve covering the face, usually the maxillary and mandibular branches Sensory loss over this area is characteristically absent Pain is so severe to cause grimaces, a tic douloureux Prompt response to carbamazepine is diagnostic Post-herpetic neuralgia follows the zoster eruption of the ophthalmic branch of the trigeminal nerve After all causes of facial pain are excluded, there remains a patient usually female where the doctor is tempted to attribute depression or a psychological cause and call this condition atypical facial pain Spinal cord lesion causes a sensory level with loss of sensation below this level A band of hyperasthesia at the level of lesion is a very useful and reproducible sign The sensory level becomes more credible if the level is elicited also on the back of the patient A hemisection of the cord (Brown–Sequard Syndrome) produces loss of dorsal column sensation (vibration) and limb weakness on the same side as the lesion with loss of pain and temperature sensation on the opposite side A syringomyelic lesion (syrinx usually at around C4–T5 cord) usually affects the crossing spinothalamic tracts causing a cuirass like suspended sensory loss (for pain and temperature) over the chest and inner part of the arms Dissociated sensory loss is an interesting phenomenon resulting from anatomical distribution of sensory nerve fibers where some and not all modalities of sensation are lost, for example pain and temperature loss but vibration is intact Other than in the above two conditions (Brown–Sequard syndrome and syringomelia), it can occur in lesions affecting the lateral medulla where the lateral spinothalamic tract runs discretely lateral to the medical lemiscus This occurs in Wallenberg’s syndrome Some peripheral neuritis can have dissociated sensory loss in arms or trunk due to preferential affection of the small unmyelinated pain fibers in the peripheral nerve Sensory changes affecting the whole of the opposite side of body with simultaneous presence of pain and anesthesia is called anesthesia dolorosa This could occur in a thalamic lesion, usually vascular (Dejerine–Roussy syndrome) but often mistaken as hysteria Astereognosis occurs in parietal cortex lesions Stereognosis is the ability to recognize the size, shape and texture whilst the eyes are kept closed of a readily identifiable object, say a dollar coin placed in the hand of a patient who has no obvious sensory disturbance 964 A Clinical Approach to Medicine While peripheral neuritis causes a glove and stocking distribution of paresthesia and sensory loss (with generalized muscle weakness and wasting of muscles and diminished tendon jerks), entrapment neuropathies cause symptoms and signs limited to the nerve distribution A good example is carpal tunnel syndrome where pain and sensory loss occurs over the first three digits and the lateral half of the fourth digit As pathology is a focal demyelination of the median nerve at the wrist, tapping the nerve or stretching the nerve by wrist flexion or extension causes tingling over the affected fingers (Tinel and Phalens sign respectively) Typically the pain awakens the patient at night Another good example is meralgia paresthetica, which is the result of lateral femoral cutaneous nerve of thigh entrapment at the groin The patient has painful paresthesia with sensory loss over the anterolateral surface of the thigh Hansens disease should be suspected if there is patchy sensory loss due to intradermal affection of the nerve This is usually associated with thickened nerve PATIENTS WHO PRESENT WITH PARALYSIS OR WEAKNESS OF LIMBS Diagnosis can be made easier by considering the problem as a hemiplegia, paraplegia, quadrepligia or isolated paralysis Hemiplegia is weakness of an arm, leg and sometimes the face on one side of the body This occurs in pyramidal tract lesion of the brain usually in the opposite cerebral cortex or internal capsule A small capsular lesion can cause a more extensive weakness than a lesion in the cortex for obvious reasons The site of the lesion is deduced from the associated neurologic finding Aphasia or a visual field defect localizes to the opposite cortex Pure hemiplegia localizes to the internal capsule Crossed hemiplegia localizes the lesion to the brain stem Examples of this are Webers syndrome (3rd nerve palsy with opposite hemiplegia, a lesion of the midbrain), Millard–Gubler syndrome (Ipsilateral 6th or 7th cranial nerve palsy with contralateral hemiplegia, a lesion in the pons) The most common cause of this is a vascular lesion Rarely does Brown–Sequard syndrome at the cervical level cause a hemiplegia Paraplegia occurs in disease of the spinal cord, spinal root or peripheral nerves Parasaggital lesions in the brain and hydrocephalus can cause leg weakness Spinal cord lesions affect bladder control in addition Approach to the Patient with Neurological Disease 965 Acute paraplegia is usually from trauma, metastatic tumor or an epidural abscess Prompt laminectomy surgery for an epidural abscess is rewarding An occasional case of Potts disease (tuberculosis of spine) usually affects the mid-thoracic spine, causing a gibbus deformity Anterior spinal artery thrombosis or dissecting aortic aneurysms can infarct the spinal cord and present acutely The more common transverse myelitis we see in the ward is post-infectious or is acute demyelination Acute demyelinating myelitis with optic neuritis is Devics disease This is the common form of demyelinating disorder in Singapore and is believed to be the local variant of multiple sclerosis Cervical disc disease causing myelopathy is seen more commonly than spinal cord tumor Cervical root pain usually preceeds cord compression by the disc A tiny ventral pontine infarct can manifest as a locked-in state, which is a unique deefferented state where all muscles are paralyzed except the extraocular muscles Guillain-Barre Syndrome causes an ascending lower motor type of paralysis which usually progresses over a week to become quadreparesis This is the commonest acute peripheral neuritis seen in our wards In general, neuropathic disorders cause distal limb weakness and disorders of neuromuscular junction or muscles cause proximal weakness Isolated paralysis is usually from a lesion of a peripheral nerve The acute ulna nerve palsy or the peroneal nerve palsy is usually a pressure palsy The affected muscles are supplied by the particular nerve Weakness causing a wrist drop is usually from a radial nerve palsy, and rarely can be a cortical lesion L5 radiculopathy (lumbar disc prolapse) can cause a foot drop This is differentiated from a peroneal nerve palsy because the tibialis posterior is also weak This is supplied by the posterior tibial nerve originating from the L5 root Mononeuropathy multiplex occurs in or more nerves in more than one involved extremity (eg left ulna neuropathy and right peroneal neuropathy) This is typically found in vasculitis Other causes are leprosy and diabetes Monoplegia is weakness of all the muscles of a limb, though a detailed examination may disclose weakness of another limb, making this a hemiplegia Atrophy of the muscles makes one suspect a lower motor neurone palsy (other signs are diminished reflexes and fasciculation) where the lesion can be in the nerve, root or anterior horn cell Poliomyelitis, brachial neuritis, brachial plexus trauma, monomelic motor neurone disease should be considered Monoplegia without muscular atrophy is probably due to a lesion of the motor cortex (usually vascular and rarely a tumor) 966 A Clinical Approach to Medicine Hysterical paralysis causes diagnostic difficulty, for example in paralysis of a leg The Hoover sign is helpful: When the patient is asked to lift the paralyzed leg while lying down, the other heel pushes down With the examiner’s hands under the heels, pressure is felt by the examiner on the non-paralyzed side In hysterical paralysis the contralateral heel does not press down as the patient makes no effort to move Recent advances of technology has opened up new vistas of investigation and management of neurological diseases However, one must not forget that clinical neurology is very much an art and no amount of investigation can replace the clinical wisdom NYSTAGMUS Doctors often get into difficulty in interpreting nystagmus by mixing up different classifications because the mechanism is speculative Nystagmus is a rhythmic oscillation of the eyes, usually involuntary and conjugate This results from dysfunction of the vestibular end organ, vestibular nerve, brainstem or cerebellum The slow phase of jerk nystagmus is responsible for generation of nystagmus where as the fast saccade is the corrective movement bringing the fovea back to target The leaky brainstem integrator is unable to maintain constant output to the gaze center in order to hold the eyes in an eccentric position This causes the slow phase of the nystagmus and is often caused by the effect of alcohol, and anticonvulsants Vestibular nystagmus is either central or peripheral end organ in origin Vestibular end organ problem causes imbalance of peripheral vestibular input to the brainstem gaze center Labyrinth disease usually suppresses labyrinthine input there by simulating the nystagmus of cold water caloric test, which stimulates the horizontal semicircular canal The mixed vertical and torsional nystagmus seen in position-induced nystagmus suggests posterior semicircular canal irritation This plane relates to the geometric relationship of the semicircular canal The doctor needs to evaluate the nystagmus critically He will have to describe the character of the nystagmus (Table 1), differentiate a peripheral from a central vestibular cause (Table 2) and localize it anatomically (Table 3) Testing for nystagmus while the patient wears frenzel goggles to impair visual fixation brings out peripheral nystagmus This is usually done by the ENT surgeons Approach to the Patient with Neurological Disease 967 Table Jargon of Nystagmus 1) Wave form a) Pendular b) Jerk 2) Plane a) Horizontal b) Vertical (upbeat and downbeat) c) Torsional d) Combination of above e) Is there a spontaneous alteration of direction? This requires observation over a period of time, and occurs in periodic alternating nystagmus 3) In relation to gaze a) Nystagmus in primary position b) Gaze-evoked nystagmus 4) Positional — provoked by head posture Etiology 1) Physiological — optokinetic, end-point (on extreme gaze), caloric 2) Pathological a) congenital — accompanied by poor vision, albinism b) acquired — commoner type than congenital Anatomical Localization 1) Central — vestibular projections in the brainstem or cerebellum 2) Peripheral — vestibular end organ or acoustic nerve Table Central versus Peripheral Vestibular Nystagmus Feature Peripheral Central a) Plane Mixed horizontal-torsional b) Direction Unidirectional c) Abolishing fixation by Frenzel goggles d) Vertigo, tinnitus and deafness e) Other signs Apppears or increases Pure vertical, pure horizontal Pure torsional or mixed Can be bi-directional (changes direction with gaze) No change Prominent Less prominent No Brainstem or cerebeller 968 A Clinical Approach to Medicine Table Axioms in Nystagmus 1) Jerk nystagmus in central or peripheral 2) In jerk nystagmus, the amplitude increases with gaze in the direction of the fast phase (Alexander’s Law), which is conventionally defined as the direction of nystagmus 3) Pendular nystagmus is either congenital or acquired from central cerebellar and brainstem disease, usually multiple sclerosis 4) When anticonvulsants and psychoactive drugs are excluded, gaze-evoked vertical nystagmus indicates acquired central disease 5) Pure vertical or pure torsional nystagmus almost never occurs with peripheral vestibular disease Congenital nystagmus is characteristically pendular or jerky in primary position and remains horizontal whether patient looks up or down or to a side (uniplanar) There is a “null zone” (a field of gaze where nystagmus in minimal and acuity is best) and nystagmus dampens with convergence Nystagmus with Specific Localizations Downbeat nystagmus (fast phase down) in primary position or lateral gaze is characteristically seen in lesions of the cervicomedullary junction at foramen magnum region Upbeat nystagmus occurs in lesions at the ponto-medullary junction or superior cerebellar vermis Pure torsional nystagmus indicates brainstem disease See-saw nystagmus is a unique type with torsional and pendular characteristics (rising eye intorts and falling eye extorts) frequently associated with lesions of the mesodiencephalitic junction (Cajal nucleus) and chiasm Convergenceretraction nystagmus on attempted upward gaze is a component of dorsal midbrain syndrome (Parinaud’s syndrome) Ocular bobbing (rapid downward movement of eyes followed by a slow drift up, occurring 2–15 times per minute) occurs in comatose patients with massive pontine lesion A lesion in the medial longitudinal fasciculus gives rise to internuclear ophthalmoplegia characterized by ipsilateral adduction failure and nystagmus in abducting eye (described as ataxic nystagmus) on looking away from the side of the lesion Drugs and toxins may cause nystagmus in any direction 57 Headache Einar Wilder Smith, Wong Meng Cheong, Lim Shih Hui and Pavanni Ratnagopal BASIC CONCEPTS AND EPIDEMIOLOGY OF HEADACHES Headache is one of the most common human maladies afflicting people of all societies and cultures Studies that examined the lifetime and yearly prevalence have shown high rates in most regions where these have been conducted In Asia, Europe and the United States, estimates of the lifetime prevalences of any form of headache, tension headache and migraine in the general adult population are approximately 90%, 70–80% and 10–25% respectively The head is defined as all structures above the neck, whereas the face is part of the head and is defined as the area between a line drawn between the lateral epicanthus and the superior border of the ear pinna and the chin In this chapter, all types of aches and pains located in the head and face are discussed 969 970 A Clinical Approach to Medicine Headache Pathophysiology The head is prone to hurt because the scalp and face have some of the body’s richest supplies of pain receptors in order to protect the sensitive and important contents and attachments The eye, nasal and oral passages all reside here When diseased, they can all result in headache or facial pain The pathophysiology of headache is complex and differs with the type of headache Overall, it can conveniently be divided into pain generation in the sensitive structures of the head and its attachments, and the subsequent transmission and processing of pain Pain in and around the head can be generated by many different structures The pain-sensitive innervation of the forehead, orbits, anterior and middle fossae of the skull is largely derived from branches of the ophthalmic division of the trigeminal nerve and, to a lesser extent, from the second trigeminal division The sphenopalatine branches of the facial nerve innervate naso-orbital region The 9th and 10th cranial nerves, as well as the first cervical nerves, convey pain from the inferior surface of the tentorium and the posterior fossae Consequently, pain from the supratentorial structures is referred to the first two divisions of the trigeminal nerve and pain from the infratentorial structures is referred to the back of the head and neck Structures that are not pain-sensitive include the brain parenchyma, the bony skull, and the ependyma and choroid plexuses Many types of headache are a result of the stimulation of the painsensitive intra- and extracranial vessels Both migraine and cluster headache are caused by dilatation of intra- and extracranial vessels Intracranial mass lesions cause pain through the displacement of vessels Inflammation of arteries underlies the headache of temporal arteritis Pain in sinus disease is due to the stimulation of pain-sensitive sinus walls and is relieved when aeration is restored and the inflammation subsides Headaches of ocular origin (hypermetropia and astigmatism) are either the result of sustained contraction of frontal, temporal or occipital muscles or are due to raised intraocular pressure, with or without inflammation Any disease of the neck ligaments, muscles and vertebral joints is capable of resulting in headaches The pain in these conditions is thought to arise from secondary protective spasm of the muscles or directly from the pain-sensitive joints and ligaments Headache 971 Meningeal irritation due to infection or bleeding is due to direct stimulation of the meningeal trigeminal nerve endings A further headache mechanism is due to low cerebrospinal fluid pressure Here, pain is a result of the downward displacement of intracranial contents and the subsequent traction of vessels The recent identification of the “trigeminovascular system” has helped in the developing of a new theory for the generation of the migraine headache Cells located in the caudal trigeminal nucleus have been identified as the anatomical locus for pain transmission in migraine Anti-migraine drugs, such as dihydroergotamine and the triptans, can directly inhibit these cells A CLINICAL APPROACH TO HEADACHES History Taking In a patient with a headache, the most important factor that leads to an accurate diagnosis is the history In most cases, detailed history taking alone will allow an accurate etiological classification of the headache Table lists the important features to be sought during a physical examination Table Physical Examination in Headache Patients General physical examination • Blood pressure (malignant hypertension as headache, diastolic of Ͼ120 mmHg) • Meningism (this should include the Lasegue, Kernig and Brudzinski’s signs) • Temporal artery: pain on palpation, absent pulsation and prominence • Signs indicating a local affection of the skull – Sinusitis: percussion sensitivity over the sinuses and streaks of pus at the back of the throat – Otitis: check ear with otoscope – Check skull form for deformities or enlargement (hyperostosis with Paget’s disease, meningiomas or certain osteosclerotic metastasis) – Glaucoma/iridocyclitis: check eye pressure and anterior eye chamber – Temporo-mandibular joint disease: check for asymmetrical bite and pain over the joint – Consider dental pain Neurological examination Signs of raised intracranial pressure (optic discs for papilledema) Cranial nerves Other signs of focal neurology 972 A Clinical Approach to Medicine HEADACHE CLASSIFICATION Table is a simplified version of the International Headache Society’s classification of headaches Table Classification of Headache and Facial Pain (modified from the International Headache Society Classification) 1) Migraine a) Migraine without aura (common migraine) b) Migraine with aura • Typical aura (“classical migraine”) • Atypical aura (basilar migraine and hemiplegic migraine) 2) Tension-type headache a) Episodic tension-type headache • Evidence of scalp/neck muscle involvement • No evidence of muscle involvement b) Chronic or continuous tension-type headache • Evidence of scalp/neck muscle involvement • No evidence of scalp/neck involvement 3) Cluster Headache and chronic paroxysmal hemicrania a) Episodic cluster headache b) Chronic cluster headache c) Chronic paroxysmal hemicrania 4) Miscellaneous benign dysfunctional headaches Includes ice cream headache, cough headache, exertional headache, sexual headaches and so forth 5) Post-traumatic headaches 6) Headache associated with vascular diseases a) Subarachnoid hemorrhage b) Vasculitides c) Arterial dissections d) Intracranial venous thrombosis e) Arterio-venous malformations 7) Headache from other intracranial disease a) Altered CSF pressure • High, such as pseudotumor cerebri • Low, such as post lumbar puncture or spontaneous intracranial hypotension b) Intracranial mass lesion c) Intracranial inflammation 8) Headaches associated with substances or their withdrawal a) Acute use or exposure • Nitrates, monosodium glutamate and methylalcohol b) Chronic use or exposure • Ergotamine, analgesics and benzodiazepines • H2 blockers, some NSAIDs and antibiotics Headache 973 c) Withdrawal • Alcohol, caffeine, ergotamine, analgesics and so forth 9) Headaches associated with diseases of the skull, neck, eyes and sinuses 10) Cranial neuralgias a) Trigeminal neuralgia b) Occipital neuralgia c) Glossopharyngeal neuralgia d) Herpes zoster e) Tolosa–Hunt syndrome 11) Others a) Neck-tongue syndrome Table Diagnostic Criteria for Migraine and Tension Headache 1) Diagnostic criteria for migraine without aura a) At least attacks of headaches that fulfill criteria (b) and (d) b) Headaches lasting four to 72 hours each c) Headache has at least two of the following characteristics: • Unilaterality • Pulsatility • Intensity that is great enough to affect normal activities • Headache aggravation by exercise d) Headache is accompanied by at least one of the following: • Nausea and/or vomiting • Photophobia • Phonophobia e) No evidence from the history or examination of any other disorder which could be causing the headaches 2) Diagnostic criteria for migraine with aura a) One or more transient focal neurological aura symptoms (usually visual) b) Gradual development of aura symptoms after more than four minutes c) Aura symptoms that last from four minutes to an hour d) Headache follows or accompanies aura within an hour 3) Diagnostic criteria for tension-type headache Multiple attacks of headache with the following characteristics: a) Headaches must last half an hour to a week each b) Headache has at least two of the following: • Bilateral • Non-pulsatile • Moderate intensity • Not aggravated by physical activity c) The headache is not accompanied by anything or, at the most, by a little hypersensitivity to light or noise d) No evidence from the history or examination of any other disorder that could be causing the headaches Table lists the diagnostic criteria for migraine and tension headache 974 A Clinical Approach to Medicine OTHER TYPES OF HEADACHES Indomethacin Responsive Headaches Because of their sometimes dramatic response to indomethacin, it is worth considering this group of headaches in a differential diagnosis Paroxysmal hemicrania and hemicrania continua are invariably responsive to indomethacin Other short-lasting headaches, such as exertional or cough headache, ice-pick headaches, idiopathic stabbing headache and headache associated with sexual activity, are partially responsive to indomethacin Headache Due to Low CSF Pressure This often occurs after dural puncture Though less common, there may be spontaneous rupture of the dural membrane The headache consistently appears when the body is in a vertical position and abates when it is lying down It usually disappears after one or two days of bed rest and taking plenty of fluids Persistent post-dural puncture headaches have been successfully treated with epidural blood patches HANDHELD CELLULAR TELEPHONE INDUCED HEADACHES There was a recent epidemiological study in Singapore on central nervous system symptoms of users of handheld cellular phones and headache was the most prevalent symptom compared with non-users It was also related to the increased duration of use of the handphone (min/day) and headache was reduced considerably among those who used hands-free equipment Headache Due to High CSF Pressure (Pseudotumor Cerebri) Pseudotumor cerebri (also called benign intracranial hypertension) is an uncommon condition more commonly found in young to middle-aged overweight females It is diagnosed in the presence of headache with bilateral papilledema and (optional) VI nerve palsy Other features of the neurological examination, CSF and imaging of the brain (CT or MRI) must Headache 975 be normal In a proportion of cases, the condition is related to treatment with corticosteroids, vitamins or antibiotics The treatment consists of alleviating raised intracranial pressure using diuretics (frusemide, diamox and hydrochlorothiazide) or ventriculo-peritoneal shunting In grossly overweight patients, weight reduction alone can result in remission Patients can become blind and therefore warrant careful follow-up to prevent this Optic nerve sheath fenestration can be used to treat the progressive loss of vision INVESTIGATION OF HEADACHE The most important part of the investigation of headache is the history and examination Most headaches fall into the category of tension headache or migraine and not require further investigation Plain views of the skull are of little help in the work-up of headaches Their usefulness is limited to the rare patient with headache due to Paget’s disease or multiple myeloma Plain views of the paranasal sinuses can identify air/fluid levels in sinusitis Plain films of the cervical spine (ϩ/Ϫ views in hyperextension/hyperflexion) identify cervical spondylosis or cervical bone destruction If an intracranial lesion is suspected or needs to be excluded, brain scanning with CT is usually sufficient CT scanning is particularly useful in the imaging of areas that consist mainly of bones, such as the orbit, sinuses, mastoid or base of the skull, as well as in identifying intracranial blood MRI imaging is superior in situations where accurate imaging of the posterior fossa is required or more detailed views are needed Lumbar puncture is required to confirm the diagnosis of meningitis and pseudotumor cerebri Although iron deficiency anemia can be associated with headache (and can respond to iron therapy), hemoglobin levels are rarely helpful in the investigation of headache The ESR (or CRP) is of great value in helping to establish the diagnosis of temporal arteritis (TA) If TA is present, the ESR will be greatly raised (Ͼ 70 mm in the first hour) Because of the long ensuing period of treatment with steroids and its associated complications, we recommend establishing a definite diagnosis of TA with temporal artery biopsy A psychiatric referral may be helpful when diagnosis of atypical facial pain is considered for an evaluation of possible depression 976 A Clinical Approach to Medicine TREATMENT OF HEADACHES The treatment of headaches encompasses the treatment of an underlying secondary cause, such as an intracranial space occupying lesion or infection, as well as symptomatic or prophylactic treatment with pharmacological agents A wide range of analgesics can be used for symptomatic headache treatment Treatment of Tension-type Headache Explanation and reassurance form the mainstay of therapy The patient needs to know what the presumed mechanism of headache is Hence explaining that the headache is due to fatigue, worry, stress or poor posture is important Physical measures can be quite useful Correction of poor body posture is helpful Also, short neck muscle massage several times a day and a hot shower sometimes help Chronic tension-type headache with no response to physical measures may respond to a three to six-month course of antidepressants, such as amitriptylline (10–20 mg) or fluoxetine (20 mg) at night Other options include doxepin, desipramine or nortriptylline The tricyclic antidepressants are generally more effective than the serotonin re-uptake inhibitors (fluoxetine), but are also less well tolerated Treatment of Migraine Migraine attacks can be triggered off by a variety of factors The avoidance of triggering factors, such as certain foods, alcohol, caffeine or smoking, should be watched out for Analgesics Paracetamol, on its own, may be helpful, but often a “resistance” seems to develop with its long usage Over-the-counter analgesics should not be used more than three times a week This is because it can result in headache due to its abuse If caffeine or codeine is mixed with simple analgesics, a medication induced headache is more likely to occur If acetylsalicylic acid is used, a high enough dosage (1000 mg) Headache 977 should be used and its combination with 10 mg or 20 mg of metoclopramide increases gastrointestinal absorption and effectiveness Specific Anti-migraine Drugs Ergotamine or dihydroergotamine are reserved for moderate to severe attacks Because of its powerful vasoconstrictive action, ergotamine should not be used in patients with ischemic heart disease, peripheral vascular disease or arterial hypertension Sumatriptan was the first HT agonist available for the treatment of acute migraine At the time of writing, three different triptans are available although one more is in the process of completing clinical trials and hopefully be launched soon Prophylactic Treatment All pharmacological prophylactic treatments take one or more months for their maximum effectiveness to be realized The usual dosages of commonly used drugs are given in Table Recently, botulinum toxin has been found to be useful in relieving certain types of migraine headaches and some of these patients even underwent removal of the corrugator supercilii muscles if they responded to Botox Table Prophylactic Anti-migraine Agents Action Drug Range of Effective Dose (mg/day) Effective Dose (mg/day) Non-specific Beta-blockers Specific beta-1 Tricyclic Anti-depressants Calcium channel blockers Anti-epileptics Vitamin Propranolol 20–360 mg 80–240 Atenolol Amitriptylline 25–150 25–300 50–100 75–150 Flunarizine Verapamil Valproate Riboflavin 5–10 120–160 500–1500 400 120 500–800 400 978 A Clinical Approach to Medicine REFERENCES Ho KH, Ong BK, Lee SC, Headache and self assessed depression scores in Singapore University undergraduates, Headache 37(1):26–30, 1997 Ho KH, Chong PN, Headache characteristics in university graduates presenting to medical attention, Singapore Med J 37(6):583–584, 1996 Rasmussen BK, Jensen R, Schroll M, Oleson J, Epidemiology of headache in a general population—a prevalence study, J Clin Epidemiol 44(11):1147–1157, 1991 58 Meningitis and Encephalitis Pavanni Ratnagopal, Einar Wilder Smith and Tan Ban Hock INTRODUCTION AND HISTORY Meningitis and encephalitis are devastating diseases of infancy, childhood and adulthood Despite antibiotic therapy, the morbidity and mortality remains high Tuberculous meningitis was first described in 1768 by Robert Whytt who initially described it as “dropsy in the brain” Gaspard Vieusseux’s description of an outbreak of “cerebrospinal fever” in Geneva (1805) was probably the first description of meningococcal meningitis This was followed in 1806 by the first epidemic of spotted fever to be documented in America in Medfield, Massachusetts In 1810, a medical student, Nathan Strong, first recognized meningism as a diagnostic sign for meningitis Vladimir Mihailovich Kernig described his maneuver for detecting meningeal irritation in 1882 and Josef Brudzinski described his observations in 1909 Heinrich Quincke pioneered the technique of lumbar puncture in 1891 At the turn of the century, Jochmann in Germany and Flexner in New York demonstrated the protective effect of antimeningococcal serum 979 980 A Clinical Approach to Medicine in experimental meningococcal infections in animals The discovery of the antibacterial activity of sulfonamides in the early 1930s ushered in the antibiotic era PATHOGENESIS AND PATHOPHYSIOLOGY Bacterial Meningitis The most common bacteria that causes meningitis, Hemophilus influenzae, Neissaeria meningitidis and Streptococcus pneumoniae initially colonize the nasopharynx by secreting IgA proteases that breakdown the mucous barrier and allow bacterial attachment to the epithelium Once these bacteria gain access to the bloodstream, a polysaccharide capsule helps avoid phagocytosis by neutrophils The mechanisms by which bacteria enter the CSF are largely unknown although it is speculated that it is through the choroid plexus of the lateral ventricles and other areas of altered blood brain permeability Since the CSF is an area of relatively impaired host defence with few phagocytic cells, low protein concentration, no IgM and low levels of complement (in particular C3 and C4), bacteria initially multiply with little opposition Meningeal inflammation develops as toxic components of the bacterial cell wall are released with cell lysis Antibiotics that kill Gramnegative bacteria by cell wall lysis with subsequent release of endotoxin have been shown in experimental models to be associated with a dramatic increase in vasogenic brain edema There is also a strong correlation between CSF endotoxin concentration and the development of seizures and morbidity and mortality in children with Gram-negative meningitis The purulent subarachnoid exudate of meningitis is mainly due to CSF neutrophilic pleocytosis As the infective process develops alterations in cerebral blood flow can occur due to raised intracranial pressure, loss of intracerebral vascular autoregulation, vasculitis and thrombosis of cerebral arteries, veins and major sinuses This in turn may lead to ischemic infarcts Viral Meningitis The common viruses causing meningitis are from the enteroviruses group, followed by the mumps virus, arboviruses, and the herpes simplex virus Enteroviruses are a major subgroup of picarnoviruses and include the polioviruses, coxsackieviruses, echoviruses and more recently discovered Meningitis and Encephalitis 981 agents that are simply designated as enteroviruses They can survive for prolonged periods in sewage as well as in chlorinated water, if sufficient organic debris is present Most of these agents can be isolated by cell cultures and humans are their natural host Infection is generally asymptomatic, but nervous system manifestations include aseptic meningitis and less commonly encephalitis, transverse myelitis or a poliomyelitis-like syndrome Enteroviral infections of the nervous system may leave significant sequelae like mental retardation and cerebral palsy in young children under year of age and fatigue and weakness in adults Mumps virus is a paramyxovirus spread by respiratory droplets About half the patients with parotitis will have CSF pleocytosis without neck stiffness Aseptic meningitis may be a presenting feature of mumps, but can also develop two or three weeks into the disease Viral meningitis generally causes a lymphocytic pleocytosis, with the cell counts less than 1000/L CSF glucose is usually normal and protein is either normal or slightly elevated Specific treatment may be withheld if the patient is well and CSF changes show those typical for a viral etiology The differential diagnosis of lymphocytic “aseptic meningitis” includes partially treated bacterial meningitis and tuberculous meningitis and poor inflammatory response in an immunesuppressed patient Therefore, in an ill patient, antibiotics often need to be used before the diagnosis can be finalized Fungal and TB Meningitis In fungal and TB meningitis, there is a subacute or chronic basal meningitis with inflammatory foci of organisms and associated infiltrates of lymphocytes, macrophages, and multinucleate giant-cells In cryptococcal meningitis, the subpial cortical inflammatory response is lacking, and there are subarachnoid clusters of cystlike cavities filled with organisms (“soap bubbles”) in the cerebral cortex with little or no surrounding inflammation The site of primary infection is usually from the lungs and less commonly from the skin Primary lesions may occur in the mouth and pharynx in paracoccidioidomycosis and in the gastrointestinal tract in histoplasmosis Encephalitis In general there is diffuse and widespread CNS infection as opposed to a localized inflammation Specific viruses affect specific anatomic areas or subpopulaton of cells, a phenomenon known as “tropism” The best known examples are the herpes simplex virus, which causes lesions in the 982 A Clinical Approach to Medicine limbic system, and polio virus, which affects the anterior horn cells of lower motor neurons Encephalitis can occur either by hematogenous spread after viremia or by retrograde spread along nerves like in rabies and herpes simplex World-wide, the important organisms usually include the herpes simplex, herpes zoster, HIV, polio, rabies, equine encephalitis and St Louis encephalitic viruses Microscopic changes include perivascular cuffing by lymphocytes and plasma cells, neuronal necrosis, inclusion bodies, microglial proliferation and glial nodules Hemorrhagic necrosis is common in herpes simplex encephalitis Calcification can be detected in some neonates infected in utero by with encephalitic producing agents like CMV and AIDS viruses ETIOLOGIC ORGANISMS Bacterial Meningitis The commonest organisms encountered are Streptococcus pneumoniae in adults and N meningitidis in children and young adults Table Commonest Organisms Uncommon Organisms Neonates Gp B Streptococcus Escherichia coli Listeria Monocytogenes Klebsiella-Enterobacter species Citrobacter diversus Salmonella species Childhood Hemophilus influenza type B (Hib) Neisseriae meningitides Streptococci pneumoniae Listeria monocytogenes Adults (16–50 yrs) Strep pneumoniae Neisseriae meningitides Hemophilus influenzae Listeria monocytogenes Borrelia Syphilis Gonococcus Adults (Ͼ 50 yrs) Strep pneumoniae Escherichia coli Klebsiella pneumoniae Hemophilus influenzae Pseudomonas organisms Enterobacter species Serratia species As above Meningitis and Encephalitis 983 Streptococcal pneumoniae is most common in USA and some areas of Europe but Neisseriae meningitidis is more common in Northern Europe and the Sahara belt in Africa In Singapore we have recently described an unusual outbreak of Group B Streptococcal meningitis in adults (E Wilder Smith, personal communication) The usual predisposing conditions were lacking in the overwhelming majority of cases Meningococcal meningitis caused by N meningitidis presents acutely with fever, vomiting, lethargy, neck stiffness and headache The classical diffuse erythematous maculopapular rash may rapidly become petechial and purpuric The fulminant illness, called the Waterhouse–Friderichsen syndrome presents with adrenal hemorrhage and a disseminated intravascular coagulopathy There is good protection from meningococcal vaccine for A & C, W135 and Y polysaccharide Fungal Meningitis This occurs primarily, but not solely, in individuals who are in a state of immunosuppression, for example, in those who have: • • • • the acquired immune deficiency syndrome (AIDS); an organ transplantation; immunosuppressive chemotherapy or chronic corticosteroid therapy; or lymphoreticular malignancies The most common fungi causing meningitis are Cyptococcus neoformans and Coccidioides immites, although Histoplasma capsulatum, Blastomyces dermatitidis and Candida species are increasingly reported C neoformans is a yeast-like fungus found in pigeon droppings, decaying fruits and vegetables, milk and soil C neoformans has a predilection for the CNS and spreads from a primary pulmonary infection to the meninges by hematogenous spread, and is the most common cause of central nervous system (CNS) infection in the transplant patient C neoformans may present as an acute illness with fever, headache, photophobia and an altered sensorium, or as an indolent illness with headache and low grade fever Fungal meningitis has a tendency to infect the basilar meninges and so may present with cranial nerve palsies CNS coccidioidomycosis may present as an acute illness or follow a subacute 984 A Clinical Approach to Medicine chronic cause Meningitis is the predominant clinical manifestation of CNS histoplasmosis Mental status abnormalities are common, including stupor, confusion, personality changes and cognitive deficits The CSF studies generally show a lymphocytic pleocytosis with an elevated protein content and decreased glucose concentration The India ink stain is positive in about 50% of HIV-negative individuals but positive in 75–80% of HIV-positive individuals Latex agglutination testing for the cryptococcal antigen is highly specific and sensitive and should be performed in all CSF specimens The serum cryptococcal antigen titers are also often positive in patients with cryptococcal meningitis and can be useful in monitoring the response to therapy The organism takes about to 10 days to grow The organism in Coccidioides immitis meningitis grows rapidly in about days but large volumes of CSF are needed Histoplasma capsulatum is positive in about 25–50% of cases, typically requiring as long as 45 days to grow The Histoplasma polysaccharide antigen can be measured in urine, blood and CSF, and has the same diagnostic significance as the cryptococcal antigen but this test is not widely available Tuberculous Meningitis Tuberculous meningitis does not develop acutely from hematogenous spread of tubercle bacilli to the meninges The neurologic complications of tuberculous meningits are initiated by a hypersensitivity reaction to the discharge of tubercle bacilli and tuberculous antigens into the subarachnoid space A thick exudate is produced and fills the basilar cisternsand surrounds the cranial nerves and major blood vessels at the base of Table Signs and Symptoms of Tuberculous Meningitis Symptoms Signs Prodromal Anorexia Weight loss Cough Night sweats CNS Headache (worse in recumbancy) Meningismus Altered level of consciousness Adenopathy Adventitious sounds Choroidal tubercles Fever Nuchal rigidity Papilledema Focal neurologic signs Positive tuberculin test Meningitis and Encephalitis 985 the brain, constricting the vessels that comprise the circle of Willis Within a matter of days, a proliferativ arachnoiditis develops The inflammatory exudate in the basilar cisterns obstructs the flow of CSF, with resultant obstructive hydrocephalus, and blocks resorption of CSF by the arachnoid granulations as fibrous adhesions develop Cerebral ischemia and infarction develop as a result of vasculitis due either to a direct invasion of arterial walls by mycobacteria or to compression of the blood vessels at the base of the brain from the adjacent arachnoiditis At the early stages of TB meningitis, the CSF may show very few white blood cells and a mild protein elevation but subsequently a repeat study shows a progressive increase in the protein concentration and a progressive decrease in the glucose concentration and a shift to a mononuclear pleocytosis The most important prognostic factor that is reported repeatedly in tuberculous meningitis is the level of consciousness at the initiation of therapy The mortatility rate of patients who are comatose prior to the onset of therapy is 50–70% Other factors affecting the outcome adversely are: 1) 2) 3) 4) 5) 6) 7) age (mortality is highest in the young and the very old); malnutrition/debilitating disease; the presence of miliary disease; hydrocephalus; cerebrovascular complications; low CSF glucose concentration; and elevated CSF protein concentration The diagnosis of tuberculous meningitis is made, and empiric therapy begun, based on a strong clinical suspicion and laboratory data suggest the diagnosis The initiation of therapy should not await bacteriologic proof of tubercle bacilli by smear or culture UNUSUAL TYPES OF MENINGITIS Aseptic Meningitis Viral meningitis and aseptic meningitis are terms used interchangeably but should not be The defining criteria of aseptic meningitis were described by Wallgren in 1925 and is as follows: 1) acute onset; 2) meningeal signs and symptoms; 986 A Clinical Approach to Medicine 3) CSF abnormalities typical of meningitis with a predominance of mononuclear cells; 4) absence of bacteria on smear and by culture of CSF; 5) no parameningeal focus of infection; and 6) self-limited benign course The classic CSF abnormalities are a mononuclear or lymphocytic pleocytosis with absence of bacteria The differential diagnosis of a CSF lymphocytic pleocytosis is much broader than one disease entity and includes infectious and non-infectious etiologies Generally, patients whose symptoms have not resolved within a week to ten days should have a repeat lumbar puncture In aseptic meningitis, the investigations other than that of CSF should be geared towards the most likely etiologies Table Differential Diagnosis of CSF Lymphocytic Pleocytosis Infectious etiology Viral Enterovirus Mumps Lymphocytic choriomeningitis Herpes simplex virus Human immunodeficiency virus Arthropod-borne virus Non-viral Mycobacterium tuberculosis Listeria monocytogenes Mycoplasma pneumoniae Rickettsia rickettsii Treponema pallidum Borrelia burgdorferi Cryptococcus neoformans Partially treated bacterial meningitis Non-infectious etiology Systemic lupus erythematosus Sarcoidosis Migraine Traumatic lumbar puncture Chronic benign lymphocytic meningitis Vasculitis Meningeal carcinomatosis Medications (ibuprofen, isoniazid, azathioprine, trimethoprim) Source: Connolly and Hammer (1990), and Wilhelm (1992) Meningitis and Encephalitis 987 Enteroviruses are the commonest cause of aseptic meningitis, accounting for Ͼ80% of cases of identified etiology They are transmitted primarily by the fecal-hand-oral route They have a worldwide distribution and is generally seen all year round Mumps virus remains an important cause of aseptic meningitis and often follows the onset of parotitis by several days to weeks The introduction of the mumps vaccine in the late 1960s has decreased the incidence markedly The herpes simplex virus is the most frequent of the herpes viruses causing CNS disease, and it is more commonly associated with HSV type genital infections An increasingly recognized cause of aseptic meningitis over the last decade is the human immunodeficiency virus (HIV) HIV may cause an acute aseptic meningitis at the time of initial infection and seroconversion along with the mononucleosis-like syndrome of fever, malaise, rash, myalgias and arthralgias One prospective study of high-risk adults noted symptoms suggestive of aseptic meningitis in out of 12 patients at the time they underwent HIV seroconversion Of interest is carcinomatous meningitis with leptomeningeal spread, the clinical presentation depending on the extent of the disease along the neuraxis Headache is the most frequent complaint, being severe and constant, either diffuse or located at the base of the skull with radiation into the neck, and frequently worse on awakening in the morning There is often associated neck pain and stiffness, though the meningismus is much less severe than that described in purulent meningitis Cognitive abnormalities consisting of lethargy, confusion or memory loss are also common initial complaints Focal or generalized seizures may develop CSF examination is the single most important test for the diagnosis of leptomeningeal metastases The median survival from the time of diagnosis of leptomeningeal metastases is 4–6 weeks, unless aggressive treatment is initiated The purpose of treatment is to prolong survival and stabilize the neurologic function The standard therapy is radiotherapy to symptomatic areas followed by intrathecal chemotherapy Chronic Slow Viral Infections The Icelandic pathologist Bjorn Sigurdsson first used the term slow infection in 1954 in reference to a chronic degenerative disease of the brain in sheep known as rida or scrapie These slow infections have criteria: a 988 A Clinical Approach to Medicine long period of latency; a regular protracted course after clinical signs have appeared; and it usually ends in serious disease or death The infection is limited to a single host species, and anatomical lesions are restricted to a single organ or tissue Subsequently slow viral infections were divided into two groups: those transmitted by conventional identifiable viruses; and those spongiform encephalopathies associated with a fundamentally distinct molecular pathogen, the prion Prion stems from the word proteinaceous infectious particle The prion diseases may be infectious, inherited or sporadic Infectious types (iatrogenic Creutzfeld–Jakob disease (CJD), kuru) is due to horizontal transmission of infectious prions Inherited diseases (familial CJD, Gerstmann–Straussler–Scheinker syndrome or fatal familial insomnia) is due to a mutaion in the protein coding region of the PrP gene Chronic viral infections in the nervous system are associated with the persistence of all or part of the viral genome They cause a variety of syndromes, several of which are distinctive for the specific viruses and associated neuropathology Some of the more distinct syndromes are: subacute sclerosing panencephalitis (SSPE) due to measles, progressive multifocal leukoencephalopathy (PML) due to papovavirus, and progressive rubella panencephalitis (PRP) due to rubella virus These typify the classic course of conventional slow virus infection: neurological deterioration leading to death within months to years CLINICAL PRESENTATION The triad of headache, fever and stiff neck is the classical presentation of bacterial meningitis In addition, photophobia, vomiting and lethargy or altered level of consciousness may also be present If there are further signs of confusion or coma, and/or seizures, overlapping encephalitis is likely to be present The symptoms and signs vary with different age groups In addition to the previously mentioned signs and symptoms, vomiting and poor feeding are seen in very young children The classical signs of bacterial meningitis are meningism as demonstrated by nuchal rigidity and Kernig’s and Brudzinski’s signs In a recent study at Yale University by Thomas et al., the diagnostic accuracy of Kernig’s sign, Brudzinski’s sign and Nuchal rigidity was assessed in 297 patients with CSF results and it was only diagnostic in severe meningeal inflammation In the broad spectrum of adults with Meningitis and Encephalitis 989 suspected meningitis, classical meningeal signs did not have diagnostic value In the elderly this can be difficult to interpret at times When neck stiffness is due to meningitis, the neck usually resists flexion and can still be rotated from side to side, but if due to cervical spondylosis, parkinsonism or paratonic rigidity, any movement meets with resistance Raised intracranial pressure (ICP) is an expected complication of meningitis, especially of bacterial meningitis The Cushing reflex — bradycardia, hypertension and irregular respiration, dilated unreactive pupils, unilateral or bilateral sixth nerve palsies, papilledema, projectile vomiting and decerebrate posturing, may be seen in extreme cases In a patient with a pure encephalitic picture, neck rigidity with Kernig’s or Brudzinski’s may not be necessarily present The symptoms and signs of encephalitis are rather similar to those of meningitis except for the element of confusion and coma being more distinctly seen and seizures having more prominence Seizures may possibly be a sign of cortical venous thrombosis with hemorrhage and this should be considered as part of the differential diagnosis If bacterial meningitis is left untreated, mortality rate is nearly 100% In developed countries the mortality rate is stuck at 5–10% and underdeveloped countries at 40% INVESTIGATIONS The following tests should be performed in all cases of meningitis ϩ/Ϫ encephalitis: 1) CT Scan Brain — If clinical signs not suggest raised ICP, the LP can be done without a prior CT Scan, but should be considered in centers where scan facilities are available 2) Lumbar Puncture — should be done as soon as possible with stains and cultures for bacterial, fungal and tuberculous organisms as a Table CSF Results in Common Conditions Normal Viral Bacterial TB/Fungal Cells Glucose Protein Globulin Up to Lymphocytes Lymphocytes Polymorphs Lymphocytes Serum/gluc ratio 0.6 N ratio ↓ ratio ↓ ratio 0.2–0.4 Neg May be ↑ ↑ ↑ markedly Neg ϩ ϩ 990 A Clinical Approach to Medicine routine Viral studies and additional uncommon viral and bacterial studies should be requested for if suspected The opening CSF pressure is generally increased in all the conditions but mostly in acute bacterial meningitis Although CT Scan and lumbar punctures are the main investigations, the usual investigations for a generalized septic process should still be carried out, including a blood culture, chest X-ray, urine microscopy and culture MANAGEMENT The most important aspects in managing patients with meningitis and encephalitis is ascertaining whether the patient needs emergency supportive treatment The most serious consequences of meningitis and encephalitis are seizures and raised intracranial pressure which may lead to cerebral coning and death Once these are dealt with, then specific antiviral, antibacterial or antifungal/TB treatment can be instituted Currently there are very few antiviral agents available, the commonest one being acyclovir which is usually given for at least to 10 days at a dosage of 10–12 mg/kg (over one hour infusion intravenously) hourly Antibacterial therapy as a broad spectrum coverage without culture results or sensitivity include Gram-positive and Gram-negative organisms Table Recommended Antimicrobial Therapy of Common Bacterial Meningitis Organism Antibiotic Total Daily Dose (Dosing Interval) Neisseria meningitides Penicillin G 20–24 million U/day IV (every hrs) or Ampicillin 12 g/day IV (every hrs) Ceftriaxone or cefotaxime plus Vancomycin Ceftriaxone 2–4 g/day IV (every 12 hrs) or Cefotaxime g/day IV (every hrs) Ceftazidime g/day IV (every hrs) Ceftriaxone or cefotaxime Vancomycin g/day IV (every hrs) Streptococci pneumoniae Gram-negative bacilli (except Pseudomonas aeroginosa) Pseudomonas Aeroginosa Hemophilus influenzae type B Staphylococcus aureus (methicillin resistant) Listeria monocytoges Enterobacteriaceae Ampicillin 12 g/day IV (every hrs) Third generation cephalosporins Source: Roos KL, Tunkel AR, Scheld WM, Acute bacterial meningitis in children and adults, in: Scheld WM, Whitley RJ, Durack DT (eds.), Infections of the Central Nervous System, Raven Press, New York, pp 335–409, 1991 Meningitis and Encephalitis 991 For a long time, intravenous ceftriaxone has been the standard recommendation With the advent of penicillin resistant streptococci pneumoniae however, recent reviews have recommended the combination of Vancomycin and Ceftriaxone as empirical treatment Anti-TB drugs used commonly are rifampicin, PZA, INH and streptomycin, and although the duration of treatment is for to months for lung lesions, most physicians would continue for months to a year at least, if not longer for meningitis Steroid therapy has been used as an adjunct to TB treatment to decrease brain edema, decrease CSF outflow resistance, decrease the production of inflammatory cytokines and number of leukocytes, thus minimizing damage to the blood brain barrier Antifungal treatment generally is geared towards the specific organism, with amphotericin being used commonly in the initial treatment of cryptococcal meningitis Chronic recurrent meningitis in immunosuppressed patients may need prophylactic coverage, for example in AIDS patients, cryptococcal meningitis may recur and so prophylaxis with fluconazole may have to be used This page intentionally left blank 59 Seizures and Epilepsy: Diagnosis, Investigation and Treatment in Adults Lim Shih-Hui, Andrew Beng-Siong Pan, Einar Wilder–Smith, Puvanendran K INTRODUCTION Epilepsy is a common neurological disorder It has been estimated to affect about per 1000 of the population at any one time and the accumulated risk of having at least one epileptic seizure over an 80-year life span is in 10.1 The cumulative incidence of epilepsy for Singapore children by age years is 3.5 per 1000.2 There is no significant difference in the incidence among males and females, with significant lower incidence in Malays compared to Chinese and Indians The costs to society and to the individual are considerable, reflecting the increased morbidity in people with epilepsy There is also evidence of increased mortality in adults with epilepsy In this chapter, diagnosis and general management of seizure and epilepsy in adult are discussed Status epilepticus and pediatric epilepsy are excluded 993 994 A Clinical Approach to Medicine DEFINITION OF EPILEPTIC SEIZURES AND EPILEPSY Epileptic seizures are symptoms of cerebral dysfunction, resulting from an imbalance of excitatory and inhibitory influences within a neuronal aggregate, leading to paroxysmal hypersynchronous discharges of neurons of the cerebral cortex The clinical manifestations are extremely variable Signs and symptoms of seizures are determined by the function of the cortical area involved Epileptic seizures are usually self-limited, lasting a minute or two, and may be followed by a period of postictal cerebral depression manifested clinically as diffuse or localized neurologic deficits Not all patients with seizures have epilepsy Epilepsy is defined as a disorder characterized by or more unprovoked epileptic seizures due to primary brain abnormality One episode of epileptic seizure, therefore, does not constitute epilepsy Epileptic seizures could also be reactive, known as reactive seizures, acute symptomatic seizures, provoked seizures or situation-related seizures.3 These seizures occur at the time of systemic disturbance or in close temporal association with a documented brain insult Systemic disturbance causing reactive seizures include electrolyte imbalance (e.g hypocalcemia, hypomagnesimia, hyponatremia, hypoglycemia or nonketotic hyperglycemia), drug-induced (e.g amitryptyline or aminophylline)4 and drug or alcohol withdrawal, toxic insults (e.g carbon monoxide poisoning or acetylsalicylic acid overdose) and eclampsia Primary brain insults causing reactive seizures include meningitis/ encephalitis, trauma, acute stoke, and tumor These seizures usually resolve spontaneously, with symptomatic treatment, and/or with treatment of the underlying reversible cause Patients with reactive seizures should not be labeled as having epilepsy ETIOLOGY OF EPILEPSY The cause of epilepsy is believed to be multifactorial, involving both genetic and acquired factors There are potential genetic contributions to the appearance of an epileptic disorder: 1) variations among individuals in their susceptibility to epileptic symptoms given a transient epileptogenic insult or to chronic epilepsy given a specific structural lesion are in large part genetically determined; 2) some specific cerebral disturbances that give rise to secondary epilepsies are genetically transmitted, such as Seizures and Epilepsy 995 tuberous sclerosis and phenylketonuria; and 3) the primary epilepsies reflect genetic impairment in cerebral excitability and synchronization.5 Acquired lesions that give rise to secondary epilepsies may be bilateral and so diffuse that seizures are generalized from the start, or the lesions may be localized to smaller areas of the brain, giving rise to partial seizures or generalized seizures with focal features Common pathological substrates of secondary epilepsies include developmental defects, hippocampal sclerosis, neoplasms and other tumors, and cerebral damage due to trauma, vascular accidents, and infection DIAGNOSIS OF EPILEPTIC SEIZURE AND EPILEPSY As many other neurologic, psychiatric and systemic disorders can have intermittent symptoms, diagnosis of epileptic seizures requires first determining whether the intermittent “ictal” event is in fact epileptic in nature In order to so, the physician must be aware of the various phenomenologies of epileptic seizures (Table 1) These phenomena depend on the part of the cerebrum being activated by seizure activity Once it is determined that the event was epileptic, the next diagnostic step is to decide whether it is a reactive seizure or the first manifestation of epilepsy If a reversible and/or treatable cause (e.g hypocalcemia, brain tumor) is successfully treated and seizure no longer recurs, the patient should not be labeled with the diagnosis of epilepsy When seizures persist or recur, either because an underlying treatable cause has not been found or treatment of it has not resulted in the remission of seizures, a diagnosis of epilepsy is then made Subsequent diagnostic evaluation is aimed at determining what type(s) of seizures are occurring and whether the clinical features constitute a recognized epileptic syndrome The epileptic seizure classification describes the types of seizures only (Table 2), while the epilepsy syndrome classification describes the syndromes in which seizures occur (Table 3) Epileptic seizures should be classified because it allows appropriate selection of antiepileptic drug (AED) treatment (Table 1) while classification of epilepsy syndromes help to determine the prognosis (e.g response to treatment) as well as type of investigation The International League Against Epilepsy (ILAE) classifies seizures using seizure semiology and EEG findings.6 In clinical practice, EEG information may not be available or diagnostic (vide infra) Thus one has Potentially Effective AEDs Seizure Phenomenology 1st Choice Monotherapy 2nd Choice Monotherapy or as Add-on loss of consciousness, vocalization, bilateral sustained contraction followed by rhythmic twitching bilateral rhythmic twitching/jerking brief, sudden bilaterally synchronous muscle jerks without impaired consciousness bilaterally synchronous sustained contractions, with or without impairment of consciousness, often causing patient to fall bilaterally synchronous loss of tone / posture of head, limbs and/or body, with or without impairment of consciousness; often result in falls lapse of consciousness, at times associated with minor movements such as eye blinking or facial twitching VPA, CBZ, PHT LTG, PB, PRM, CZP, CLB VPA LTG, CZP, CLB, PB, PRM LTG, CZP Consciousness preserved • Rhythmic jerking/twitching (clonic) or sustain contraction (tonic) of certain part of body including eye/ head (with deviation) • Tingling, numbness, pain burning sensation of certain part of the body CBZ, PHT, VPA Therapy Generalized Tonic-clonic Clonic Myoclonic Tonic Atonic Absences (Typical and Atypical) Partial Simple Partial (SPS): • Motor • Somatosensory LTG, CZP LTG, ESM, CZP, CLB LTG, GBP, VGB, TPM, VGB, PB, PRM, CZP, CLB LEV A Clinical Approach to Medicine Adapted from ILAE Seizure Classification 996 Table Seizure Type, Phenomenology and AEDs of Choice • Visual • Autonomic • Psychic Complex Partial Partial Seizures with Secondary Generalization Unclassifiable • Flashing lights, visual hallucination • Flushing, pallor, epigastric sensations, sweating, changes in pupillary sign, tachycardia • hallucination/illusions (visual, auditory or olfactory), disturbance of memory (déjà vu or jamais vu, memory flashback, amnesia), emotional (fear, sadness, pleasure, anger) and others loss of consciousness, may follow a SPS, may be associated with oro-alimentary (e.g lip smacking, chewing, swallowing) and/or limb (e.g fumbling, scratching) automatism, and vocalization Above partial seizure evolving into generalized, clonic or tonic-clonic seizures Histories from patient and/or witnesses are not detailed or specific enough to allow a differentiation between partial or generalized epileptic seizures; seizure during sleep; no witness VPA or CBZ Seizures and Epilepsy CBZ ϭ Carbamazepine; CZP ϭ Clonazepam; CLB ϭ Clobazem; ESM ϭ Ethosuximide; GBP ϭ Gabapentin; LTG ϭ Lamotrigine; PB ϭ Phenobarbital; PHT ϭ Phenytoin; PRM ϭ Primidone; TPM ϭ Topiramate; VPA ϭ Valproic Acid; VGB ϭ Vigabatrin; LEV ϭ Levetiracetam 997 998 A Clinical Approach to Medicine Table International Classification of Epileptic Seizures (abbreviated) 1) Partial (arising from a focal or local cortical lesion, most commonly the temporal lobe) • Simple partial (no loss of consciousness) • Complex partial (loss of consciousness; may start with loss of awareness or may follow a simple partial seizure; may be with or without automatisms, e.g lip smacking, rubbing hands, walking, running with no recollection) • Partial evolving to secondary generalized with tonic, tonic-clonic or clonic features 2) Generalized (with bilateral discharges involving subcortical structures — convulsive or non-convulsive; EEG shows bilateral discharges; consciousness is lost at the onset except in myoclonic seizures; motor features bilateral) • Absence (last seconds; ϩ/Ϫ minor automatisms) • Myoclonic (may be simple or multiple jerks, often upper limbs) • Tonic • Tonic-clonic • Clonic • Atonic (sudden loss of posture of head, limbs and/or body): 3) Unclassified (usually used when an adequate description is not available, e.g often in seizures from sleep; no eyewitness) Adapted from Commission of Classification and Terminology of the International League against Epilepsy (Epilepsia 1981; 22: 489–501) and Scottish Intercollegiate Guidelines Network (SIGN) on Diagnosis and Management of Epilepsy in Adults (1997) to depend on good history taking to classify seizures (Table 4).7 The International Classification of Epilepsies and Epileptic Syndromes8 divides epileptic disorders into those due to inherited epileptogenic cerebral dysfunction (primary or idiopathic epilepsy) and those due to specific structural abnormalities, which may be genetic (such as tuberous sclerosis) or acquired (secondary or symptomatic epilepsy) For practical purposes, an abbreviated form of the International Classification of Epilepsy Syndromes is recommended (Table 3) Most adults presenting with epileptic seizures have a symptomatic localization-related epilepsy In reactive seizures, ictal events are usually generalized However, they may be partial when pre-existing localized cerebral disturbances make one area of the brain more epileptogenic than others (e.g in the case of seizures secondary to alcohol withdrawal, this may be partial if the alcoholic patient had a previous cerebral contusion; presence of a previous stroke will make hypoglycemic seizure partial) Seizures and Epilepsy 999 Table International Classification of Epileptic Syndromes (abbreviated, pediatric syndromes excluded) 1) Localization-related epilepsies • Idiopathic (age-related; common — benign Rolandic Epilepsy, rare — primary reading epilepsy, benign occipital epilepsy) • Symptomatic (most commonly temporal lobe epilepsies, but also frontal parietal, or occipital epilepsies) 2) Generalized epilepsies • Idiopathic (age-related) – juvenile absence epilepsy – juvenile myoclonic epilepsy – epilepsy with tonic-clonic seizures on awakening – others not defined above – epilepsies with seizures precipitated by specific modes of activation, e.g photic stimulation • Idiopathic or symptomatic – epilepsy with myoclonic absences • Symptomatic (e.g inherited metabolic or congenital disorders) 3) Epilepsies undetermined whether focal or generalized 4) Situation-related Seizures occurring only when there is an acute metabolic or toxic event (e.g alcohol, drugs, eclampsia, non-ketotic hyperglycemia) Adapted from Commission of Classification and Terminology of the International League against Epilepsy (Epilepsia 1989; 30: 389–399) and Scottish Intercollegiate Guidelines Network (SIGN) on Diagnosis and Management of Epilepsy in Adults (1997) A clear history from the patient and a witness (when possible) gives the most important information leading to a confident diagnosis Primary care physicians (e.g general practitioners) and doctors in Accident & Emergency Departments can play a vital role in obtaining detailed witness accounts while the events are still fresh in witnesses’ minds DIFFERENTIAL DIAGNOSIS The diagnosis of epilepsy is not always straightforward On one hand, epilepsy may be under- or misdiagnosed and not treated appropriately On the other hand, patients with non-epileptic disorders may be wrongly diagnosed as epilepsy and treated with antiepileptic drugs Among the most common disorders which need to be distinguished from epileptic seizures are vasovagal syncope and psychogenic seizures 1000 A Clinical Approach to Medicine Table Taking a History in Patients With or Suspected of Having a Seizure Disorder 1) 2) 3) History of attacks from the patient • frequency of attacks • circumstances and trigger factors • symptoms before and during the attacks • duration of symptoms • symptoms following the attack • injury, tongue biting and incontinence History of attacks from a witness • frequency of attacks • detailed description of observations before and during the attacks (including level of responsiveness, motor phenomena, vocalization, color, breathing, pulse) • detailed description of behavior following the attacks History should include the following diagnostically relevant factors • age • sex • past medical history, including head injury and febrile convulsions • past psychiatric history • social history • family history • alcohol and drug use Vasovagal syncope is a more common cause of sudden loss of consciousness in patients presenting to a hospital emergency department (40%) than epilepsy (29%).9 It should be considered when there has been a potential trigger such as fear, pain, sudden standing from squatting or supine posture, micturition, and cough Its motor, sensory and/or autonomic features may simulate epileptic seizures For example, myoclonic jerks lasting less than 10 seconds, head turning, automatisms (lipsmacking, chewing), upward deviation of the eyes, vocalization and incontinence may occur in syncope.10 Sensory symptoms, including visual hallucinations and even out-of-body experiences can also occur Although there may be a transient throbbing headache after syncope, postictal stupor, prostration or malaise are usually absent Some patients with a firm diagnosis of “epilepsy” actually have psychogenic seizures (also known as pseudoseizures, non-epileptic seizures or hysterical seizures) The clinical features suggestive of psychogenic seizures are listed in Table 5.11–14 Studies show that experienced epileptologists are wrong in distinguishing between psychogenic Seizures and Epilepsy 1001 Table Epileptic versus Psychogenic Seizures 1) Features suggestive of psychogenic seizures • asymmetrical thrashing movements of the limbs • side-to-side head movements (rather than bilaterally symmetrical tonic-clonic movements) • pelvic thrusting (especially forward) • opisthotonic posturing • lack of stereotypic pattern with repeated events • talking or screaming throughout the seizure • long duration • bilateral involvement without impairment of consciousness • sudden return to consciousness following a prolonged generalized seizure • resistance to eye opening in an otherwise unresponsive patient • aversion of the eyes away from the examiner when the lids are elevated • recurrent episodes of prolonged unresponsiveness lasting more than a few minutes • induced and/or stopped by suggestion 2) Epileptic phenomena that could be seen in psychogenic seizures • pupillary dilation • urinary and fecal incontinence • tongue-biting • other injuries • Babinski responses 3) Seizures that appear to be “bizarre” but could still be epileptic if the followings are present • turning to a prone position during seizure • nocturnal occurrence • short ictal duration • stereotyped patterns of movements • associated with MRI and/or EEG abnormality 4) Predisposing factors for psychogenic seizures • female sex • previous childhood sexual abuse • previous psychiatric history • sexual maladjustment • depression • morbid anxiety and epileptic seizures from videotapes 20% to 30% of the time.15 On one hand, psychogenic seizures can have features of epilepsy.16 On the other hand, ictal events that appear not to make neurophysiological sense or have bizarre features, can occasionally be epileptic.17–20 Patients with both epileptic and psychogenic seizures pose the most difficult diagnostic 1002 A Clinical Approach to Medicine dilemma In general the diagnosis of psychogenic seizures should be considered when an organic disorder is deemed unlikely, and psychological as well as psychiatric assessments provide supportive evidence The most important information in this regard is documented secondary gain Other conditions which may be mistaken for epilepsy include normal phenomena (e.g déjà vu may be normal), transient ischemic attack (need to differentiate from simple partial seizures), paroxysmal movement disorders (could be mistaken for partial motor seizures), transient global amnesia (amnesia lasting from 30 minutes to a few hours), migrainous aura (a march of less than a minute suggests partial seizures; over several minutes suggests migraine), sleep-related episodes (e.g hypnic jerks and periodic movement of sleep), cardiac arrhythmias, postural hypotension (e.g autonomic neuropathy), hyperventilation, and other psychiatric disorders (panic attacks, episodic dyscontrol, dissociative states) In patients presenting with transient loss of consciousness, the history and physical examination may be sufficient for diagnosis in 85% of patients in whom a diagnosis is established However, diagnosis can sometimes be difficult and specialist investigation with long-term EEG and/or video monitoring, prolactin assays and cardiac studies may be necessary (vide infra) INVESTIGATIONS Electroencephalogram (EEG) The EEG is the only available investigation to record and evaluate the paroxysmal electrical discharges of cerebral neurons Properly performed by experienced technicians and carefully studied and interpreted in the cortex of a well-described clinical context by experienced neurologist, it is the most important investigation for epilepsy It is also harmless and relatively inexpensive It is a common misconception that diagnosis of epilepsy can only be made by EEG Very often clinicians dismissed a diagnosis of epilepsy because EEG did not show epileptiform discharges (spikes or sharp waves) It is important to emphasize that EEG is only diagnostic of epilepsy when ictal epileptiform discharges are recorded, especially if accompanied by behavioral changes (either observed by experienced Seizures and Epilepsy 1003 medical/paramedical personnel or captured during video-EEG monitoring) However, it is rare to record a seizure in 20–30 minute routine EEG recording Nevertheless, even without an ictal event, EEG can support a clinical diagnosis of epilepsy if interictal epileptiform discharges were recorded The pattern and location of interictal epileptiform abnormalities also help to characterize the type of epileptic disorder or epileptic syndrome An interval of 20–30 minutes of EEG may record epileptiform discharges in 29–38% of adult patients who have epilepsy.21 With repeated EEG recording this increases to 59–77%, with little extra gain obtained after five routine EEGs.22 The chance of recording epileptiform discharges can be enhanced by prolonging each EEG recording period and/or obtaining a sleep recording (especially after prior sleep deprivation) If and when possible, EEG should be obtained shortly after a seizure, as epileptiform discharges are more likely to be found hours or days after an epileptic seizure It is important to emphasize that epileptiform discharges may be recorded in 1.8–4% of individuals who never have or develop epilepsy.23 Thus, “not all fits spike and not all spikes fit” EEG can be used to predict seizure recurrence Patients with epileptiform discharges on EEG performed within the first few weeks after a first seizure are significantly more likely to have a second seizure if untreated, compared with those showing non-epileptic abnormalities or with a normal EEG If performed later, the EEG does not appear to be predictive of recurrent seizures.24,25 Patients with generalized epileptiform EEG abnormalities may have a higher risk of seizure recurrence.26 Such findings should be considered when counseling the patient who has initially declined treatment When a clinical diagnosis of epilepsy is doubtful and routine EEG is non-diagnostic or supportive, it may be necessary to admit the patient for long-term EEG recording with video monitoring The purposes of this are to increase the yield of recording interictal epileptiform discharges and to capture the habitual seizures during the period of monitoring The recording of habitual seizures help to differentiate psychogenic from epileptic seizures, characterize different seizure types so that AED treatment can be optimized, and identify suitable candidates for epilepsy surgery.27 In selected patients, intracranial EEG monitoring is necessary to define the location and extent of epileptogenic zone before planning for further definitive epilepsy surgery.28,29 1004 A Clinical Approach to Medicine Structural Neuro-imaging Computed tomography (CT) scanning will identify a focal lesion in a clinically relevant proportion of patients presenting with partial and generalized tonic-clonic seizures, including a significant proportion of patients with no focal abnormalities on neurological examination and EEG Some of the abnormalities identified by CT scanning may be treatable by surgery However, CT scanning may fail to show a focal abnormality in a significant proportion of patients with focally abnormal neurological examination and/or EEG.30,31 Magnetic resonance imaging (MRI) of the brain detects lesions that are not detected by CT scanning The number of such lesions detected has increased as sophistication of MRI techniques employed and the quality of magnetic resonance images have improved MRI abnormalities that can be missed on CT scan include mesial temporal sclerosis (hippocampal atrophy and signal change), cortical dysgenesis, tumors and cavernous hemangiomas A significant proportion of patients with these lesions will be potentially treatable by surgery.32,33 Therefore, if MRI is available and affordable, this will be the neuro-imaging of choice in the evaluation of clinically focal epilepsy As seizures of idiopathic generalized epilepsy rarely occur for the first time after age 25 years, patients presenting with first seizure over the age of 25 years will nearly always have a localization-related epilepsy Thus brain imaging should always be performed in these patients to identify the cause of epilepsy and to elucidate potentially treatable lesions MRI brain is preferable to CT scan for the reasons explained above In patients under the age of 25 years, brain imaging is unnecessary if a firm diagnosis of an “idiopathic generalized epilepsy syndrome” has been made on the basis of the clinical history and EEG findings If a firm diagnosis of idiopathic generalized epilepsy cannot be made, brain imaging is necessary Neuro-imaging, especially MRI, should be performed in patients with chronic epilepsy to determine the cause of epilepsy as well as to identify suitable surgical candidates In a local study, approximately quarters of patients with epilepsy for more than years had a focal structural abnormality demonstrated on MRI Of these, about 75% had either mesial temporal sclerosis or other temporal lobe abnormalities that might potentially be treated by surgery.34 Seizures and Epilepsy 1005 Other Investigations In patients presenting with first seizure, investigations such as full blood counts, renal function tests, liver function tests, serum glucose, calcium, magnesium and resting ECG are indicated Depending on the clinical presentation, 24-hour ECG holter monitoring, drug toxicology, and cerebrospinal fluid examination may also be warranted Tests like serum calcium and magnesium should not be routinely performed in patients who are known to have epilepsy admitted for seizure recurrence due to poor compliance Instead, these patients should have blood AED levels taken routinely (vide infra) Serum prolactin determination is useful as the levels are elevated following generalized, complex partial, and some simple partial seizures However, a normal serum prolactin level during a seizure without impairment of consciousness does not rule out epilepsy In patients being evaluated for surgery, neuropsychological assessment (useful for characterizing functional deficits for psychosocial prognosis and rehabilitation), intracarotid amobarbital procedure (to lateralize language area and assess memory function) and ictal Single Photon Emission Computed Tomography (study blood flow during seizures and correlate with EEG and MRI localization of epileptogenic zone) would be useful.35 DRUG TREATMENT OF SEIZURES AND EPILEPSY The main aim of treating epilepsy is to render the patient completely seizure-free with appropriate use of AEDs If seizures could not be completely suppressed with AEDs, the aim is to reduce seizure frequency and severity without unacceptable medication side effects Ideally all patients with definite or suspected epilepsy should be referred to a neurologist for further investigation and treatment, except in exceptional circumstances, e.g elderly incapacitated patients with stroke However, general physicians and other non-neurological internists could initiate the initial treatment of epilepsy, if they are confident of the diagnosis, have easy access to EEG and neuro-imaging information and are of the opinion that the patient needs treatment However, when seizures are not adequately controlled within a reasonable period of time (weeks for frequent seizures or a few months for less frequent seizures), these patients should be referred for neurological consult 1006 A Clinical Approach to Medicine When to Start Treatment The issue of whether to commence AED treatment after a first seizure remains controversial Studies of selected hospital populations report seizure recurrence rates after a first seizure of around 20–30% after two years.36,37 After five years the rate may be as high as 30% in idiopathic seizures and 45% in patients with remote symptomatic seizures However, three studies in general populations in which patients were seen within a week of the first seizure give much higher estimates of seizure recurrence of 67–80% after first untreated seizure.38–40 Treatment of patients with tonic-clonic seizures without a clear metabolic or structural cause reduces risk of seizure recurrence from 51 to 25%.41 Patients with first unprovoked generalized tonic-clonic seizures should be treated with an AED if history reveals that he already has myoclonic and/or absence seizures, which was previously undiagnosed The decision to treat simple and complex partial seizures will depend on the seizure frequency, severity (including the impact of seizures on work, studies and quality of life), and patient preference Seizures arising from alcohol withdrawal, metabolic or drug-related causes should not be treated with AEDs Treatment may be considered if there are recurrences suggestive of epilepsy Patients should not be treated if there is uncertainty about the diagnosis The risk of a second seizure rises when the EEG is epileptogenic, the neurologic examination is abnormal, or the MRI reveals a structural abnormality, with the risk typically Ͼ 50% in these patients In patients with partial seizures and abnormal EEG and imaging studies, the risk rises further to near 80% After two unprovoked seizures, the risk of a third unprovoked seizure is 73%.42 These individuals should receive AED therapy Patients with single seizure, simple partial seizure, and seizures resulting from medications, metabolic disturbances or alcohol withdrawal may not need treatment Which Antiepileptic Drug (AED)? Choice of drugs depends on drug (efficacy, side effect profile, ease of use, availability and affordability) as well as patient factors.43 Efficacy of an AED refers to the effectiveness of the AED in preventing or reducing the recurrence of a particular seizure type (Table 1) For seizures that cannot be classified based on history, sodium valproate is Seizures and Epilepsy 1007 the drug of first choice for those presenting under the age of 25 years, and carbamazepine is the choice for those presenting over the age of 25 years Potential AED side effects and their appearance not only affect the physicians’ choice but also determine the acceptance of the drug by the patient For example, potential teratogenicity may make physicians avoid using valproate in female patients who are planning to have children Not all patients will develop side effects and not all side effects are unacceptable For example, weight gain from valproate and hirsutism from phenytoin are probably less acceptable in female patients than in males Preparation of AEDs also affect the severity of dose related side effect AED in control-release formulation is preferable as the occurrence of dose related side effect is less likely and higher dosages are possible One of the most important factors in deciding which drug to prescribe is the cost of AEDs and their affordability to patients Although newer AEDs might be more effective and less toxic than older AEDs, their usage in this part of the world is limited by their relatively high cost In Singapore, older AEDs such as phenytoin, phenobarbitone, carbamazepine and valproate are subsidized by our government whereas newer AEDs such as lamotrigine, gabapentin, topiramate and vigabatrin are not It has been estimated that the cost of having one newer AED in a 2-drug combination is times the cost of 2-drug combinations without a newer AED.44 Patients who require or more AEDs are likely to be medically refractory, unemployed or under-employed, and dependent on other family members for financial support Thus, taking newer AED on a long-term basis can be quite costly for many patients and their families Newer AEDs are usually used as add-on treatment for patients with refractory partial seizures not responding to conventional AEDs Ease of use of an AED affects the patient’s compliance to medication For example, AEDs that have a long half-life and can be given once per day are preferable In addition, the availability of other treatment options such as epilepsy surgery might affect the pattern of AED usage If presurgical evaluation facilities and surgical expertise are available, candidates with good surgical potential are likely to be offered surgery as an alternative to long-term AEDs Monotherapy Whichever AED is chosen, it is important to maintain patients on monotherapy as compliance is better, side effects are less and there is no 1008 A Clinical Approach to Medicine problem of drug-to-drug interaction Even in a tertiary referral hospital where epilepsy patients are expected to have difficult-to-control seizures, monotherapy is achievable in the majority of patients Approximately twothirds of epilepsy patients seen at the Singapore General Hospital were on monotherapy.43 Many patients being referred for management of “failed” monotherapy actually had not been given maximum tolerated doses of AED Some patients on polytherapy could also be converted to monotherapy Regardless of the blood level, by increasing the dosage of the same AED gradually to the maximum tolerated dose, seizures could be controlled in many patients It is important to emphasize that there is no standard dose for any AED Every patient has his/her own necessary dose Screening laboratory studies (e.g baseline hematology, liver function test and serum electrolytes) should be obtained before initiation of AED treatment These studies can identify patients with special risk factors that could influence drug selection, and can be used as a baseline for future monitoring of hematological, biochemical and liver functions AED Serum Level Monitoring The main indications for AED serum level monitoring are assessment for compliance in patients who not respond to medication and assessment for drug toxicity Serum level monitoring is not necessary for adjustment of AED doses in otherwise healthy and asymptomatic patients Exceptions are those patients who not complain (e.g mentally retarded) of side effects and when phenytoin dose needs to be increased The latter is because phenytoin has variable rates of hepatic metabolism, and because a small increase in dose can result in a large increase in serum level (saturation kinetics) Published “therapeutic ranges” should only be used as approximate guides While some patients achieve seizure control at serum levels below the therapeutic range, others require and tolerate a serum level above the upper limit of the “therapeutic range” Serum levels may be useful when there are possible interactions between AEDs and/or other drugs Carbamazepine, phenytoin and barbiturates are hepatic enzyme inducers while sodium valproate is an enzyme inhibitor Changes in the dose of one may alter the serum levels of others Serum level estimations should not be done so soon after a change in dose as the new plateau level may not have been reached Seizures and Epilepsy 1009 Alternative Monotherapy and Polytherapy Patients who fail one conventional AED because of inadequate efficacy or unacceptable side effects could respond well to another conventional AED given as monotherapy Before considering alternative AED(s), one should review the patient’s diagnosis, current AED dosage, and compliance If the patient has been given the maximum tolerated dose of one AED and if his diagnosis and compliance are not doubted, an alternative monotherapy should be tried before attempting combination therapy This is usually done by introducing a second AED specific for the patient’s seizure type The side effect profile of the second AED must be acceptable Once the patient’s seizures are adequately controlled, the first AED can be gradually withdrawn If seizures recur with repeated attempts to withdraw the first AED, it would be better letting the patient continue with the combination therapy It needs to be emphasized that even when combination therapy is unavoidable, the patient should be given the minimum number and dosage of AEDs that are required to achieve adequate seizure control without unacceptable medication side effects There is no guidelines as to which combination is superior to another In patients with refractory partial seizures, a large meta-analysis of 29 randomized placebo-controlled trials on 4091 patients showed no significant differences in the efficacy or tolerability of lamotrigine, gabapentin, topiramate, and vigabatrin as add-on treatment.45 Patients with absence seizures not adequately controlled by valproate can have lamotrigine added For myoclonic and atonic seizures, lamotrigine or clonazepam can be added to valproate For primary generalized tonic-clonic seizures, lamotrigine would be a good add-on AED.46 Epilepsy Surgery The probability of responding to another AED progressively declines with each AED tried and failed The percentage of successful seizure control falls from approximately 70% with the first AED used to about 40% with the second AED.47 When more than two AEDs have failed, the probability of achieving complete or nearly complete seizure freedom on a long-term basis is nil.48–51 Seizure control in this very small fraction of patients is often short-lived and no longer than a year In studies using investigational 1010 A Clinical Approach to Medicine AEDs, it is very uncommon for patients to become seizure-free for more than a year Furthermore, combination AED therapy is associated with a higher risk of side effects For many of these patients, especially those with a focal structural pathology (lesional epilepsy), surgery presents a much better treatment option with a probability of excellent outcome at 75–95% and risk of major complications at 1% or lower.52,53 In addition, another 10% of patients can be expected to have at least 75% reduction in their seizure frequency Whether the more modest outcome in this group of patients will result in meaningful improvement in their quality of life depends on the occupational, social and cultural expectations for each patient Patients should be considered for epilepsy surgery evaluation if their epilepsy is intractable despite having: 1) a correct seizure-type and epilepsy syndrome diagnosis; 2) optimal use of at least two AEDs appropriate for the seizure-type; 3) good compliance; and 4) no major medical or psychosocial disturbance that interferes with seizure control Seizure control or improvement that is likely to reverse disability or improve quality of life is the other important consideration Patients who not respond to different monotherapy and have tried various combination therapies must be referred for video-EEG monitoring to confirm that seizures are indeed epileptic in nature, as well as to identify potential epilepsy surgery candidates Localized resections are particularly effective in temporal lobe epilepsy Experience at SGH showed that 80% of patients with medically refractory temporal lobe epilepsy either became seizure-free or had more than 90% reduction in seizure frequency after temporal lobectomy.54 AED could be stopped in about 40% and reduced in another 40% of patients after surgery Focal resection can also be beneficial for many forms of neocortical epilepsy due to well-circumscribed lesions Corpus callosum sections can abolish disabling drop attacks, and hemispherectomies or large multilobar resections can yield gratifying results in patients, usually infants and small children, with catastrophic secondary generalized epilepsies In surgically remediable epilepsies, early intervention provides the best opportunity to avoid psychosocial disability.55 Vagus Nerve Stimulator (VNS) This consists of leads wrapped around the vagus nerve in the neck tunneled and connected to a pulse generator embedded in a subcutaneous Seizures and Epilepsy 1011 pocket created infra-clavicularly The VNS has been shown to effect a mean seizure reduction of about 25% to almost 30% in short-term followup and over 40%56 in long-term follow-up of adults and children with intractable partial onset seizures More recent reports have suggested efficacy in generalized seizures57 in adults and in children.58 It has also been shown to be efficacious in patients with Lennox Gastaut Syndrome.59 Its main indication currently is in patients with intractable partial onset or generalized seizures where AEDs either not afford adequate control or inflict intolerable side-effects Discontinuing Drug Therapy The Medical Research Council Antiepileptic Drug Withdrawal Study Group conducted a large multicenter randomized trial of continued antiepileptic treatment versus slow withdrawal in adults and children with epilepsy who had been seizure-free for at least two years.60 Patients who had their AED therapy slowly withdrawn were found to be more likely to have a seizure recurrence over the next 12 months than patients on continued therapy Seizures are more likely to recur after AED discontinuation if a patient has a history of generalized tonic-clonic seizures, is taking more than one AED at time of withdrawal, is experiencing one or more seizures after the start of treatment, has a history of myoclonic seizures, has partial seizures that have “never generalized” and has epilepsy for ten years or more Patients in whom seizure recurrence is less likely are those who have been seizure-free for five or more years.61 Discussion of whether to withdraw AEDs should take into account the patient’s need to work and/or study, fear of seizures, attitude to prolonged AED therapy and benefits and risks to both patient and society from a recurrent seizure Withdrawal can be attempted if patients have been seizure-free for 2–5 years REFERENCES Hauser WA, Hesdorffer DC, Epilepsy: Frequency, Causes and Consequences, Demos Pr, New York, pp 378, 1990 Lee WL, Low PS, Murugasu B, Rajan U, Epidemiology of epilepsy among Singapore children, Neurol J Southeast Asia 2:31–35, 1997 1012 A Clinical Approach to Medicine Hauser WA, Annegers JF, Epidemiology of acute symptomatic seizures, in Engel JJ, Pedley TA (eds.), Epilepsy: A Comprehensive Textbook, Lippincott–Raven Publishers, Philadelphia, pp 87–91, 1997 Jain KK, Drug-induced seizures, in Gilman S, Goldstein GW, Waxman SG (eds.), Neurobase, 2nd ed., Arbor Publishing, San Diego, 1999 Engel J, Epilepsy, in Gilman S, Goldstein GW, Waxman SG (eds.), Neurobase, 2nd ed., Arbor Publishing, San Diego, 1999 Commission on Classification and Terminology of the International League Against Epilepsy, Proposal for revised clinical and electroencephalographic classification of epileptic seizures, 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non-epileptic attack disorder Part II Previous childhood sexual abuse in the aetiology of these disorders, Seizure 1:27–32, 1992 14 Boon PA, Williamson PD, The diagnosis of pseudoseizures, Clin Neurol Neurosurg 95(1):1–8, 1993 15 King DW, Gallagher BB, Murvin AJ, Smith DB, Marcus DJ, Hartlage LC, Pseudoseizures: diagnostic evaluation, Neurology 32:18–23, 1982 16 Lesser 1985 (pg.5) 17 Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH, Complex partial seizures of frontal lobe origin, Ann Neurol 18:497–504, 1985 18 Sussman NM, Jackel RA, Kaplan LR, Harner RN, Bicycling movements as a manifestation of complex partial seizures of temporal lobe origin, Epilepsia 30:527–531, 1989 19 Saygi S, Katz A, Marks DA, Spencer SS, Frontal lobe partial seizures and psychogenic seizures: comparison of clinical and ictal characteristics, Neurology 42:1274–1277, 1992 20 So NK, Mesial frontal epilepsy, Epilepsia 39 (Suppl 4):S49–61, 1998 Seizures and Epilepsy 1013 21 Doppelbauer A, Zeitlhofer J, Zifko U, Baumgartner C, Mayr N, Deecke L, Occurrence of epileptiform activity in the routine EEG of epileptic patients, Acta Neurol Scand 87:345–352, 1993 22 Salinsky M, Kanter R, Dasheiff RM, Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: an operational curve, Epilepsia 28:331–334, 1987 23 Zivin L, Marsan CA, Incidence and prognostic significance of epileptiform activity in the EEG of non-epileptic subjects, Brain 91:751–778, 1968 24 Van Donselaar CA, Schimsheimer RJ, Geerts AT, Declerck AC, Value of the electroencephalogram in adult patients with untreated idiopathic first seizures, Arch Neurol 49:231–237, 1992 25 Hopkins A, Garman A, Clarke C, The first seizure in adult life Value of clinical features, electroencephalography, and computerised tomographic scanning in prediction of seizure recurrence, Lancet 1:721–726, 1988 26 Hauser WA, Anderson VE, Loewenson RB, McRoberts SM, Seizure recurrence after a first unprovoked seizure, N Engl J Med 307:522–528, 1982 27 American Academy of Neurology, Assessment: intensive EEG/video monitoring for epilepsy, Neurology 39:1101–1102, 1989 28 Lim SH, Pillay P, Lüders HO, Boenigk H, Use of intracranial neurophysiologic recording techniques in the evaluation for epilepsy surgery in children, Singapore Med J 33(2):131–138, 1992 29 Pillay PK, Lim SH, Chee M, Awad I, Luders H, Epilepsy surgery in children and adults, Ann Acad Med Singapore 22(3 Suppl):501–512, 1993 30 Ramirez–Lassepas M, Cipolle RJ, Morillo LR, Gumnit RJ, Value of computed tomographic scan in the evaluation of adult patients after their first seizure, Ann Neurol 15:536–543, 1984 31 Schoenenberger RA, Heim SM, Indication for computed tomography of the brain in patients with first uncomplicated generalised seizure, BMJ 309:986–989, 1994 32 Kuzniecky RI, Jackson GD (eds.), Magnetic resonance in epilepsy, Raven Press, New York, 1995 33 Cascino GD, Jack Crjr (eds.), Neuroimaging, in Epilepsy: Principles & Practice, Butterworth–Heinemann, Newton, MA, 1996 34 Tan EK, Lim SH, Lim W, Tan KP, Magnetic resonance imaging in patients with chronic partial epilepsy: identification of potential epilepsy surgery candidates, Neurol J Southeast Asia 2:37–43, 1997 35 Goh SWA, Lim SH, Post-ictal single photon emission computed tomography (SPECT) in lateralization of epileptogenic zone, Neurol J Southeast Asia 2:110, 1997 36 Cleland PG, Mosquera I, Steward WP, Foster JB, Prognosis of isolated seizures in adult life, BMJ 283: 1364, 1981 37 Hauser WA, Rich SS, Annegers JF, Anderson VE, Seizure recurrence after a first unprovoked seizure: an extended follow-up, Neurology 40:1163–1170, 1990 1014 A Clinical Approach to Medicine 38 Hart YM, Sander JWA, Johnson AL, Shorvon SD, National general practice study of epilepsy: recurrence after a first seizure, Lancet 336:1271–1274, 1990 39 Goodridge DM, Shorvon SD, Epileptic seizures in a population of 6000 II: Treatment and prognosis, BMJ 287:645–647, 1983 40 Elwes RD, Chesterman P, Reynolds EH, Prognosis after a first untreated tonic-clonic seizure, Lancet 2:752–753, 1985 41 First Seizure Trial Group, Randomised clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure, Neurology 43:478–483, 1993 42 Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE, Risk of recurrent seizures after two unprovoked seizures, N Engl J Med 338(7):429–434, 1998 43 Lim SH, Tan EK, Chen CLH, Pattern of anti-epileptic drug usage in a tertiary referral hospital in Singapore, Neurol J Southeast Asia 2:77–85, 1997 44 Tan EK, Lim SH, Chen CLH, Cost of drug and surgical treatment for medically refractory epilepsy in Singapore, Neurol J Southeast Asia 1:76, 1996 45 Marson AG, Kadir ZA, Hutton JL, Chadwick DW, The new antiepileptic drugs: a systematic review of their efficacy and tolerability, Epilepsia 38:859–880, 1997 46 Brodie MJ, Yuen AW, Lamotrigine substitution study: evidence for synergism with sodium valproate, Epilepsy Res 26:423–432, 1997 47 Schmidt D, Richter K, Alternative single antiepileptic drug therapy for refractory epilepsy, Ann Neurol 19:85–87, 1985 48 Dasheiff R, McNamara D, Dickinson L, Efficacy of second line antiepileptic drugs in the treatment of patients with medically refractive complex partial seizures, Epilepsia 27:124–127, 1986 49 Ojemann L, Dodrill C, Natural history of drug-resistant seizures: clinical aspects, Epilepsy Res (Suppl 5):13–17, 1992 50 Hermanns G, Noachtar S, Tuxhorn I, et al., Systematic testing of medical intractability for carbamazepine, phenytoin, and phenobarbital or primidone in monotherapy for patients considered for surgery, Epilepsia 37:675–679, 1996 51 Camfield P, Camfield C, Antiepileptic drug therapy: When is epilepsy truly intractable, Epilepsia 37(Suppl 7):S60–S65, 1996 52 So E, Radhakrishnan K, Silbert P, et al., Assessing changes over time in temporal lobectomy: Outcome by scoring seizure frequency, Epilepsy Res 27:119–125, 1997 53 Radhakrishnan K, So E, Silbert P, et al., Predictors of outcome of anterior temporal lobectomy for intractable epilepsy A multivariate study, Neurology 51:465–471, 1998 54 Lim SH, Pillay P, Effect of temporal lobectomy on seizure frequency and antiepileptic drug requirement in patients with medically refractory focal epilepsy, Neurol J Southeast Asia 2:110–111, 1997 55 Lüders HO (ed.), Epilepsy Surgery, 2000 (in press) Seizures and Epilepsy 1015 56 Morris GL, Mueller WM, Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy The Vagus Nerve Stimulation Study Group E01-E05, Neurology 53(8):1731–1735, 1999 57 Labar D, Murphy J, Tecoma E, Vagus nerve stimulation for medication-resistant generalized epilepsy E04 VNS Study Group, Neurology 52(7):1510–1512, 1999 58 Pardwardhan RV, Stong B, Bebin EM, Mathiesen J, Grabb PA, Efficacy of vagal nerve stimulator in children with medically refractory epilepsy, Neurosurgery 47(6):1353–1358, 2000 59 Ben–Menachem E, Hellstrom K, Waldton C, Augustinsson LE, Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to years, Neurology 52(6):1265–1267, 1999 60 Medical Research Council Antiepileptic Drug Withdrawal Study Group, Randomised study of antiepileptic drug withdrawal in patients in remission, Lancet 337:1175–1180, 1991 61 Medical Research Council Antiepileptic Drug Withdrawal Study Group, Prognostic index for recurrence of seizures after remission of epilepsy, BMJ 306:1374–1378, 1993 SUGGESTED READING Engel JJ, Pedley TA (eds.), Epilepsy: A Comprehensive Textbook, Lippincott–Raven Publishers, Philadelphia, 1997 This page intentionally left blank 60 Neuromuscular Disorders Lo Yew Long and Pavanni Ratnagopal INTRODUCTION The peripheral nervous system motor pathway consists of the anterior horn cell, motor roots, plexi, peripheral nerve, neuromuscular junction and muscle This section will discuss conditions involving each level In general, neuromuscular diseases have predominant lower motor neuron affectation, but it should be understood that many have concomitant upper motor or central nervous system involvement Some of these conditions will be elaborated in other sections of this publication APPROACH The accurate localization of the levels of lower motor neurone involvement requires a good history, thorough physical examination and appropriate investigations The presence of cortical features should alert one to the presence of an upper motor lesion and bladder/bowel disturbances and a sensory level often suggest cord pathology 1017 1018 A Clinical Approach to Medicine 1) History The tempo of onset of signs and symptoms often lends a clue in finding the underlying etiology Sudden onset of deficits often point to a vascular mechanism, while a more gradual onset over some hours may signify an inflammatory or infective process Metabolic process like hypokalemic periodic paralysis often present with rapid onset of weakness over hours as well More protracted presentation may point to neoplastic or degenerative processes Although it is frequently assumed that neuromuscular disorders often present with distal patterns of weakness, some conditions, e.g acquired demyelinating polyneuropathies, can show proximal loss of power.1 The presence of cramps is often non-specific and can be a result of anterior horn cell, peripheral nerve or muscle disorders They must be distinguished from clonus which is a upper motor feature Similarly, pain can also be due to thalamic sensory stroke syndromes Neuralgic or root pain often conforms to a peripheral nerve or root distribution, in contrast to plexus lesions, which can have a more diffuse pattern Although the bulk of plexus lesions are of traumatic and inflammatory origin, they can have surprisingly few sensory symptoms A history of preceeding trauma, infections, vaccinations and familial tendencies is often helpful in the management of inflammatory plexopathies, as well as neuropathies in general Numbness is a frequent complaint that should not be taken to mean hypoesthesia Varied sensations ranging from pain, dysthesia, and hyperesthesia can be interpreted as numbness by the patient Autonomic symptoms should not be forgotten in the assessment of the peripheral nervous system.2 Postural giddiness, dry mouth, impotence and loss of sphincter control must be elicited The importance of a well-documented drug history, past medical history, especially of endocrine conditions, as well as family history, is often helpful in establishing the etiology Finally, a systemic review should probe the presence of cardiorespiratory symptoms that may have an underlying neuromuscular etiology 2) Physical Examination Observation of general appearance should be done systematically to detect any Cushingnoid appearance, cachexia or syndromic facies Examination of pupils, speech, cranial nerve abnormalities and Neuromuscular Disorders 1019 fundoscopy can be instituted as appropriate The presence of ptosis is often an important lead to extend the examination to assess fatigability of various muscle groups Bulbar palsy and tongue fibrillation may suggest an anterior horn cell disorder Peripheral inspection must include checking for muscle atrophy, trophic changes, burns, deformities, fasciculations and involuntary movements Most peripheral nerve disorders have diminished tone in the limbs when tested However, it is to be borne in mind the occurrence of underlying cord or upper motor lesions may mask this feature Although the most peripheral motor neuropathies manifest distal weakness, some acquired forms of polyradiculoneuropathies can present with predominantly proximal distribution of weakness The hallmark physical finding of root lesions is the demonstration of weakness in muscles from different peripheral nerve innervation sharing the same root levels Reflexes corresponding to the affected root levels can also be diminished Lesions involving the plexus are often difficult to differentiate from multiple root or peripheral nerve lesions, particularly if they are mild As a rule, plexopathies often but not invariably have sensory involvement of a less well defined distribution as would be expected of radicular lesions It may also be difficult to separate root from plexus pathologies distinctively, and both can sometimes coexist In such situations, electrophysiological techniques are often required, as an extension of clinical testing, in their localization The complete examination should also include testing joint position sense, vibration, gait, cerebellar function and other systems 3) Investigations It is important that the clinician understands the diagnostic capabilities and limitations of various neurophysiological investigations It would be inappropriate to address cord abnormalities with nerve conduction and electromyography, which are contributory to the localization of peripheral nerve, plexus and root lesions The astute attending neurophysiologist or neurologist would assess each case clinically and tailor relevant investigations to the patient’s needs Electrophysiological studies play a complementary role to neuroimaging by determining if structural lesions seen with CT scan or MRI are of any functional relevance The findings of active denervation and axon loss are usually indicative of a more severe lesion as 1020 A Clinical Approach to Medicine opposed to findings of focal demyelination Moreover, in certain noncompressive or inflammatory pathologies, imaging for structural lesions may be normal despite evidence of denervation elicited with neurophysiological techniques Conventional nerve conduction studies are useful in confirming peripheral sensory or motor neuropathies as well as mononeuritic entrapment neuropathies They are often inadequate in addressing proximally-situated lesions in the plexus and less conventional nerve conductions are often required for more comprehensive localization Mixed nerve conduction studies may be useful in these situation.3 The finding of normal sensory conduction in the presence of sensory root symptoms localizes the lesion proximal to the dorsal root ganglion (preganglionic).4 Needle electromyography provides direct evidence of denervation in muscles sampled, each of which have fairly unchanged levels of root innervation Hence, it is mandatory in all cases where localization of root or plexus pathologies are suspected Electromyographic sampling is also helpful in differentiating a lesion undergoing active denervation from one of longstanding duration, as well as demonstrating unique changes in radiation induced nerve injuries.5,6 For conditions with co-existing peripheral nerve and spinal cord pathologies, transcranial magnetic stimulation and somatosensory evoked responses are useful diagnostic adjuncts Delays in central motor conduction time can be demonstrated with magnetic stimulation and is electrophysiological evidence of corticospinal tract dysfunction Similarly, conduction abnormalities pertaining to the somatosensory evoked response pathways addresses dysfunction in the dorsal columns The techniques of repetitive nerve stimulation and single-fibre electromyography are highly specialized investigations for assessing neuromuscular transmission, particularly if it is performed close to the site of maximal weakness.7 However, these sensitive tests are not specific for myasthenia gravis and may be abnormal in other conditions with neuromuscular junction defects The autonomic nervous system is often involved in peripheral neuropathic conditions and various indirect autonomic function tests are increasingly becoming standard test panels The sympathetic skin response addresses the sudomotor autonomic component while Neuromuscular Disorders 1021 vasomotor reflex testings assesses autonomic reactivity in the vascular system Muscle and nerve biopsy is sometimes necessary if less invasive investigations prove unfruitful for diagnosis They are sometimes helpful in the exclusion of rarer conditions with pathognomonic histological features This systematic discussion outlines the diagnostic approach followed by neurologists when faced with a likely neuromuscular disorder A reasonable list of differentials can be considered according to infective, neoplastic, toxic, metabolic, autoimmune, degenerative, vascular, iatrogenic or congenital etiologies ANTERIOR HORN CELL SYNDROMES Motor Neuron Diseases The anterior horn cell syndromes, more commonly known as motor neurone disease (MND), were first recognized as distinct clinical entities by Aran’s report in 1850 of 11 patients with “progressive muscular atrophy” There is no completely satisfactory classification but a working group of the World Federation of Neurology in 1990 in El Escorial, Spain was proposed, shown in Table Epidemiology The incidence of MND is 1–2 per 100 000 and the prevalence is 4–6 per 100 000 in most parts of the world Clinical picture Weakness is the most common presenting complaint and is usually painless The atrophy may be noticed even before functional loss The weakness may be bulbar or pseudobulbar or limb involvement initially but will eventually become generalized It is usually a mixed picture of upper and lower motor neurone involvement Fasciculations, previously thought to be the hallmark of the disease, may be fairly florid initially but disappears or subsides with progression.8 No actual sensory deficit and sensory symptoms are not infrequently reported by patients Dementia is not a common feature in amyotrophic 1022 A Clinical Approach to Medicine Table Diagnostic Criteria for MND (ALS) The diagnosis of ALS requires the presence of: • LMN signs (including EMG features in clinically normal muscles) • UMN signs Progression of the disorder Diagnostic categories: • Definite ALS: UMN signs in regions Probable ALS: UMN plus LMN signs in two regions with UMN signs rostral to LMN signs Possible ALS: UMN plus LMN signs in one region, or UMN signs in two or three regions, such as monomelic ALS, progressive bulbar palsy, and primary lateral sclerosis Suspected ALS: LMN signs in two or three regions, such as in progressive muscular atrophy, and other motor syndromes The diagnosis of ALS requires the absence of: • Sensory signs and sphincter disturbances • Visual disturbances • Autonomic dysfunction • Parkinson’s disease • Alzheimer type dementia The diagnosis of ALS is supported by: • Fasciculations in one or more regions • Neurogenic change in EMG studies • Normal motor and sensory nerve conduction • Absence of conduction block lateral sclerosis (ALS) and if found, should raise the possibility of the Western Pacific types like those from the Marianas and Kii Peninsular ALS from Guam also can be considered and is attributed to the cycad nut, which is a known neurotoxin Diagnostic criteria The World Federation’s criteria set at El Escorial in 1990 were based on clinical evidence and not take into account the vagaries of clinical practice.9 Pathology The essential pathologic feature is a loss of neurons in the ventral horn cells and degeneration and atrophy of the remaining ones Neuromuscular Disorders 1023 Table Differential Diagnosis of MND Cervical Myelopathy Autoimmune neuropathies Thyrotoxicosis Diabetic amyotrophy Radiation induced neurogenic disorders Post poliomyelitis progressive muscular atrophy Myopathies Multifocal motor neuropathy Investigations The purpose of investigations is to exclude other diagnosis, and to support the diagnosis of MND There are no biochemical or pathological markers of the disease Nerve conduction tests and electromyography help support the diagnosis Prognosis The median survival for all sporadic MND patients is about 3–5years from onset of symptoms Management strategies Riluzole, a glutaminergic modulator, has been tried but is unsuccessful Ventilatory failure is usually a terminal event Multifocal Motor Neuropathy This is a rare disorder of the peripheral nerves that was first described in 1982 by Lewis et al These patients had predominantly motor symptoms and signs but sensory abnormalities were well delineated Clinical features This is characterized by progressive weakness and muscular atrophy The atrophy is usually severe and nearly always present in some muscles at the time of diagnosis Reflexes are present or mildly weak This is a disease that usually runs an indolent course over several years, and 1024 A Clinical Approach to Medicine possibly even decades from case reports, but rapid progression has also been documented Antiganglioside antibodies, especially anti-GM1 have been sometimes associated with this.10 Electrodiagnosis This is the most important test to differentiate between MND and MMN Conduction block is a very important feature to try and distinguish between the two conditions Treatment In almost all the cases some form of immune modulation has been tried ranging from very high dose steroid therapy to plasmaphereisis and intravenous immunoglobulins Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a genetic motor neurone disease characterized by wasting of the skeletal muscles caused by progressive degeneration of the anterior horn cells of the spinal cord The disorder produces weakness and atrophy of the voluntary muscles It involves the legs more often than the arms There are many types It is an autosomal recessive disorder linked to chromosome 5q11-q13 Investigations and management The main diagnostic test is in the electromyography where there would be signs of acute or subacute denervation changes Myasthenia Gravis Myasthenia gravis (MG) is a distinctive disease, being an autoimmune disease Mary Walker in the 1930s initiated the use of acetylcholinesterase drugs after learning that MG had similar clinical manifestations to curare poisoning This remained the mainstay of treatment of the disease until the mid-1960s Neuromuscular Disorders 1025 Clinical picture The clinical hallmark of MG is muscle weakness The weakness is distinctive due to its fatigable nature The course of MG is that of a monophasic illness generally It can be ocular or generalized and after a few months, will usually remain so in one course or the other It was found that if symptoms were purely ocular for months, there was a 60% chance that they would remain so indefinitely The likelihood of remaining ocular purely rose to 84% at year, 88% at years and 92% at years Subsequently, the patients become generalized beyond two years of symptoms in only 15% of patients The bulbar muscles are often involved with the ocular muscles and later the limb muscles are also affected Osserman classification Grade 1: Focal disease (usually ocular) Grade 2: Generalized disease that is mild (IIa) or moderate (IIb) Grade 3: Severe generalized disease Grade 4: A crisis with life-threatening impairment of respiration Intramuscular temperature can influence neuromuscular transmission, with it being optimal in a temperature that is a few degrees Centigrade lower than that of body temperature Clinically it can be seen that patients become weaker when they become infected and febrile The temperature change is also more clearly seen in countries with marked seasonal changes Diagnosis It is imperative that the diagnosis be established unequivocally History and physical examination are the most important, but in addition to this, diagnostic testing is also necessary Diagnostic testing The following are suggested: • • tensilon test (Edrophonium test); repetitive nerve stimulation; 1026 A Clinical Approach to Medicine • • assay for anti-acetylcholine receptor antibody; or single fiber electromyography The Tensilon test is useful only if there is an objective clinical sign that responds Repetitive nerve stimulation is done by repeated electric shocks at a rate of per second with action potentials recorded over the muscle A rapid reduction in the amplitude of the evoked muscle action (decremental response of 10–15%) is considered a positive response Single fiber electromyography detects delayed or failed neuromuscular transmission and is present in 88–92% of patients but its specificity is limited A radioimmunoassay for the anti-acetylcholine-receptor antibody is specific for myasthenia gravis and detectable in only about 85% of all patients and in about 50% of purely ocular patients Management The outlook for patients has improved tremendously dramatically since 1958, especially in recent years Previously the mortality was 30% but now with optimal care, the rate is practically zero In general, four methods of treatment are in use: • • • • anticholinesterase agents; surgical thymectomy; immunosuppression; and short-term immunotherapies DISEASES OF THE NERVE ROOT, PLEXUS AND PERIPHERAL NERVES DISEASES OF THE NERVE ROOT These conditions are often termed radiculopathies and can coexist with peripheral neuropathies For example, Guillain–Barre syndrome is often thought to be a disease of peripheral nerves but the radicles are involved in a great majority of cases The motor or sensory root can be selectively involved or in combination Most root problems are due to degenerative causes (spondylolythic radiculopathy) or traumatic avulsions, followed by space occupying conditions Neuromuscular Disorders 1027 Cervical and Lumbar Radiculopathy Although this condition often presents with insidious onset of motor or sensory symptoms in a root distribution due to root impingement by bony overgrowths, it can rarely present with rapid onset of symptoms due to a disc prolapse In such situations, it is prudent to exclude myelopathy as well as vascular causes Cervical spondylolithic radiculopathy most commonly affects the C7, C6 and C5 root levels Traumatic cervical root avulsions are most commonly the result of shoulder or neck trauma occurs in tandem with significant brachial plexus injury In the evaluation of lumbar radiculopathies, two types of lesions should be excluded A conus lesion may be the result of tumors cysts or other space occupying lesions It presents with sensory disturbances in the perianal region, impotence and loss of sphincter control Loss of ankle jerks and S1 myotomal weakness can result from lesion extension A cauda equina lesion involving T12 or L1 and lower levels can lead to simultaneous upper and lower motor features This and the presence of pain, relative asymmetry and higher root levels of involvement help to distinguish it from a conus medullaris lesion Electromyography is required in addition to nerve conduction studies in the diagnosis of these proximally-situated lesions and is complementary to neuroimaging DISEASES OF THE PLEXUS Brachial plexus lesions can be due to traumatic or non-traumatic causes The upper plexus can be forcefully stretched by a heavy backpack or traction forces The lower plexus is often a site for invasive neoplastic disease from the lung apex (Pancoast’s tumor) Traumatic root avulsions of the lower plexus often result in an ipsilateral Horner’s syndrome The brachial plexus is also susceptible to radiation injury and metastatic disease, especially from the breast Electrophysiological studies are often required in the management of plexopathies as many conditions, other than space occupying lesions, cannot be clearly imaged The findings of grouped repetitive potentials (myokymia) with electromyography is highly correlated with radiation plexitis The lumbosacral plexus is most commonly affected by neoplasms either from direct invasion or metastases Other causes of lumbosacral 1028 A Clinical Approach to Medicine plexopathy are compression from hematomas, especially with anticoagulation, radiation and inflammatory neuritis which occurs to a much lesser extent than in the brachial plexus The site of lesion in diabetic amyotrophy is uncertain, but is thought to possibly involve the lumbar roots, femoral nerve and lumbar plexus.11 Brachial Neuritis (Neuralgic Amyotrophy) This is a well-defined classically, presenting with severe acute pain of the shoulder region followed by rapid weakness and wasting of the shoulder girdle and upper limb muscles, which become prominent features as the pain begins to subside The distribution of weakness is variable, although muscles around the shoulder girdle are most commonly involved Sensory symptoms are not marked, but may occur in a root or nerve distribution Lesions conforming to a peripheral nerve distribution or a patchy plexopathy may occur Recurrent and familial cases are well-described The diagnosis is often incorrect initially as patients are often thought to have a frozen shoulder, cervical spondylosis, entrapment neuropathy or even a cerebrovascular event due to the acuteness of onset The underlying pathology is often thought to be of axon loss, but demonstration of focal demyelination has been made using electrophysiological techniques and autopsy samples.12 Brachial neuritis is linked to several precipitating factors like preceeding viral infection, trauma, vaccination and surgical procedures The disease carries a relatively good prognosis with 80–90% of patients expecting to fairly completely recover by years Recovery can begin as late as months into the disease and can proceed beyond to years Early and severe muscle wasting carries an unfavorable prognosis However, with supervised rehabilitation, most patients have a high degree of functional recovery DISEASES OF THE PERIPHERAL NERVES These can be broadly and conveniently classified into immune-mediated neuropathies, neuropathies secondary to medical conditions, inherited neuropathies and entrapment neuropathies Diseases of the motor neuron will be discussed separately Neuromuscular Disorders 1029 Guillain–Barre Syndrome This is an acute form of neuropathy in which two-thirds of cases have an identifiable form of infection These can range from minor upper respiratory infections to more severe forms like HIV infections and Borreliosis A pure motor axonal form is associated with distal weakness, preceeding Campylobacter jejuni infection and anti-GM1 antibodies A sensory demyelinating form with predilectation for respiratory and cranial nerve involvement is linked to anti-GM2 antibodies The Miller Fisher variant of ataxia, areflexia and ophthalmoplegia is associated with anti-GQ1b antibodies Classically, this condition has an acute or subacute onset and runs a monophasic course over weeks Relapses are extremely rare Presenting symptoms are usually motor weakness and occasionally distal sensory complaints It is not uncommon to find mainly proximal rather than distal weakness Early loss of limb reflexes and facial weakness are common findings Sensory findings are often minimal and could be limited to loss of position or vibration sense It is important to watch for respiratory insufficiency in patients who have severe weakness, ambulatory difficulty or a forced vital capacity below liter Autonomic neuropathy can manifest in variation of heart rate and blood pressure fluctuations but many cases probably have subclinical involvement only Nerve conduction studies usually show slowing of conduction velocities or conduction block suggesting demyelination and F wave abnormalities indicating proximal segment or root involvement Less commonly, small motor amplitudes suggest axon loss which carries a less favorable prognosis Transcranial magnetic stimulation studies have demonstrated subclinical prologation of central motor conduction time, which normalizes in tandem with clinical recovery.13 Brain sulcal changes, likely due to an underlying immunological reaction, has also been shown on MRI recently Lumbar puncture typically shows elevated protein and few or no cells Intravenous immunoglobulin (0.4 g/day for days) has been shown to be equally efficacious as plasma exchange (1.5 times plasma volume for exchanges) in the treatment of this condition It is important to recognize early patients who are likely to progress and institute intensive monitoring for respiratory and autonomic instabilities 1030 A Clinical Approach to Medicine Chronic Inflammatory Demyelinating Polyneuropathy This is a progressive or relapsing type of immune-mediated neuropathy which generally runs a course of at least months presenting with insidious onset of proximal or distal limb weakness and sensory symptoms, particularly affecting large fibre modalities of touch and vibration.14 Facial nerve pathologies, facial weakness and respiratory insufficiency are extremely rare Central nervous system demyelination has been reported In addition to weakness and sensory deficits, sensory ataxia and enlarged nerves are infrequent findings An elevated cerebrospinal fluid protein above 45 mg/dL is found in at least 80% of patients with less than 10 cells/mm3 Nerve conductions show diminished motor conduction velocities, conduction block and abnormal sensory studies Clinically, it is important to exclude conditions that causes neuropathy presenting in a similar fashion: HIV infection, autoimmune disease, diabetes mellitus, monoclonal gammopathies, lymphoproliferative diseases, drug intoxication, toxins ingestion and paraneoplastic neuropathy The condition has been shown to respond to steroids, plasma exchange and intravenous immunoglobulin Azathioprine, cyclophosphamide, cyclosporine and interferons has been reported anecdotally to be effective However, these reports have not been validated in randomized, placebo-controlled trials Collective experience suggest that although 90% respond to treatment if instituted early, as high as 50% relapse in the subsequent years Diabetic Neuropathy Diabetic neuropathy is the most common form of neuropathy secondary to an underlying medical condition Diabetic affectation of the nervous system can be in various forms Most commonly, patients present with symmetrical large fibre type sensorimotor peripheral neuropathies involving large fibre modalities Less commonly seen is small fibre neuropathy with prominent pain and autonomic features in insulin dependent longstanding diabetics Painful, asymmetrical wasting of proximal thigh muscles constitute diabetic amyotrophy, which may represent a form of femoral mononeuropathy, although the exact site of involvement is uncertain Diabetic patients are prone to entrapment neuropathies involving median, ulnar, common peroneal and even cranial nerves Neuromuscular Disorders 1031 Other Secondary Forms of Neuropathy Chronic alcohol consumption damages peripheral nerves from a combination of direct toxicity, dietary insufficiency and impaired absorption Alcoholic neuropathy presents with insidious onset of symptoms, but acute onset over days is also seen.15 Initial complaints are distal pain and paresthesia, with motor weakness and muscle atrophy seen mainly in advanced cases Nerve conduction studies show an axon loss pattern of denervation and sensory symptoms may be improved with vitamin B1 administration Peripheral neuropathy often develops in patients with severe chronic renal impairment or undergoing long-term hemodialysis Symptoms usually develop abruptly with an initial lower limb predilection Loss of vibration sense and proximal muscle weakness are typical features The neurological deficits have been shown to improve with regular hemodialysis Amyloidosis is known to cause sensorimotor axonal peripheral neuropathy with dysautonomia and conspicuous lower limb involvement Sarcoidosis should not be forgotten as a rare cause of distal sensorimotor polyneuropathy Critical illness neuropathy is known to develop in severely ill, ventilated patients with sepsis and organ failure Inherited Neuropathies This is a group of diseases showing sensorimotor peripheral nerve involvement and increasing evidence of genetic basis in their pathogenesis Charcot–Marie–Tooth (CMT) or Hereditary Motor and Sensory Neuropathy presents with distal muscle weakness and atrophy, impaired sensation and diminished tendon reflexes Most cases will manifest by the late twenties but the clinical presentation and severity is wide Type disease generally denotes individuals with a hypertrophic demyelinating neuropathy while Type refers to individuals with axon loss neuropathy Genetic mapping to chromosome 17 (CMT1A), chromosome (CMT1B), and the X chromosome (CMTX) has been demonstrated in CMT Type CMT Type subtypes has been linked to chromosomes and but as well worked up as Type Hereditary Sensory and Motor Neuropathy Type III (HSMN III) or Dejerine–Sottas disease is a severe, generalized form of sensorimotor neuropathy with infantile onset Marked thickening of affected nerve is 1032 A Clinical Approach to Medicine a characteristic feature, as well as pes cavus, kyphoscioliosis, incoordination and even facial palsies.16 HSMN IV or Refsum’s disease is characterized by deafness, anosmia, night blindness, retinitis pigmentosa, cerebellar signs and raised serum phytanic acid levels Hereditary neuropathy with liability to pressure palsies is an autosomal dominant disorder with focal sausage-like thickenings of the peripheral nerves due to recurrent bouts of remyelination Sensory symptoms and pressure-induced reversible weakness of the ulnar, radial, peroneal nerves and even a brachial plexopathy occurs Friedreich’s ataxia presents with sensory deficits while acute intermittent porphyria affects motor fibres more commonly than sensory fibres.17 Demyelinating neuropathies are known neurological deficits in Fabry’s disease and leukodystrophies Entrapment Neuropathies Entrapment neuropathies usually result from recurrent damage to peripheral nerves but it should be differentiated from an underlying peripheral neuropathy For example, patients who have diabetic neuropathy may have underlying carpal tunnel syndrome, which can be easily overlooked Neurophysiological investigations will be helpful as an extension of clinical examination in such circumstances Carpal tunnel syndrome is the most common of all entrapment neuropathies It is more common in females, presenting with dysthesia or paresthesia in the median nerve distribution Symptoms may be referred retrogradely to the elbow or shoulders They are made worse by maneuvers that narrow the carpal tunnel diameter Treatment is aimed at abolishing symptoms and preventing motor wasting of the abductor pollicis brevis muscle The ulnar nerve is usually compressed at the elbow region in tardy ulnar nerve palsy or between the heads of the flexor carpi ulnaris in the cubital tunnel syndrome.18 It should be differentiated from distal ulnar neuropathies, most commonly at the canal of Guyon’s and the palm Electrophysiology, using a combination of segmental mixed nerve conduction and side to side comparison, helps establishes the diagnosis In the lower limbs, common peroneal nerve injury at the head of fibula may result from leg crossing or injury at this site The deep branch Neuromuscular Disorders 1033 is most commonly affected with minimal sensory loss over the web of skin between first and second toes It must be distinguished from foot drop arising from lumbosacral root lesions, sciatic nerve injury and upper motor neuron causes Meralgia parasthetica presents with pain and numbness over the anterolateral thigh and is due to entrapment of the lateral femoral cutaneous at the anterior superior iliac spine region It should be distinguished from L2L3 radiculopathy and a good guide is the presence of the knee jerk Nerve conduction tests are helpful in its diagnosis.19 DISEASES OF THE MUSCLE This section will be discussed under the sections of muscular dystrophies, metabolic myopathies, inflammatory myopathies and myotonia Muscular Dystrophy Both Duchenne muscular dystrophy and Becker muscular dystrophy are classified as dystrophinopathies They result from the absence, deficiency or presence of altered forms of dystrophin, a structural protein found in normal muscle The responsible gene is on the short arm of the X chromosome at locus Xp21 Most cases are due to duplication or deletion of segments within the gene, the rest being attributed to point mutations Duchenne muscular dystrophy represents the severe form with complete absence of dystrophin Presentation is as early as years old with clumsiness, difficulty walking and calf hypertrophy The disease is progressive and patients are wheelchair-bound by 10 years Severe contractures develop in addition to scoliosis and the usual cause of death is cardiomyopathy or respiratory failure In Becker muscular dystrophy, which is a milder form, presentation is usually in the first decade but can be as late as the fourth The clinical features are similar to Duchenne’s but much milder and many can walk even after 20 years of age Leg cramps and muscle pains are prominent features Treatment of these conditions comprises physiotherapy, corrective surgery and bracing The use of steroids is controversial and has never been conclusively shown to be of benefit in trials.20 The limb girdle dystrophies are presently grouped as sarcoglycanopathies There are known forms of sarcoglycans (alpha, beta, 1034 A Clinical Approach to Medicine gamma and delta), a structural muscle protein, each coded by a separate gene that may be defective Patients present with truncal and limb girdle weakness and occasional calf hypertrophy A deficiency of gamma sarcoglycan is observed to be associated with severe weakness while other forms have variable severities Diagnosis is usually made clinically, aided by electromyography, raised creatinine kinase and biopsy Facioscapulohumeral dystrophy is an autosomal dominantly inherited condition with the responsible genetic defect localized to the long arm of chromosome in many but not all cases Presentation is usual in the teen years with mild facial weakness, weakness of scapular fixators despite relative preservation of the deltoids Hip flexor, ankle dorsiflexor weakness, lumbosacral lordosis and impaired hearing is common Treatment is supportive with surgical scapular stabilization, orthosis and tendon transfers Oculopharyngeal dystrophy is also an autosomal dominant condition presenting with mild ptosis and weakness of eye muscles from the third decade It is progressive and eventually facial weakness and dysphagia develops Patients die from emanciation or pneumonia unless aspiration is prevented with a permanent gastrostomy The condition should be differentiated from myasthenia gravis, which shares the same clinical features Metabolic Myopathy This encompasses myopathic conditions secondary to endocrine conditions as well as those from inborn errors of metabolism Thyrotoxic myopathy is probably the most common of the endocrine myopathies and tends to affect males more frequently Typically, patients complain of muscle twitching and shoulder weakness Hyperthyroidism is also associated with myasthenia gravis, hyperkalemic periodic paralysis and ophthalmoplegia Hypothyroidism also causes proximal muscle weakness, hypertrophy and painful spasms Delayed relaxation of contracted muscle, as well as ankle jerks, is a common occurrence in myxoedema Systemic administration of steroids causes myopathy usually affecting the pelvic girdle and thigh Diseases of the adrenal and pituitary gland also causes non-specific muscle weakness as in Cushing’s syndrome, acromegaly and Addison’s disease In hyperparathyroidism, pelvic girdle weakness, brisk reflexes and even extensor plantar responses have been reported Distinction from Neuromuscular Disorders 1035 motor neuron disease can be made electrophysiologically Finally, hypercalcemia secondary to metastases, myeloma or chronic renal disease can also cause neuromuscular weakness Muscle weakness can also occur secondary to glycogen storage disease, disorders of lipid metabolism and mitochondrial disease Inflammatory Myopathy Dermatomyositis can present at any age group and its diagnosis depends on the combination of the typical skin rash and muscular involvement Associated collagen vasculopathy and underlying malignancy are wellknown associations Pain and tenderness of weak muscles are often absent and the typical heliotrope rash over the eyelids can become generalized Polymyositis is more common in adults and it is unclear if it represents a spectrum of diseases which includes dermatomyositis Weakness is the usual presenting feature and may run a fulminant course at its onset Neck flexion and diaphragmmatic weakness can occur Sphincter and extraocular muscles are often spared Tendon reflexes are normal until late in the disease In cases of extensive muscle atrophy, serum creatinine kinase levels may be normal despite active disease Electromyography is helpful in the diagnostic work-up, documentation of treatment response and diagnosing steroid myopathy Most cases respond to high dose and subsequent tapering steroid regimes Myotonia This refers to a clinical state of painless delayed muscle relaxation, which can be distinguished from the painful state of muscle cramps However, electromyographic myotonic discharges without overt clinical myotonia can result from hyperkalemic periodic paralysis, hyperthyroidism, acid maltase deficiency, malignant hyperpyrexia and cholesterol-lowering drugs In myotonic dystrophy (dystrophia myotonica), an autosomal dominant condition which presents in early adulthood, a hatchet-faced appearance from wasted temporalis and masseter muscles is typical but not invariably seen Sternomastoid atrophy, ptosis, frontal balding, cataracts, gynecomastia and testicular atrophy are associated features Cardiac conduction abnormalities, respiratory symptoms, bowel disturbances and low intelligence can occur The myotonia is typically distal, 1036 A Clinical Approach to Medicine diminishes with exercise and responds to membrane stabilizing agents like phenytoin, quinine and mexiletine A congenital form presents neonatally with hypotonia, club feet, mental retardation but no overt clinical myotonia Myotonia congenita occurs in forms: Thomsen’s (autosomal dominant) and Becker’s (autosomal recessive) The former appears in infancy and remains mild throughout life, compared with the latter which shows more severe lower limb myotonia Some patients develop severe muscle hypertrophy reaching a Herculean appearance Life expectancy is normal and involvement of other systems does not occur The defect is in the chloride channel and the affected gene resides on chromosome 7q35 Paramyotonia congenita of Eulenberg is a autosomal dominant condition closely associated with hyperkalemic periodic paralysis which can occur simultaneously The myotonia intensifies rather than improve with exercise and cold exposure results in prominent eyelid, tongue and limb muscle myotonia Proximal and distal muscles are involved equally The genetic defect lies in chromosome 17q resulting in mutation of the sodium channel and is dominantly inherited Acetozolamide may be useful in prophylaxis of paralysis and the myotonia responds symptomatically to the agents mentioned before REFERENCES Barohn RJ, et al., Chronic inflammatory demyelinating polyradiculopathy Clinical characteristics, course and recommendations for diagnostic criteria, Arch Neurol 46:878–884, 1989 Bannister R, Autonomic Failure, Oxford University Press, Oxford, 1992 See SJ, Lo YL, Mixed nerve potentials in brachial plexopathy, Clin Neurol Neurosurg 104:16–19, 2002 Aminoff MJ, et al., Relative utility of different electrophysiologic techniques in the evaluation of brachial plexopathies, Neurology 38: 546–551, 1988 Gorkhaly M, Lo YL, Segmental neurogenic muscle hypertrophy associated with radiation injury, Clin Neurol Neurosurg, in press, 2002 Lau DPC, Lo YL, Wee J, Tan NG, Low WK, Vocal fold paralysis following radiotherapy for nasopharyngeal carcinoma Laryngeal electromyography findings, J Voice, in press, 2002 Stalberg E, Trontelj J, Single Fibre Electromyography, Mirvalle Press, Old Woking, Surrey, 1979 Neuromuscular Disorders 1037 Leigh PN, Ray–Chaudhuri K, Motor Neurone Disease, J Neurol Neursurg Psychiatry, 57:886–896, 1994 World Federation of Neurology Research Group on Neuromuscular Diseases and Subcommittee on Motor Neurone Diseases/Amyotrophic Lateral Sclerosis, J Neurol Sci 124(Suppl):96–107, 1994 10 Adams D, Steck AJ, Perruisseau G, et al., Predictive value of anti GM1 antibodies in Neuromuscular diseases, Neurology 40(Suppl 1): 299, 1990 11 Chokroverty S, et al., The syndrome of diabetic amyotrophy, Ann Neurol 2:181–186, 1977 12 Lo YL, et al., Motor root conduction in neuralgic amyotrophy: evidence of conduction block, J Neurol Neurosurg Psychiatry 66: 586–590, 1999 13 Lo YL, Ratnagopal P, Transcranial magnetic stimulation studies in the Miller Fisher syndrome: evidence of corticospinal tract abnormality, J Neurol Neurosurg Psychiatry 71:210–214, 2001 14 Gorson KC, et al., Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatments in 67 consecutive patients with and without a monoclonal gammopathy, Neurology 48: 321–328, 1997 15 Behse F, et al., Alcoholic neuropathy: Clinical, electrophysiological and biopsy findings, Ann Neurol 2:95–100, 1977 16 Chance PF, Survey of inherited peripheral nerve diseases, Electroenceph Clin Neurophysiol 103(1):12, 1997 17 Lo YL, Dan YF, Lee MP, Ratnagopal P, Segmental mixed nerve conduction studies in ulnar neuropathy, J Clin Neurophysiol 18:456–459, 2001 18 Lo YL, Ratnagopal P, Leoh TH, Dan YF, Lee MP, Yong FC, Clinical and electrophysiological aspects of distal ulnar neuropathy, Acta Neurol Scand 105:390–394, 2002 19 Lo YL, et al., Electrophysiological features in the management of meralgia paraesthetica, Ann Acad Med Singapore 27:530–532, 1998 20 Dubowitz V, 47th ENMC International workshop: treatment of muscular dystrophy, Neuromuscular Disorders 7:261–267 This page intentionally left blank 61 Stroke Chang Hui Meng and Christopher Chen INTRODUCTION Stroke is a common condition, resulting from a pathological disruption of cerebral blood flow, and this produces diverse and variable clinical stroke syndromes The magnitude of the problem is reflected not only by the mortality that results, but also the morbidity and disabilities that follow Additional stroke attacks compound the initial physical and cognitive disabilities already inflicted The costs on family and society is enormous, for instance in America, the estimated annual cost of stroke care is about US$40 billion EPIDEMIOLOGY AND LOCAL FIGURES Stroke is the second leading cause of death worldwide, with an estimated 4.6 million deaths The risk of stroke increases exponentially with age, with the genu of curve at 55 years The incidence is more common in men (1.25 times), even though more women die annually In Singapore, it accounts for 10–12% of all deaths annually, and is one of the leading 1039 1040 A Clinical Approach to Medicine causes of mortality The average life expectancy of Singaporean has increased from 65.8 years in 1970 to 77.3 years in 1998 Coupled with an aging society, the magnitude of the problem will increase in Singapore At the Dept of Neurology, Singapore General Hospital, approximately 1400 stroke patients (excluding subarachnoid hemorrhage) were hospitalized in 1998, with a slight male predominance (54%) and a mean age of 65 years (range 23–96 years old) Most of these were ischemic strokes (92.6%) as hemorrhagic strokes were usually admitted to Neurosurgery Dept The ethnic distribution approximated our population constitution, with 83.8% Chinese, 8.8% Malays, 5.8% Indians and 1.7% other races Racial differences in ischemic and hemorrhagic stroke have been described, with hemorrhagic strokes occurring more frequently in Orientals compared with Caucasians APPROACH TO STROKE Stroke refers to any damage to the central nervous system (brain or spinal cord) caused by disturbances to the blood supply This disruption of blood supply may be due to occlusive/stenotic lesions (causing ischemic infarcts) or hemorrhage (causing either intracerebral hematoma or subarachnoid hemorrhage) A cerebral artery or a vein may be involved, when a cerebral vein is occluded, the syndrome is referred to as Cerebral Vein Thrombosis (CVT) CVT is an uncommon cause of stroke, and the etiologies and management differ from arterial occlusive strokes They will not be discussed in this chapter The term “Stroke” or “Cerebrovascular Accident” is usually used when the event occurs suddenly, and implies that permanent brain damage has occurred On the other hand, “Transient Ischemic Attack” (TIA) is used when the symptoms are transient, and has been arbitrarily defined as neurological deficits that resolve within 24 hours In actuality, studies have shown that true TIAs last less than an hour In the carotid circulation, they last an average of 15 minutes, and in the vertebrobasilar system, less than 10 minutes usually Transient ischemic attacks that last beyond hour often are due to small strokes with rapid resolution of clinical signs The term Cortical Infarct with Transient Signs (CITS) has been used to describe this condition Ischemic stroke accounts for 80–85% of all strokes, with hemorrhagic stroke accounting for the remaining Hemorrhagic strokes may present as parenchymal/intracranial hemorrhage (ICH) or subarachnoid hemorrhage (SAH) It accounts for about Stroke 1041 10% of all strokes Common causes of ICH include hypertension, congenital or acquired coagulopathies (of which anticoagulant use is important), drugs (amphetamine, cocaine), amyloid angiopathy, arteriovenous malformations and aneurysms SAH are most commonly caused by arteriovenous malformation and aneurysms Stroke and TIA are syndromes of diverse mechanisms and etiologies The clinical syndrome is a reflection of the underlying vascular abnormality, and cerebral structures that have been damaged Identifying the stroke type, mechanism and etiology aids in identifying patients at increased risk of early neurologic or medical complications, including death and long-term disability, and in preventing recurrent strokes Management of stroke requires basic knowledge of the nervous system and the underlying vascular supply A brief review of the cerebral supply is given below, (anatomical variations exist), followed by mechanisms of stroke, etiologies and stroke syndromes BASIC CEREBRAL SUPPLY AND ANATOMY The vessels to the brain come off the aortic arch, from right to left in the following order: right brachiocephalic trunk (innominate artery), the left common carotid artery (CCA) and left subclavian artery The right CCA is the first vessel off the brachiocephalic trunk, followed by the vertebral artery (VA), thyrocervical and costocervical trunk, after which the trunk continues as the right subclavian artery Both CCA run up the neck, where they usually bifurcate at the level of the 4th or 5th cervical vertebrae into the external carotid artery (ECA) and internal carotid artery (ICA) The ECA gives off early branches to supply the thyroid gland, and musculature of the face (superior thyroid, lingual, facial, occipital, auricular, maxillary and superficial temporal artery), while the ICA courses intracranially through the temporal bone, until it reaches the cavernous sinus This portion of the ICA, within the carotid sinus, is known as the carotid siphon because of its curvature The ophthalmic artery exits anteriorly from here to supply the eye, while the ICA continues into the supraclinoid portion where the anterior choroidal and posterior communicating arteries are given off The ICA finally bifurcates into the anterior (ACA) and middle cerebral artery (MCA) The MCA courses laterally in the brain, giving off penetrating vessels known as the lenticulostriates that supply the basal ganglia The MCA 1042 A Clinical Approach to Medicine finally bifurcates or trifurcates into anterior and inferior trunks that supply most of the temporoparietal lobe The ACA courses medially and anteriorly to supply the medial frontal hemisphere, as well as the caudate nucleus (via the recurrent artery of Heubner) It gives off the callosomarginal artery, which courses along the sulcus of same name, while the artery continues as the pericallosal artery The VA originate from the subclavian artery, and courses up the neck until it enters the transverse foramina of the 5th or 6th cervical vertebra, coursing through the foramina of the cervical vertebra till it reaches the 2nd or axis vertebra It loops up and laterally around the transverse process of the 1st or atlas vertebrae courses medially, where it gives off muscular branches (which may anastomize with branches of the occipital artery) It pierces the dura, and joins the opposite VA to form the basilar artery (BA) at the medullopontine junction The VA is sometimes divided into segments: V1 refers to the first portion before it enters the cervical vertebra foramen, V2, the segment within the transverse foramen, V3, the segment around the “atlas loop,” and V4 the segment after A major cerebellar artery, the Posterior Inferior Cerebellar Artery (PICA) if given off the intracranial VA The BA traverses the dorsal surface of the pons, giving off a second major cerebellar artery, the Anterior Cerebellar Artery (AICA) Small medial and circumferential penetrating vessels arise off the BA to supply the pons The BA bifurcates into the Posterior Cerebral Arteries (PCAs) at the midbrain The Superior Cerebellar Artery (SCA), the last major cerebellar artery is given off just before this The PCAs supply the midbrain, occipital lobe, medial inferior temporal lobe and thalamus The polar arteries branch off the posterior communicating arteries to supply the anterior thalamus, the thalamic-subthalamic arteries (also known as thalamoperforaters) arise from medial PCA to supply the posteromedial thalamus, branching distally from the PCAs, the thalamogeniculate and posterior choroidal arteries supply the ventrolateral thalamus, and the anteroposterior (including part of the lateral geniculate body) respectively The cerebellar arteries provide the major vascular supply to the cerebellum, and portions of the brainstem as well The carotid circulation is also referred to as the anterior circulation, and the vertebrobasilar circulation, as the posterior circulation Connections exist between the anterior and posterior circulation, which allow for collateral supply when one or more vessel becomes compromised Within the intracranial vessels, the anterior communicating artery Stroke 1043 (A comm) connects both ACAs The posterior communicating artery (P comm) connects the carotid siphon with the PCA Connections also exist within the extracranial vessels and intracranial vessels; from the ECA, the frontal and supratrochlear arteries may provide anastomic link with the ophthalmic artery, while the occipital artery of the ECA anastomizes with the VA Under pathological conditions, the cerebral vessels may also supply blood to the upper extremities as in the case of the subclavian steal syndrome where blood flows retrogradely from VA to the subclavian artery A summary of these potential channels is given below Table Potential Sources of Collateral Flow to the Brain With Anterior Circulation Occlusive disease Frontal and supratrochlear branches of ECA with ophthalmic artery of ICA Meningeal branches of ECA, via the lacrimal branches to the opthalmic artery Meningeal branches of ECA to cortical branches of the hemisphere Anterior communicating artery between left and right ACA Posterior communicating artery between carotid siphon and PCA With Posterior Circulation Occlusive disease Branches from costocervical and thryocervical trunk with VA (V2) in the neck Occipital artery from ECA with VA (V3) Posterior communicating artery between carotid siphon and PCA STROKE MECHANISMS Traditionally, stroke mechanisms are divided into thrombotic, embolic or hypoperfusion Thrombosis Thrombosis refers to vascular occlusion by local disease within the vessel Most commonly, this is due to atherosclerosis, where fatty and fibrous plaques form within the vessel wall, and either slowly occlude the lumen from increasing size, or suddenly rupture and occlude the lumen When the surfaces of the plaque are ulcerated, small platelet and fibrin clumps may form, break off and flow further downstream to occlude a smaller caliber vessel (artery-to-artery embolism) Atherosclerotic plaques, common in an elderly population, are usually found at arterial bifurcation, where the hemodynamic stress is believed to have a contributory role Other conditions that may occlude the vessel lumen include arterial dissection and fibromuscular dysplasia, which occur more often in the young 1044 A Clinical Approach to Medicine Embolism Embolism refers to the sudden obstruction of a blood vessel from an occluding material that has originated upstream in the circulatory system (either from the heart or blood vessels) and traveled downstream into the cerebral circulation The occluding material may be a blood clot, air embolus, small pieces of plaque, bacterial containing, tumor or injected particulate material If it originates from the heart, the mechanism is described as cardioembolism, otherwise it originates from a vessel (e.g aortic and carotid artery plaques), where it is referred to as artery-toartery embolism In paradoxical embolism, a clot from the venous circulation has entered the arterial circulation to finally occlude a cerebral artery This occurs when there are existing right to left cardiac shunts (e.g atrial or ventricular Septal Defect) concomitantly with a venous source of thrombosis (such as deep vein thrombosis in the legs) Hypoperfusion Hypoperfusion occurs when cerebral perfusion pressures fall Global hypoperfusion occurs in massive cardiac failure, cardiac arrest, and massive blood loss In such cases, global damage will be inflicted, with the watershed areas of vascular territories most affected Focal hypoperfusion may occur if severe occlusive disease exists in one vessel This stenotic vessel impedes adequate blood flow, resulting in symptoms referable only to this vascular territory A severe carotid arterial plaque hence may be symptomatic by embolising small clots distally (artery to artery emboli) or result in hemodynamically significant decrease in perfusion pressure (focal hypoperfusion) A single arterial lesion may cause symptoms via different mechanisms STROKE ETIOLOGIES The most common cause of stroke is atherosclerosis and cardiac diseases in the elderly Many non-atherosclerotic vascular diseases exist (see Table 2) Atherosclerosis Atherosclerotic plaques are intramural depositions of fatty and fibrinous materials, with predilection for certain sites: the aortic arch, origin of the Stroke 1045 Table Causes of Ischemic Stroke 1) Atherosclerosis 2) Cardiac diseases: Arrhythmias (atrial fibrillation, Sick Sinus Syndrome), poor left ventricular function, dilated ischemic and non-ischemic cardiomyopathies, intracardiac clots, left ventricular aneurysm, valvular diseases (mitral stenosis), mitral annulus calcification, mitral valve prolapse, right to left shunts (e.g Patent foramen ovale, atrial or ventricular septal disease), atrial septal aneurysm, bacterial or non-bacterial endocarditis, prosthetic valves, atrial myxomas, etc 3) Hematologic conditions: deficiencies of Protein C, Protein S and antithrombin III, resistance to activated factor V, plasminogen activator inhibition or deficiency, polycythemia, thrombocytosis, leucocytosis, sickle cell disease, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulopathy, thombotic thrombocytopenic purpura, cryoglobinuria, etc 4) Drugs: cocaine, heroin, L-arginase, amphetamines, ergot drugs, etc 5) Inflammatory: syphilis, tuberculosis, HIV, systemic lupus erythematosus, anticardiolipin syndrome, giant cell arteritis, polyarteritis nodosa, Crohn’s disease, rheumatic arthritis, scleroderma, Takayasu’s disease, isolated angiitis of the central nervous system, etc 6) Arterial dissection 7) Migraine 8) Related to female hormones: high-dose estrogen contraceptive pills, pregnancy, puerperium 9) Genetic/metabolic: Marfan’s syndrome, pseudoxanthoma elasticum, homocystinuria, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and strokes), familial hyperlipidemias, etc 10) Others: fibromuscular dysplasia, Moya Moya disease, Behcet’s disease, CADASIL, etc ICA, origin of VA, carotid siphon, main MCA, distal intracranial VA and basilar artery It is a common disease of the elderly Intracranial disease is more common in Chinese, Blacks and Japanese Extracranial ICA bifurcation disease is more common in Whites Symptomatic extracranial ICA stenosis occurs within cm of its origin from CCA and often presents with warning TIAs These may be retinal TIAs (also known as Amaurosis Fugax or Transient Monocular Blindness) where usually a painless, dark shade descending over the ipsilateral eye is described Symptoms for hemispheric TIAs would depend on which side was affected For the dominant hemisphere (usually the left brain), aphasia maybe present, besides visuomotor-sensory deficits It is rare for patients to describe symptoms of neglect, seen with involvement of the non-dominant lobe These TIAs 1046 A Clinical Approach to Medicine are often due to small broken-off plaques that embolise distally to the ophthalmic artery or ICA branches, though in the presence of severe stenosis, a hemodynamic component may be present In TIAs secondary to ICA stenosis, the ipsilateral eye, and contralateral limbs are affected The risk of stroke with TIA is 24–29% over years, with the highest risk described in the first month (4–8%) and 12–14% within the first year Hemispheric TIAs are also associated with a higher stroke risk than retinal TIAs A 5-year retrospective review of all Doppler examinations in our department confirmed that extracranial ICA disease is not common in a predominantly Chinese population We retrospectively reviewed 5235 carotid Doppler studies over a 5-year period from 1994 Ninety three percent of these patients had presented with symptoms and signs of TIA or stroke Only 6.6% of patients studied had severe (more than 70% stenosis) or occluded extracranial carotid disease 4.3% had symptoms of stroke within the last months, the remaining one-third had symptoms beyond months This has important bearings as large clinical trials have confirmed the superior benefit of carotid endarterectomy over best medical treatment in the management of severe recently (within last months) symptomatic carotid stenosis, provided disabling strokes have not occurred Cardiac Sources of Stroke Approximately 15–20% of all ischemic strokes are cardioembolic The prevalence of cardioembolic stroke in young strokes is high (23–36%), partly because of the lower prevalence of atherosclerotic disease Atrial fibrillation is the most common cause, myocardial infract, rheumatic valvular disease and prosthetic valves are also common In the evaluation for cardiac sources of stroke, arrhythmias, valvular abnormalities and cardiac wall abnormalities need to be excluded The clinical history may give clues, palpitations, rheumatic fever or myocardial ischemia may be elicited The presentation is often sudden, with maximal neurological deficits at onset, and very rarely preceding TIAs Clinical examination may give clues to the underlying cardiac disease, splinter hemorrhages, Roth’s spots on fundoscopy are signs of systemic embolisation Echocardiography is useful for structural imaging of the heart, valves and intracardiac clots Transesophageal echocardiography (TEE) is superior though more invasive than transthoracic echocardiography (TTE) The aortic arch and left atrial appendage are studied better However, it is comparatively more invasive The use of echo contrast Stroke 1047 agents, or bubbles (agitated saline) improves the detection of intracardiac shunts A 24-hour cardiac rhythm monitoring is useful when the suspicion for paroxysmal arrhythmias is high Cerebral imaging with either CT or MRI may reveal multiple vascular territorial infarcts Arterial Dissection Arterial dissection occurs when blood extrudes into the vessel wall Blood may enter the subintimal plane or media-adventitial plane Symptoms may arise because of luminal compression by the subintimal hematoma, clot formation within a stenosed lumen with distal embolisation or aneurysmal dilatation, especially in subadventitial hematoma, with rupture and subarachnoid hemorrhage Dissections are common in young strokes Extracranial arterial dissection is more common than intracranial dissection In the neck, the ICA is most often involved, usually some distance after its origin (unlike atherosclerotic plaques) and may extend rostrally for a variable distance, though it rarely extends intracranially The first and third portions of the VA are next most commonly involved sites Intracranially, the ICA and MCA stem are usually involved Intracranial vertebrobasilar artery dissections are very rare The most common symptom is pain, in the neck or head Antecedent trauma may be absent or mild and a temporal relationship is not always established Angiography usually establishes the diagnosis A tapering occlusion is characteristic (rat’s tail sign) Axial Magnetic Resonance Imaging (MRI) of the involved vessel may reveal the false and true lumen, and is a less invasive procedure STROKE SYNDROMES Various terminologies have been used to describe stroke syndromes and subtypes These give clues not only to the underlying cerebral and vascular abnormality, and mechanism, e.g small (or large) vessel stroke and cardioembolic stroke, but help prognostic neurologic outcomes, and recurrence Obstruction of branch or large cerebral vessels results in a constellation of signs and symptoms that allows the physician to identify the offending vessel Such strokes have also been described as “Large Vessel Strokes or Disease.” The table below describes the clinical manifestation that may occur 1048 A Clinical Approach to Medicine Table Clinical Signs and Symptoms Vascular Territory Cerebral Structures Supplied Signs & Symptoms Middle Cerebral Artery (MCA) Frontal, parietal and temporal lobes Hemiplegia involving face and arm, more so than leg Hemianesthesia Hemianopia Global aphasia or neglect Upper division MCA Frontal-parietal lobe Predominantly brachiofacial weakness and sensory loss Expressive (Broca’s) aphasia or neglect Lower division MCA Temporo-parietal lobe Minimal weakness and sensory loss Upper quadrantnopia or hemianopia Receptive (Wernicke’s) aphasia or constructional apraxia Anterior Cerebral Artery (ACA) Medial frontal lobe, Corpus callosum Predominantly leg weakness Apathy and abulia Transcortical motor and sensory aphasia Left limb apraxia (Anterior disconnection syndrome) Incontinence Recurrent Artery of Heubner Caudate nucleus Anterior limb of internal capsule Behavioral changes: abulic and apathetic or agitated and hyperactive Mild dysphasia or neglect Mild motor weakness Anterior Choroidal Artery Globus pallidus, lateral geniculate body, posterior limb Internal capsule, medial temporal lobe Hemiplegia of face, arm and leg Hemianesthesia Hemianopia with sparing of middle sector (30Њ to 60Њ) Posterior Inferior Cerebellar Artery (PICA) Inferior cerebellum, Dorsolateral medulla Lateral Medullary Syndrome Anterior Inferior Cerebellar Artery (AICA) Middle cerebellum, pons Hemiataxia Characteristic VIII cranial nerve palsy Superior Cerebellar Artery (SCA) Superior cerebellum, Upper pons Hemi or quadriataxia Characteristic IV cranial nerve palsy Stroke 1049 Table Continued Vascular Territory Cerebral Structures Supplied Signs & Symptoms Basilar Artery (BA) Pons Quadriparesis Multiple cranial nerves palsies Thalamicsubthalamic artery Posteriormedial thalamus Vertical gaze abnormalities Abnormal/decrease conscious level Memory and cognitive abnormalities Polar artery Anterolateral thalamus Apathy, abulia Memory abnormalities Mild-moderate aphasia or neglect Thalamogeniculate artery Ventrolateral thalamus ϩ/Ϫ Posterior limb of internal capsule Hemianesthesia Mild hemiparesis Hemiataxia or hemichorea Dejerine Roussy syndrome (above features, with delayed disturbing pain in hemianesthetic limbs) Posterior choroidal artery Pulvinar, habenula, anterior thalamus, lateral geniculate body Uncommon, characteristically, sectoranopia (from 60Њ to 120Њ) Posterior Cerebral Artery (PCA) Midbrain, thalamus, occipital lobe, medial inferior temporal lobe Hemiparesis, hemianesthesia, hemiataxia Vertical gaze abnormalities Hemianopia, visual disturbances Alexia without agraphia (Posterior disconnection syndrome) Memory abnormalities Mild-moderate aphasia and neglect Occlusion of small penetrating vessels in the brain produces “Small Vessel Stroke/Disease”, which have also been called “Lacunar strokes.” As the damage is small and restricted, patients with lacunar strokes would not have concomitant language, spatial or visual impairments, unless these were sustained from previous strokes Five clinical lacunar 1050 A Clinical Approach to Medicine syndromes have been described: pure motor, pure sensory, motorsensory, ataxic hemiparesis and clumsy-hand-dysarthria These are clinical syndromes, which not identify the underlying area of brain damaged However, lacunes have a predilection for certain sites, the putamen, pallidum, pons, thalamus, caudate nucleus, internal capsule, corona radiata and cerebral peduncles Another classification, commonly used in our institution is the Oxfordshire Community Stroke Project (OCSP) The OCSP is a simple clinical (based on history and physical examination) classification for acute stroke which predicted functional recovery, mortality and recurrent strokes In OCSP, strokes are classified into primary intracerebral hemorrhage (PICH), total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI), and posterior circulation infarct (POCI) Radiological findings are included in the final assessment Patients with TACI have the full constellation of signs seen in large vessel occlusive disorder, e.g in the dominant Middle Cerebral Artery, this would be dysphasia, motor and sensory weakness, and hemianopia At the other spectrum, patients with LACI would have one of the lacunar syndromes described with no language, spatial or visual deficits Patients with PACI have intermediate signs The natural history of stroke is influenced by the stroke subtype and comorbidities The 30-day mortality is highest in intracerebral hematoma (48–82%) and lowest in ischemic infarct (8–15%), with subarachnoid hemorrhage inbetween (42–46%) Within the ischemic strokes, large vessel occlusive infarcts, large volume infarcts, TACIs and cardioembolic strokes have been shown to fare much worse than LACIs or small vessel strokes Stroke progression is a difficult parameter to assess One database showed that about a quarter of strokes admissions had unstable course, of which three-quarters were attributable to stroke progression Progression was most often in large vessel occlusive disease Progression in lacunar strokes had the best prognosis for recovery The risk of recurrent stroke is similiarly affected by the stroke subtype and co-morbidities The risk of recurrent stroke is highest in the first 30 days of stroke (up to 4%) and averages about 5–25% at one year It is highest in symptomatic severe carotid stenosis, up to 30% within years, and lowest in lacunar strokes Other predictors of stroke recurrence hemispheric stroke, hypertension, atrial fibrillation and heart failure Stroke 1051 INVESTIGATIONS Investigations are planned to confirm the diagnosis of stroke and the area damaged, and further elucidate the underlying mechanisms and etiologies Imaging of the nervous system should be aimed at the following issues: 1) identification of the lesion — that it is a stroke, and not other cerebral lesions such as tumor; 2) differentiation between ischemic and hemorrhagic stroke; 3) localization and quantification of the size of stroke; 4) determination of the age of stroke; and 5) identification of other previous strokes Vascular imaging, on the other hand, helps to confirm the mechanism and etiology of stroke, and also prognostic the risk of recurrent stroke: 1) the vessel involved, and if an occlusive lesion is present; 2) the severity of the occlusive disease, and what further brain tissues are at risk for damage; 3) the cause of the occlusive lesion; and 4) the state of the other cerebral vessels: are there occlusive disease in other parts, what are the collateral support like, are there any vascular variants present Structural Imaging Computed tomography Computed Tomography (CT) head is a simple, readily available test that allows a rapid and accurate differentiation of infarcts from hemorrhage It is also relatively inexpensive, compared with some of the newer imaging modalities available Early CT infarct signs are mainly attributable to a combination of vasogenic and interstitial edema: • • • • loss of the gray-white differentiation due to edema of the gray matter sulcal effacement due to mass effect of the edema compression of the ventricles due to mass effect of the edema “insular ribbon sign” where there is diminished attentuation of the gray matter in the insular cortex and claustrum, again due to edema 1052 A Clinical Approach to Medicine • • the definition between the lentiform nucleus and internal capsule is lost or obscured a hyperdense middle cerebral artery may be seen, due to an acute thrombosis Chronic infarcts show up on CT scans as • • • atrophy (a clearly delineated defect) with dilatation of the adjacent ventricles and sulci Wallerian degeneration, where there is denervation atrophy of damaged tracts (e.g motor tracts from internal capsule, to cerebral peduncle, pons, medulla and pyramidal tracts), which is rare dystrophic calcification, which is rare CT scan does suffer from certain disadvantages It is not as sensitive as MRI in detecting early ischemic infarcts, especially if they are small (lacunes or spinal cord infarcts) or adjacent to bony structures (such as the posterior fossa) Magnetic resonance imaging MR imaging depends on the reaction of body tissue nuclei (the hydrogen nuclei is most commonly manipulated) to radio frequency pulses in the presence of a powerful magnetic field The collected data is manipulated by a computer to provide the final image Hydrogen nuclei are the most common protons in the body, found in water, fats and many other tissues Water and fat protons have been most extensively imaged with MRI Other nuclei can also be studied, using MR spectroscopy These include fluorine, carbon and phosphorus However, because these nuclei are less abundant in the human body, they produce weaker signals, and the final image collected has poorer spatial resolution Manipulation of various MR parameters allows images to be obtained with differing qualities T2-weighted and especially diffusion weighted imaging allows early visualization of acute lesions by demonstrating the increase in tissue water that accompanies acute infarcts T1-weighted sequences provide good anatomic definition, and are useful for detecting subacute-chronic infarcts Perfusion imaging (also referred to as hemodynamicallyweighted MRI) gives a reflection of the cerebral blood flow, and may allow the identification of ischemic tissue at risk for further infarction Advancement with technology has allowed the time for MR imaging to Stroke 1053 be shortened (echoplanar imaging) MRI is more sensitive than CT, in particular with small and early ischemic strokes However it does not define hemorrhage as well, though there are sequences (e.g fluid attenuated inversion recovery or FLAIR) that are sensitive to the presence of blood Neurovascular Imaging Ultrasound imaging and Doppler sonography Ultrasound is a frequency that is beyond the range perceptible to human ears It can make the motion of blood audible by the Doppler effect, and also allow a visual display of the vascular tissues imaged Transcranial Doppler (TCD) ultrasound is based upon the use of a range-gated pule-Doppler ultrasonic beam of MHz frequency to assess the hemodynamic characteristics of major intracranial arteries The TCD takes advantage of ultrasonic “windows” in the skull, where the bone is sufficiently thin to allow penetration of the ultrasound waves The sonographer is unable to see the vessels being insonated, however, using set criteria, the sonographer is able to identify major arteries imaged Cerebral veins can also been studied New techniques available now allow for direction visualization of the vessels imaged Its applications include the detection of severe stenosis intracranially, vasospasm in subarachnoid hemorrhage, assessing collateral circulation, assessing brain death and detecting vascular malformations Computed tomographic angiography and magnetic resonance angiography Both CTA and MRA study the cranial vessels non-invasively There is a limit to the spatial resolution of smaller vessels, which is still best studied on angiography Cerebral angiography This has long been held to be the gold standard for diagnostic imaging of the cerebral vasculature There is a small but significant risk of major stroke or death, during or soon after angiography This risk is about 0.5%, and is associated with advanced age, elevated serum creatinine, 1054 A Clinical Approach to Medicine hypertension, and a lengthy angiographic time The risk for minor stroke and TIA is usually about 1% However it gives more precise information on the cerebral vasculature, the nature, severity and extent of underlying vascular lesions, the identification of other lesions present and the extent of collateral flow present Other Imaging Modalities Single-photon emission computed tomography (SPECT) Single photon gamma-emitting radionuclides are used in SPECT imaging to provide information about perfusion (and to a smaller extent neuroreceptor distribution) in cerebrovascular disorders SPECT can demonstrate local hypoperfusion in acute stroke, and identify the cerebral perfusion reserves in the presence of an extracranial occlusive disease Current SPECT perfusion techniques utilize either the cerebral clearance of a radionuclide or the retention of a radionuclide-tagged-ligand, which is fixed intracranially according to blood flow Positron emission tomography (PET) Like SPECT, PET is another functional neuroimaging technique Positronemitting radionuclides are tagged to physiologically active compounds, and given to patients Cerebral metabolism and blood flow is assessed with CT studies on distribution of these radionuclides with time Unfortunately, these radionuclides have very short lives, and a dedicated cyclotron is required on-site for synthesis of these compounds The equipment and maintenance makes this very costly, which is why PET is still a mainly research tool Others Other investigations should be dictated by the patient’s presentation and physician’s clinical suspicions In particular, young patients with stroke should be aggressively investigated for treatable conditions Lifestyle factors should be analyzed, as the co-existence of many contributory diseases increases the risk of stroke and its recurrence For instance, in a young woman with acute stroke and a history of migraine, smoking and the use of contraceptive pills should be stopped Laboratory tests should Stroke 1055 include screening for hematologic, inflammatory and infective causes Cardiac diseases should be actively excluded TREATMENT OF STROKE Stroke is an acute neurological emergency Currently, there are effective strategies that help to reduce neurologic disabilities and mortality All patients with acute stroke should be admitted for management and investigations Unfortunately, most stroke patients present late to medical institutions At our institution, only 26.6% presented within hours of symptoms onset to the Emergency department, with an additional 13% presenting between 6–12 hours after symptom onset Men tended to seek medical attention slightly earlier than women (41.3% of men presented within 12 hours of symptom onset, compared with 37.7% women) These figures are worrying as for effective management of stroke should be instituted as early as possible to minimize stroke complications Management of acute stroke can be divided into an acute phase, and a chronic management cum rehabilitation phase These phases overlap, in the acute stage, the thrust of management is stabilization of stroke and medical conditions, though simple rehabilitation is usually initiated at this early stage if the patients are medically stable In the chronic management phase, the goals are to prevent further strokes (secondary prevention), treat co-existing diseases, and rehabilitate the patient’s functional status to the best possible Frequently this phase is initiated in the acute care hospital and continued in a step-down facility such as a rehabilitation hospital or a community hospital It does not end with discharge but merges into home care and day care rehabilitation MANAGEMENT OF ACUTE STROKE General An acute stroke pathway can be used to guide the management and investigation of stroke in a timely fashion In our institution, a multidisciplinary stroke clinical pathway, involving physicians, nurse, therapists, dieticians and social workers has been developed (Fig 1) Unstable patients such as those with progressive strokes, large or brainstem strokes are better 1056 A Clinical Approach to Medicine managed in the Acute Stroke Unit, where the neurological and medical parameters are monitored at close intervals The Acute Stroke Unit is a geographical area for the multidisciplinary care of Stroke patients Such Stroke Units have been shown to reduce hospitalizations and improve the outcomes of stroke patients by decreasing medical complications, neurological dependence and mortality Studies have shown a 20–30% reduction in death, dependency and discharge to institutional care Frequent neurological assessments allow for early detection of neurological deterioration, which should be a trigger for additional evaluation Deterioration could be attributable to neurological factors (such as progression of infarct, hemorrhagic transformation of the infarct, a new infarct or cerebral edema from existing infarct) or non-neurological factors (such as sepsis, metabolic abnormalities like hyper or hyponatremia) These causes should be rapidly identified and corrected if possible Protection of the airway and maintenance of oxygenation remains of paramount importance The routine use of oxygen supplementation is of unproved benefit, but determination of oxygen saturation by pulse oximetry or arterial blood gas measures is recommended Oxygen should be given if the patient is hypoxic The cause of the hypoxia also should be sought Airway integrity should be monitored, especially if the patient has depressed consciousness or evidence of brainstem dysfunction Intubation and ventilatory assistance may be needed Patients frequently have an elevated blood pressure after stroke and the management of hypertension is controversial Arterial hypertension can be seen with either hemorrhagic or ischemic stroke After the initial stress of the event is over, the blood pressure tends to decrease gradually without any medical therapy To date, there are no data about any specific level of systolic or diastolic blood pressure that is harmful to a patient with stroke Hypertension in the acute phase should not be treated unless there indications for aggressive treatment, which includes hypertensive encephalopathy, renal or myocardial compromise, or an acute aortic dissection Thrombolytic therapy necessitates a more energetic response Whether cerebral hemorrhage is an indication for aggressive control of arterial hypertension to prevent continued bleeding is uncertain Pyrexia should be managed quickly Data suggests that hyperthermia exacerbate brain damage Pneumonia secondary to aspiration is the most common cause of fever appearing during the first 24 hours after stroke Subsequently, fever usually is secondary to pulmonary or urinary tract Stroke 1057 infections A fever should not be ascribed to the stroke until an infectious etiology is eliminated Fever also can point to a cause of stroke such as infective endocarditis Hypothermic treatments for stroke are experimental, but early use of antipyretics (or even cooling blankets) in the febrile patient seems advisable while the search for the cause of the fever is underway Fluid and electrolyte management is an important aspect of early care Many patients are dehydrated from poor intake or use of diuretics Early intravenous fluid support is indicated, especially if oral intake is restricted Achievement of a normal blood volume seems appropriate in most patients A mild fluid restriction is advised for patients who are at risk for increased intracranial pressure The usual intravenous fluid used is normal saline as experimental and epidemiological evidence suggests that high levels of blood glucose may be detrimental for outcomes after stroke There is no data to show that the aggressive control of the blood glucose improves neurologic recovery Treatment of an elevated or low level of blood glucose is advised, but no specific protocol can be recommended for treatment after stroke Food intake sometimes is avoided during the first 24 hours after stroke, especially in the presence of a reduced level of consciousness, dysarthria, impaired gag reflex, or wet cough Swallowing evaluation should be used liberally If adequate oral intake is not feasible, enteral feeding can be started, either via a nasogastric tube or via a percutaneous gastrostomy Early mobilization is advised in order to reduce the risk of aspiration and the development of deep vein thrombosis Sitting or standing determinations of blood pressure will help detect a postural drop, which could induce neurologic worsening when the patient begins mobilization SPECIFIC MEASURES Antithrombotics Both the International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST), which combined, enrolled over 40 000 patients demonstrated a small but beneficial effect of early antiplatelet with aspirin in acute stroke, less than 48 hours IST used an aspirin dose of 300 mg for 14 days, while CAST applied 160 mg for weeks Acute antiplatelet therapy was also 1058 A Clinical Approach to Medicine studied in one arm of the Italian Streptokinase study Together, these results show that with early aspirin therapy, for every 1000 patients treated, there would be about recurrent strokes prevented, less deaths and less deaths/fatal strokes with a slight increase in hemorrhagic strokes of Although the effect is modest, the ease of administration, wide availability and low cost argues for its use in acute ischemic stroke without any contraindications A dose range of 160 to 300 mg is recommended The Antiplatelet Trialists Collaboration determined that the lowest, effective aspirin dose for the prevention of recurrent ischemic stroke is 75 mg Hence it may be reasonable to convert patients to a lower dose of aspirin after to weeks Anticoagulation IST also studied the effect of heparin in all types of stroke Heparin subcutaneously administered was not shown to be of any benefit in decreasing the risk of recurrent stroke in the immediate post stroke period Heparin did decrease the risk of ischemic stroke, but was associated with a greater risk of hemorrhagic stroke, which negated its beneficial effect The role of low molecular weight heparin in acute stroke is still not clear An earlier study in Hong Kong revealed some beneficial effect, which has not been reproduced in subsequent studies Anticoagulation is proven treatment in prevention of cardioembolic strokes However, the time of initiation from the onset of an acute stroke, to prevent a recurrent stroke is not clear The risk of recurrent stroke in the first weeks after an initial stroke in the setting of atrial fibrillation has been described to be as high as 21%, however, recent large clinical trials showed that this might not be true There is no consensus on the appropriate timing to start anticoagulation soon after an acute infarct to prevent another stroke A balance needs to be made between the risk of hemorrhagic transformation and recurrent stroke The role of anticoagulation in patients with high grade stenoses of either carotid or the vertebral-basilar vascular systems, and progressive strokes remains theoretically attractive but unproven While the role of heparin in the setting of acute ischemic stroke is limited, subcutaneous, low-dose heparin to prevent deep venous thrombosis and pulmonary embolism is well proven Stroke 1059 Thrombolytics The advantages of clot-busting agents have always been attractive The removal of an offending clot would allow tissue salvation, and prevent further neuronal death Its effectiveness in acute coronary syndromes lends further support for studies of its usage in strokes However, considerations for its usage must be tempered by knowledge of its safety profile In a meta-analysis of about 12 thrombolytic trials by Wardlaw, it was demonstrated that the odds ratio of increased dependency or death was reduced at months to 0.75 Unfortunately there was a real increase in early deaths (odds ratio 1.99) and symptomatic or fatal hemorrhage (odds ratio 3.62 and 4.44 respectively) Thrombolytic agents are efficacious, but only if the correct dose and route is administered to appropriate patients Thrombolytic agents studied are either fibrinolytic (induce lysis of the fibrin clot via activation of plasmin) or fibrinogenolytic (reduce fibrinogen, the substrate for formation of the fibrin clot) Streptokinase and Urokinase are early fibrinolytic agents used with low fibrin specificity, while tissue-Plasminogen Activator (t-PA) and Pro-urokinase are newer generation agents Ancrod, synthesized from viper venom, is a fibrinogenolytic agent, with some fibrinolytic activity as well The NINDS t-PA trial was the first to demonstrate the efficacy of intravenous tissue-Plasminogen Activator (t-PA) in the setting of ischemic stroke if administered to appropriately selected patients The main exclusion criteria are treatment beyond three hours, intracranial hemorrhage on the CT, a blood pressure greater than 185 systolic or diastolic greater than 110 (or aggressive antihypertensive therapy to reach these blood pressure limits), and a minimal neurologic deficit All stroke types, less than hours, were recruited The dose of t-PA was 0.9 mg/kg bodyweight, up to a maximum of 90 mg The initial 10% dose was given as a bolus, and the remaining 90% infused over hour The results were in favor for thrombolytic treatment, where treated patients were more than 30% more likely to have mild or no neurological deficits at months, with no increase in mortality or severe strokes, despite a 10 times increase in hemorrhagic transformation Unfortunately, this positive result has not been reproduced in other thrombolytic trials with t-PA However, these trials had slightly differing criteria for recruitment In June 1996, the FDA approved the use of recombinant tissue plasminogen activator (rt-PA) for 1060 A Clinical Approach to Medicine acute (Ͻ hrs) ischemic stroke in the US Tissue-Plasminogen Activator is not licensed outside of the US for acute stroke One t-PA trials, the European Co-operative Acute Stroke Study (or ECASS I study) suggested that patients with large areas (greater than 1/3 of the middle cerebral artery territory) of ischemic damage have a higher mortality and hemorrhage risk when given t-PA Based upon the results of the ECASS study, many stroke physicians would not recommend treatment of patients with large areas of hypodensity on the baseline CT scan, even if the patients have a clearly defined time of onset of less than three hours Streptokinase has been shown to be associated with a high morbidity and parenchymal hemorrhage in recent studies It has been postulated that the negative results of streptokinase might have been related to higher relative doses of streptokinase used, the associated use of aspirin and heparin, the later time of treatment from onset, and a lack of a protocol for managing blood pressure Two other thrombolytic trials, intra-arterial Pro-urokinase in acute MCA occlusive strokes less than hours, and Ancrod in acute ischemic strokes less than hours have reported beneficial outcomes in 1999 Neuroprotective Agents Many neuroprotectant agents have been tested in Phase II and III studies None have currently been shown to be effective MANAGEMENT OF STROKE RELATED COMPLICATIONS Early deaths from stroke are usually due to neurologic causes, such as herniation from a large hemispherical infarct or hemorrhage, or brainstem ischemia or hemorrhage Subsequent deaths are typically due to medical complications, such as infection or pulmonary embolus Cerebral Herniation It is a common cause of early death in the severe stroke patient, and prevention and treatment of cerebral edema remains an elusive goal Stroke 1061 Although fluid overload is to be avoided in the early phase, there is little evidence that fluid restriction reduces the incidence of edema, indeed the resulting dehydration and hyperviscosity may exacerbate stroke Hypoosmolar fluids such as 5% dextrose should be avoided Cerebral edema typically presents on the third to fifth day post-stroke There is no evidence it will respond to corticosteroids, and their use is discouraged Treatment of symptomatic edema remains controversial Mild fluid restriction may be helpful Elevation of the head of the bed to 30Њ is advised Antihypertensive agents, that produce vasodilatation, such as nitroprusside, should be avoided In an emergency, elevated intracranial pressure can be quickly lowered by intubation and hyperventilation Reduction of CO2 by to 10 mmHg lowers intracranial pressure 25% to 30%, but the effect is short-lived Hyperventilation is usually followed by additional therapy, such as osmotic diuresis or surgery Mannitol (0.25–0.5 g/kg IV) can be administered Monitoring of electrolyte status and osmolarity is needed if several doses of mannitol are given Osmolarity should not exceed 310 mOsm Furosemide can be used as an additional diuretic with mannitol, especially if cardiac function is compromised Intracranial pressure monitoring with a subdural catheter or intraventricular catheter can help guide therapy, but its value has not been established in the stroke patient Placement of a ventricular catheter for cerebrospinal fluid drainage can relieve pressure if hydrocephalus is present Resection of large ischemic lesions can be life-saving, but may leave the patient with severe residual deficits Successful avoidance or reduction of cerebral edema remains an elusive goal for experimental stroke therapy Cerebellar infarction with edema represents a special problem requiring early diagnosis as it is eminently treatable with surgery, including relief of hydrocephalus by ventriculostomy and removal of cerebellar tissue via suboccipital craniectomy Seizure Seizure activity tends to occur early in acute stroke, with an incidence of 4–8% Most seizures are partial in onset, and status epilepticus is rare Control of seizures is usually easy following typical guidelines Prophylactic use of anticonvulsants is not helpful 1062 A Clinical Approach to Medicine GENERAL MANAGEMENT OF STROKE Death during the acute-phase hospitalization for stroke is usually from medical complications, including heart problems, pneumonia, and pulmonary emboli Preventing these complication is one of the main contributions of a dedicated stroke unit Venous thromboembolic disease appears to be uncommon in our population compared to the West Prophylactic measures include compression stockings, heparin or the low molecular weight heparins Effective prevention of deep vein thrombosis may lower the risk of developing pulmonary embolus Pulmonary embolus should be suspected in the stroke patient with sudden hypoxia, breathlessness and respiratory alkalosis in the setting of a normal chest film Infections of the lungs and urinary tracts are common Aspiration and consequent chest infections are often found in post-stroke patients and have been shown both to worsen the outcome of stroke as well as contribute to mortality after a stroke This may be due to bulbar weakness, poor conscious level, or both Patients at high risk for or with dysphagia should not be fed orally Alternative routes of feeding, such as intravenous fluids, nasogastric or feeding gastrostomy should be employed There is no demonstrated advantage of any feeding route over the other A 3-month study at our institution revealed that dysphagia was common in acute strokes, 25% of patients had dysphagia, decreasing to 12% the seventh day Large strokes (TACIs) were most likely to develop dysphagia, and the presence of dysphagia independently predicted an increase risk of poor neurologic outcome, and recurrent chest infections Bladder and bowel movements need to be regulated Urinary catheters should be avoided if possible, and intermittent catheterization is preferred if bladder drainage is needed Depression may hinder rehabilitation Although antidepressants may not reach effectiveness during the short stay of the acute hospitalization, early institution of antidepressants (especially serotonin re-uptake inhibitors such as fluoxetine) should be considered in the high-risk patient Treatment of confusion and agitation should be approached with caution, because many psychoactive drugs may retard cerebral recovery Low doses of benzodiazepines may be appropriate Stroke 1063 Proper body positioning and alignment are important aspects of care Careful attention should be paid to the effects of immobility These include joint stiffness and the potential for contractures and bed sores in the stroke patient STROKE PREVENTION Risk factors for ischemic stroke can be divided into modifiable and nonmodifiable factors Non-modifiable risks include age, genes, sex and race Although these factors cannot be modified, their identification helps to predict those at risk, and more aggressive treatment of risk factors that can be modified Secondary Prevention of Stroke Antiplatelet agents There are a number of antiplatelet agents available Aspirin acts on the enzyme, Cyclo-oxygenase, irreversibly inhibiting the production of the potent vasoconstrictor and platelet activator, Thromboxane A Ticlopidine and clopidogrel are chemically related thienopyridine derivatives Both drugs selectively, and irreversibly inhibit ADP-induced platelet aggregation These drugs have long lasting effect, platelet aggregation and bleeding time require 4–8 days to return to baseline Dipyridamole is a phosphodiesterase inhibitor with vasodilatory effect as well Aspirin is the most well-studied drug, and its effectiveness welldemonstrated The optimal dose is still not clear, doses from 30 mg to 1300 mg have been shown to be effective, though at higher doses, side effects involving especially the gastrointestinal system was common Patients with stroke or TIA have an annual risk of stroke of 5–10% In the Antiplatelet Trialist Collaboration, the risk of non-fatal stroke is reduced by 23%, and vascular death by 14% However, cumulative evidence from aspirin trials alone, suggest that the benefit on vascular death, non-fatal strokes and myocardial infarcts offered by aspirin may be lower, about 13% Ticlopidine has been compared with aspirin, and even though there was a 6% relative risk reduction in favour of ticlopidine, the confidence intervals were large Furthermore, patients on ticlopidine experienced more adverse effects, in particular diarrhea 1064 A Clinical Approach to Medicine and skin rashes Neutropenia was also seen in up to 2%, and the usage of ticlopidine mandates regular blood count monitoring in the first months The second European Stroke Prevention Study (ESPS-2) demonstrated that 400 mg daily of dipyridamole was as effective as low dose (50 mg) aspirin daily The combination of these drugs had a synergistic effect in stroke prevention These results have been questioned as dipyridamole was not shown to be an effective drug in earlier studies, however, such high doses as those in ESPS-2 were not studied The CAPRIE Study showed that clopidogrel 75 mg was slightly more effective than 325 mg of aspirin a day in preventing the combined outcome of ischemic stroke, myocardial infarction and vascular death An absolute difference of 0.5% was found, i.e for every 1000 patients treated, clopidrogrel would prevent events more than aspirin Clopidogrel has a good safety profile as compared against aspirin and ticlopidine, however, it is quite costly The newer glycoprotein IIb/IIIa receptor blockers block the final common pathway of platelet aggregation The safety and efficacy of these drugs in ischemic strokes have still to be established The choice of secondary stroke prevention with aspirin alone, aspirin and dipyridamole, ticlopidine or clopidogrel would be dictated by patient’s tolerance to these drugs, the availability and costs of these drugs Blood pressure control While there are no large trials on management of blood pressure in the setting of an acute stroke, several recent trials have demonstrated a beneficial effect for treating blood pressure in patients with previous stroke, even in those who not have hypertension Rashid et al performed a meta-analysis on the effect of blood pressure lowering in stroke patients Seven randomized trials with over 15 000 patients using mainly angiotensin converting enzyme inhibitors (ACE), diuretics or betablockers were analyzed There was a significant benefit in reducing recurrent strokes and myocardial events, with no benefit seen in vascular mortality Two trials, Post-stroke Antihypertensive Treatment Study (PATS) and Perindorpil Protection Against Recurrent Stroke Study (PROGRESS), contributed two-thirds of the data These trials used either an ACE or a diuretic In PROGRESS, treatment also appeared more effective in Asian patients and patients with hemorrhagic strokes Stroke 1065 Lipids Previous trials using non-statin drugs (such as fibric acid derivatives) did not show a reduction in the incidence of stroke The recent statin trials in patients with cardiovascular disease revealed that long-term statin therapy substantially reduced the risk of recurrent cardiovascular events, including first ever stroke (primary prevention of stroke) The beneficial effect of statin in stroke patients was confirmed when the Heart Protection Study was published in 2000 Twenty thousand patients were recruited, 65% of patients had established coronary heart disease and 16% had prior stroke Patients received up to 40 mg of simvastatin daily Statin treatment led to a 24% reduction in relative risk of major vascular events and a 25% reduction in relative risk of ischemic stroke The benefit was seen in stroke patients with and without any coronary heart disease However, this reduction was all attributed to lowered coronary events without an apparent decrease in stroke recurrence (secondary prevention of stroke) There were less carotid revascularization procedures (endarterectomy or carotid stenting) with statin therapy This landmark paper showed that long-term statin therapy was beneficial in stroke patients There are ongoing trials to determine if statin therapy in stroke patients will lead to a reduction in recurrent strokes Anticoagulation For patients with a stroke or TIA who have atrial fibrillation, congestive heart failure, or another clear cardiac cause of ischemic stroke, warfarin remains the first choice unless contraindicated An INR (International Normalized Ratio) of 2–3 is aimed for, except for prosthetic valves, where 3–4 is more appropriate The role of anticoagulation in patients with ischemic stroke of noncardiac source has not been demonstrated Carotid endarterectomy The efficacy of carotid endarterectomy for patients with non-disabling stroke or TIA (within the last months) and an ipsilateral carotid stenosis that is greater than 70% is well documented in large trials The risk of stroke over years, in the surgical was 9%, compared with 26% in the medical group Mild to moderate carotid stenosis (0–50%) had no benefit, 1066 A Clinical Approach to Medicine the risk of stroke was low and any benefits of surgery was outweighed by the early peri-operative risk For those with 50–69% stenosis, there was moderate benefit Over years, the surgical arm had 15.7% stroke while the medical arm had 22.2%, giving an absolute risk reduction of about 6.5% The risk of peri-operative complications are dependent upon the surgeon’s skills, in the North American study (NASCET), the overall perioperative stroke and death was 6.5%, 1.1% were deaths, 1.8% disabling strokes and 3.7% non-disabling stroke The effect of carotid endarterctomy was durable over years The risks of surgery are increased in the presence of hemispheric TIA, contralateral carotid occlusion, ulcerated plaque, lesion imaged on CT or MR on the symptomatic side and left sided procedure The most common peri-operative medical complication was myocardial infarct Endarterectomy was 1.5 times more likely to trigger medical complications if patients had history of myocardial infarct, angina or hypertension The benefit is seen more for men than women For women there is no benefit if the stenosis is less than 70% and for men when it is less than 50% Angioplasty and stenting Percutaneous transluminal angioplasty (PTCA) and intravascular stenting of the extracranial vessels are being examined for safety, efficacy, and long-term durability as an alternative to carotid endarterectomy and other revascularization procedures PTCA of intracranial vessels (carotid, middle cerebral artery stem, vertebral artery, and basilar artery) has also been performed in a small number of symptomatic patients refractory to maximal medical treatment While technically feasible, procedure-related stroke and death rates have been substantially higher than for patients undergoing extracranial procedures Both extracranial and intracranial PTCA (with or without stenting) are considered investigational, as they have not been fully evaluated in clinical trials Primary prevention of stroke Ideally, the prevention of a first stroke is better than the prevention of a recurrent stroke The National Stroke Association issued a consensus in 1999, identifying hypertension, myocardial infarct, atrial fibrillation, diabetes, hyperlipidemia, symptomatic severe carotid stenosis, and Stroke 1067 life-style factors (smoking and excessive alcohol use) as modifiable primary preventive risk factors which would make an impact on first ever stroke if controlled because of their prevalence Hypertension is the most prevalent and modifiable risk factor for stroke It is more prevalent in the elderly A 1998 survey in Singapore revealed that 27% of the population aged between 30–69 years old are hypertensive by WHO criteria (blood pressure у 140 systolic or у 90 diastolic) The relative risk of hypertension for stroke is as high as times While the prevalence of hypertension increases with age, the impact of hypertension may decrease with age The odds ratio for stroke is at 50, and decreases to at 90 years Studies have shown that with appropriate treatment, risk of strokes may be reduced by about 40%, irrespective of age Screening for hypertension in elderly patients, and regular monitoring for good control is recommended Up to 3% of acute myocardial infarcts will develop stroke, the risk increases to 6% in those with anterior wall infarctions The risk is greatest in the first month (30%) Most of these strokes are thought to be embolic, from intracardiac clots, but some strokes are probably due to co-existing cerebral atherosclerotic disease and cardiac hemodynamic factors The risks for developing intraventricular clots are higher in large myocardial infarcts and congestive cardiac failure Anticoagulation, to a target INR (International Normalized Ration) of 2.0 to 3.0 has been shown to reduce embolic strokes in patients at high risk for cardiac embolism (poor left ventricular function, atrial fibrillation and intracardiac clots) Atrial fibrillation may occur in the setting of acute myocardial infarction, and is an independent risk factor Unlike hypertension, the impact of atrial fibrillation persists with increasing age Atrial fibrillation in association with mechanical valves, mitral stenosis, intracardiac clots and dilated left ventricles predicts a high risk of stroke Non-valvular atrial fibrillation (NVAF) is also an important risk factor for stroke The SPAF studies also identified elderly patients (Ͼ 75 years) with previous thromboembolism, hypertension and congestive cardiac failure as high risks, with stroke rates at approximately 20% per year Paroxysmal atrial fibrillation appears to have as great a risk as constant atrial fibrillation Anticoagulation is generally more effective than antiplatelet therapy in preventing stroke, warfarin reduces stroke by up to 70%, and aspirin by 21%, even after considering the hemorrhagic risks involved An INR of 2.0 to 4.0 (higher ranges for mechanical valves) is recommended In 1068 A Clinical Approach to Medicine younger patients, less than 65 years of age with no high risks, the annual stroke rate is low, about 1% Warfarin or aspirin may be considered for such patients In the past, the relationship between lipids and stroke was not clear Many primary prevention trials of cholesterol lowering with statins (hydroxyl methylglutaryl coenzyme A reductase inhibitors ϪHMG CoA reductase inhibitors), mainly in patients with coronary arterial disease, have revealed risk reduction in stroke about 30–40% This was not shown with other cholesterol lowering agents It is postulated that the beneficial effects of statins may involve non-lipid mechanisms, such as plaque stabilization, modification of inflammatory responses, and thrombus formation The beneficial effect of statins to prevent stroke recurrences in stroke patients without coronary disease has not been demonstrated yet In a 1998 survey, 9% of Singaporeans were found to have diabetes mellitus, and 15% with impaired glucose intolerance by WHO criteria The older population (above 40 years old) and Indians were more commonly affected Epidemiological data suggests that the relative risk of stroke in diabetics is increased 1.5 times, and studies have shown that tight glycemic control reduces microvascular complications such as neuropathy, retinopathy and nephropathy, but the effect on macrovascular complications like stroke is not so clear Guidelines have been established for management of diabetes The risk of stroke in asymptomatic carotid stenosis ranges from 2–5% In the Asymptomatic Carotid Atherosclerosis Surgery (ACAS) trial, patients with 60–99% stenosis who were randomized to endarterectomy had an absolute risk reduction of stroke of 5.9% over years compared with medical treatment The trial used ultrasound screening only to detect carotid disease, to avoid the 0.5–1% risk of stroke with cerebral angiography The trial surgeons also had very low operative complication rates The prevalence of asymptomatic carotid stenosis in Singapore is not known, though our experience in this hospital has been that symptomatic carotid stenosis is uncommon, and one may extrapolate (though it may not be accurate) to presume that asymptomatic disease is uncommon Mass screening for asymptomatic carotid disease is not cost-effective currently Furthermore, because of the low annual risk of stroke with asymptomatic disease, and the mild benefit with endarterectomy, which could easily be negated with higher surgical complication rates (in ACAS, stroke and deaths was 1.5%), surgery for asymptomatic disease is not Stroke 1069 routinely advocated With symptomatic severe carotid stenosis, endarterectomies can prevent stroke in years In asymptomatic patients, 67 endarterectomies are required to prevent stroke Life-style factors such as smoking, excessive alcohol use and sedentary life have been shown to be associated with stroke Studies reveal that the relative risk of stroke for smokers is 1.5 times, and increases with heavy smokers Even passive smokers are affected A J-shaped relationship exists between alcohol use and stroke, with the risk of ischemic and hemorrhagic stroke being lowest in mild to moderate drinkers Alcohol may exert a protective influence on coagulopathy and lipids Heavy consumption is associated with higher risks of stroke Regular exercise (at least 3–5 times weekly) has well-established benefits for prevention of cardiovascular disease Table Risk Factors for First Ischemic Stroke Well-documented, modifiable risk factors Transient ischemic attack Asymptomatic carotid stenosis Hypertension Cardiac disease • Atrial fibrillation • Infective endocarditis • Mitral stenosis • Recent large myocardial infarct Cigarette smoking Sickle cell disease Less well-documented risk factors Cardiac diseases • Cardiomyopathy • Segmental wall motion abnormalities • Non-bacterial endocarditis • Mitral annular calcification • Mitral valve prolapse • Valve strands • Aortic stenosis • Patent foramen ovale and atrial septal aneurysm • Spontaneous echocardiographic contrast Well-documented, potentially modifiable risk factors Diabetes mellitus Hyperhomocysteinemia Left ventricular hypertrophy Non-modifiable risk factors Age Gender Race Hereditary factors • • • • • • • Hyperlipidemia Oral contraceptives Excessive alcohol Physical inactivity and obesity Elevated hematocrit Hyperinsulinemia Migraine 1070 A Clinical Approach to Medicine REHABILITATION AND DISCHARGE PLANNING Early institution of rehabilitation efforts, including language, swallowing, physical, and occupational therapy is advised by expert consensus, rather than based on proven data Early mobilization of patients can reduce the incidence of deep vein thrombosis and aspiration pneumonia Whether a delay in the institution of rehabilitation therapies reduces the level of recovery has not been proven Patient and family education about stroke, recovery, and prevention are important components of the rehabilitation process Ideally, discharge planning should begin on the day of admission and should incorporate a consensus from all involved persons The specifics of discharge planning will depend on the extent of neurologic deficit or involvements the patient experiences Accurate assessment of cognitive and functional abilities is important in determining how dependent the patient will be at discharge and what resources will be necessary to employ at discharge Cognitive assessment should include these key aspects: attention, orientation, memory, language, reasoning, judgment, spatial skills, motor coordination, and social skills Depression is the major emotional disturbance seen post-stroke Early recognition of depression is important when assessing a patient’s motivation for rehabilitation and recovery Functional status includes aspects of cognition, but also includes physical motor function, mobility, speech and language function, and measures of activities of daily living All of these aspects are crucial to stroke survivors to help them become integrated into a functional family and social life 62 Parkinson’s Disease: Diagnosis and Treatment Tan Eng King and John Thomas INTRODUCTION Parkinsonism is manifested by a combination of the following five main features, namely rest tremor, rigidity, bradykinesia, loss of postural reflexes and freezing phenomenon.1,2 Parkinson’s Disease (PD), an idiopathic and commonest form of parkinsonism is a progressive neurodegenerative disease characterized by loss of dopaminergic cells in the substantia nigra pars compacta and presence of Lewy bodies It affects predominantly the elderly population The mean age of PD patients seen in tertiary referral centers in Singapore was about 65 years old, similar to reports in many countries With the advancing age of the population, the prevalence of the disease will increase The mortality is to times as high among affected persons compared to age-matched controls In fact, neurodegenerative diseases (PD, motor neuron disease and dementia) are projected to surpass cancer as the second most common cause of death among the elderly by the year 2040 in the United States.3 This projection is relevant to many countries in Asia due to rapidly aging population 1071 1072 A Clinical Approach to Medicine In the West, the prevalence of PD is estimated to be approximately : 1000, and annual incidence around : 10 000.4 The exact prevalence of PD in Singapore is not known, but estimated to be around : 2000 In a survey in Singapore General Hospital, we found about 800 admissions involving 500 PD or parkinsonism patients over a 2.5-year period GENE/ENVIRONMENTAL ETIOLOGY The relative role of genetic and enviromental factors in the pathogenesis of Parkinson’s disease (PD) has been the focus of research and debate.5 The discovery of MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)induced Parkinsonism in intravenous drug users6 led to numerous epidemiologic studies evaluating potential enviromental causative agents, though no specific agent has thus far been identified Studies of genetic polymorphisms of candidate genes have thus far been inconclusive.7–9 Eight gene loci have been identified by linkage analysis on human chromosome 4q21-23 (PARK 1), 6q25-27 (PARK 2), 2p13 (PARK 3), 4p15 (PARK 4), 4p13 (PARK 5) and more recently 1p35-p36 (PARK 6), 1p36 (PARK 7) and 1p (PARK 8) In 1997, Polymeropoulos et al.10 found a missense mutation A53T in the alpha-synuclein gene in a family with autosomal dominant (AD) mode of inheritance for parkinsonism This mutation was subsequently found in other families, all were of Greek and Southern Italian origin In 1998, Kruger et al.11 described a second mutation A30P in the same gene in a German family However, these mutations were not found in sporadic and most familial PD patients, indicating that these are extremely rare A mutation in the ubiquitin carboxy-terminal hydroxlase gene on 4p13 has also been identified in a family with AD inheritance Autosomal recessive parkinsonism was initially described in Japanese families While they manifest typical signs of PD, they tend to be associated with young age of onset, diurnal fluctuations, dystonia, early but severe levodopa-induced dyskinesias, and slow progression of disease Neuropathological features thus far did not show any Lewy bodies, a hallmark of PD In 1997, investigators mapped the locus to chromosome 6q25.2-27 (PARK 2) in consanguineous Japanese families Subsequent linkage analysis found non-Japanese PARK families in Europe, the United States, and the Middle East In 1998, Kitada et al.12 from Juntendo University, Tokyo, identified homozygous deletions of exon or Parkinson’s Disease 1073 exons 3-7 of the Parkin gene in Japanese families with autosomal recessive parkinsonism DIAGNOSIS A definite diagnosis of PD can only be made pathologically A clinical diagnosis can frequently be made if a patient presents with ipsilateral rest tremor, bradykineisa and rigidity, and these symptoms and signs progress to involve the contralateral side, and the patients respond well to levodopa However, even amongst specialists, misdiagnosis rate can be as high as 12.5% In addition to motor dysfunction, PD patients may develop neuropsychological complications such as depression and dementia Hallucinations or confusion are usually associated with later stages of the disease and with use of high doses of levodopa or other anti-parkinsonian medications In a preliminary study, we found 26% and 16% of our PD patients exhibit depression and impaired cognition respectively Other seldom emphasized problems include autonomic dysfunction manifested by urinary or bowel disturbances and impotence DIFFERENTIAL DIAGNOSIS A high index of suspicion is required to exclude treatable secondary causes in all patients who present with parkinsonism (Table 1) It is important to take a history of encephalitis, exposure to heavy metals and toxins, taking of anti-psychotic medications (e.g neuroleptics) On clinical examination, one should particularly assess for the presence of Kayser–Fleischer Ring (Wilson’s disease), supranuclear gaze abnormality (supranuclear gaze palsy), postural hypotension, pyramidal tract signs, cerebellar signs (multiple system atrophy), dementia (dementia of Lewy body), limb apraxia (cortico-basal ganglionic degeneration) If there is predominantly lower body parkinsonism, no tremor, brisk reflexes, and imaging showed microvascular ischemic changes in the subcortical region or basal ganglia, “vascular parkinsonism” is a likely diagnosis Recently, familial spinocerebellar ataxias have been found to present with pure parkinsonism Essential tremor (ET) is manifested by postural tremor involving the limbs, head, trunk and voice, with no bradykinesia and rigidity 1074 A Clinical Approach to Medicine Table Causes of Parkinsonism 1) Idiopathic Parkinson’s disease 2) Secondary parkinsonism Drugs (e.g neuroleptics) Heavy metals and toxins (e.g copper, iron, manganese, carbon dioxide) Infections (e.g encephalitis) Vascular (e.g multi-infarcts) Others (e.g head trauma) 3) Parkinson’s-plus syndromes Progressive supranuclear gaze palsy Multiple system atrophy Cortico-basal ganglionic degeneration Dementia of Lewy body Others (e.g familial spinocerebellar ataxia, etc.) INVESTIGATIONS There is generally little need for investigations in typical PD patients to establish the diagnosis However, if there are suggestions of secondary causes of parkinsonism in history and examination, checking for ceruloplasmin, thyroid function, toxicology studies, imaging (Magnetic Resonance Imaging), electrophysiologic and neuropsychological testings may be warranted Functional imaging studies (e.g Positron Emission Tomography) may be useful to detect asymptomatic cases, monitor progress after PD transplant surgery, and assist in diagnosis in some patients MEDICAL TREATMENT The replacement of dopamine deficiency forms the fundamental basis of drug treatment in PD Pharmacologic therapy is only initiated if activities of daily living are affected Levodopa remains the cornerstone of drug treatment in PD.1,13 It is usually prescribed in combinations with a decarboxylase inhibitor (which prevents the peripheral breakdown of levodopa so that more can be available in the brain) in the form of Madopar® or Sinemet® Slow release formulations such as Madopar HBS® and Sinemet CR®, and fast release formulation, Madopar Dispersible® are also available Due to the disabling complications as dyskinesias and motor fluctuations associated with long-term levodopa use, it is prudent to delay the use of Parkinson’s Disease 1075 Table Drugs for Parkinson’s Disease Patients 1) Levodopa 2) Dopamine agonists 3) Catechol-O-methyltransferase inhibitors 4) 5) 6) 7) 8) Monoamine oxidase inhibitors Anti-cholinergics NMDA receptor anatagonist Anti-oxidants Anti-depressants Ergots Bromocriptine Pergolide Carbergoline Lisuride Non-ergots Pramipexole Roprinole Piribedil Apomorphine Entacapone Tolcapone Selegiline Benzhexol Amantadine Vitamins A, C, E Ttricyclics (e.g amitrptyline) SSRI (e.g fluoxetine) 9) Muscle relaxants 10) Laxatives this drug This is especially so in the younger group of patients Should levodopa be started, it is advisable to step up the dose gradually to a minimal dose which can produce maximal results with little side-effects For instance, Madopar® is prescribed at 62.5 mg twice a day and subsequently over days or weeks A course of levodopa up to 1–2 g/day may be needed before one can conclude that patient has no response to the drug Regular checking for postural hypotension and adjusting the timing of levodopa to reduce nausea and vomiting may be required Domperidone, given half an hour before levodopa is useful in overcoming gastrointestinal symptoms associated with levodopa Prescribing levodopa at a lower dosage but at more frequent intervals can alleviate levodopa-induced dyskinesias Wearing off periods can be reduced with the longer-lasting levodopa formulations Dopamine agonists (DA) have been shown to be effective as monotherapy in early stages of PD and as an adjunctive treatment to levodopa in advanced PD.13 While DA are less effective than levodopa in the symptomatic treatment of advanced PD, they are increasingly used early, particularly in young-onset PD because of their levodopa sparing effects 1076 A Clinical Approach to Medicine and their putative role as neuroprotective agents Whether DA are comparable to levodopa in early PD is currently being investigated Recent published trials comparing the ropinirole and pramipexole monotherapy with levodopa suggest that the risk of dyskinesias is less with the DA than with levodopa, but motor improvement is more robust with levodopa monotherapy than with the DA agonists DA agonists directly activate dopamine receptors, bypassing the presynaptic synthesis of dopamine There are two main classes of dopamine receptors: the D1 class (comprised of subtypes D1 and D5), linked to the enzyme adenylate cyclase, and the D2 class (comprised of subtypes D2, D3, and D4), coupled to G proteins that inhibit adenylate cyclase Bromocriptine, an ergot compound, was the first to be introduced more than 25 years ago Currently there are a number of DA available including ergots such as pergolide, lisuride and cabergoline, and nonergots such as piribedil, apomorphine, ropinirole, and pramipexole Bromocriptine and pergolide are frequently referred to as “old” DA, and pramipexole and ropinirole as “new” DA, simply because the latter two DAs have only been introduced in the market in recent years, and are still not available in many countries, particularly in Asia Recently, hypersomnolence in the form of “sleep attacks” was a concern for patients on the non-ergots (e.g pramipexole) However, subsequent studies suggest that this adverse effect is likely a class effect.14 Other potential complications with DA therapy include nausea, postural dizziness, hallucinations, retroperitoneal fibrosis, and peripheral edema.15 Tolcapone and Entacapone, both catechol-O-methyltransferase (COMT) inhibitors, extend the action of levodopa by preventing its breakdown They are used in conjunction with levodopa and effective for patients who develop motor fluctuations Side-effects include worsening of the dyskinesias associated with peak doses of levodopa, hypotension, constipation and urine discoloration Fatal cases of liver toxicity have been reported with Tolcapone and hence monitoring of liver function is recommended for this drug Amantadine, a NMDA receptor antagonist has been demonstrated to be effective for levodopa-induced dyskinesias Selegiline, a monoamine oxidase inhibitor is frequently used in early stages of the disease It has been suggested that it may have neuroprotective potential and helps delay the introduction of levodopa Anti-cholinergics (such as benhexol) are used for tremor and rigidity However, they have to be used with Parkinson’s Disease 1077 caution, especially in the elderly as they can cause confusion, cognitive impairment, and hallucinations They can also aggravate constipation, urinary retention and lead to an increase intraocular pressure Anti-depressants such as selective serotonin reuptake inhibitor (SSRI) and tricyclics compounds are useful to treat depressive symptoms in PD However side-effects like acute dystonia, akathisia, and aggravation of parkinsonism may occur in some patients Putative neuroprotective agents such as vitamin E or other anti-oxidants are also frequently used by some physicians, though their therapeutic effect in PD has not been proven It cannot be overemphasized that physiotherapy, speech therapy, psychotherapy are important in a number of patients Support from family members, caregivers and friends, and participation in educational programs provide the necessary social framework to support the medical care by the physicians SURGICAL TREATMENT Surgery for Parkinson’s disease is enjoying a significant renaissance around the world We are now in a position to significantly improve the lives of the patients who are worst afflicted by the disease, in whom medical therapy has reached its limits, who would previously have been confined to their beds and left to die There are several reasons for this renewed interest 1) The widespread recognition that there are limits to the benefits of medical treatment in many patients with the disease Problems arise from declining response to medication with time, from unpredictable responses such as on-off phenomena and from side-effects of medication such as dyskinesias 2) The vast improvement in our understanding of the pathophysiology in the circuitry of the basal ganglia that underlie many of the symptoms of Parkinson’s disease 3) The fantastic improvement in MRI brain imaging that allows us to visualize the many component subnuclei in the basal ganglia that are involved in the disordered circuits This makes it possible to target these subnuclei 4) The significant advancement in neurosurgical technical accuracy and safety that arose with the introduction of computer workstations for surgical planning 1078 A Clinical Approach to Medicine There are two standard approaches in the surgical treatment of Parkinson’s disease The traditional approach is to silence the subnuclei that are hyperfunctioning by destroying them with heat (thermocoagulation) The alternative approach achieves the same result by depolarizing the relevant subnuclei with high frequency stimulation (deep brain stimulation) The main targets of surgery are the subthalamic nucleus (STN), the medial globus pallidus (GPi) and the ventrointermediate nucleus (Vim) of the thalamus, which are very closely related anatomically and physiologically Intervention in the STN and GPi improves the symptoms of tremor, rigidity and bradykinesia contralaterally Drug induced dyskinesias are also significantly improved Interruption of the Vim nucleus of the thalamus mainly reduces contralateral tremor by 80% The surgical target is decided upon after careful study of the patient’s symptoms by the movement disorder team Bilateral problems will require bilateral surgery Post-surgery the patient ideally will achieve his best on-drug performance with less medication, spend about 70–80% of the day at this maximum performance status without significant on-off phenomena and be free of drug-related dyskinesias This usually translates to a very significant improvement in their independence and quality of life In choosing between thermocoagulation and deep brain stimulation (dbs), the usual considerations are: 1) Thermocoagulation lesions are irreversible once made The effects of dbs are scalable with the amount of current delivered This applies to the desired effects as well as the unwanted effects of surgery 2) Bilateral surgical destructive lesions (thermocoagulation) can pose special problems because of the increased incidence of unwanted side-effects such as speech, swallowing and cognitive deficits These problems can be avoided by using dbs 3) Thermocoagulation lesions are maintenance-free once made They are relatively “low-tech” Optimization of stimulation parameters after dbs placement is labor intensive and requires frequent doctor visits About 10–20% of dbs patients may face problems related to wire-breakage or disconnection DBS patients will also face the cost of the implants and the need to replace the batteries every 3–5 years For patients in Singapore deep brain stimulation is usually the better choice Thermocoagulation best serves patients who live far away from the tertiary medical centers and those in third-world countries Parkinson’s Disease 1079 Patients selection for surgery is a delicate task The patients will have been on follow-up for some time with the movement-disorder clinic and will have been tried on a number of drugs Those selected for surgery will, in general, satisfy the following criteria: 1) They will have clinically confirmed Parkinson’s disease 2) They will have disabling symptoms despite maximal medical therapy However they should be medication responsive and not bedridden 3) They will not be suffering from severe dementia 4) They will have normal MRI brain studies 5) They will not have any significant concurrent medical illness 6) They will have given informed consent to surgery Prior to surgery there will be a period of detailed inpatient assessments where the patient’s functional status while on medication and off medication is objectively documented on validated scoring systems Video-recordings of these assessments are made to allow pre- and post-op comparisons as well as blinded assessments The surgery is performed under local anesthesia using stereotactic neurosurgical techniques The surgical team will include the movement disorder neurologist treating the patient The patient will have been off medication for at least 12 hours prior to surgery The patient will be mildly sedated, but able to speak and perform movements during the operation The placement of the surgical probe in the correct nucleus is confirmed by recording the electrical activity of the nucleus in response to joint movement (both active and passive) and by the clinical effect of electrical stimulation delivered to the target The surgery is safe with an overall risk of adverse outcome in the region of 2–4%, which includes both minor and major complications (which include paralysis, vegetative survival and death) The complications can be divided into those related to general risks of stereotactic procedures as well as the general medical risks of patients undergoing surgery Most patients tolerate surgery extremely well The usual patient will be ambulant the day after surgery The hospital stay is usually 3–4 days The beneficial effects of lesion surgery are apparent immediately postoperation If deep brain stimulators are placed the stimulation is usually turned on a couple of weeks after surgery to allow objective assessment in the outpatient clinic The patient’s medical therapy will be modified once the stimulation parameters have been optimized 1080 A Clinical Approach to Medicine Patients with advanced Parkinson’s disease are now in a much better position than they were even 10 years ago The combination of new medications and effective surgical therapy can deliver them from the fate of immobility, invalidism and an early death REFERENCES Jankovic J, Marsden CD, Therapeutic Strategies in Parkinson’s Disease, in Jankovic J, Tolosa E (eds.), Parkinson’s Disease and Movement Disorders, 3rd ed., Williams & Wilkins, Baltimore, pp 191–220, 1998 Tan EK, Parkinson’s disease surgery: advances and future strategies, Int J Clin Pract 53:623–626, 1999 Lilienfield DE, Perl DP, Projected neurodegenerative disease mortality in the United States, 1990–2040, Neuroepidemiology 12:219–228, 1993 Ben–Shlomo Y, Sieradzan K, Idiopathic Parkinson’s disease: epidemiology, diagnosis and management, Brit J Gen Pract 45:261–268, 1995 Langston JW, Epidemiology versus genetics in Parkinson’s disease: progress in resolving an age old debate, Ann Neurol 4(3suppl1): S45–52, 1998 Langston JW, Ballard P, Tetrud JW, Irwin I, Chronic parkinsonism in humans due to a product of meperidine-analog synthesis, Science 219:979–980, 1983 Tan EK, Khajavi M, Thornby I, Nagamitsu N, Jankovic J, Ashizawa T, Variability and Validity of Polymorphism Association Studies in Parkinson’s disease, Neurology 55:533–539, 2000 Tan EK, Nagamitsu S, Matsuura T, Khajavi M, Jankovic J, Ondo W, Ashizawa T, Alcohol dehydrogenase polymorphism and Parkinson’s disease, Neurosci Lett 305(1):70–72, 2001 Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T, Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology 54:1195-1198, 2000 10 Polymeropoulos MH, Lavedan C, Leroy E, et al., Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease, Science 276:2045–2047, 1997 11 Kruger R, Kuhn W, Muller, et al., Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease, Nat Genet 18:106–108, 1998 12 Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, et al., Mutations in the Parkin gene cause autosomal recessive juvenile parkinsonism, Nature 392:605–608, 1998 13 Tan EK, Jankovic J, Choosing dopamine agonists in Parkinson’s disease, Clin Neuropharmacol 24:247–253, 2001 Parkinson’s Disease 1081 14 Tan EK, Lum SY, Fook–Chong SM, Teoh ML, Yih Y, Tan L, Tan A, Wong MC, Evaluation of somnolence in Parkinson’s disease: comparison with age- and sex-matched controls, Neurology 58:465–468, 2002 15 Tan EK, Ondo W, Clinical characteristics of pramipexole-induced peripheral edema, Arch Neurol 57:729–732, 2000 This page intentionally left blank 63 Alzheimer’s Disease and Other Dementias Alexander P Auchus and Christopher Chen DEMENTIA Dementia is a clinical syndrome defined by an acquired and persistent loss of intellectual function severe enough to interfere with social or occupational functioning Dementia generally involves global or multifocal impairment of higher brain functions, affecting memory (amnesia), language (aphasia), visuospatial and visuoconstructive abilities, skilled motor coordination (apraxia), abstraction, judgment, insight, personality, and other functions to variable extents Dementia is to be distinguished from mental retardation in that it is acquired, and from delirium in that it is usually persistent and accompanied by a normal level of alertness Dementia is also distinguished from syndromes of focal higher brain dysfunction, such as aphasia or agnosia Although certain cognitive changes occur with advancing age, dementia is not a normal consequence of aging It is estimated that about 5–10% of population over age 65 in the United States are demented This figure rises to at least 25% to 30% by age 85, and some studies even suggest a prevalence of almost 50% by this age Dementia is an expensive 1083 1084 A Clinical Approach to Medicine condition The annual cost for care of dementia victims in the US tops US$30 billion The increasing percentage of elderly in the population, coupled with the high costs of caring for demented patients, will make dementia an even more devastating medical, social, and economic problem in the near future The etiologies of dementia are many Alzheimer’s disease accounts for over half of cases in most series from developed countries (USA, Canada, United Kingdom, Western Europe, Scandinavia) Vascular dementia (formerly termed “multi-infarct dementia”) is usually the next most common etiology Vascular dementia may be more common in Asia than in the West Other etiologies include metabolic disorders (chronic renal, hepatic, pulmonary, or cardiac failure), toxic disorders (especially iatrogenic), nutritional disorders (B-1, B-12, folate deficiencies), alcoholism, movement disorders (Parkinson’s, Huntington’s, Wilson’s), psychiatric disease (especially depression), hydrocephalus, chronic subdural hematoma, traumatic brain injury, anoxic brain injury, CNS infections (including HIV), and CNS neoplasms (metastases, glioma, meningioma) Treatable causes of dementia are found in 20% of patients under age 65, as opposed to only 5% over age 65 Depression is also common among the elderly, and disturbances of thinking and memory frequently accompany depression Detecting dementia may be difficult, especially in the higher functioning patient Though some families may deny even gross cognitive changes in their relatives, history from family and close friends usually provides the most reliable data on the patient’s cognitive status.1,2 Inquiries into how patients spend their day, whether any previously independent tasks have had to be subsumed by others (such as shopping, managing personal finances, and driving) are essential aspects of the history in a patient suspected of having dementia Consideration should also be given to complaints of anxiety, low mood, and to vegetative signs of depression (loss of appetite, loss of libido, and sleep disturbance) A careful neurologic examination and mental status examination are also essential and may uncover relevant findings For example, a dementia characterized by impairments in memory, language, and praxis, without any abnormal motor findings is most commonly due to Alzheimer’s disease In contrast, a patient with forgetfulness, slowing of mental processes, as well as the presence of extrapyramidal signs (e.g rigidity, bradykinesia) suggests Parkinson’s disease, another movement disorder, Alzheimer’s Disease and Other Dementias 1085 or hydrocephalus Dementing illnesses due to metabolic and toxic processes are often accompanied by neuropathy Vascular dementia is usually associated with asymmetric pyramidal findings (such as increased deep tendon reflexes, hemiparesis, Babinski signs) and a stepwise deteriorating course Rapidly progressive dementias suggest the possibility of infectious etiologies, including Creutzfeldt–Jakob disease Since precise diagnosis is essential for guiding treatment options and family counseling, referral to specialty clinics should be considered ALZHEIMER’S DISEASE Alzheimer’s disease is the most common cause of dementia worldwide The age of onset in AD is frequently the early seventies The memory disturbance begins insidiously, affecting short-term or recent memory (e.g orientation, news events, etc.) and, to a lesser extent, remote memory The patient has increasing difficulty with activities of daily living, and changes in personality often develop — apathy being most common Impairment of higher cortical function occurs either early or late in the course, though each modality is not affected equally Language dysfunction begins with word-finding and naming difficulties, and progresses to fluent aphasia with impaired comprehension Visuospatial dysfunction is manifest by spatial disorientation Motor signs develop late, with the variable appearance of extrapyramidal rigidity, gait impairment, frontal release signs, and spasticity with hyperreflexia Myoclonus, or rarely seizures, may develop late in the course Behavioral problems commonly arise during the course of AD and include delusions, hallucinations, affective disturbances, personality changes, anxiety, agitation, aggression, wandering, sleep-wake cycle disruption, and catastrophic reactions Electroencephalography (EEG) may be normal but will frequently reveal a diffuse slowing down The CT or MRI also may be normal or may show diffuse cortical and hippocampal atrophy The brain weight is usually low with marked atrophy of the temporal, parietal, and frontal lobe cortices, and particularly the hippocampal formation Involvement of the association areas is most marked, with sparing of the primary motor, sensory, and visual cortex The ventricles are usually dilated (hydrocephalus “ex vacuo”) Hallmark pathological findings in AD include neurofibrillary tangles (NFT) and senile plaques (SP) in association with loss of neurons and synapses NFT are abnormal 1086 A Clinical Approach to Medicine accumulations of twisted neurofibrils known as paired helical filaments composed of a hyperphosphorylated form of the tau protein SP are spherical structures composed of degenerating neurites surrounding a central core of amyloid The amyloid core consists primarily of insoluble deposits of a 42 amino acid peptide, derived from a larger amyloid precursor protein In addition, amyloid deposition is found in the blood vessels (“amyloid angiopathy”) of the meninges and cortex While small numbers of SP and NFT are seen in the hippocampus and cortex in normal aged brains, in AD they are more numerous and widespread They occur predominantly in the frontal, temporal, and parietal cortex and in the hippocampus and amygdala Outside of cortex and hippocampus, select subcortical nuclei are also critically affected The nucleus basalis of Meynert (nbM), a basal forebrain nucleus, and the major source of cholinergic innervation for the neocortex and hippocampus, almost always displays significant cell loss, NFT and SP The dorsal raphe nucleus and to a lesser extent, the locus ceruleus, are also affected in many cases Tremendous interest has focused on the neurochemical alterations in AD, motivated in part by the prospects for neurotransmitter replacement therapies as have been successfully employed in Parkinson’s disease Brain acetylcholine loss in AD appears to be to pathological involvement of the subcortical neurons in the nucleus basalis of Meynert The loss of cortical cholinergic innervation is of interest because most evidence has favored a key role of the cholinergic system in memory dysfunction For example, the degree of depletion of cortical cholinergic markers correlates with the amount of cognitive impairment Also, anticholinergic medications can cause cognitive dysfunction that resembles AD, and lesions of the basal forebrain area produce memory and related deficits in experimental animals and humans Moreover, cholinomimetics are proven efficacious therapy for AD, as further discussed below Inheritability of at least some forms of Alzheimer’s disease has been recognized for decades The term “familial Alzheimer’s disease” (FAD) is used primarily to refer to families in which several members show the disease phenotype, usually with a segregation pattern that suggests autosomal dominant inheritance The age of onset varies among different families, with symptoms in some families presenting earlier than age 60, and in fact, often in the forties and early fifties (early-onset FAD), and other families with onset after 60 years (late-onset FAD) Myoclonus, seizures, a more rapid course, and occasionally other clinical features Alzheimer’s Disease and Other Dementias 1087 have been suggested to be more common in early-onset FAD, but otherwise FAD is clinically and histologically similar to sporadic cases Sporadic cases of AD, with no evidence of familial clustering or autosomal dominant pedigrees, are responsible for the bulk (Ͼ 95%) of AD cases Extraordinary advances in understanding the genetic and molecular basis of AD have occurred Several chromosomal loci have been identified which are linked to various forms of AD For example, early onset FAD can occur with mutations of the amyloid precursor protein gene on chromosome 21, the presenilin gene on chromosome 14, or the presenilin gene on chromosome Loci on chromosome 21 are associated with late-onset FAD and sporadic AD (see below) An important advance has been the discovery of Apolipoprotein E (ApoE) as a major susceptibility gene for late-onset FAD and sporadic AD There are three ApoE alleles, e2, e3, and e4, which differ only in the positions of two amino acid The e4 allele of the ApoE gene has been found to be strongly associated with both sporadic AD and with lateonset FAD, such that the inheritance of the e4 allele appears to be a powerful risk factor for AD The presence of the e4 allele is not only associated with an increased chance of ultimately developing AD, but is also associated with an earlier age of disease onset However, the fact that about 20% of the late-onset AD patients have no e4 suggests that other factors are also involved in the pathogenesis of the disease The predictive quality of the e4 allele has been confirmed in a number of studies in Canada, Europe and Asia Although ApoE appears to play a major role in the neurobiology of AD, and the e4 allele is the most important risk factor yet identified, its use as a genetic marker for diagnostic or predictive testing is still debated As mentioned earlier, there are many cases of AD without the e4 allele, and many individuals who carry the e4 allele without developing AD Alzheimer’s disease is accompanied by a reduction in brain levels of the neurotransmitter acetylcholine Pharmacological agents (cholinesterase inhibitors) that inhibit the enzyme responsible for metabolizing acetylcholine, produce an effective increase in brain acetylcholine neurotransmission, and have been shown clinically to improve both cognitive and global function in AD patients Four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) have been approved by regulatory bodies for use in AD Efficacy has been demonstrated in multicenter, randomized, double-blind, placebo-controlled clinical trials for each of 1088 A Clinical Approach to Medicine these cholinesterase inhibitors The magnitude of cognitive effect is similar for the various cholinesterase inhibitors, and corresponds roughly to the amount of cognitive decline expected to occur in AD patients over approximately nine months Some studies have also shown cholinesterase inhibitors to improve certain behavioral problems and functional performance on activities of daily living in AD patients The toxicity of cholinesterase inhibitor therapy varies considerably between the various agents Tacrine can produce severe hepatotoxicity, and its use is no longer recommended Gastrointestinal side-effects (nausea, vomiting, diarrhea) are the most common side-effects and are dose related Cholinesterase inhibitors are started at a low dose, and doses are subsequently increased as tolerated AD is a neurodegenerative disease in which additional neurons continue to die throughout the course of the illness Interventions designed to slow or stop this neurodegeneration might retard the progression of AD One intervention using the antioxidants selegiline and alphatocopherol (a form of vitamin E) has received formal scientific study.3 In a two-year randomized clinical trial, manifestations of severe dementia (loss of basic activities of daily living, institutionalization, death) were significantly less likely to develop in AD patients receiving selegiline (5 mg BD), alpha-tocopherol (1000 IU BD) or the combination of the two compared to AD patients receiving placebo The median delay in appearance of one of the manifestations of severe dementia in the active treatment groups was approximately months compared to the placebo group These treatments did not improve patients’ cognition; rather, treatment appeared to delay the appearance of manifestations of severe dementia Treatment with selegiline or alpha-tocopherol was well tolerated These preliminary findings, together with the favorable safety and cost profile of alpha-tocopherol, suggest that it can be recommended for most patients with AD One randomized clinical trial using a purified extract of the ginkgo biloba plant has shown a very small beneficial effect (approximately onethird of the effect size generally obtained with cholinesterase inhibitors) on cognitive function in AD patients However, this study did not show any benefit on patients’ global function (in contrast, cholinesterase inhibitors improve global function) These facts, together with the troubling issues of uncertain purity and potency of health food store acquired ginkgo products, prohibit any recommendation of ginkgo biloba in the treatment of AD patients.4 Alzheimer’s Disease and Other Dementias 1089 VASCULAR DEMENTIA Vascular dementia (VaD) is a controversial entity, as it is often difficult to ascertain if the cerebrovascular lesions seen at autopsy or radiologically are responsible for the patient’s dementia A patient’s dementia cannot be ascribed to VaD merely because one or more strokes are present in any site or size In addition, there is much confusion over the type and extent of cerebrovascular disease that results in dementia It appears that dementia may be seen only when a certain amount of brain volume loss occurs in certain critical locations; usually this involves multiple bilateral lesions VaD generally affects a younger population compared to AD The following clinical features suggest the presence of a vascular dementia: 1) abrupt onset; 2) stepwise deterioration; 3) focal neurological signs; and 4) history of stroke In addition, at autopsy, a mixed picture of both AD and VaD can be seen Subcortical ischemic vascular dementia (SIVD) is a common form of VaD (especially in Asia) occurring in patients with persistent hypertension and systemic vascular disease.5 Patients may lack a history of acute strokes and instead, present with progressive dementia and prominent gait impairment Pathologically, there is ischemic demyelination in the cerebral white matter and associated lacunar infarctions in the basal ganglia, thalami, and corona radiata One form of vascular dementia is that due to recurrent cerebral emboli This usually presents as sequential strokes, often involving multiple arterial distributions When multiple cerebral emboli are suspected, identification and treatment of the embolic source (valvular heart disease, mural thrombus, etc.) will halt the progression of the dementia, and some spontaneous recovery may follow OTHER DEMENTIAS Parkinsonian Dementias Dementia complicates Parkinson’s disease (PD) in 35–55% of patients The dementia of PD is characterized by slowed mental processing, impaired problem solving, decreased spontaneity, and visuospatial dysfunction Aphasia and severe amnesia are uncommon in the dementia of PD Other diseases that may produce dementia with associated parkinsonian features include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB) 1090 A Clinical Approach to Medicine DLB deserves special mention, as it is often quoted to be the second most common degenerative dementia (after AD) DLB is recognized by the presence of prominent visual hallucinosis, prominent fluctuations in alertness, and spontaneous motor signs of parkinsonism.6,7 Frontotemporal Dementias Pick’s disease is the most well known of the frontotemporal dementias (FTD) The FTDs are neurodegenerative disorders preferentially involving the frontal and temporal lobes that present in the fifth or sixth decade (earlier than AD) They generally produce one of three clinically recognizable patterns: 1) a disinhibition syndrome characterized by prominent changes in personality and judgment; 2) progressive non-fluent aphasia; and 3) “semantic” dementia, in which patients lose their knowledge of words and their meanings Short-term memory, calculations, and visuospatial skills are often initially spared FTD may be suspected when the CT or MRI shows characteristic atrophy selectively involving the frontal and temporal lobes.8 “REVERSIBLE” DEMENTIAS Although AD and VaD may be the most common causes of dementia, there are other causes which deserve special mention since dementia due to these etiologies may sometimes be reversible Most reversible dementias can be identified with a thorough history and examination coupled with the following ancillary studies: a full blood count, an electrolyte and metabolic panel, a thyroid stimulating hormone level, and a vitamin B-12 level A brain imaging study (either CT or MRI) is also recommended to exclude mass lesions, hydrocephalus, and to identify multiple brain infarctions When clinically indicated, additional laboratory testing (e.g HIV, EEG, LP) or empirical therapeutic trials (e.g antidepressants) may be useful.1,2 Metabolic Disorders The brain is very sensitive to disruptions in metabolic homeostasis Rapid changes in the body’s metabolic parameters commonly produce an acute confusional state (delirium) When metabolic changes occur Alzheimer’s Disease and Other Dementias 1091 more gradually, a dementia-like state may develop As in acute confusional states, metabolic dementia is characterized by prominent inattention, and by fluctuations in cognitive performance Other clues suggesting a metabolic (or toxic) cause are prominent disturbances of motor function including postural tremor, myoclonus, and asterixis Common metabolic derangements that can produce dementia include hypoxia, uremia, hyponatremia, hypercalcemia, hyperammonemia, Wernicke–Korsakoff syndrome (B-1 deficiency), vitamin B-12 deficiency, hypothyroidism, and cerebral hypoperfusion (e.g severe congestive cardiac failure) Correction of the underlying medical illness responsible for these metabolic derangements often halts the progression of cognitive impairment and sometimes reverses the impairment completely Toxic Dementia Numerous toxins can impair brain function and produce dementia; however, pharmacotherapeutic agents and chronic alcohol abuse are the most common causes of toxic dementia Dementia produced by drug toxicity is characterized by reduced concentration, poor attention, fluctuating course, and motor signs (tremor, asterixis, myoclonus), and thus resembles a typical delirium Although excessive doses of nearly any pharmacologic agent can impair cognitive function, some patients will develop cognitive toxicity on “therapeutic” doses of medication Again, this is particularly true in the elderly (and especially when the patient is taking several medications) Fortunately, reduction or discontinuation of the offending agent(s) often produces a reversal of the cognitive problems.9 Toxic dementia is most likely to complicate treatment with psychotropic medications The psychotropic medications which are most commonly associated with a reversible dementia include sedative/ hypnotics (especially benzodiazepines and barbiturates), antipsychotics, tricyclic antidepressants, and lithium Sedative/hypnotics with long halflives (e.g flurazepam and diazepam) are especially prone to producing toxic dementia in elderly patients receiving daily doses Antipsychotics often produce toxic dementia as a result of both their anticholinergic properties and via secondary parkinsonism with bradyphrenia (slowed thinking) The secondary amine tricyclics (amitriptyline and imipramine) possess higher anticholinergic activity than the tertiary amine tricyclics (nortriptyline and desipramine) and are consequently more likely 1092 A Clinical Approach to Medicine to impair cognition The selective serotonin reuptake inhibitors (fluoxetine, paroxetine, others) have been less commonly associated with toxic dementia Toxic dementia from pharmacotherapeutic agents is probably the most important reversible dementia It is critical to emphasize again that significant drug-induced cognitive impairment can occur in patients receiving “therapeutic” doses, and even in patients with “therapeutic” serum drug levels A trial period of drug discontinuation is often necessary to determine whether the dementia is due to drug intoxication Reversal of the dementia syndrome through such a simple therapeutic maneuver is greatly rewarding for both patient and clinician Depression Major depression is commonly associated with cognitive impairment Many depressed patients experience impaired concentration and forgetfulness Reduced motivation and overall reduced functional ability are also commonly seen in patients with depression Consequently, it is not uncommon for patients with major depression to present with symptoms of dementia, and approximately 10% of patients seen at dementia clinics have depression as the primary cause of their cognitive difficulties The “dementia of depression” is characterized by slowness of response, reduced attention, poor concentration, and poor memory (although recognition is usually much better than is spontaneous recall) Aphasia, agnosia, and apraxia are uncommon in the dementia of depression Associated symptoms of sleep disturbance, appetite change, low energy levels, and depressed moods, are often encountered A past history of depression or a family history of depression is also common in these patients Treatment of major depression with antidepressant medication or with electroconvulsive therapy often relieves the mood disturbance and improves or reverses the cognitive deficits REFERENCES Mayeux R, Foster NL, Rossor M, Whitehouse P, The clinical evaluation of patients with dementia, in Whitehouse PJ (ed.), Dementia, F A Davis, Philadelphia, 1993 Barclay L, Evaluation of dementia, in Barclay L (ed.), Clinical Geriatric Neurology, Lea and Febiger, Philadelphia, 1993 Alzheimer’s Disease and Other Dementias 1093 Sano M, Ernesto C, Thomas RG, et al., A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease, New Engl J Med 336:1216–1222, 1997 LeBars PL, Katz MM, Berman N, et al., A placebo controlled randomized trial of an extract of ginkgo biloba for dementia, JAMA 278: 1327–1332, 1997 Erkinjuntti T, Subcortical vascular dementia, Cerebrovasc Dis 13 (Suppl 2):58–60, 2002 McKeith IG, Galasko D, Kosaka K, et al., Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop, Neurology 47:1113–1124, 1996 McKeith IG, Perry EK, Perry RH, Report of the second dementia with Lewy body international workshop: diagnosis and treatment, Neurology 53:902–905, 1999 Neary D, Snowden JS, Gustafson L, et al., Frontotemporal lobar degeneration A consensus on clinical diagnostic criteria, Neurology 51:1546–1554, 1998 Salzman C, et al., Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents, Int J Geriatr Psych 7:89–93, 1992 This page intentionally left blank Obstetrics and Gynecology This page intentionally left blank 64 Medical Disorders in Pregnancy Tan Hak Koon Medical disorders in pregnancy or obstetric medicine is becoming increasingly important for both obstetricians and physicians Pregnancy is a unique state where the physiology of the mother is greatly altered to accommodate the newly developing “organ” — the fetus The objectives are to provide the fetus with adequate nutrition for its growth and development, and to allow the mother to survive the process of reproduction Understandably, pregnancy has a significant impact on the well-being of a mother with an underlying medical condition At the same time, the fetus is also vulnerable to changes in the maternal condition Care of the pregnant woman with a medical condition requires knowledge of how the disease may be affected by the pregnancy and vice versa Concern for the welfare of the fetus may influence the management of maternal conditions and particularly the choice of drugs Both physicians and obstetricians must be familiar with the normal physiological adaptation to pregnancy and the common medical disorders which may be encountered in order to ensure the safety and wellbeing of both mother and the fetus 1097 1098 A Clinical Approach to Medicine The field of obstetric medicine is vast since virtually any medical condition may complicate a pregnancy Medical problems may complicate pregnancy during the pre-conception, antenatal or postnatal periods In recent years, the incidence of medical conditions in pregnancy is increasing steadily Women today are delaying childbearing as a consequence of marriage at a later age and pursuit of professional goals Pregnancy after the age of 35 is becoming more common Age-related medical disorders, such as diabetes mellitus and hypertension, are encountered more frequently in pregnancies Advances in medicine have enabled some girls who would have died prematurely from their medical or congenital disorders in the past to survive into reproductive age and bear children today This is particularly true for girls with congenital heart disease who had undergone complex heart surgery Other successful medical treatments like renal dialysis or transplantation have made childbearing a reality for patients suffering from chronic renal failure These high-risk pregnancies however, is often associated with changes beyond the limit of the normal physiological response and cause decompensations, which lead to severe morbidity or mortality of either the fetus or the mother, or both Some of the more commonly seen medical problems in pregnancy are discussed GESTATIONAL DIABETES MELLITUS (GDM) Pregnancy is a state of physiological insulin resistance and relative glucose intolerance This is largely due to anti-insulin hormones secreted by the placenta, particularly human placental lactogen, glucogen and cortisol The insulin production of normal women approximately doubles during pregnancy Glucose intolerance increases progressively with increasing gestation Gestational diabetes is defined as “carbohydrate intolerance” of variable severity with onset or first recognition during the present pregnancy It includes women with pre-existing but previously unrecognized diabetes GDM is the most common medical complication and metabolic disorder of pregnancy Local incidence of GDM has been reported to be from 5–13% The World Health Organization (WHO) has proposed criteria equivalent to those for diagnosis of impaired glucose intolerance in the Medical Disorders in Pregnancy 1099 non-pregnant state A woman is diagnosed as having GDM if either their fasting or 2-hour level is Ͼ 7.8 mmol/L following a 75 g oral glucose tolerance test There is no consensus in advocating universal biochemical screening for all pregnant women for GDM Most centers still screen only women with clinical risk factors such as advanced maternal age, family history of diabetes, previous GDM, previous macrosomic baby, previous unexplained stillbirth, obesity, glycosuria, polyhydramnios or macrosomia in current pregnancy Poor diabetic control during periconceptual period is associated with early pregnancy losses and recurrent miscarriages It is also related to an increased incidence of congenital malformations in the fetus, especially cardiovascular and neural tube defects Intrauterine growth retardation, sudden intrauterine death, fetal hyperinsulinemia and macrosomia, polyhydramnios, perinatal morbidity and mortality are significantly increased in infants of diabetic mothers with poor blood sugar control Neonatal morbidity such as fetal macrosomia, respiratory distress, hypoglycemia, polycythemia and jaundice are recognized sequale of diabetic pregnancy Besides, diabetic mothers, especially those with nephropathy and hypertension, have an increased risk of pre-eclampsia Women with history of GDM have up to 50% lifetime risk of developing gestational diabetes mellitus The major objective of management is to attain normoglycemia, pregnant women with gestational diabetes should be managed in joint pregnancy-diabetic clinics attended by obstetricians, diabetologists, dieticians, trained nurses and midwives who are experienced in the care of those women All women with established diabetes who seek fertility should attend pre-pregnancy counselling sessions for risk assessment It also allows for optimization of diabetic control prior to conception and treatment of possible complications such as hypertension, nephropathy and retinopathy Regular antenatal follow-up and frequent home glucose monitoring since early pregnancy are essential Strict adherence to low sugar, high fiber and low fat diet is important in pregnancy to achieve normoglycemia Insulin therapy is indicated in the presence of persistent fasting or post-prondial hyperglycemia A combination of short acting and intermediate acting insulin are often necessary in more severe cases Regular checks of maternal blood pressure and urinalysis as well as regular ultrasound assessment of fetal growth and well-being are advised 1100 A Clinical Approach to Medicine Pregnancies with well-controlled GDM should be allowed to continue until 38–40 weeks in the hope of a spontaneous labor and vaginal delivery Cesarean section is only performed for usual obstetric indications Monitoring of blood sugar level and insulin requirement during the intrapartum period is important For those in whom the diagnosis of the GDM is made during pregnancy, a formal oral glucose tolerance test should be performed at weeks post-natally to assess the degree of impairment of glucose tolerance HYPERTENSIVE DISEASE IN PREGNANCY As a result of vasodilatation, blood pressure begins to decrease in early pregnancy It reaches a nadir at around 20–22 weeks before rising to pre-pregnancy level until term Blood pressure should be taken with the pregnant woman sitting or lying on her lateral side rather than supine position Phase V (disappearance) rather than IV (muffling) of korotkoff sound should be taken as the diastolic reading as it is more reproducible and correlates better with intra-arterial measurement of diastolic blood pressure Hypertension, which complicates up to 10% of all pregnancies, is one of the most common medical problems encountered in pregnancy Preeclampsia, which affects up to 10% of primiparous women, remains one of the leading causes of maternal mortality and continues to contribute significantly to perinatal morbidity and mortality Hypertension is defined as a diastolic blood pressure Ͼ 90 mmHg on occasions, a rise of systolic blood pressure of 30 mmHg and diastolic increase of 15–25 mmHg above the earliest recorded value It may be divided into essential hypertension, pregnancy-induced hypertension and pre-eclampsia Pregnant women suffering from essential hypertension are usually diagnosed as hypertensive prior to pregnancy or in the first trimester Secondary causes such as renal or cardiac disease, Cushing’s Syndrome, Conn’s Syndrome or pheochromocytoma must be excluded These women have a significantly increased risk of developing superimposed pre-eclampsia Pregnancy-induced hypertension may be defined as hypertension occurring in the second half of pregnancy but in the absence of proteinuria It usually appears in the second half of pregnancy and resolves within weeks of delivery Medical Disorders in Pregnancy 1101 Chronic hypertension in pregnancy should be treated to reduce the risk of severe hypertension and cerebral hemorrhage, and possibly to prolong the pregnancy, even though there is no conclusive evidence to suggest that it reduces the risk of superimposed pre-eclampsia Methyldopa is still the drug of choice in pregnancy as it does not give rise to any serious adverse effect on the fetus Pre-eclampsia is a pregnancy specific multi-systemic disorder of protean manifestation It occurs as a result of a cascade of events involving inflammation, endothelial dysfunction and unbalanced oxidation set into motion by a pathogen released by a dysfunctional placenta Its risk factors include primiparity, multiple pregnancies, pre-existing hypertension, past history of pre-eclampsia, renal impairment, diabetes, anti-phospholipid syndrome and hydatidiform mole Although the classic signs of pre-eclampsia are hypertension, proteinuria of Ͼ 0.3 g/24 hrs and edema, their absence does not exclude the diagnosis Diffuse vascular endothelial dysfunction may cause widespread circulatory disturbances involving the renal, hepatic, cardiovascular, central nervous and coagulation systems The severity, timing and order of onset of different clinical features vary enormously Several possible crises may develop in severe cases, including eclampsia or grand mal convulsion, renal failure, hepatic rupture, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet), cerebral hemorrhage, disseminated intravascular coagulation and pulmonary edema Severe pre-eclampsia may lead to intrauterine growth retardation (IUGR), placental abruption, and intrauterine death The cornerstone of clinical management of pre-eclampsia remain early detection, control of blood pressure, close monitoring of the progression of the disease and fetal surveillance, and ultimate delivery when either maternal or fetal well-being is compromised or when fetal maturity is achieved Pregnant women suffering from pre-eclampsia require close monitoring of symptoms, blood pressure, proteinuria, renal and liver functions, platelet count and clotting factors Patient with severe pre-eclampsia and impending eclampsia should be transferred to intensive care unit and managed jointly by obstetrician, anesthetist, physician and neonatologist Magnesium sulphate which acts as a cerebral vasodilator is the drug of choice for primary and secondary prophylaxis in eclampsia The only cure for pre-eclampsia is delivery In the absence of coagulopathy, women with pre-eclampsia are encouraged to have epidural 1102 A Clinical Approach to Medicine analgesia in labour or for cesarean section Intensive monitoring of blood pressure, fluid balance, hematology and biochemistry are necessary postpartum Low dose aspirin remains the only prophylaxis for pre-eclampsia It should be started preferably at 12 weeks gestation VENOUS THROMBOEMBOLISM (VTE) IN PREGNANCY During pregnancy, increased venous stasis due to the compressive action of an increasingly gravid uterus on major veins and the hypercoagulate state as a result of physiological increase in circulatory clotting factors like fibrinogen, factors VIII, IX and X, and a decrease in fibrinolytic activity, all predispose to an increased risk of VTE Venous thromboembolism is the leading cause of maternal mortality in the developed world Pulmonary embolism was the main cause of death in the last two triennial reports on Confidential Enquiries into Maternal Deaths in the United Kingdom Similarly, an audit of autopsies of cases of maternal mortality in Singapore from 1992 to 1995 found that there were cases of pulmonary embolism, giving an incidence of 4.9 fatal pulmonary embolism for 100 000 maternities The risk factors associated with VTE development include advanced maternal age (Ͼ 35 years), operative delivery, prolonged bed rest, obesity and thrombophilia The presence of deep vein thrombosis (DVT) may be suspected in the presence of swelling, redness, pain and tenderness of the calf The gold standard for diagnosis of DVT remains to be venography, which can be performed with abdominal shielding to ensure minimal radiation to the fetus However, duplex doppler ultrasound is a more convenient and less invasive method, which is more widely used to accurately detect DVT Pulmonary embolism can present in a myriad of ways ranging from chest pain and tachycardia to cardiopulmonary collapse A high index of suspicion must be employed in women who present with chest symptoms or atypical dyspnea Basic investigations like chest X-ray, arterial blood gases and electrocardiography are established initial diagnostic tests The diagnosis can be confirmed with a ventilation-perfusion scan (V/Q), which will show areas of ventilation/perfusion mismatch Pulmonary angiography is usually reserved for pre-embolectomy cases Medical Disorders in Pregnancy 1103 Heparin has been the standard treatment of VTE as it does not cross the placenta and has no teratogenic effects, unlike warfarin However, the monitoring of conventional unfractionated heparin (UH) with activated partial thromboplastin tissue (APTT) is often poorly performed, leading to the possibility of introgenic overdosage of heparin which may give rise to potential hemorrhage problems in pregnancy Prolonged use of UH also carries the risk of osteoporosis and thrombocytopenia There is a recent move away from using intravenous UH towards low molecular weight heparin (LMWH) for the treatment of deep vein thrombosis in both acute and chronic phase LMWH can be given subcutaneously in fixed dose, thus minimizing or avoiding the need for monitoring The simplified therapeutic regimen is more convenient and allows outpatient treatment LMWH also has a lower risk of hemorrhage and osteoporosis In clinical practice, UH is preferred over LMWH in the acute phase of pulmonary embolism because of its rapid onset of action and wide expertise in its use Pregnant women with pulmonary embolism should be closely monitored in intensive care units and co-managed by hematologist and intensive care specialists All pregnant women at high risk of recurrent thrombosis should receive thromboprophylaxis during the antenatal period, intrapartum as well as up to weeks postpartum CARDIAC DISEASE IN PREGNANCY Pregnancy and peripartum period are associated with important cardiovascular changes Endogenous hormones cause peripheral vasodilatation leading to a fall in systemic arterial blood pressure during the first trimester This reaches a nadir in mid pregnancy and returns to pregestational level before term The blood volume increases substantially from early pregnancy to mild pregnancy by as much as 50% Cardiac output also increases by around 40% during pregnancy due predominantly to an increase in stroke volume, but also by a lesser increase in heart rate Blood volume expands further immediately after delivery as a result of autofusion of 300–500 ml of blood due to uterine contraction and relief of aortocaval compression Pre-pregnancy counselling of women with heart disease and detailed assessment of the cardiac status are of utmost importance The hemodynamic significance of any lesion and functional class (New York Heart 1104 A Clinical Approach to Medicine Association, NYHA), the presence of cyanosis and pulmonary hypertension must be properly asssessed Poor pregnancy outcome is more likely if the women is in poor functional status, (NYHA Class III and IV) and in the presence of pulmonary hypertension Maternal morbidity is 30–50% in the presence of Eisenmenger’s syndrome Close collaboration between the attending cardiologist and obstetrician is important to ensure maternal well-being and satisfactory fetal outcome Congenital Heart Disease The incidence of congenital heart disease in pregnancy is increasing This is because more women with severe defects who underwent successful corrective surgery as children are now able to have children themselves Majority of congenital heart disease seen are ventricular septal defects (VSD), patent ductors arteriosus (PDA) and atrial septal defects (ASD) Maternal risks are usually small and fetal outcome satisfactory for simple acyanotic defects because there is usually minimal hemodynamic change of significance However, women suffering from cyanotic heart disease are at a significantly higher risk Maternal hypoxemia increases risks of miscarriage, intrauterine growth retardation and preterm labour Women with Eisenmenger’s syndrome should be managed in an intensive care unit by cardiologist, anesthetist, hematologist and obstetrician Mortality usually occurs during the peripartum and postpartum period The fetuses must be screened after delivery as they are at a higher risk of having congenital heart defects (2–5%) Rheumatic Heart Disease (RHD) Rheumatic heart disease in pregnancy is still a common problem despite improved socio-economic conditions and widespread use of antibiotics for the treatment of streptococcal pharyngitis By far the most common type of RHD in pregnancy is mitral stenosis, which makes up about 80% Most patients with moderate to severe mitral stenosis demonstrate a worsening of functional status in pregnancy, especially during late pregnancy, labor and postpartum period Restriction of physical activity and even hospitalization are needed for symptomatic patients to prevent hemodynamic deterioration Intercurrent infection must be treated promptly Cardiac medication like diuretics for pulmonary edema or beta-blockers to slow the heart Medical Disorders in Pregnancy 1105 may be needed or increased Antibiotic prophylaxis should be prescribed for high-risk patients with prosthetic valves or history of endocarditis Latrogenic premature delivery may be indicated for severely decompensated cases Close hemodynamic monitoring from the onset of labour to 24-hour postpartum is necessary for symptomatic patients Balloon valvotomy and closed mitral valvotomy are associated with high risks in pregnancy and only indicated for severe cases Peripartum Cardiomyopathy This rare condition is specific to pregnancy It may occur months before term and up to months postpartum Patients present with signs and symptoms of congestive cardiac failures and echocardiography shows an enlarged heart with global dilatation of all four chambers with markedly reduced left ventricular function Early elective delivery is indicated if the condition is diagnosed antenatally as the maternal mobility may be as high as 50% Women should be counselled against further pregnancy since there is a significant risk of recurrence ASTHMA IN PREGNANCY As a result of increased metabolic rate and consumption of oxygen, there is a significant increase in oxygen demand in normal pregnancy The minute ventilation increases up to 50%, mostly due to an increase in tidal volume There is also a reduction in arterial carbon dioxide partial pressure PaCO2 and a mild compensated respiratory alkalosis due to maternal hyperventilation Asthma is one of the most common medical conditions seen in pregnancy in Singapore The diagnosis is often obvious by eliciting a history of typical symptom of breathlessness or wheezy breathing, worse at night and in the early morning There may be provoking trigger factors like upper respiratory infection, exercise, pollen, etc The degree of reversible bronchoconstriction can be measured with a peak expiratory flow rate (PEFR) or forced expiratory volume in one second (FEV 1) Asthma may improve, deteriorate or remain unchanged during pregnancy Those with only mild disease are unlikely to experience any serious problems in pregnancy However, patients with severe asthma are at greater risk of deterioration This is especially so for those who reduce or even completely stop the medication due to fears of its safety Asthma has 1106 A Clinical Approach to Medicine no adverse effects on pregnancy outcome on most women Fetal growth and well-being are only affected in severe, poorly controlled cases with chronic maternal hypoxemia The treatment of asthma in pregnancy is essentially no different from the treatment of asthma in non-pregnant women Current emphasis is in the prevention, rather than the treatment of acute attacks The main aim of treatment is to achieve virtual total freedom from symptoms so that the lifestyle of the pregnant women is not affected All common drugs used to test asthma appear safe in pregnancy and lactation Corticosteroids, both inhalational and oral, are safe in pregnancy There is no evidence for an increased incidence of congenital malformation or poor fetal outcome as a result of inhalational steroids The risk of abortion, stillbirth, fetal anomaly or neonatal death are not increased with the use of oral steroids, even though oral steroids can increase the risk of gestational diabetes mellitus and cause a deterioration of blood sugar control Likewise, Beta agonists are safe in pregnancy Acute severe asthmatic attacks are potentially dangerous and should be treated vigorously The treatment is no different from severe asthma in the non-pregnant state Cesarean section is only performed when there is an obstetric indication RENAL DISEASE IN PREGNANCY Renal plasma flow rises early in pregnancy and may increase by up to 60–80% throughout pregnancy Similarly, glomerular filtration rate (GFR) increases and creatinine clearance rises by 50% This results in a fail in the serum levels of creatinine Protein is increased and the upper limit in pregnancy is 300 mg per 24 hours As a result of a rise in the etiological factors like uncontrolled diabetes mellitus, chronic hypertension, glomerulonephritis and collagen vascular disease, the incidence of chronic renal disease has increased significantly in Singapore in recent years Advancement in treatment modalities like dialysis has improved the reproductive function of women with chronic renal diseases However, these women face significant risks during pregnancy There may be accelerated decline in renal function, escalating hypertension and proteinuria Patients are also more likely to suffer Medical Disorders in Pregnancy 1107 from early miscarriages, pre-eclampsia, intrauterine growth retardation, preterm delivery and fetal distress The outcome of pregnancy and any adverse effect on underlying renal disease are both influenced by the degree of renal impairment the presence and severity of hypertension and protenuria, as well as the underlying etiological factors In general, women with mild impairment without hypertension usually have successful pregnancy outcome Women with chronic renal disease should be managed jointly by an obstetrician and a renal physician Pre-pregnancy assessment of renal function and optimization of blood pressure control should be made Women with severe renal impairment should ideally be counselled against pregnancy as they face a real risk of end-stage renal disease As soon as pregnancy is diagnosed, a renal function test should be performed to provide a baseline with which to compare trends in pregnancy In view of the increased risk of pre-eclampsia, treatment with low dose aspirins should be considered especially for those with hypertension or poor obstetric history Careful monitoring and control of blood pressure is important Regular assessment of renal functions, and regular ultrasound assessment of fetal growth and well-being should be done Admission should be considered if the women develops worsening hypertension, deteriorating renal function or superimposed pre-eclampsia Early elective delivery is indicated in severe cases Pregnancy in Dialysis Patient Women on hemodialysis or chronic ambulatory peritoneal dialysis are often sub-fertile Even if they are pregnant, the chance of a successful pregnancy outcome is low (20–30%) Pregnancy is associated with marked increase in requirement for dialysis The problems of fluctuation in fluid balance, electrolyte imbalances, bleeding due to heparinization, anemia and infection occur commonly and these patients must be managed in a tertiary center with full facilities Pregnancy in Renal Transplant Recipients Successful renal transplantation significantly improves the reproduction function of women with end-stage renal failure Pregnancy probably had no adverse long-term effect on renal allograft function or survival 1108 A Clinical Approach to Medicine However, renal impairment does occur in about 15% of pregnancies and therefore, close monitoring and surveillance are necessary Pregnancy outcome is optimal in those with near normal renal function and those without hypertension or recent episodes of graft rejection The doses of immunosuppresive drugs should be maintained at pre-pregnancy levels Cesarean sections are only performed for obstetric indications THYROID DISEASE IN PREGNANCY The changes in thyroid function in pregnancy are complex The levels of thyroid binding globin (TBG) increase due to an increase in hepatic synthesis, as well as an increase in the half-life of TBG This results in the elevation of both total thyroxine (total T4) and total triiodothyronine (T3) The free thyroxine (free T4) index, however, tends to yield low values in pregnancy Hyperemesis gravidarum in early pregnancy may be associated with a biochemical thyrotoxicosis or gestational transient thyrotoxicosis (GTT) with transient elevation of free T4 levels Serum concentrations of thyroid stimulating hormone (TSH) fall in early pregnancy as the concentration of human chorionic gonadotrophin (hCG) increase HCG has thyrotropic activity The levels of free T4 and free T3 decline by about 10–20% during the second and third trimester Hyperthyroidism Hyperthyroidism is more common in women than men (ratio 10:1) Majority of cases of hyperthyroidism in pregnancy are due to Graves’ disease (95%) and have already been diagnosed or on treatment Toxic nodular goiter or toxic adenoma are less commonly seen Thyrotoxicosis must be differentiated from GTT, which resolves spontaneously Many typical features such as heat tolerance, tachycardia, palpitations, vomiting and goiter are common in normal pregnancy However, the most distinctive features are tremor, weight loss, lid lag and exophthalmos The diagnosis is made by finding a raised free T4 or free T3 and suppressed TSH levels Severe and untreated thyroxicosis is associated with anovulation and infertility It also increases the risk of miscarriage, intrauterine growth Medical Disorders in Pregnancy 1109 retardation, premature labour and perinatal mortality significantly Thyroid storm may occur in severe thyrotoxicosis especially during the peripartum period Grave’s disease often improves during the second and third trimester as the levels of TSH receptor stimulating antibodies fall The aim of treatment is to control the thyrotoxicosis as rapidly as possible with the lowest possible dose of anti-thyroid medication Pregnant women should be clinically euthyroid with a free T4 level at the upper end of normal range Both carbinizole and propylthiouracil (PTU) can be used in pregnancy even though PTU is probably preferable for newly diagnosed cases in pregnancy as it crosses the placenta and into breast milk Women already on maintenance dose need not be switched to PTU in pregnancy Beta-blockers are safe for short-term use in pregnancy for control of thyrotoxic symptoms Fetal or neonatal thyrotoxicosis is uncommon This is due to transplacental passage of thyroid stimulating antibodies Newborns of thyrotoxic mothers should be examined by neonatalogist Hypothyroidism Just like hyperthyroidisis, hypothyroidism is more common in women than men The incidence of hypothyroidism in pregnancy is estimated to be between 0.05% and 0.7% Most cases are due to previous thyroidectomy, Hashimoto’s thyroiditis or post-ablative Grave’s disease Untreated hypothyroidism during pregnancy is associated with intrauterine growth retardation, premature labour, low birth weight babies, abruptio placenta and pre-eclampsia Children born to hypothyroid mothers are also showed to have significantly lower IQ scores Pregnancy itself probably had no effect on hypothyroidism Clinical features of hypothyroidism include lethargy, tiredness, weight gain, cold intolerance, bradycardia and delayed relaxation of tendons Serum-free T4 level is low Levo-thyroxine is the drug of choice for thyroid replacement therapy Hypothyroid pregnant women also are already on thyroxine replacement require on upward adjustment of this daily thyroxine dosage in order to maintain eythyroidism, sometimes up to as much as 40% Neonatal hypothyroidism is a rare condition that must be promptly treated because of its serious consequences 1110 A Clinical Approach to Medicine Postpartum Thyroiditis Postpartum thyroiditis which usually presents between to months’ postpartum is caused by a destructive autoimmune lymphocystic thyroiditis It may present with either transient hypothyroidism or hyperthyroidism or first hyperthyroidism and then hypothyroidism Most patients recover spontaneously and treatment is not always necessary It is, however, a significant predictor of future hypothyroidism EPILEPSY IN PREGNANCY Epilepsy is the most common chronic neurological disorder that can complicate a pregnancy Most cases of epilepsy are idiopathic with no underlying cause However, secondary epilepsy may occur with women with previous brain surgery, intracranial mass lesion, pre-eclampsia, cerebrovascular events, cerebral infection or after metabolic conditions Most women suffering from epilepsy in pregnancy have already been diagnosed but all women suffer from a first fit occurring in pregnancy should be thoroughly investigated for secondary causes The frequency of fits is not altered in most pregnant women However, about a third of women may experience more fits as a result of poor control Poor compliance with anticonvulsants due to fears regarding teratogenesis, decreased serum drug levels due to nausea and vomiting in early pregnancy or increased volume of distribution and increased drug clearance in pregnancy are possible reasons for deterioration of the condition The incidence of miscarriage in epileptics is not increased, unless there is associated abdominal trauma during the fit Similarly, episode seizure is unlikely to result in intrauterine growth retardation or intrauterine deaths as the fetus is relatively resistant to short episodes of hypoxia However, status epilepticus is dangerous for both mother and fetus and should be treated promptly Commonly used anticonvulsants like phenytoin, primidone, phenobarbitone, carbamazepine and valprocate all cross the placenta and are teratogenic Possible fetal anomalies associated with these drugs include neural tube defects, orofacial defects, congenital heart defects and musculoskeletal defects There is very little difference in the level of risk between individual drugs but the risk increases with the number of drugs used Medical Disorders in Pregnancy 1111 Ideally all women suffering from epilepsy should be counselled prepregnancy about the risks The control of epilepsy should be optimized and the anticonvulsants used should be reviewed The control should be with only one drug alone if possible to reduce the risk of teratogenesis All women taking anticonvulsants should be given folic acid daily for at least 12 weeks prior to conception This should be continued throughout pregnancy All pregnant women suffering from epilepsy should be reviewed regularly by both obstetrician and neurologist There is no need to change the anticonvulsants in pregnancy if the woman is well controlled on either phenytoin, carbamazepine or valprocate Phenobarbitone should be slowly weaned if possible to reduce the risk of neonatal withdrawal convulsions Serum drug levels should be monitored in women suffering from regular fits Screening for congenital anomalies with maternal alpha fetoprotein and detailed ultrasound scan at 20 weeks should be performed All neonates should receive vitamin K Breast-feeding while taking anticonvulsants is safe as only a small fraction of anticonvulsants is secreted into breast milk All mothers should also be informed of the increased risk of the child developing epilepsy later in life IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) IN PREGNANCY During a normal pregnancy, the platelet count tends to fall progressively, although usually within the normal limits In practice, a pregnant woman is not considered thrombocytopenic unless the platelet count is below 100 ϫ 109/L Thrombocytopenia detected in the initial stages of pregnancy is less likely to be due to pregnancy itself, and the possibility of an underlying pathology must be considered Idiopathic thrombocytopenic purpura (ITP) occurs as a result of autoantibodies against platelet surfaces antigens, causing peripheral platelet destruction by the reticuloendothelial system The diagnosis of ITP in pregnancy is one of exclusion, and should only be made after excluding other causes of thrombocytopenia such as infections, autoimmune disease, pre-eclampsia and drugs Pregnancy does not affect the course of ITP Theoretically, maternal antiplatelet IgG can cross the placenta and cause fetal thrombocytopenia, 1112 A Clinical Approach to Medicine and it is difficult to accurately assess fetal risk as there is no relation between the maternal platelet count or antibody levels to fetal platelet count Most agree now that the fetal risk is small and the incidence of neonatal intracranial hemorrhage in women with ITP is 1% or less For pregnant women suffering from ITP, regular monitoring of platelet counts is necessary Capillary bleeding and purpura are unlikely to occur if the maternal platelet count is Ͼ 50 ϫ 109/L and spontaneous mucosal bleeding usually does not occur if platelet count is Ͼ 20 ϫ 109/L Treatment is only indicated for symptomatic cases or when the platelet is Ͻ 50 ϫ 109/L Corticosteroids are the first-line therapy Intravenous gamma-globulin is not contraindicated in pregnancy and can be used for resistant cases It is useful in instances where a rapid response is required Splenectomy is not advisable in pregnancy and is performed in extreme cases Platelet transfusion is usually given as a last resort for symptomatic cases or pre-operatively There is no conclusive evidence to suggest that cesarean section is less traumatic for the fetus and reduces the risk of neonatal intracranial hemorrhage compared to vaginal delivery Therefore, cesarean section is only required for the other obstetric indications Monitoring of neonatal platelet levels is necessary and treatment is indicated for neonates with severe thrombocytopenia SYSTEMIC LUPUS ERYTHEMATOSIS IN PREGNANCY Systemic lupus erythematosis (SLE) is a chronic systemic connective tissue disease with a reported prevalence of 5–100/100 000 Women are affected much more commonly than men (ratio 9:1), particularly those in childbearing age (15:1) The incidence in women of childbearing age is per 1000 women and may be increasing The exact cause of SLE is unknown, but it involves both a genetic predisposition and environmental trigger factors Its clinical features include joint involvement, skin involvement, serositis, neurological and hematological manifestations The diagnosis of SLE can be made by using specific clinical and laboratory criteria by American Rheumatic Association Antinuclear antibody (ANA) is the most common autoantibody found in SLE but anti-double standard DNA is the most specific Serum compliment levels are useful in assessing disease activity Other anti-phospholipid antibodies may be detected Medical Disorders in Pregnancy 1113 SLE in pregnancy poses serious clinical challenge as it is associated with both maternal and fetal morbidity and mortality It is associated with increased risks of spontaneous miscarriage, intrauterine growth retardation, intrauterine death, preterm delivery and pre-eclampsia This is especially so for active disease, in the presence of anti-phospholipid antibodies and significant renal involvement with hypertension Pregnancy itself may exacerbate SLE and increases the likelihood of a flare, even though flares may be difficult to diagnose as features like facial erythema, hair loss, fatigue, edema also occur in normal pregnancy Pre-pregnancy counselling is of utmost importance in the management of women suffering from SLE The disease should be adequately controlled as pregnancy outcome is better if conception occurs during remission These women should be managed in joint clinic, with rheumatologist and obstetrician, where regular monitoring of disease activity and fetal growth can be performed Regular monitoring of blood pressure, renal function, antibody titer and complement levels allow early diagnosis of disease flares, which must be actively treated Corticosteroids are the drugs of choice in controlling the disease It is not associated with an increased risk of stillbirth and congenital malformation Azathiopine is probably safe in pregnancy with no significant adverse effect in fetus NSAIDs and aspirin are not teratogenic, although NSAIDs is associated with fetal oligohydramnios and premature closure of the ductus arteriosus NSAIDs should be discontinued at 34–36 weeks of pregnancy All newborns must be assessed by neurologist for neonatal lupus syndromes which occur in 5% of pregnancies with SLE The risk of congenital heart block is about 2–5%, especially in anti-Ro positive mothers HUMAN IMMUNODEFICIENCY VIRUS (HIV) IN PREGNANCY The incidence of HIV infection is fast increasing worldwide It is estimated that about 50 million people are infected with HIV, of which at least 40% are women The prevalence rates of HIV in pregnancy, though vary greatly geographically, are showing an upward trend in all reported series HIV may be transmitted through unprotected vaginal or anal intercourse, sharing of contaminated needles, use of unscreened blood products or vertical transmission either antepartum, intrapartum or postpartum 1114 A Clinical Approach to Medicine Early HIV infection is characterized by a high viral load The main target of HIV is the CD4 lymphocyte and lymphocytes are gradually lost during the latent phase Both cell-mediated immunity and humoral immunity are reduced, leading to development of opportunistic infections and malignancy HIV infection can be diagnosed by detecting HIV antibody to part of the viral membrane or envelope The test usually becomes positive within weeks to months after exposure as the levels of P24 antigen are falling Viral DNA may be detected with polymerase chain reaction (PCR) and the main predictor of disease progression is the CD4 lymphocyte count Transplacental transfer of maternal HIV antibody may persist for up to 18 months, making the HIV status of the infant difficult to determine without PCR Pregnancy probably does not have a major adverse effect on the progression of HIV infection in asymptomatic women Similarly, HIV infection has not been shown to adversely influence pregnancy outcome, increase miscarriage rate or the rate of congenital abnormality However, recurrent opportunistic infections may occur in women with advanced disease and poor nutritional status Vertical transmission of HIV from mother to fetus may occur either in utero, during the time of delivery or by breast-feeding postnatally The rate of vertical transmission ranges from 20–40% Two-thirds of the vertical transmission seems to occur during delivery, especially in cases of advanced maternal disease and prolonged rupture of membranes Breastfeeding is also shown to double the transmission rate Pregnant women infected with HIV should be managed jointly by an obstetrician, a HIV specialist, a pediatrician and other medical personnel with experience in this area In view of the reduced life expectancy of the women and the increased risk of vertical transmission, the option of termination of pregnancy should be offered The use of Zidovudine (AZT) monotherapy has been shown to reduce the risk of vertical transmission and should be encouraged CD4 counts should be checked regularly and prophylactic antibiotics for opportunistic infection should be used if CD4 counts drop below 200/mm3 Although a blanket policy of cesarean section is not universally acceptable, women infected with HIV should be informed of the benefit of reduction of transmission with elective cesarean section Medical Disorders in Pregnancy 1115 Universal precautions should strictly be observed by all medical staff during delivery All babies born should be immediately seen by a neonatologist for further management Breast-feeding, which significantly increases the risk of vertical transmission, should be discouraged as formula feeding is readily available in Singapore Many physicians are less than familiar with the physiological adaptation to pregnancy and medical disorders that are encountered in obstetric practice Similarly, obstetricians may not feel confident to manage all medical complications of pregnancy since many of these conditions are seen infrequently in general obstetric practice A multi-disciplinary approach and close collaborative effort by obstetricians, physicians, anesthetists and neonatologists with strong support from para-clinical services are essential to ensure that patients receive optimal care FURTHER READING Nelson–Piercy C, Handbook of Obstetric Medicine, Isis Medical Media, 1997 deSwiet M, Medical Disorders in Obstetric Practice, 3rd Blackwell Scientific Publications, Oxford, 1994 Medical Disorders in Pregnancy Annals, Academy of Medicine, Singapore 31(3):8, 2002 Redman CWG, Roberts JM, Management of Pre-eclampsia, Lancet 341(8858):1451–1454, 1993 Royal College of Obstetricians & Gynaecologists, Thromboembolic Disease in Gynaecology and Pregnancy: Recommendation for Prophylaxis, RCOG, London, 1995 American Diabetes Association, Gestational Diabetes Mellitus, Diabetes Care 22:574–576, 1999 Mir N, Bingham JS, The Management of HIV Infection during Pregnancy, Maternal Child Health 21:64–68, 1996 Confidential Enquiries into Maternal Deaths in the United Kingdom 1994–1996, HMSO, London This page intentionally left blank Pediatrics This page intentionally left blank 65 Practical Genetic Counseling Ho Lai Yun DEFINITION Genetic counseling is a process whereby an individual or family is given information about a real or a possible genetic problem It is a dynamic communicative and educational process The objective is to assist them to: 1) understand the medical facts, including the diagnosis, probable course of the disorder, and the available management; 2) appreciate the way heredity contributes to the disorder, and the risk of recurrence; 3) understand the options for dealing with the risk of recurrence; 4) choose the course of action that seems appropriate for them in view of their risk, their family goals, and their ethical and religious standards, and to act in accordance with that decision; and 5) come to terms with the issues they face and make the best possible adjustment to the disorder Genetic counseling is directly concerned with human behavior, so it must be based on an understanding of the psychological meanings of 1119 1120 A Clinical Approach to Medicine health and illness, procreation, and parenthood The responsibility of the counselor must include helping the family adjust psychologically and socially to their genetic condition Achievement of these goals requires proper training and an understanding of the genetic counseling process so that the information will not be misunderstood, misinterpreted, or misused, with potentially tragic consequences INDICATIONS OF GENETIC COUNSELING Anybody who has reason to suspect that there might be an increased risk of producing a child with a birth defect should at some stage receive formal genetic counseling This would include: 1) Couples who have previously had an unexplained stillbirth or neonatal death; 2) Couples who already have given birth to a child with a birth defect or medical problem; 3) Couples who have a child with mental retardation or developmental disabilities; 4) Couples who have relatives with known genetic disorders; 5) Couples who have a family history of any of the above; 6) Mothers who have had recurrent pregnancy loss; 7) Mothers exposed to possible teratogenic drugs, infections, radiation or other occupational hazards during or before pregnancy; 8) Mothers with pre-existing diseases, where either the disease or its treatment may have adverse effects on the infant; 9) Advanced parental age: maternal age over 35 and paternal age over 40; 10) Couples in consanguineous marriages; 11) Couples who have a previous child with a chromosomal abnormality or are themselves a translocation carrier; and 12) Family history of psychiatric disorder ACCURATE DIAGNOSIS The cornerstone of genetic counseling is to establish and confirm the diagnosis Because even the best counseling cannot make up for an inaccurate diagnosis, a great degree of diagnostic precision is required For Practical Genetic Counseling 1121 example, a patient with muscular dystrophy can be correctly managed with the use of splints, wheelchairs and physiotherapy, without knowing precisely the type of muscular dystrophy Genetic counseling in such a patient or family will require a precise diagnosis, confirmed by appropriate blood, EMG and muscle biopsy studies The number of genetic disorders described is increasing exponentially and the disorders may be very rare A specialist cannot rely solely on his own personal experience, but must be familiar with the literature He may require the help of specialists in other fields to differentiate and confirm a diagnosis Genetic Heterogeneity Genetic heterogeneity should be recognized At the clinical level, two or more disorders may have the same phenotype, e.g both Marfan syndrome and homocystinuria have dislocations of the lenses with a similar physical habitus, but Marfan syndrome is autosomal dominant, whereas homocystinuria is autosomal recessive At least 20 different forms of muscular dystrophy that are clinically similar have been identified Both sexlinked and autosomal recessive forms are known At least two, Becker and Duchenne dystrophy, are sex-linked conditions that are allelic but clinically quite distinct, the latter being much less severe Genetic heterogeneity can now be demonstrated at the molecular level, even when there appears to be no differences in phenotype or mode of inheritance Nongenetic factors can mimic genetic factors (phenocopies); a good history and clinical and laboratory studies may help in differentiation The possibility of non-paternity must also be considered Review of Medical Records Establishing a diagnosis involves reviewing the relevant medical records, which can be a difficult task to accomplish completely The rate of progression of symptoms and signs, the development of the physical findings, and the results of prior laboratory tests, are all best determined from the medical records The status of the family members can sometimes be assessed from examination of their medical records A relative may seem to have the same problem but the medical records could reveal an entirely different problem 1122 A Clinical Approach to Medicine Medical History The medical history should include a thorough account of any untoward reproductive outcome, including spontaneous abortions, stillbirths, and abnormal infants Issues to be addressed in the pregnancy history include problems conceiving, bleeding, maternal illnesses or exposures, medications, cigarette smoking, amounts of alcohol intake, and possible exposures to teratogens Information such as onset and intensity of fetal activity may help to differentiate a prenatal from a postnatal problem It is often helpful to ask if this pregnancy was different from others in any way A perinatal history should be obtained A family history should always be taken in a pedigree form with a minimum of three generations Parental ages should be recorded Besides the known association between advanced maternal age and chromosomal abnormalities like Down syndrome, advanced paternal age is known to confer increased risk for new dominant mutations The possibility of consanguinity should be explored It is necessary to probe deeply into the medical background and development of all first-degree relatives (siblings, parents, and offspring), second-degree relatives (uncles, aunts, nephews, nieces, and grandparents), and third-degree relatives (first cousins), and, in all cases, objective documentation should be sought when possible Information about ethnic background may be valuable Physical Examination The physical examination should document features that vary from the usual or normal structure Minor abnormalities are stressed as well as more obvious defects Clinical impressions may be misleading and accurate measurements are required to confirm features such as widely spaced eyes or disproportionate short stature These observations should be interpreted with regard to normal standards and familial variant developmental patterns Photographs may be taken to document significant findings Recording of the fingerprint pattern (dermatoglyphics) may provide important clues to the diagnosis, e.g a predominance of whorls in Turner syndrome and ulnar loops in Trisomy 21 It may also be necessary to examine parents, siblings, and even more distant relatives to make a diagnosis Practical Genetic Counseling 1123 Laboratory Investigations The need for specific laboratory tests varies with the situation Because these tests are expensive, they should be ordered with care, but certainly done when important Chromosomal analysis is indicated in any child with multiple major or minor anomalies that is not etiologically welldefined, particularly if associated with mental retardation or developmental delay It is also important to karyotype patients who have apparently clear-cut diagnoses if there are any atypical features or if the patient has features of two or more distinct syndromes Karyotyping is also recommended for fetuses, stillbirths, and neonatal deaths that only have one obvious anomaly because of the possibility of finding other birth defects during a more thorough evaluation Skeletal radiographs are obtained on any patient with disproportionate short stature and on many patients with proportionate short stature Craniofacial radiographs may be useful for anomalies of the skull or face Other special studies like ultrasonography, or computed tomography may be indicated in selected cases Post-mortem Examination Post-mortem is one way of establishing a precise diagnosis This is of particular importance in a child with malformation or retardation when a clinical diagnosis is not possible Fetuses, stillbirths, and neonatal deaths should have thorough post-mortem examinations Post-mortems need to be planned in advance so that specific tissues can be obtained for biochemical study, electron microscopy or histochemistry It is best to raise the issue of a post-mortem before death occurs, especially if death can be anticipated It may work better than asking permission immediately after the death when families are in grief When permission has been granted, the parents should return to discuss the autopsy findings MOLECULAR GENETIC ANALYSIS Advances in DNA technology that can provide precise definitions of the mutation or utilize linkages to a specific genetic marker has revolutionalized genetic counseling In the past, the chromosomal location of specific genes was inferred from pedigree information for the X chromosome and 1124 A Clinical Approach to Medicine linkage to specific protein markers for autosomes Now, the location of many genes on the chromosomes is known, linkage to specific DNA markers has been established, and many genes of clinical importance have been cloned and sequenced The number of conditions that shows linkage to known genetic markers or to DNA probes grows rapidly Some of the conditions for which DNA-based diagnosis has been accomplished include cystic fibrosis, hemophilia A, Huntington disease, thalassemia, phenylketonuria, etc It is now possible to store samples of DNA from patients who are likely to die and relatives such as grandparents so that subsequent family members may benefit from the advancing technology WHEN DIAGNOSIS IS UNCERTAIN Unfortunately, despite the most intensive efforts, a definitive diagnosis cannot always be established because the appropriate investigations might not have been obtained while the relevant person was alive or there is inadequate information Of the children presenting with retardation or dysmorphic features, about one-half will not have a precise diagnosis In such cases, advice can only be given on the basis of a probable diagnosis and a large body of empirical data used for counseling While an inability to label a child with a specific diagnosis is disappointing and frustrating, it should not disadvantage the child as management can be based on periodic assessment and planning Parents should be told that all reasonable steps have been taken to look for known disorders The evolution of knowledge and new techniques make re-study of old problems necessary ESTIMATION OF RISKS Risk is a numerical estimate of the probability of a particular genetic disorder occurring in a subsequent child and in members of the family In some counseling situations, calculation of the recurrence risk is relatively straightforward and requires little more than a reasonable knowledge of Mendelian inheritance The risks of recurrence in this group are high but most of the diseases are rare Sometimes, these strictly genetic risks are modified by Bayesian methods of calculation to take into account information about specific family members, age of onset, penetrance, and laboratory tests results Such calculations may be more complex but are Practical Genetic Counseling 1125 particularly useful to estimate the likelihood that a person is the carrier of an X-linked condition or of an incompletely penetrant autosomal dominant trait Nowadays, however, molecular diagnostic technology has greatly refined the ability to determine heterozygosity in many situations The risk with chromosomal translocations varies according to the chromosome involved With better chromosome staining technique, many more translocations are identified; some involve only small pieces of a chromosome There are many common disorders in which there is a genetic component and where the inheritance pattern cannot be explained simply in terms of Mendelian inheritance or chromosomal rearrangement These disorders are due to the cumulative action of a number of genes together with environmental influences This is called polygenic or multifactorial inheritance Examples of multifactorial inheritance include neural tube defects, congenital heart diseases, cleft lip and palates, congenital pyloric stenosis, and diabetes mellitus It is the most common pattern of inheritance responsible for the family tendency or predisposition to various disorders Fortunately the risks of recurrence are usually small When risks cannot be predicted by formal genetic methods, empirically derived estimates of risks are used The empirical risk is defined as the probability of occurrence of a specified condition based upon prior experience and observation, and is determined by estimating the frequency of the condition in the relatives of affected persons When empirical figures are used, however, the populations used to calculate the risks must be representative of the population from which the particular family is drawn COMMUNICATION OF INFORMATION The ability to share threatening or unpleasant information incorporates both the science and the art of clinical medicine All interactions must be open and honest, reflect a genuine sense of caring, and built on a firm foundation of trust Such relationships cannot be developed instantaneously; they must be nurtured and allowed to evolve over time Inform the family as soon as possible Most families prefer to be told as soon as a problem is suspected, even if it is incomplete and uncertain Although this often refers to bad news, it is equally important that good news should not be withheld when available 1126 A Clinical Approach to Medicine Parents also need to be reassured that they not have, or are not at risk for, a certain disorder after investigations Choose the right time and the right place for the right information The counseling session should be held in a suitable environment that provides protection and security A private and quiet setting that is free of distractions or interruptions, such as supervising young children during the session, will afford an opportunity for reflection and the provision of meaningful support Information should not be transmitted over the telephone, in the corridor, or crowded waiting room, or when strangers are present The family must have the clinician’s undivided attention Choosing the right time for counseling is very important The couples who have just produced a child with a birth defect or whose child has just died from a major congenital malformation will usually want some time to come to terms with their loss before considering a possible recurrence in future pregnancies On the other hand, leaving counseling until a pregnancy is advanced may produce an emotional crisis, which could have been avoided by anticipation In families where there is a risk of producing a child with a birth defect, they should be informed of the availability of counseling service, and counseling should certainly be offered at the time they become concerned about the family history or are contemplating having children The key people must be present Every effort should be made to ensure that both parents are present when difficult information about their child is discussed When appropriate, other important people (e.g grandparents) may be allowed at the discretion of the parents The inclusion of more than one parent provides an additional source of support and relieves one family member of the responsibility of transmitting information and answering questions for the others Prioritize the message Before talking to the family, the clinician must identify the most important message to convey — what is the most important message for the family to understand? When multiple issues are to be addressed, it is Practical Genetic Counseling 1127 important that the core message relate closely to the primary concerns that have prompted medical intervention The most salient information should be delivered at the beginning in a brief, direct, and sensitive manner It is not unusual that the family will stop listening after being told the traumatic news Proper language should be used It is important for the family to trust that the clinician undergoing the counseling knows them and their child, and is genuinely interested in helping them Always refer to the child by name and acknowledge specifically his or her personal characteristics It would be a disaster if the sex of the child is mentioned wrongly, and it would be even worse if the fetus is referred to as “it” The communication of information should be versed in language that is straightforward and understandable Technical terms should be avoided where possible Unfamiliar words and medical terms should be written out so that the parents can subsequently search for relevant information about that condition Visual aids such as diagrams, pictures, photographs, sample pedigrees, and other written materials should be freely referred to Translation, if necessary, should be verbatim It is not unusual to find that the interpreter is digesting the information and passing it on in such a way that it is inaccurate and that any decisions made reflect the interpreter’s beliefs and wishes Appreciate parents’ reaction During the counseling session, the clinician must be able to assess the cognitive and emotional dimensions of the parents’ verbal and nonverbal reactions, and be prepared to stop, to listen, and to wait for a reaction and guidance from the family on the direction of the dialogue Families vary dramatically in the extent to which they feel comfortable sharing their inner feelings It is important for the clinician to encourage the parents to express and explore their own feelings, and to allow and support a range of emotions, including tears, anger, and withdrawal Ask the question, “How you feel about what I have just shared with you?” rather than trying to be sympathetic by saying, “I understand how you feel” 1128 A Clinical Approach to Medicine Answer concerns and questions honestly and openly Sufficient time should be allocated for parents to ask questions All questions must be answered directly and openly Some persons come “armed” with questions they want answered They would have visited the library or searched websites in an attempt to find literature about the disorder or asked medical friends to so Sometimes, this results in wrong or dated information However, most families are fairly naïve with regard to biology and medicine and they not have sufficient background to ask all of the questions that may have significant impact on their decisions It is useful to place oneself in the position of the family member by asking, “if I were in this position, what kinds of information would I want to know?” When the answer is unclear, it is important to distinguish between responses to questions that cannot be answered because of the limitations of the clinician’s knowledge (e.g “I not know the answer to your question, but I will find out for you”) and responses to questions that are essentially unanswerable (e.g “It is difficult to say what your child will be like years from now”) In the latter case, it is helpful to explain why the question cannot be answered and to discuss the process by which the professional and family together can try to reach a greater understanding, if not a definitive conclusion It is also important to raise and answer questions that the parents not identify (e.g whether the child’s condition is in any way their fault) Balance the message It is important for the clinician to assess at the end of a counseling session the family’s understanding of the child’s problem, and whether the perceptions are reasonably balanced, given the seriousness of the child’s condition Some parents may react with a sense of despondency and hopelessness Others may seem not to hear the gravity of the situation A skilled and sensitive clinician will listen to the parents and make a judgement about whether they are overly pessimistic or excessively optimistic In the former, it is necessary to underscore a sense of hope with specific examples of potential positive outcomes (e.g “Your child will always continue to gain new skills”) In the latter case, it may be necessary to acknowledge the grounds for optimism but gently remind the family about concerns and their probable sequelae (e.g “Your child will always Practical Genetic Counseling 1129 need special help in school”) No family should leave the counseling session without any sense of hope Do not make assumptions We also sometimes assume that we know what the parents will want to do, because of their ethnic group, social class, or religious beliefs Yet, in practice, we are often surprised We must all guard against making assumptions and thereby making decisions for people Discuss the next step At the end of each counseling session, there should be no ambiguity with respect to the division of responsibilities between parents and the professional regarding subsequent management and care Specific plans for further consultations, referrals, evaluations, and arrangements for appropriate therapeutic, educational, and supportive services should be discussed Requests for second opinion should be honored and facilitated, and not interpreted as threatening and distrust Check whether the message has been heard It is useful to determine whether the family has heard and understood the important content of the counseling The counseling session may be so intimidating and so full of factual information that the amount and accuracy of information retained by many persons on follow-up at a later date is often disappointing The process of providing information is usually an ongoing one Whilst it is possible for a family to be counseled in a single visit, a repeat counseling session is often required to reinforce the points covered and to answer queries from the family Providing written material about the disorder is often helpful Pamphlets, booklets, and other literature may provide additional information It may be helpful to follow the sessions with a written report summarizing the important points discussed in simple language Ongoing process Providing information to a family is always an ongoing process Often, the clinician will need to meet with the family on more than one occasion, 1130 A Clinical Approach to Medicine initially because of critical medical circumstances and then later to obtain additional information or to discuss test results However, even when all the available information has been provided, it is appropriate for the family to keep in touch on a regular basis because of the possibility that there is a new development in diagnostic and management techniques, new methods of prenatal diagnosis or carrier detection, and so forth NON-DIRECTIVE APPROACH The clinician is accustomed to issuing therapeutic directives, and patients are invariably dependent on such instructions in order to improve their health status However, there is universal agreement that genetic counseling should be non-directive and non-coercive This approach does not tell families what they should do, but rather what they could Each disorder has a unique set of complications, diagnostic possibilities, and natural history The family brings to the counseling session a unique set of personal and cultural experiences The counseling clinician also brings to the case his or her own set of values These values may affect the way in which counseling is provided if great care is not taken to avoid judgemental or directive advice The intrinsic danger of using a directive approach is the opportunity for the counselor to insinuate his or her own religious, cultural, eugenic, or other beliefs or dictates of conscience into the counseling that is offered, subconsciously or inadvertently An optimistic counselor may tell anxious individuals not to worry, whereas a pessimistic one might unwittingly exaggerate the significance of even small risks In the non-directive approach, the counselor should recognize his own biases and try to remain impartial and objective when providing information without dictating a particular course of action Of course, completely non-directive counseling is probably unrealistic, particularly if the counselor is familiar with the long-term burden of a genetic disorder and he may have concerns about society at large The natural tendency for counselors to interject their own biases by either verbal or non-verbal messages is always present HELP WITH DECISION MAKING Counseling is a process that cannot be hurried and it is not appropriate to try and elicit a response of what options a couple might choose at the Practical Genetic Counseling 1131 session but to allow them time to reflect The counselor should attempt to provide a balanced presentation allowing the couple to make intelligent and reasoned decisions for their future and to support them in their choice There is a well-established maxim that it is the couple and not the counselor who have to live with the consequences of the decision While the principle of a non-directive approach should be upheld, it is incorrect to provide a mass of medical facts and leave the couple adrift without specific guidance The counselor may need to help them try different alternatives “on for size,” imagining how each would feel with a particular decision and how the possible outcomes of each choice might affect their lives If the responses of different family members — particularly the husband and wife — are different and would lead to incompatible decision, the counselor needs to help them resolve the conflict This can be done by working with them on values clarification Which of the alternatives is most consonant with what they believe? Which would be most harmful to their relationship (family, status, lifestyle, self-image, etc.)? Sometimes it may help to have each party articulate what he or she perceives as the “best case” and “worst case” outcomes of each decision and why The counselor may also have to guide the couple towards what is acceptable not only medically but also morally and socially, and what is within the law PERCEPTION AND ACCEPTABILITY OF GENETIC RISKS The provision of a recurrence risk does not simply involve conveying a stark risk figure in isolation Recurrence risks should not only be quantified, but also be qualified and placed in context The perception of risk may be of more importance in family decision making than the actual numerical value of the risk Many families may not be able to appreciate the concept of probability and need a careful discussion to give meaning to any risk estimate Many people may think that a in risk means that the next three children will be unaffected It is therefore important to emphasize to families that chance has no memory and the chance of their having an affected child is the same with each pregnancy, irrespective of whether or not they have already had any affected children A simple illustration like tossing a coin may help to explain the concept: it cannot be expected to remember whether it came down heads or tails at the last throw and cannot 1132 A Clinical Approach to Medicine therefore be expected to know what it should be at the next throw Continuing the coin analogy, the good side of the coin should also be emphasized For example, a couple faced with a probability of in that their next baby will be affected should be reminded that there are chances out of that their next baby will not be affected How different people perceive the same genetic risk varies widely, from overly cautious to reckless What may seem high to one person may be interpreted as low or moderate by another A useful point of reference is to compare the risk with the background risk in the general population If the risk of any child born with any major birth defect is in 30 in a population, it will be the baseline figure that any family in that population either accepts or ignores It is reasonable to tell the families that risks of in and in can be considered high; risks of less than in 100 are low; and other risks are intermediate THE BURDEN OF THE CHOICE Several studies have indicated that the factor that most influences parents when deciding whether or not to have another child is the nature of the long-term burden associated with a risk rather than its precise numerical value Burden is a mathematically undefined quantity that combines elements such as severity, chronicity and duration, availability of therapy, religious attitudes, financial costs, social discomfort, education, and the like Parents of a baby recently diagnosed to have a genetic condition may have little idea of what lies ahead for the child and themselves It is necessary to give the parents an understanding of what is going to be involved in the care of the child including the length of survival, the quality of life, treatment and complications, and the cost The judgement of burden is a very personal one A physical handicap may be a severe burden for one family, whereas another may find that tolerable but a mental handicap unacceptable Some parents are prepared to accept a in risk of producing a child with a lethal condition like Pompes disease, knowing that the child will not survive long or be normal Therefore, individuals differ significantly when estimating the burden and acceptability of a condition It is particularly important for the couples to realize that in general there is no “right” or “wrong” decision to be made, but that the decision should be the right one for their own particular situation It is also important that the counselors not judge Practical Genetic Counseling 1133 “success” or “failure” in terms of a particular outcome, and that they give support to families whatever their decisions may be LIFE-PLANNING AND REPRODUCTIVE DECISIONS There are also alternatives that may improve the family-at-risk’s chances of having healthy children In general term, adoption is a perfectly reasonable option, although in practice the number of couples wishing to adopt far exceeds the number of babies and children available for adoption Some form of reproductive assistance may be applicable to some families Artificial insemination by donor is genetically appropriate if a disease is recessive or if the father is the carrier of an autosomal dominant condition, but it is of limited appeal and many couples and ethnic groups may find it unacceptable In vitro fertilization with donor ovum may be possible if the mother is the carrier In both situations, the risk of the same genotype in the donor must be excluded Prenatal diagnosis with selective termination of an affected fetus is now an accepted option for families at high risk of having a child with a serious birth defect that may or may not be genetic in nature The availability of prenatal diagnosis nowadays gives many high-risk couples the courage to try again for a healthy baby PRENATAL DIAGNOSIS The ability to diagnose fetal abnormality has become increasingly sophisticated, and the once reclusive fetus has become the unborn patient Normal and abnormal fetal anatomy can now be accurately delineated by powerful non-invasive imaging techniques The fetal genome can be probed for defects by chorionic villus sampling, amniocentesis and fetal blood sampling As technology improves, the indications for and accuracy of prenatal diagnosis can only increase Nowadays, a large proportion of pregnant women undergo at least one ultrasound study during pregnancy, and more congenital abnormalities are being detected before birth even in low-risk women Pregnancy screening tests for specific disorders like neural tube defects, Down syndrome, and hemoglobinopathies will help to select out at-risk pregnancies for more elaborate investigations Prenatal diagnosis not only gives women the option to interrupt an abnormal pregnancy but also allows the physician to give 1134 A Clinical Approach to Medicine optimal care during and immediately after delivery When intrauterine therapy and even fetal surgery become more feasible, prenatal diagnosis will become even more important in the process of genetic counseling Couples must know the difference between prenatal genetic screening (e.g maternal serum alpha-fetoprotein screening) and prenatal genetic diagnosis The former is generally not designed to detect all affected fetuses; there must be an acceptable balance between false-positive and false-negative results On the other hand, prenatal genetic diagnosis indeed attempts to detect each affected fetus When offering prenatal diagnosis, it is critical that extremely clear counseling should be given to the couple, spelling out the expectations and limitations of the testing prior to any procedures The focus of the diagnostic procedure must be explained It is very easy for the woman to conclude that a normal test result shows that the baby will be “normal” when in fact only a short list of conditions has been excluded It is therefore important to point out that a condition or conditions for which the unborn child had a risk higher than that of the general population have been focused upon After these conditions have been excluded, the pregnancy still stands at the same risk for many other potential problems as others in the population Couples must understand that undergoing prenatal screening or diagnostic testing cannot guarantee a normal child Although the possibility of an abnormal test result should be discussed beforehand and the options considered, it may not be necessary for the woman to make a decision prior to learning the test results The implications of the diagnosis must be reviewed with care, sensitivity, and accuracy The options for the woman are to terminate the pregnancy or to carry it to term The decision to terminate must be made in collaboration with the obstetrician who will perform the procedure so that the process can be described and possible complications reviewed The choice of procedure depends on the stage of pregnancy, and the complications are specific to the particular procedure A recent extension of prenatal diagnostic techniques is pre-implantation diagnosis An ovulated egg is removed and fertilized in vitro with the husband’s sperm It is then cultured in the laboratory up to the eight-cell stage One cell is carefully removed and the DNA sequence is amplified by polymerase chain reaction The resultant amplified DNA is then studied using appropriate gene probes to see if the pre-embryo carries a particular genetic disorder If not, it is implanted in the mother’s uterus and Practical Genetic Counseling 1135 the pregnancy is allowed to continue Since the techniques of reimplantation diagnosis obviate the possibility of abortion, it could well become the preferred methods of prenatal diagnosis in future although such methods may be limited to certain specialized centers because of the technical problems CARE OF THE FAMILY The emotional impact of having a child with birth defects on the family is considerable and should be carefully explored Psychological defences underlie all genetic counseling sessions If not appreciated, these defences can impede the entire counseling process Families and individuals will usually go through predictable stages of emotional response when a child is found to have a genetic disorder: first there is denial, then a sense of loss and grieving, then anger and seeking someone to blame, followed by resignation, acceptance, and the search for meaningful and useful action Depending on which stage they are experiencing, information will be received in very different ways In addition, different family members will often be at different stages They will need an opportunity to ventilate their fears and anxieties The counselor or members of the counseling team must understand the process of mourning and contribute to the emotional healing process in the family Many families have difficulty in knowing how to let friends and other family members know about the problems the affected child has It is important to help the family find the language to deal with their particular situation It is also important to help the family find ways to break the silence that their friends often maintain because of their own discomfort regarding the problems of the child or their concern over embarrassing the family If the child has obvious physical abnormalities, the family needs to prepare themselves to deal with the curiosity and rudeness of strangers They should be encouraged to smile and be interactive on their “good days”, while they should feel free to respond to rudeness by identifying it as rudeness on their “bad days” Discussing these feelings and experiences with other parents who have a similarly affected child can be helpful to a family in normalizing and validating their feelings and in finding alternative ways to deal with difficult situations It is important to remind the family that the decisions and plans they have made need to be discussed regularly among the family members, 1136 A Clinical Approach to Medicine since many things can change over time The family of a child with Down syndrome may find it helpful to sit down at appropriate time and ask how each member is coping Are the normal children being neglected? Does all the activity of the family center around the child with a disability? Is the marital relationship suffering because the parents have little time alone together? By recognizing such problems, a family can plan changes for the coming year, making sure that time is set aside for the entire family, and that each family member receives special attention This reassessment will help maintain the cohesion of the family and allow members to cope with the stresses of disability without sacrificing their own needs The parents of a child born with an abnormality need to become experts on that abnormality Frequently, their experience will provide them with more information and knowledge than most physicians have, particularly in the case of a rare condition They are encouraged to develop their knowledge through appropriate reading and to seek out other parents or a support group for families of children with their particular disorder In reading medical information, a family will probably need a certain amount of interpretation so that they not go off on tangents In the long run, such knowledge and support will be useful in obtaining the best possible care for their child, as well as helping to realize the child’s full potential FURTHER READING Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds.), Principles and Practice of Medical Genetics, 4th ed., Churchill Livingstone, London, 2002 Harrison MR, Evans MI, Adzick NS, Holzgreve W (eds.), The Unborn Patient: The Art and Science of Fetal Therapy, 3rd ed., WB Saunders, Philadelphia, 2001 Rodeck CH, Whittle MJ (eds.), Fetal Medicine: Basic Science and Clinical Practice, Churchill Livingstone, London, 1999 Twining P, McHugo JM, Pilling DW (eds.), Textbook of Fetal Abnormalities, Churchill Livingstone, London, 2000 Milunsky A (ed.), Genetic Disorders and The Fetus: Diagnosis, Prevention, and Treatment, 4th ed., The John Hopkins University Press, Baltimore and London, 1998 Stevenson RE, Hall JG, Goodman RM (eds.), Human Malformations and Related Anomalies, Oxford Monographs on Medical Genetics No 27, Oxford University Press, New York and London, 1993 Practical Genetic Counseling 1137 Mueller RE, Young ID (eds.), Emery’s Elements of Medical Genetics, 10th ed., Churchill Livingstone, London, 1998 Brock DJH, Rodeck CH, Ferguson–Smith MA (eds.), Prenatal Diagnosis and Screening, Churchill Livingstone, London, 1992 Harper PS, Practical Genetic Counselling, 5th ed., Butterworth– Heinemann, Oxford, 1998 This page intentionally left blank 66 The Child with Learning Problems Ho Lai Yun INTRODUCTION The child with learning problems has a marked disadvantage in a society that places an extremely high value on achievement, rewarding individuals who are successful and ignoring or punishing those who are not Children who deviate from “normal” pathways of academic achievement and progress usually create concern, anxiety, and stress for parents, teachers, and those who are attempting to help the child reach his full potential Many will resort to seeking medical assistance Yet medical practitioners, including pediatricians, are ill equipped to offer adequate help Past medical apathy may have been the result of little or no formal training in his area, the time-consuming nature of the problem, and the lack of assignment of a specific role In addition, uncertainty surrounds terminology, classification is still in a state of evolution, manifestations may be deceptive, and causation remains essentially hypothetical As each discipline tends to perceive problems in its own context, management therefore varies with seasonal fashions Appropriate educational resources are both stretched and limited and eventual outcome is doubtful 1139 1140 A Clinical Approach to Medicine Learning problems are common, with a conservative estimate of some 5–15% of school-aged children struggling with learning or requiring special help The prevalence varies with definitions and diagnostic criteria These problems affect more boys than girls, the most commonly quoted ratio being approximately 4:1 Although learning problems are fundamentally educational problems, the complex nature of disorders of learning has prompted increased involvement of medical professionals There are important roles for the pediatricians in the care of these children These include: 1) The early screening and detection of the developmental dysfunction and exclusion of neurological and other health problems 2) Careful evaluation to elucidate the nature and extent of the underlying dysfunctions, the possible etiological factors, the behavioral complications, and other important environmental factors 3) Participation in multidisciplinary management teams 4) Application and supervision of medical therapies 5) Coordination of evaluative, therapeutic, consultative, educational, and counseling services 6) Long-term monitoring and management 7) Advocacy for the child and family in the community, and particularly within the school system EMOTIONAL SEQUELAE OF LEARNING DISORDERS Problems in learning often occur at critical points in a child’s development During the interval from three through nine years, children initiate attempts at independent functioning and definition of self-identity The developmental changes formulate the basic structure of their future personality A complex relationship exists between the physical, cognitive, and emotional components of a child’s development The child with learning problems experiences numerous obstacles that prevent a healthy interaction between these factors Considerable emotional damage can result from protracted periods of anxiety and stress emanating from a tense or disappointing learning experience Frequently, the emotional components of the learning disability represent a more serious threat than does the specific learning disorder per se (Fig 1) Parental responses to the underachieving child are often unrealistic and harsh, expressing their feelings of guilt and disappointment in the The Child with Learning Problems 1141 POOR SELF-CONCEPT Negative self-image Lack of self-esteem Lack of motivation Loss of confidence Feeling unworthy ENVIRONMENTAL CHANGES Repeated failures Lack of success experiences Increasing tensions Recurrent stresses Mounting anxiety Continual frustrations Fear of failure Persistent negative feedback Family and peer pressure NEGATIVE PSYCHOSOCIAL FACTORS Weak family supports Poor peer interaction Academic difficulties Inadequate coping skills Physical and emotional handicaps CHILDHOOD and ADOLESCENT PROBLEMS Psychosomatic complaints Depression (Self-mutilation, suicide, apathy, withdrawal) Anxiety and acting-out behaviors (Aggression, oppositional tendencies, attention-seeking, hyperactivity, tics) Antisocial behaviors (Juvenile delinquency, runaway, substance abuse) Fig Emotional sequelae of school failure form of anger and hostility The bottom line of repeated frustrations, anxieties, and negative reinforcements is a loss of self-esteem and a lack of selfconfidence The disrupted balance can ultimately result in disturbed behaviors at home and in the classroom The child often enters the examination room with his eyes and head down, realizing that once again he is expected to perform for someone who will reveal his lack of ability He frequently exhibits defensive behaviors, attempting to excuse what he anticipates to be a poor performance The child becomes increasingly frustrated with his inability to perform a task successfully, exhibiting aggressiveness toward the examiner in the form of resistance, poor cooperation, lack of attention, or a flippant attitude Lack of success experiences generates additional emotional stress The child anticipates difficulty in almost every situation and becomes emotionally paralyzed with fear of failure and expected rejection Because school attendance is mandatory and the child cannot leave physically, he compensates by withdrawing psychologically, daydreaming and thinking more pleasurable thoughts of enjoyable times He avoids what he regards to be aversive stimuli: the teacher, the writing board, and classmates Occasionally, he may manifest psychosomatic complaints and symptoms of school phobia If the academic environment 1142 A Clinical Approach to Medicine remains uncomfortable, the child may participate in school truancy or, in some instances, school vandalism Hyperactivity is a very disturbing and disrupting classroom behavior for teacher and peers It has been assumed to be associated only with attention deficit hyperactivity disorder However, hyperactivity may also be situational, induced by an emotional state such as anxiety, tension, and frustration, and is sometimes overlooked in haste to define an organic etiology The child who reacts aggressively to the teacher frequently craves attention, gaining recognition by acting-out behaviors Eventually, the effects of poor self-concept extend beyond the school environment to involve behaviors at home Chronic feelings of worthlessness, lack of confidence and motivation, and depression, if unattended to, may result in serious adolescent and adult personality disorders Numerous investigations have revealed that an overwhelming number of youth offenders are severely retarded in reading The reading disabilities are not caused by antisocial and rebellious attitudes that made them difficult to teach, but by underlying specific learning disabilities Perceptual handicaps causing poor academic skills are also found in a large number of youth offenders The severity of the reading disability is directly proportional to the seriousness of the perceptual deficits, confirming a relationship between learning disorders and delinquent behavior In addition, many juvenile delinquents present a history in which there are prominent characteristics of attention deficit hyperactivity disorder such as short attention span, poor impulse control, and distractibility The child who is continually frustrated may attack the system that causes his discomfort, that is, the school and society in general FACTORS AFFECTING LEARNING Many children with learning problems not have a single identifiable cause A number of factors are likely to contribute to a child’s problems These can include constitutional or intrinsic factors within the child or factors within the environment It is the interaction of these factors, which over time leads to the dysfunction, that presents as learning difficulties Within the Child • Perinatal stress While any form of perinatal stress may be a potential contributor to subsequent learning problems, there is no clear one-to-one relationship The Child with Learning Problems 1143 Prematurity, intrauterine growth restriction, hypoxia, and other perinatal factors are sometimes associated with subsequent developmental difficulties However, the majority of children with learning problems not have any abnormal perinatal history Conversely, a significant number of children with perinatal stress subsequently have normal academic achievement The beneficial effects of a favorable environment may modify the potential of a poor outcome resulting from perinatal stress significantly • Chronic disease and health problems Children with any form of chronic disease may have learning problems The disease itself may be responsible (e.g seizure disorder) or in some instances the treatment of the disease may contribute (e.g side-effects of medications) There may be frequent absences from school because of hospitalizations or episodes of illness A child with chronic disease may have low self-esteem and self-confidence, resulting in decreased motivation Peer relationships may be affected, as his peer group may perceive the child as being different in some way The child may be less active and not able to participate in regular classroom and physical activities Parents and teachers may sometimes unwittingly reinforce the sick role in these children However, there are many children with chronic and disabling illnesses who not appear to suffer any learning problems, and, in fact, a number seem to be spurred on to later achievement • Genetic factors It is commonly said that cognitive ability, intelligence and other personality traits are inherited A family history of learning disabilities may be present and in some children there does seem to be an inherited basis for their problems However, it is only in a minority of children that a specific genetic diagnosis or a recognizable syndrome can be made and are associated with decreased cognitive ability and learning difficulties • Sensory impairment Children with subtle hearing problems are at increased risk of learning problems This applies not only to those with sensorineural deafness, but particularly to those with repeated ear infections, leading to chronic otitis media and fluctuating conductive hearing loss, which often is unsuspected and undetected These children may develop 1144 A Clinical Approach to Medicine subtle language and academic problems, as well as problems with attention and behavior Similarly, children with any form of visual problems that affect acuity or eye movements will be at risk • Temperamental styles and personality traits Children are born with unique temperamental characteristics that define their particular behavioral styles These characteristics are derived from constitutional, intrauterine, central nervous system, and postnatal environmental factors These temperamental characteristics not, in and of themselves, cause problems Rather, the “Goodness of Fit” between the child’s temperament and the demands and expectations of the parents, teachers, or caregivers is important in avoiding and resolving conflicts that may lead to suboptimal learning experiences and difficulties • Developmental differences or weaknesses The major contributing factor to the learning problems in many children is weaknesses in one or more areas of development These are often subtle and not apparent during physical or neurological examination, and only elicited by detailed neurodevelopmental assessment It is only when the child is asked to perform specific age appropriate developmental tasks that these weaknesses become apparent Areas of development that are important for achieving learning competence include: language (receptive and expressive), auditory and visual sequencing, perceptual skills, motor skills (gross and fine motor functions), and attention Each child possesses a unique profile of strengths and weaknesses in these areas of development The concept of “differences in learning styles” is introduced to emphasize the different approaches to academic and other tasks that children naturally use according to their available strengths and areas of relative weaknesses These differences are the manifestations of complex profiles of distinct but interdependent biologically based capacities Within the Home • Stability and supportive qualities of the family These factors, as well as the physical and emotional health of the child, all determine the degree to which the child, can mobilize his intrinsic abilities for learning Children living in deprived socio-economic circumstances are at greater risk of reduced learning outcome There are The Child with Learning Problems 1145 multiple factors responsible, including suboptimal housing, inadequate medical care and nutrition, family disruptions, lack of early stimulation and learning experiences, poor role models, low parental education and expectations, and exposure to different combination of abuse and neglect • Cultural differences Children from different cultural backgrounds may have problems with language, with adapting to a new culture, and coping with the different values and aspirations of their peer group on the one hand and family on the other Maternal social isolation and depression are known to be associated with poor language acquisition in children and subsequent poorer learning Within the School Schools themselves exert powerful pressures and expectations, which may or may not match or take into account an individual child’s strengths and weaknesses Therefore, the educational experience may be positive or negative Class size, teacher personality, staff stability, cultural mix, resource availability, methods used, disciplinary attitudes, and peer contacts and relationship — all may influence children’s responses to learning, and their reception of education offered Children may vary in their school performance from year to year, depending on who is their teacher or the degree of acceptance with peer groups Fear, anxiety, uncertainty and diminished self-esteem can then block learning RECOGNIZABLE CLINICAL TYPES OF LEARNING DISORDERS The following broad clinical types of learning disorders have been recognized: • Global developmental delays or retardation in learning capacity refer to the learning delay and difficulties associated with overall reduced intellectual capacity Many children in this group always function below normal levels academically They struggle because their ability is in the borderline range, and they have particular difficulties with language skills 1146 A Clinical Approach to Medicine • • • Associated learning disorders refer to the learning difficulties children have because of another disorder, such as cerebral palsy, seizure disorders, or a hearing or visual defect Some of these disorders are behavioral in nature; such as autistic spectrum disorder, conduct disorders, and disorders associated with emotional and social adjustment Attention deficit A number of children have problems in focusing attention and maintaining concentration Many are also described as being overactive, fidgety, impulsive and distractible All these behaviors may contribute to problems in learning, as well as social difficulties Some of these children have attention deficit hyperactivity disorder, which is part of their intrinsic make-up In others, the behaviors are situational, resulting from emotional problems or anxiety, which are the sequelae of underlying developmental weaknesses such as auditory sequencing or language deficits, or hearing defects Specific learning disability SPECIFIC LEARNING DISABILITY Learning disability is a generic term that refers to a heterogeneous group of disorders manifested as significant difficulties in the acquisition and use of listening, speaking, reading, writing, reasoning, or mathematical abilities These disorders are intrinsic to the individual and are presumed to be due to central nervous system dysfunction Even though a learning disability may occur concomitantly with other disabling conditions (e.g sensory impairment, mental retardation, social and emotional disturbance) or environmental influences (e.g cultural differences, insufficient/inappropriate instruction, psychogenic factors), it is not the direct result of those conditions and influences This definition emphasizes the heterogeneity of learning disabilities, recognizes that it extends beyond childhood, and acknowledges that there is comorbidity with other developmental disabilities and cultural disadvantages Learning disabilities may represent a deficit in one aspect of learning but more commonly affect multiple areas of function and in some cases are global Seven areas in which a child might exhibit learning disabilities have been specified: basic reading skills, reading comprehension, oral expression, listening comprehension, written expression, mathematical The Child with Learning Problems 1147 calculation, and mathematical reasoning Reading disability or dyslexia is the most common of these disorders The concept of specific learning disabilities has moved from minimal brain damage to dysfunction More recently, it has been proposed that the condition be considered more as a matter of “developmental differences” Developmental variation with respect to learning and school performance is determined by the maturity and efficiency of such neurodevelopmental modalities as cognition, speech and language, memory, social functioning, motor and sensory capabilities, and attention Specific neurodevelopmental weaknesses will in turn prevent learning in one or more academic areas It has been a defining principle that such weaknesses are unexpected, given the overall intellectual functioning of the child Learning disabilities thus are not simply the result of global delays in learning capacities, of major sensory impairments, or a consequence of major social or emotional stressors CLINICAL MANIFESTATIONS The specific patterns of academic performance and behavior represent the final common pathways and the convergence of multiple forces, including interacting cognitive strengths and deficits, environmental or cultural factors, temperament, educational experience, and associated deficits in the areas of executive function, attention, and emotional and social adjustment Learning problems emerge when external expectations require performance in the area(s) of the child’s vulnerability or weaknesses There are four distinct periods of challenges: Preschool Level For the child in the preschool age, school readiness requires the ability of the child to “settle”, i.e to inhibit motor impulses to allow attention and focus on demand Basic language and communicative skills, as well as numerical concepts, are necessary Sensory capacities to discriminate auditory and visual differences in spoken sounds and letter shapes respectively are also required Fine motor competency must be sufficient for pencil use Social demands require the child to be able to take turns and express his own needs verbally Children may adapt poorly to their 1148 A Clinical Approach to Medicine first year or two of school because of specific weaknesses in any of the previously mentioned areas or because of global immaturities, commonly seen among boys and in children who are chronologically young at the start of the school Among the characteristics displayed by preschool children with learning disabilities are inadequate motor development, language delays, speech disorders, and poor cognitive and concept development Common examples are the 3-year-old who cannot catch a ball, hop, jump, or play with manipulative toys; the 4-year-old who does not use language to communicate, has a limited vocabulary, and cannot be understood; and the 5-year-old who cannot count to 10, name colors, or work puzzles In addition, preschoolers often exhibit behaviors of hyperactivity and poor attention Early School Years The period in the early school years is heavily focused on the acquisition of basic academic skills in reading, writing, spelling, and arithmetic The child at this stage is absorbing tremendous amount of rote knowledge with respect to symbol systems of letters, words, numbers, and the rules by which they are combined Children are asked to use a broad array of facilities in concert Delays in language understanding and usage will put early learners at risk of failure Memory is heavily relied upon in all its forms, such as active working memory, recent recall, long-term information storage and retrieval Motor output in writing may be frustrating and rate-limiting for children with fine motor delays These basic learning skills should be almost automatic and require minimum efforts by the end of primary school Therefore, children with learning disabilities often fail not only in reading, but also in mathematics, writing, or other school subjects The behaviors frequently seen in the early primary school years are inability to attend and concentrate, poor motor skills, as evidenced in the awkward handling of a pencil and in poor writing, and difficulty in learning to read Late Primary and Early Secondary School Levels Toward the later part of primary school and throughout secondary school years, the child is faced with a new set of challenges: self-organization of tasks and the processing of greater volumes of information Task requirements The Child with Learning Problems 1149 now emphasize an increased volume of received information, both written and spoken, and increased demand for written products The child is also expected to be substantially more self-reliant and responsible, both at home and at school Therefore, the child is tested on his executive functions (e.g planning, organizing, monitoring, efficiently performing tasks and activities), and his capacities to process larger volumes of information, reading, homework, and written work, which require selfmonitoring and self-modulation Emotional problems become more of an impediment after several years of repeated failure, and the children become more conscious of their poor achievement in comparison with that of their peers For some students, social problems and the inability to make and keep friends increase in importance at this age level Upper Secondary and Pre-university Levels At these levels, academic skills are increasingly used as a means of information gathering and understanding and less as an end in themselves Literature, mathematics, and both social and natural sciences all rely on basic skills acquired earlier Higher cognitive skills and abstract thinking are then required Therefore, a radical change in schooling occurs, and adolescents find that learning disabilities begin to take a greater toll The tougher demands of the curricula and teachers, the turmoil of adolescence, and the continued academic failure combine to intensify the learning disability Adolescents are also concerned about life after completing schools They may need counseling and guidance for college, career, and vocational decisions A few adolescents may be drawn into acts of juvenile delinquency As they tend to be overly sensitive, some emotional, social, and self-concept problems often accompany a learning disability at this age COMPREHENSIVE ASSESSMENT Comprehensive assessment of a child with learning problems should be multidisciplinary and broad-based to take into account all the possible constitutional and environmental factors that may contribute to the child’s problems Close communication with the child’s school is 1150 A Clinical Approach to Medicine essential The evaluation process is time-consuming and usually takes several sessions A complete review of the history is essential to gather a description of the child’s current function from multiple perspectives (parents, teachers, and, in case of older children, the children themselves) The focus is on information related to the various factors affecting learning It is also important to review the child’s early history to document developmental milestones, relevant health factors, early temperament, and the onset and course of the learning and behavioral difficulties Family history should include the composition and social circumstances of family, the education and expectations and other relevant environmental factors A review of the child’s school records and reports should be done through early liaison with the school It is equally important to have some knowledge on the school’s perception of the child’s academic and developmental strengths and weaknesses, peer relationships and classroom behaviors Questionnaires for parents and teachers have been used to provide a standard structure for obtaining a history and also to save time A complete physical, sensory, and neurodevelopmental examination should be conducted to rule out any causal or associated medical problems There are many medical conditions that can have a bearing on the learning process These include seizure disorders, allergies, anemia, hypothyroidism, and sensory impairments Unusual patterns of physical growth and maturation, the state of nutrition, and signs and symptoms of abuse and neglect should be actively pursued It is also important to rule out genetic or chromosomal abnormalities, such as Turner syndrome, Fragile X syndrome, and Williams syndrome The traditional neurological examination is usually normal, although there may be mild asymmetries of tone, qualitative differences in reflexes, or several beats of clonus The developmental examination is intended to demonstrate the child’s neurological maturity and the qualitative efficiency of motor, sensory, and position-sense functions Much has been written about “soft neurological signs” and learning disabilities These signs are developmental in nature and not have the same localizing value as the more traditional neurological signs Soft signs may be found in motor, sensory, or cognitive modalities Motor soft signs include age-inappropriate performances when standing on one foot and excessive overflow movements with rapid alternating movements and finger nose pointing Cortical sensory soft signs include The Child with Learning Problems 1151 difficulty with extinction, left-right orientation, graphesthesia, and finger identification Disappearance of these signs is linked to central nervous system maturation but their presence is also not considered abnormal prior to seven years of age Clusters of these signs are more significant than a single sign in isolation Persistence of such signs beyond the ages at which they usually disappear is associated with learning disabilities, behavioral problems, and other manifestations of neurodevelopmental dysfunction Investigations are done only with clear indications, either from the history or from the physical or neurological examination Special investigations such as EEG, CT scan, or MRI are rarely helpful Neurodevelopmental assessment should be administered to compile a profile of the child’s developmental strengths and weaknesses Any identified weaknesses should be interpreted in light of the child’s academic difficulties The most common approach for determining the existence of learning disabilities is to demonstrate a substantial discrepancy between educational achievement and intellectual potential in one or more areas of learning Usually, this entails administration of standardized tests to measure both IQ and educational achievement An IQ test may be helpful, but it should never be assumed to be a comprehensive audit of academically required cognitive function, nor should it represent the final word regarding a child’s academic potential An educational assessment should be performed, preferably by a skilled educator or an educational psychologist, to determine and document the child’s level of academic functioning, his preferred learning styles, patterns of errors, motivation and self-esteem, concentration and sensitivity to his performance The information can then be used to develop specific educational plans and remedial programs for the student Other assessments should be individualized for each child according to the findings in the above evaluation components When there are indications of the presence of significant emotional issues, either within the child or in the family context, a referral to a psychiatrist for a more in-depth mental health assessment may serve to clarify these issues It is also appropriate for a child with language weaknesses to be referred to a speech and language therapist for a formal assessment The child who fails a screening test of auditory acuity should be referred for a formal audiological assessment The social workers should be involved in connecting the child and the family to the relevant supports in the community 1152 A Clinical Approach to Medicine The evaluation process should consequently be able to describe a child on five levels: • • • • • Neurodevelopmental, with an analysis of constitutional, maturational, and developmental factors interfering with function and underlying strengths Psychosocial, elucidating factors in the environment, in the family, and in the past experience or present emotional health of the child that either enhance or compromise current performance Secondary psychological, with an account of the emotional effects of failure and the present level and stability of self-esteem Supportive, with a description of how the family, the school, and the community can help in the child’s learning problems Strategic, with an analysis of the child’s strategies for dealing with failure GOALS OF TREATMENT The goals of treatment are: • • • achievement of academic competence; treatment of associated deficits; and prevention of adverse mental health outcomes The individual child’s unique learning profile must be appreciated, and teaching must aim to challenge the child in ways in which he can successfully respond Where weaknesses are significantly disabling, teachers and parents must help the child to compensate for them by capitalizing on the available strengths and skills as much as possible Despite clear goals, it is the means by which they are met that provide the ultimate challenges Optimal management of learning disabilities requires the collaboration of teachers, parents, and pediatricians Teachers should not limit their treatment goals solely to the need for achievement of academic competence Pediatricians need to treat associated disorders, such as inattention, to facilitate academic therapy The principal components of effective management include: • multidisciplinary approach in formulating an individualized educational plan; The Child with Learning Problems 1153 • • • • • • • counseling of parents and children; educational therapy; developmental therapies; strengthening the strengths; medical treatment and pharmacotherapy; advocacy; and periodic re-evaluation COUNSELING PARENTS AND CHILDREN It is important to establish a good continuing relationship with the children and the family Counseling may be individual or group Familycentered interaction should focus on relieving guilt about the child’s problems, diffusing blame, and delivering basic information about the nature of the disability, including his strengths and weaknesses Other issues to be discussed include homework, behavior management techniques, discipline, parental expectations, and the child’s self-esteem The language used should be simple, non-technical, optimistic and upbeat, non-accusatory, and with appropriate analogies It is important to be careful not to moralize about the child’s problems Such terms as “bad”, “lazy”, and “poorly motivated” never motivate and may intensify negative self-image Reassurance may be comforting and beneficial, but its excessive use without proper basis can prevent a child from receiving appropriate services early or impede further evaluation The parents should be encouraged to create an atmosphere at home that is conducive to learning, and they can be counseled regarding the most appropriate way to motivate and encourage their child Children should also be included in discussion about their learning problems; otherwise, they are likely to fantasize uncomfortably about private conversations between professionals and their parents, and fear that they are defective Counseling should aim at explaining to the children their specific problems and strengths in understandable language, with encouragement to talk about such problems and to report how they are coping Finally, the family should be provided an ongoing source of information and relevant support groups in the community Sometimes, psychotherapeutic counseling may be indicated in family disorganization and conflict, or when significant psychopathology is 1154 A Clinical Approach to Medicine evident in the child, whose emotional needs stand in the way of learning Such counseling may need to involve the parents and sometimes the entire family EDUCATIONAL THERAPY Educational therapy is the cornerstone of treatment of learning disabilities There is no single “best” approach and therapy must be tailored to the individual needs of the child Health professionals need to know more about the educational systems and the alternatives, and educators must become more familiar with the medical and developmental aspects of school failure It is important to know that many educational interventions have not been adequately evaluated and are based on anecdotal reports and uncontrolled trials The individual teacher’s philosophies, training and skills, and particularly the teacher’s conceptualizations of children with learning disabilities will influence the professional approach and the design of programs for these children There are three basic concepts; each has implications for curriculum content and teaching methods 1) Developmental delays The fact that a child’s development in one or more areas of functioning is delayed in comparison with “normal” children has led to the assumption that it is appropriate to treat the child as younger than his chronological age Consequently, teaching materials and methods that have been shown to be useful with the young normal children are considered appropriate for the “delayed” child There is also the tendency to teach developmentally sequenced skills without questioning their relevance for each child Therefore, it can be seen in classes of children with a specific reading disability who are given reading materials that are of no interest to them, or again in classes of teenage students with global cognitive disabilities who are being taught body parts through action songs commonly used in preschool settings The positive aspect of this concept is that it implies that development is possible and that it may even be possible to catch up with normally developing peers Consequently, the professionals The Child with Learning Problems 1155 who conceive of children in this way are prepared to work hard to promote the children’s development 2) Developmental deficiency The concept that the child is considered deficient in some way and “not having what it takes” to succeed is doubtlessly the most negative way of viewing a child with a learning disability The consequence of this viewpoint is therefore to protect “the poor child” from more of life’s hard knocks and educationally to provide a watered-down version of that usually offered to the normal child 3) Developmental differences To consider the child with a learning disability as different is to recognize that he is a unique individual with specific strengths and weaknesses Consequently, the professionals not try to make the child “normal” in the sense of being the same as his peers, but assume that the child has the normal rights to develop to his maximum potentials, and be respected as an individual with personal preferences The challenge to the professionals caring for these children is that they must make both value and professional judgements about what the needs of these children are and how they can best be met Educational therapy is a combination of direct remediation of skills through specific educational programs, bypass strategies, and curriculum modifications Remediation of Skills Specific educational therapies are used to bolster weak academic skills Trained professionals, such as educational therapists, reading specialists, and mathematics tutors, devise methods and techniques based on knowledge of the child’s neurodevelopmental strengths to help him overcome academic lags and to improve decoding skills, writing ability, or mathematical computation Remediation need not focus exclusively on specific academic areas They must assist the child acquire and develop study skills, cognitive strategies, and productive organizational habits In addition, there must be a balance between the amount of time spent in attempting to remediate weaknesses and the amount of time spent on instruction of content 1156 A Clinical Approach to Medicine Specific educational programs will vary considerably according to the resources available to the school and the severity and nature of the child’s problems Many children with milder forms of learning disabilities can be maintained in a regular classroom with accommodations made for areas of weakness Therefore, the teacher must not only accept such a child in the class, but must also be fully aware of the child’s needs In other cases, they may require specialized assistance outside of regular classrooms There is a trend to “mainstream” these children with educational problems by not segregating them into “special” classes The goals are to reduce prejudice, to promote self-esteem, to provide peer models for social and academic skills, and to reduce the likelihood of labeling Students in need can leave the regular classroom for set periods per week for intensive remediation either on a one-to-one basis or in small group, in special settings such as in learning centers or resource rooms Each child will receive individualized assistance from trained teachers, whose efforts are aimed both at strengthening basic skills and at overcoming specific dysfunction, through specific exercises directed at visualperceptual motor function, sequencing, fine motor problems, or language disabilities In some instances, a remedial teacher or teaching assistant may be allowed to work in the child’s classroom As children grow older, more emphasis is placed on direct tutorial help in subject areas, with less emphasis on readiness skills For some children, the measures described above are still not sufficient because of the severity and nature of the learning problems, and they may need to attend a special school Homework is frequently an area of conflict It may not be a good idea for parents to coach their children at home or to spend much time going over homework with them in rote fashion because of tensions that may result The matching of the temperamental styles between the parents and the child will decide on the feasibility of this home tuition approach Homework should be closely monitored as attempts to improve the child’s academic ability may result in assigning too much homework This may be because the child has to make up classwork that is not completed or an inability of the child to the same amount of homework that others find reasonable Techniques to facilitate homework performance may include reading and reviewing difficult materials with the child, minimizing the need for peripheral activity such as copying of mathematics problems or writing only spelling words rather than full sentences Homework should also be limited to a pre-established time allotment Ongoing The Child with Learning Problems 1157 homework difficulty may indicate that knowledge of the topic areas has not been achieved and curricular adjustment is required Bypass Strategies and Accommodations Despite the fact that certain academic skills are impaired, it is important that the child must continue to be exposed to appropriate cognitive stimulation To provide this stimulation, teachers have to make certain accommodations in instructional methods, assignments, and methods of evaluation The healthcare team should communicate with the school the results of the child’s assessment, interpreting the findings for the teachers, and making clear the child’s developmental strengths and weaknesses Bypass strategies are techniques that enable a child to circumvent neurodevelopmental dysfunctions They not “cure” but minimize the negative academic and non-academic impacts, and allow the child to go on acquiring knowledge and skills The child who has problems with attention will need a structured classroom with little distractions, preferential seating towards the front of the class, or secret signalling from the teacher when he is “tuning out” The child who has difficulty with auditory sequencing will benefit from having verbal instructions kept simple, given in small sequences, and repeated as necessary Wherever possible, instructions should be written down as well as spoken so that the child may have the opportunity of visual reinforcement Some accommodations for problems in written expression include: minimize copying from the board and teacher will hand homework assignments to the child; use peer notes for studying (a study “buddy” and photocopying may be helpful); allow dictating assignments onto tape; substitute oral presentations for written assignment and oral tests for written tests, or allow shorter reports; use objective format rather than essay format in tests (e.g multiple choice); note spelling and punctuation errors but not penalize the child for them; and use of word-processor Children with reading difficulties will benefit from oral presentation of material, reading to the child, and books on tape Similarly, calculators can be helpful in solving mathematics problems, especially when the difficulty is with computation but not concepts Assessment and examination procedures may need to be modified, such as additional time, oral testing, or multiple choice; so are the evaluation criteria 1158 A Clinical Approach to Medicine Curriculum Modifications Many children with learning disabilities require alterations in the school curriculum to accommodate the individual developmental status and learning styles in order to succeed Modifications in course content may help, e.g children with gross motor lags may well in other areas if excused from regular physical exercises or enrolled in an adaptive physical education program; and students with memory weaknesses may need to select courses that not require an inordinate cumulative memory load Other curricular issues will become more critical as the students progress into higher grades They include the introduction of second and foreign languages, the special demands of the sciences, and the provision of specific vocational training Health professionals are often asked about the benefits of a child repeating a year, receiving a particular educational program, switching to a different school, having private tutoring, or other non-medical questions A cautious approach should be adopted in answering these requests Such decisions are generally best made at school level, with the medical team contributing to the discussion as appropriate and according to the level of his expertise and interest Repetition of grade or retention does not itself alter the natural history of learning disabilities and may have a negative effect on self-esteem and socialization The vast majority of these children not grow out of their problems An assertion that the child is immature and will catch up if left alone is inappropriate Repetition may buy time to allow the child to consolidate certain skills To be of maximum value to the child, a structured intensive remedial education program to improve on the apparent weaknesses must be planned in order to help the child to be more ready to proceed to the next level DEVELOPMENTAL THERAPIES The efficacy of direct interventions to enhance weak developmental functions is still controversial Nevertheless, some forms of developmental therapy are widely accepted Speech and language therapy offers interventions for various forms of language disabilities Occupational therapy strives to improve the motor skills such as writing problems and motor The Child with Learning Problems 1159 clumsiness Social skills training has its main objective of maintaining selfesteem and development of social skills, in order to prevent adverse mental health outcomes Efforts to build self-esteem may include special jobs within the classroom, sports, scouts, music, drama, arts and crafts, and other supervised activities In behavioral therapy, children learn about their own learning problems and are given specific exercises aimed at enhancing the weak areas For example, a child with attention problems may be taught about his impulsivity and then provided with exercises that encourage reflection, planning, and a less frenetic tempo STRENGTHENING OF STRENGTHS While the focus of management has been on correcting the child’s dysfunctions, the child’s strengths must not be lost It is important that any intervention strategy should include a strong emphasis on the ongoing identification of the child’s strengths, his affinities, potentials, and talents in which he can achieve a sense of mastery and triumph Athletic skills, artistic inclinations, creative talents, and mechanical aptitudes are among the potential assets of certain students who are underachieving academically These children need help and opportunities to develop their talents, to build on their natural and acquired proclivities, and to achieve respect and praise for their efforts Such efforts are likely to be critical in working toward the enhancement of self-esteem These personal assets can have tremendous long-term implications for the child’s transitions into young adulthood, including career choices MEDICAL MANAGEMENT The major responsibility of the medical team is to ensure appropriate treatment of any medical problems that may interfere with the child’s function, such as sensory impairments, neurological problems, seizures, or chronic medical conditions Children with allergies may have learning problems complicated by recurrent middle ear effusion, chronic nasal congestion, and fatigue Antihistamines may cause chronic fatigue and inattention in classroom Many children with learning problems also have associated symptoms, such as recurrent abdominal pain, headaches, enuresis, encopresis, or other psychosomatic complaints Proper treatment of these problems can improve function in other areas 1160 A Clinical Approach to Medicine Certain psychopharmacological agents are important adjuncts to treatment, especially in behavioral control Most commonly, stimulant medications are used in the management of children with attention deficits Whether stimulants improve learning abilities has not been established; but in the child with learning disabilities and attention deficits, stimulants may improve classroom performance When depression or excessive anxiety is a significant component of the clinical picture, antidepressants may be helpful Children receiving medication must be closely monitored It is understandable that many alternative treatment options have been offered for learning disabilities because there is no one best treatment or cure Although most of these therapies have not been proved to be ineffective, their quality and validity are otherwise unproved In addition, the cost in dollars, time, and frustration may not be inconsequential There are two broad categories of alternative treatment The orthomolecular methods include allergic hyposensitization, additive-free diets, megavitamins, sucrose-free or low-carbohydrate diets, thyroid medication, and so on The neurophysiological methods include alpha-wave conditioning, motor patterning exercises, sensory integration training, optometric training, eye muscle exercises, colored lenses, and so on Other miscellaneous therapies include anti-motion sickness therapy, chiropractics, meditation, and so on As advocates for parents and children, pediatricians can help to minimize their susceptibility to irresponsible claims Many parents seek help elsewhere when they feel abandoned by the health and educational systems Adequate continuing support and appropriate interventions with families will lessen their need to seek miracle cures ADVOCACY Advocacy means that the medical team takes the child’s part and pleads his cause with others A pediatrician can play a critical role in serving as a staunch advocate for a child with learning problems It may first need to take place with the parents who, out of concern, misunderstanding or frustration, may have been blaming or pressuring the child, with the risk of damage to his self-esteem Parents must be helped to reshape, rebuild and to adjust their view of the child A pediatrician can be especially helpful in advocating for a child in school Through judicious letter writing on behalf of the child and by The Child with Learning Problems 1161 close interaction with the school, he can provide much-needed advocacy for an underachieving youngster Teachers and principals should be helped to understand the child’s learning difficulties There is a need to represent the rights of the child to ensure that he is not overexposed to criticism and humiliation in front of peers He may also need to argue strongly for the child to receive and benefit from certain remedial and educational services in the school Pediatricians can also perform advocacy by becoming vocal citizens of their communities Their roles include educating the community on the implications and the special needs of children with learning problems, taking part in policy making and resource allocation, and initiating appropriate multidisciplinary programs for the child and the family PERIODIC RE-EVALUATIONS Children with learning problems represent a heterogeneous group No two children require the same management plan, and future needs are unpredictable New problems may emerge as the child’s dysfunctions evolve and academic expectations undergo progressive changes Treatment programs are complex and require the cooperation of health and education systems Many potential gaps exist and need careful monitoring Therefore, affected children and family require vigilant follow-up and continued individualized objective advice, preferably under the guidance of a case manager The goals of monitoring visits are to foster parent-child relationships, continue mental health efforts towards improving self-esteem and socialization, convey new information, and facilitate the use of existing resources Such visits need not be more frequent than one to two per year OUTCOME The outcome in a child with learning problems is determined by the nature of the disability, its severity, associated deficits, and environmental supports With most neurodevelopmentally-based learning problems, it is common for early weaknesses to persist to varying degrees into adulthood, regardless of interventions However, most children with learning disabilities eventually attain the academic skills required for everyday function In other words, those who not achieve functional literacy in 1162 A Clinical Approach to Medicine reading and mathematics during conventional education will so as young adults, and are seldom severely handicapped This is not to say that the “gaps” have closed The deficits persist, but the functional thresholds are achieved Consequently, individual differences in skills should be accommodated and accepted, and conventional education may need to be supplemented with vocational training, other functional curricula, computers, or work study Factors that determine whether weaknesses in learning become disabling in the long run include: • • • • the child’s ability to compensate and cope through his unaffected strengths; appropriate teaching and accommodations in school programs; the development over time of self-valued and socially respected competencies; and the degree to which the child comes to understand the disability as a real but limited part of the self, and not a feature that devalues the whole CONCLUSION Children who are lacking in athletic talent, music talent or mechanical capabilities are seldom punished or subjected to sarcasm or ridicule, nor are their parents accused of neglecting or overprotecting them Should we therefore consider children with difficulties reading, writing, and so on, as having a “lack of literary talent”? Perhaps, there may be a greater need for talented mechanics than literary critics and essay writers The adult world should concentrate less on disease, defect, damage or disability, but to recognize the diversity of styles, a wide range of strengths and weaknesses, and consequently the multiplicity of end products or pathways representing mastery The educational philosophy and services should be broadened to allow for the dignity and development of such differences The pediatrician is uniquely positioned to encourage the schools and parents to understand and be responsive to the child as a whole FURTHER READING Silver LB, The Misunderstood Child: Understanding and Coping with your Child’s Learning Disabilities, 3rd ed., Times Books, USA, 1998 The Child with Learning Problems 1163 Lerner JW, Learning Disabilities: Theories, Diagnosis, and Teaching Strategies, th ed., Houghton Mifflin Company, Boston, 2000 Mercer CD, Students with Learning Disabilities, 5th ed., Merrill and Prentice Hall, Columbus, Ohio, 1997 Batshaw ML, Children with Disabilities, 5th ed., Paul H Brooks Publishing Company, Baltimore, Maryland, 2002 Levene MD, A Mind at a Time, Simon and Schuster, New York, 2002 Levene MD, The Myth of Laziness, Simon and Schuster, New York, 2003 Levene MD, Brooks R, Shonkoff J, A Pediatric Approach to Learning Disorders, John Wiley & Sons, New York, 1980 Cratty BJ, Goldman RL (eds.), Learning Disabilities: Contemporary Viewpoints, Harwood Academic Publishers, Australia, 1997 Oberklaid F, Children with school problems, Aust Paediatr J 20:271–275, 1984 10 Parry T, Fletcher J, The child with learning problems, in Vimpani G, Parry T (eds.), Community Child Health: an Australian Perspective, Churchill Livingstone, Melbourne, 1989 11 Shapiro BK, Gallico RP, Learning disabilities, Pediatr Clin North Am 40:491–504, 1993 This page intentionally left blank 67 Pitfalls in Developmental Diagnosis Ho Lai Yun INTRODUCTION The major thrust of developmental assessment is early identification and treatment of children with developmental and behavioral problems and disabilities so as to correct dysfunctions if possible, minimize the impact of a child’s disability or of prevailing risk factors, strengthen families, and establish the foundations for subsequent development Developmental assessment is fraught with difficulty, largely because all children are different, and also because so many factors may affect the course of development Detection of abnormality is not always simple and great care needs to be taken in diagnosing developmental problems at an early stage Because development is so rapid, there is the danger that diagnosis may be made inappropriately, especially where deviations from normal are slight What may initially be thought to be developmental delay may turn out to be individual variability in development, or the manifestation of a particular temperament or environmental circumstances Errors may lead to unnecessary investigations or treatment, parental anxiety, and disadvantage for the child By the same token, it is 1165 1166 A Clinical Approach to Medicine just as dangerous to falsely reassure parents that a child will “grow out of it” when insufficient data are available to make this assertion Unfortunately, it is still a common occurrence for treatment or interventions to be delayed unnecessarily because of a delay in making a diagnosis, causing bitterness and resentment In assessment and intervention, there is a fine dividing line between doing too little and doing too much Considering the range of developmental problems in infancy and childhood, one confronts a series of traps into which parents and health professionals are prone to fall into All diagnosis should be based on the history, full physical and developmental examination, special investigations where relevant, and the proper interpretation of the results NORMAL DEVELOPMENT AND NORMAL VARIATIONS A thorough knowledge of the normal patterns of development is a necessary preliminary to the study of disease Children differ widely in all aspects of development and the range of normality is quite difficult to delineate, if not impossible A line can never be drawn between normal and abnormal The so-called “norms” of development, on which most of the commonly used developmental tests are based upon, are the established average of a highly selected population, instead of on the population as a whole It is important to appreciate that there is a wide variation between different populations and within a given population Therefore, all that can be said is that the further away from the average a child is in any field of development, the less likely he is to be “normal” Failure to recognize this leads many to declare that a child should reach certain milestones by a specified age, as if all normal children are the same, with no normal variations Variation in the Rate of Development There are normal variations in the age of acquiring certain skills This can be demonstrated by considering the age range for “walking unsupported” (Table 1) At 15 months, the majority of the 10% of children not yet walking unsupported will be normal but, in a small proportion, there will be an underlying medical problem At 18 months, 97.5% (two standard deviations from the average age) of children will be walking independently Of Pitfalls in Developmental Diagnosis 1167 Table Age Range of Children Walking Unsupported Age (Months) Percentage (%) Walking Unsupported 11 12 13 15 18 25 50 75 90 97.5 those who are not, many will be normal late walkers, but a higher proportion will have an underlying medical problem, such as cerebral palsy, a muscle disorder or global developmental delay Hence, any child who is not walking by 18 months should be carefully examined Thus, 18 months can be set as a limit age for children not walking Setting the limit age earlier may allow earlier identification of problems, but will also increase the number of children labeled as “delayed” who are in fact normal Variation in Patterns of Development The pattern by which children reach key milestones varies There are well-established variants in motor development Normal infants progress from immobility to walking, but not all so in the same way The most common sequence is the child who sits/crawls-on-all-fours/stands/cruises-around-furniture/walks The average age of walking in this group of children is 13 months However, some children not follow this pattern “Bottom shufflers” are the most common variant They not crawl but shuffle around on their bottoms or sides: a sit/shuffles/stand/walk sequence They walk late, on the average by 17 months, and tend to be mildly hypotonic early on Other children crawl with their abdomen on the floor (so-called “commando crawling” or creeping) and a very few just stand up and walk The limit age of 18 months for walking applies mainly to children who have had crawling as their early mobility pattern Children who bottom shuffle or “commando crawl” tend to walk later than crawlers, so that within those not walking at 18 months, there will be some children who are simply reflecting variants of normal locomotor patterns There is even more variation in the rate of acquisition of language, social skills and behavior, e.g when children can dress themselves or are 1168 A Clinical Approach to Medicine toilet-trained Some may follow a familiar pattern It is reassuring (but no more than that) if other members of the family have followed a similar course of development and turned out well, e.g late in talking or walking But the concept of limit ages still applies to determining whether or not a child’s developmental progress is normal The knowledge of difficulties in developmental assessment and diagnosis can therefore only be acquired, after becoming thoroughly acquainted with the normal, and the normal variations that are so common, and efforts to understand the reasons for these variations FOUR FUNDAMENTAL AREAS OF DEVELOPMENT A prerequisite for appreciating and avoiding the pitfalls in developmental diagnosis is an understanding of the four fundamental areas of development 1) Motor milestones are excellent indicators of motor competence but correlate poorly with intellectual capacity 2) Language development, which is measured in terms of expressive and receptive capability, is the best predictor of intelligence 3) Problem-solving skills is perhaps the second best indicator of intellectual function and represent a measure of non-verbal intelligence They are sometimes referred to as adaptive or visual-motor milestones The evolution of both the language and problem-solving milestones is independent of motor competence They may be obscured by motor disability and, as a result, may be more difficult to demonstrate 4) Psychosocial or affective milestones consist of two subgroups founded on verbal and non-verbal intelligence, respectively Those milestones involving interpersonal interaction have a language foundation and therefore indirectly reflect verbal IQ Activities of daily living milestones are based in the visual-motor domain and depend highly on environmental exposure and practice Because of this, the activities of daily living milestones reflect intellectual potential to a variable degree, depending on the exposure a child has received Psychosocial abilities are critical in understanding the whole child and in making a meaningful statement about behavior, but they lend little additional information Pitfalls in Developmental Diagnosis 1169 to the assessment of intellectual and motor competence Thus, each of the four areas of development has its own special relevance to the diagnosis of specific motor or cognitive impairment HETEROGENEITY OF DEVELOPMENTAL DISABILITIES Developmental outcome is the end result of the complex, continuous transaction between constitutional or intrinsic factors in the child, and environmental influences and life events A child’s development will be affected differently by different biological and environmental factors This will depend on the nature of the insult, the stage of neurological development at the time, and the site of the insult While those areas of the brain that are undergoing the most rapid maturational changes are the most susceptible, it should also be remembered that the developing brain is more plastic in its ability to recover Because of the variety of insults that may occur at various stages of development, there is a wide range of neurological impairments and heterogeneity of developmental disabilities It is dangerous to assume homogeneity in the developmental delays For example, a child with cerebral palsy and severe motor handicaps, whilst at increased risk of problems in other areas of development, may in fact have normal cognitive functioning Communication disorders may severely inhibit a child’s ability to display his or her intelligence It is important therefore to define development according to the above four fundamental areas in its very broadest sense, which includes motor, sensory, cognitive, language, social, behavioral and emotional development For this reason, a multidisciplinary approach to the assessment and management of developmental disabilities is necessary The disabilities in the various areas of development are not mutually exclusive, but are found in various combinations of differing complexity NATURAL BIASES ON AGE OF DEVELOPMENTAL DIAGNOSIS The way parents and caregivers typically think about their children’s growth and development provides some natural biases in the timing at which certain developmental disabilities may be suspected 1170 A Clinical Approach to Medicine During the first to 10 months of life, growth is the primary concern of most parents The body weight and the rate of weight gain of the child are always the first questions asked at every well child visit Motor development begins to take priority after about months of life, and is the highest ranking concern by 10 to 12 months It is only much later, roughly 18 to 24 months of age in most families, that parents begin to pay greater attention to cognitive areas, especially language development These natural biases have influenced the age of various developmental diagnoses Motor disabilities are consistently identified earlier than cognitive deficits, even when severe The mean age of diagnosis for cerebral palsy is about 12 to 14 months compared to 36 to 42 months for mental retardation Thus, the pitfalls in infancy are the tendency to miss or downplay motor developmental delay until after about or 10 months of age and to disregard language developmental delay until 24 months or later PITFALLS IN ASSESSING MOTOR DEVELOPMENT Gross motor development is an easy field of development to assess and normal milestones are well-established Yet this is also a comparatively less important field in developmental assessment The pitfall is that the child who demonstrates normal gross motor development can lull one into a false sense of security Although we can be reassured about motor function, gross motor milestones are not indicative and the least predictive of intellectual competence There is known discrepancy between motor and mental development in the mentally retarded About one-third to one-half of the severely to profoundly retarded children walk at or before 15 months, the upper limit of normal On the other hand, children with motor deficits because of cerebral palsy are not necessarily mentally deficient They may never achieve ambulation or the ability to speak intelligibly, yet they may have average or above average intellects The tendency to think only of gross motor skills and omit attention to fine motor milestones is another pitfall in assessing motor development Manipulative development is far more important than gross motor development, and fine motor delays can be a better and earlier indicator of motor disability The earliest fine motor milestone is “un-fisting” of the hands (more than 50% of the time) by months of age The child with moderate or severe cerebral palsy may get his head up well in prone position by Pitfalls in Developmental Diagnosis 1171 months of age because of extensor hypertonus, and roll over occasionally because of abnormal primitive reflexes Technically this child meets gross motor milestones but his hands are still fisted 100% of the time Attention to fine motor skills also forces one to assess hand use that involves problem-solving tasks, bringing one’s attention to some aspects of early cognitive assessment Important developmental features include ambidextrous (average 20 weeks) or unidextrous (average 28 weeks) approach to an object, the rapidity with which he accidentally drops a cube, the question of whether he drops one cube when offered another, tremor or ataxia or other abnormal hand movement when reaching for an object, the transfer of a cube from one hand to another (about months), and the quality of the grasp (evolving from the crude palmar grasp of the cube at about months to the mature pincer grasp between the tip of the thumb and the tip of the forefinger at about 10 to 11 months In assessing fine motor skills, it is not enough to record just whether a child has acquired a certain skill; one has to note the maturity and the rapidity with which the child performs the task PHYSICAL EXAMINATION AND PITFALLS OF “SPOT” DIAGNOSIS For developmental diagnosis, a full physical examination is essential if serious errors are to be avoided This will include examination for neurological and physical handicap, congenital anomalies, and defects of vision and hearing All these conditions may profoundly affect development and developmental tests, and any significant abnormality carries some increased risk of associated mental retardation An essential part of the physical examination is the head circumference in relation to the child’s weight Serial measurements are essential to show a falling off from the centile distribution, which is an important indication of a brain defect Other causes of unusual head measurements, such as familial traits, must also be known Failure to diagnose subluxation or dislocation of the hip as a cause of limited abduction of the hip might well lead to a diagnosis of cerebral palsy, the limited abduction having been wrongly ascribed to adductor spasm The presence of obesity may be a factor in delaying gross motor function Irrelevant physical features include the age of closure of the anterior fontanelle, age of appearance of teeth, an epicanthus, or simian crease and its variations 1172 A Clinical Approach to Medicine During the physical examination, general features are noted and more attention should be paid to the child’s positive achievement and those skills he does best, rather than the negative ones The most important features for the assessment are features that cannot be readily scored: the quality of vocalization, the child’s interest in surroundings, alertness, responsiveness, understanding, his concentration and memory, the glint in the eyes, and signs suggestive of mental subnormality such as bruxism when awake, persistence of hand regard after 20 weeks, or mouthing, slobbering, and casting at an age when the child should have grown out of it It should also be noted that a child might be able to suppress his behavior in a structured environment This should be appreciated in the assessment of a child with attention deficit hyperactivity disorder Developmental diagnosis must never be made on clinical impression Neither should a “spot” diagnosis be made in a casual manner It may be easy at a glance from a distance to diagnose Down syndrome and some other syndromic disorders associated with mental subnormality, it is difficult for parents to accept such instant diagnosis from a doctor, followed by his confident statement on the outlook The concept that retarded individuals look retarded is prevalent among the general public and even among the medical professionals Many children with odd facies often may be just taking after one of his parents Nevertheless, there remains a bias against the intellectual competence of the unusual-appearing child The converse situation is also a pitfall Mental superiority may be wrongly diagnosed in a two- or three-yearold child because of charm of manner, absence of shyness and good looks The retarded child with good looks or good motor skills is typically identified late Children with autism are most often described as attractive children These superficial physical attributes, especially if present in a happy or uncomplaining infant, obscure other clear indicators of developmental deficits Attractive children may manifest any degree of cognitive deficit from learning disability through profound retardation On the other hand, the child deemed to be facially dysmorphic is not necessarily cognitively deficient PITFALLS IN ASSESSING LANGUAGE DEVELOPMENT There is often a failure to appreciate the importance of early language development to the early recognition of mental subnormality Infants and Pitfalls in Developmental Diagnosis 1173 young children by their nature not express themselves in the examination room They are usually shy, subdued or failed to cooperate in certain tests Some children may be genuinely apprehensive in unfamiliar environment, having crossed the stage of stranger anxiety Therefore, obtaining a precise history of the infant’s language milestones becomes very important Unfortunately, neither the milestones themselves nor the phrasing of the questions to elicit an accurate history are intuitively obvious In addition, there is a tendency among parents and professionals to excuse language delay until the child reaches about two years of age Even children who are congenitally deaf with no speech at all are characteristically identified around this age The pitfall to be aware of is the concept that language development does not begin until one year of age and is not worthy of concern until two years of age Avoiding the pitfall hinges on the ability to obtain an accurate history and the knowledge of early language development, both require further professional training and education Having a table of linguistic and auditory milestones that is easily accessible and that can be routinely consulted upon during well child visits is of great help (Table 2) PROBLEMS IN EARLY IDENTIFICATION OF AUTISTIC SPECTRUM DISORDER There is strong evidence that children with autistic spectrum disorder can be reliably identified between 18 to 39 months of age Systematic review of early videotapes demonstrates prelinguistic communication abnormalities in infancy Parent questionnaires and other structured screening instruments often retrospectively reveal impairments in pretend play, proto-declarative pointing, joint attention, social interest, and social play as early as 18 months A wait-and-see or reassuring attitude towards parents’ concern over the child’s delayed language acquisition, especially in boys, is the most important factor for late diagnosis There are problems in identifying developmental delays in socialization and other non-verbal communication behaviors because most health professionals are inadequately or poorly trained in screening these areas of child development The Denver Developmental Screening Test is not sensitive and specific for autistic spectrum disorder The nature of impairments is usually subtle They often represent the absence of normative behaviors (such as not imitating, not 1174 A Clinical Approach to Medicine Table Clinical Linguistic and Auditory Milestones Alert week Social smile Cooing 1–1.5 months months Orient to voice Orient to bell (I) “Ah-goo” months months months Laugh 4–5 months Razzing Babbling Orient to bell (II) “Mama/dada” Gesture/games Orient to bell (III) months 6–7 months months months 9–10 months 9–10 months Dada/mama (appropriate) One word One-step command (gesture) Two words Three words Immature jargoning One-step command (no gesture) 4–6 words One body part Mature jargoning body parts 2-word combination 2-word sentence 10–11 months 11 months 11–12 months 12 months 14 months 12–14 months 15 months 15 months 15 months 17–18 months 17–18 months 19–21 months 21–24 months Orienting to sound of bell (I): At months, when a bell is rung at one side of the infant’s head, the infant turns horizontally to the correct side Orienting to bell (II): At months, when a bell is rung at one side of the head, the infant localizes the sound by a visual maneuver consisting of a horizontal followed by a vertical component Orienting to bell (III): At 9–10 months, when a bell is rung at one side of the head, the infant localizes the sound by one single visual movement gesturing) rather than the presence of noticeably unusual behaviors (such as peculiar use of language) Differentiation between autistic spectrum disorder and mental retardation may be difficult Given a child’s developmental level, there may not be an opportunity to manifest the behaviors needed for diagnosis Differentiating milder autistic spectrum disorder from developmental disability may be difficult if the child has not been involved in some preschool program to evaluate their response to structured environments and exposure to other children PITFALLS IN DIAGNOSING HEARING IMPAIRMENT Hearing impairment in children may have substantial long-term consequences if untreated or treated late Deafness in infancy is not only diagnosed late but routinely goes undiagnosed for more than a year from the Pitfalls in Developmental Diagnosis 1175 appearance of symptoms The average age of diagnosis of congenital deafness is to 2.5 years Lesser degrees of hearing impairment are delayed proportionately longer in their recognition Therefore, until hearing screening in neonatal and early infancy period becomes routine and universal using sensitive technologies such as oto-acoustic emissions and brainstem auditory evoked response, effort must be made to improve the acumen in diagnosing hearing impairment Most congenital deafness is genetic and most of the time it is an isolated deficit There is every possibility that if a hearing impaired infant is evaluated on the four areas of development, he can virtually pass all developmental milestones The typical developmental profile of a congenitally deaf child is that the early motor development is normal Problem-solving skills are also within normal because they have normal intellectual and fine motor capacity Likewise, early psychosocial milestones such as recognizing parents, stranger anxiety, eating with a spoon, can all be normal Even expressive language is said to be normal in the first six to eight months of life They can coo and laugh and even begin to babble before expressive language milestones become noticeably delayed in the form of deviant babbling Receptive language depends on the infant’s failure to respond to noise and early diagnosis of deafness hinges on demonstrating this simple deficit However, this is exactly where the inexperienced can be most readily fooled By twelve months of age, babies respond mainly to gesture commands When a 12-month-old infant is given two cubes and then asked to give one back to the tester who simultaneously reaches out to receive the object, the child will comply A deaf child responds just as readily as a hearing infant An infant will respond to simple commands without the reinforcement of an accompanying gesture by only 14 or 15 months of age It may also be true that infants with deafness are more vigilant than normal-hearing infants, making such a mistake all the more likely Although the parents of hearing impaired children report suspicions about hearing per se less than half the time, they consistently report the symptoms of hearing impairment, such as inattention, delayed speech, disinterest in musical toys, but their concerns most often may go unheeded by medical professionals Another common pitfall with respect to hearing impairment is the inclination to ascribe delayed language development to recurrent episodes of otitis media It is not unusual to see referrals of children with delayed or absent speech after one year or more of temporizing because the delay 1176 A Clinical Approach to Medicine has been dismissed on the basis of middle ear disease It is true that some language dysfunction can result from the mild and transient hearing impairment associated with acute or chronic middle ear disease There is considerable controversy over the extent of and the long-term consequences of middle ear disease on language and academic performance PRECISION IN TAKING DEVELOPMENTAL HISTORY Precision in history taking is necessary if errors are to be avoided It is essential to cover, as far as possible, all fields of development: locomotion, manipulation, play and social behavior, memory, the mode of display of pleasure and displeasure, feeding behavior, sphincter control and speech Parents who express concern must not be dismissed The reliability of parent’s story must also be checked against the doctor’s own objective findings Parents of a retarded child are often unwilling to allow themselves to believe what they know is the truth At the same time, parents may have forgotten or may not even know when their child acquired various skills They may then fabricate their replies on their child’s skills, basing their answers on what they know these skills are usually acquired instead of on what they can remember In history taking, it is not enough merely to know whether a child does certain thing, but when he began to it, and how often, with what degree of maturity, and the rate of achievement in general The accuracy of the history can be improved by asking about the child’s development in relation to that of the siblings or with neighbors’ children of about the same age A simple question about the progress of these children in school will give an idea whether they are likely to be reasonably normal Asking parents to remember whether specific milestones had been reached by the child’s first birthday, checking on family photographs or videotapes, and asking parents to check milestones recorded in the child’s baby book are other ways of improving recall Another useful source is the infant’s health booklet, which will contain past measurements of weight, length and head circumference so that percentiles can be plotted to give a picture of the child’s growth pattern Imprecise histories are of limited value The information obtained will only be as good as the questions asked The following are some examples: Pitfalls in Developmental Diagnosis 1177 • • • • • • • • • • • Beginning to smile refers to smiling in response to the mother’s overtures and not to grimace or twitch when she tickles the face or the baby’s facial movement in sleep Rolling over refers to rolling completely over, rolling from prone to supine has to be distinguished from rolling from supine to prone, which comes later Grasping objects means going for an object without it being put into the hand and has to be distinguished from grasp reflex, or the ability to hold an object placed in the hand Sitting means sitting on the floor or another hard surface for seconds, either with the hands forward with support or without, not in a stroller with pillow support Holding the head up: the average child can lift his head off the couch when lying supine by about months old Beware of spasticity Creeping (on hands and knees) has to be distinguished from the earlier crawling on the abdomen Chewing has to be distinguished from sucking a biscuit Self-feeding is not equivalent to an infant of six months holding a biscuit and feeding himself with it It is not until 15 to 18 months that an average child can feed himself with a spoon and manage a cup without help The child has to go through numerous stages of trying to load the spoon, of succeeding in loading the spoon but not getting it near his mouth, and later of getting it near the mouth but rotating it and therefore spilling the contents before it enters the mouth With the cup, the child has to go through the stages of helping to hold it, of suddenly letting go when he is drinking or has had what he wants, of spilling most of the contents, until finally he can pick it up, drink and replace it with only occasional accidents Walking means walking a few steps without support Toilet-trained means that the child is mainly dry and clean day and night, and has to be distinguished from earlier conditioning when the child voids as the buttocks feel the rim of the potty, whether awake or asleep Talking means saying words with meaning, not just “mummum, dadada” When asking about language development, remember to distinguish between expressive and receptive language Expressive language is what 1178 A Clinical Approach to Medicine the child can say Ask whether the child’s words have consistent meaning The clarity of pronunciation in the first year following speech development is less important than the extent of the vocabulary and the consistent use of the same sounds for the same object or person Receptive language is how many words the child can understand, and is usually well in advance of expressive language A child of 18 months who only says four or five distinct words with meaning may have a receptive language of 200 words or more CORRECTION FOR PREMATURITY The issue of correction for prematurity during developmental assessment is still controversial By convention, infants born before term are allowed extra credit for the duration of their prematurity when evaluating their developmental progress Therefore, if birth was at 32 weeks’ gestation, eight weeks should be subtracted from the chronological age when assessing development, so that milestones would be expected to be reached two months later than a baby born at full term Similarly, when an average full term infant begins to smile in response to mother’s overtures at to weeks, the infant born three months early would be expected to smile at to weeks plus three months If the infant is of low birth weight, the duration of gestation must be ascertained to distinguish intrauterine growth restriction Current data, however, suggest that full correction for motor milestones should be allowed, but partial or no correction seems to be appropriate for language and problem-solving milestones The tendency to over-correct because the infant has been sick as a neonate represents a pitfall in the interpretation of assessments That a child is or has been sick ill represents a factor that adds uncertainty to the evaluation, but it should be dealt with separately and not injected into the sense of correction IMPORTANCE OF ENVIRONMENTAL FACTORS Many adverse environmental factors may profoundly affect development but they may not be directly related to the child’s mental endowment These factors should be actively explored and not be ignored in developmental assessment Children who are emotionally deprived, who receive little verbal stimulation, or who are lacking in experiential learning opportunities Pitfalls in Developmental Diagnosis 1179 such as the chance to practise walking or crawling, to learn to feed and dress himself, or to attend to toilet needs, when they are ready to achieve these milestones will be delayed in these skills One must also know about the cultural oddities in parental management, such as keeping the baby off his feet for fear of bowlegs and knock-knees It is also important to know if the mother is out working all day and who the main caregivers of the child are Maternal depression has been recognized as a major factor adversely affecting the child’s growth and development Besides socio-economic factors, we must also consider poor nutrition, chronic medical conditions requiring prolonged hospitalization, exposure to toxic substances, and accidents RELEVANCE OF RISK FACTORS To avoid mistakes by the omission of relevant and important factors that affect development, a detailed history is essential and it will include all prenatal, perinatal, and postnatal factors However, the importance of these risk factors must not be exaggerated When there is doubt about the level of development, the history of a risk factor, such as mental subnormality in a parent, serves only to increase that doubt A risk factor itself should never lead to a hasty diagnosis that a child is mentally subnormal A mentally subnormal parent can also have a normal child Similarly, we must be aware of the pitfall of relating backwardness in certain areas to family pattern of development The concept of “at risk” registers is to ensure the close monitoring and assessment of those most likely to be developmentally delayed The limitations of such registers must be acknowledged Many developmentally delayed children not have any identifiable etiological or risk factors, and many children who have suffered clear identifiable insults, and are very much at risk, develop quite normally Furthermore, the inclusion of all possible risk factors necessitates large numbers of children being placed on the at-risk registers, making the concept logistically difficult and practically impossible most of the time Nevertheless, there is still an emphasis on the early diagnosis of delay, and certain groups of children such as the very low birth weight infants are followed very closely and their development monitored The clear advantages of early diagnosis must be counterbalanced by the dangers of inappropriate labeling 1180 A Clinical Approach to Medicine AVOIDING PITFALLS IN DEVELOPMENTAL EXAMINATION The child is not a passive part of the developmental examination He should be given the opportunity to perform optimally He should not be tested when he is ill, sleepy or just woken, miserable for some reasons, hungry, bored, or on medications For example, it is not appropriate to conduct a developmental examination on a child with epilepsy when he is still in a state of confusion after a major seizure or when he is under the influence of sedative drugs Head control cannot be properly tested when the child is sleepy or crying One may also be misled into thinking that there is significant head lag when one pulls a child into the sitting position from lying on his back A child may refuse to sit without support during the examination if he has a wet or soiled diaper, while he is able to so normally Similarly, it would be foolish to try to developmental assessment on a 22-month-old admitted to hospital with asthma, who is in respiratory distress as well as being “high” from salbutamol medication When the child does badly in a test, a decision has to be made about whether he has really been trying A child may refuse to take part in a test because he is shy The older child may also refuse or reluctant to cooperate because he regards the tasks as too easy or just silly The presence of the parents may occasionally help the child to achieve his best in strange surroundings, but the parents should be told to resist the urge to help the child or to interfere with the tests Standardization of test materials is important The materials used must be the same as those on which the norms are established Similarly, the tests should be adapted and validated for the local population Rigid adherence to a method of testing is undesirable The tester should be able to adjust the order of the tests as soon as he sees that the child is not interested or is becoming bored The child needs encouragement in his tasks This is best done by relating to the child in a friendly, enthusiastic way, praising child for good performance, giving new challenges and supporting the child with encouragement during the assessment One should never try to correct a child or say “no” when he performs a test incorrectly Therefore, an important part of the training in assessment is to develop skills in playing with and relating to children Pitfalls in Developmental Diagnosis 1181 COMMON MISTAKES IN DEVELOPMENTAL DIAGNOSIS There are important but common pitfalls to avoid in the interpretation of signs that may sometimes indicate cerebral palsy, mental subnormality, and visual or hearing defects Cerebral palsy cannot be diagnosed on the basis of isolated retardation in motor development nor on the basis of exaggerated tendon jerks in young baby or even persistent ankle clonus, for these signs may disappear as the baby gets older The plantar responses in the first year or so are flexor unless there is pyramidal tracts disease Excessive extensor tone is a highly important pointer to cerebral palsy The infant may have good head control in ventral suspension and in the prone position, but gross head lag is obvious when pulled up from the supine to the sitting position Resistance is also felt when pulling the child up to the sitting position and he may also tend to rise onto his legs Adductor spasm in cerebral palsy may be wrongly diagnosed because of limited hip abduction due to hip dislocation or subluxation, or to muscle contracture due to the hypotonic child consistently lying in one position Spastic cerebral palsy may be wrongly diagnosed in punctate epiphyseal dysplasia on account of limited joint extension Duchenne muscular dystrophy may be missed in a child with delayed motor development Minimal involvement of the upper limbs, as seen when the child is going for cubes or building a tower, can be easily missed, and spastic paraplegia is diagnosed when the correct diagnosis is spastic diplegia Spastic paraplegia points to the possibility of a spinal lesion rather than a cerebral cause Toe walking is often attributed to cerebral palsy However, it can also be a normal variant, or can be found in congenital shortening of the Archilles tendon, unilateral dislocation of the hip, Duchenne muscular dystrophy, and has been described in children with autism Spastic children are often wrongly thought to have the mixed form of cerebral palsy because the characteristic awkwardness and splaying out of the hands is thought to be athetosis A late walker may be unsteady on his feet shortly after first walking without support and may be misdiagnosed as having the ataxic form of cerebral palsy Infants may be thought to be blind because of delayed eye following, when the delay is due only to mental subnormality Similarly, a child with 1182 A Clinical Approach to Medicine mental retardation may be thought to be deaf because of delayed response to sound Isolated delay in speech is rarely due to mental subnormality and tongue tie LIMITATIONS IN PREDICTING CEREBRAL PALSY IN PREMATURITY In premature infants, long-term neuromuscular abnormalities usually cannot be predicted with certainty in the first year of life There is known variability in the progression of muscular status Some preterm infants demonstrate muscle tone abnormalities during infancy that resolve subsequently In contrast, abnormalities can develop in an infant with initially normal tone There are also imperfect correlations between brain damage documented on specialized studies, such as cranial ultrasound, CT scan, or even MRI, and later functional outcome The absence of lesion does not preclude development of disability later, and presence of abnormality does not also preclude normal development The fact that the neonatal brain has significant plasticity for recovery may account for the difficulties in prediction “IQ” TESTS An important source of error is the over-reliance on purely objective tests to provide unitary score in developmental assessment and misinterpretation of its accuracy and predictive value Serious mistakes are made in developmental diagnosis if the various factors that affect the course of development are not properly considered, and if the normal variations are not borne in mind It is rarely desirable to assess the “intelligence quotient” (“IQ”) in terms of a single figure in a preschool child, because such a figure cannot take into account the many influential factors that are of importance Some of the tests used on the two- to three-year-old depend on the acquisition of speech; but a child may be of normal or superior intelligence and yet be late in learning to speak This will lead to the child being given an unduly low score simply because he cannot speak Observation might show that the child’s understanding of words and his ability to identify objects and to carry out simple acts on request is advanced A child might also be given a low score in other fields of Pitfalls in Developmental Diagnosis 1183 development, such as sphincter control, when his lateness in acquiring sphincter control is due to parental mismanagement and bears no relationship to his intelligence Serious fallacies would result if one were to attempt to calculate the IQ merely by converting each observation in the developmental examination into a single figure, adding all the figures up, and take the average There are confusion concerning the terms “developmental quotient” or “DQ” and “intelligence quotient” or “IQ” The DQ indicates how far a child has progressed in all aspects of development, especially behavior, in relation to the average for his age The IQ relates the child’s age to his performance, mainly in verbal and problem-solving tests, on the basis of pass or failure The DQ is affected by the environment and many other factors unrelated to the child’s genetic endowment “Intelligence” has not been satisfactorily defined It cannot be simply described as a single score or figure, and there are many different types of intelligence and of human abilities It is more sensible to describe areas of strengths and weaknesses in a child according to his age after the assessment Furthermore, most of the commonly used “IQ” tests are established on a narrowly selected population, instead of on the population as a whole It follows that there is no valid norms with which to compare the development of children not satisfying these criteria and accuracy is impossible PREDICTING OUTCOME Some conditions causing developmental delay, such as Down syndrome or severe asphyxia, are evident at or shortly after birth On the other hand, mild mental retardation may not be apparent until the child starts school We can never diagnose mental retardation on backwardness in just one or two fields of development High intelligence also cannot be predicted on advanced developmental milestones Therefore, great caution needs to be exercised in giving a prognosis about a child’s eventual outcome It has been well-established that, except for severe developmental delay, prediction of developmental outcome from test scores in infancy is often inaccurate and fraught with hazard The younger the child, and the longer the prediction period, the more inaccurate it is likely to be, especially for cognitive development It is important to consider the child at a particular point in time, and avoid making long-term predictions about a child’s ultimate potential 1184 A Clinical Approach to Medicine and achievement, because there is a wide variation in the attainment of milestones, and it is impossible to accurately assess or predict all the constitutional and environmental variables that might affect outcome CONCLUSION Development is a complex, continuous process whereby a child acquires an increasingly sophisticated repertoire of skills across multiple domains The remarkable consistency of this process allows us to monitor an individual child’s progress and to detect any deviation from normality Developmental delay and deviation is not homogenous, but varies widely according to the etiology Informal developmental screening and surveillance can be useful in reassuring normality, but care must be taken in drawing any firm conclusions about developmental status without a more formal procedure Developmental assessment can be difficult and follow-up of unusual developmental features is important What is appropriate where milestones are either delayed or advanced is to say where the child’s development is in relation to average children of that age and then help the parents with techniques of responding to the child’s strengths and weaknesses most appropriately There is also the role of anticipatory guidance to the parents Knowing the child’s level of development and what the developmental progress over the next few months is likely to be is valuable for informing parents what sort of behavior to expect This will enable guidance about child management and accident prevention to be given Furthermore, even when it may be possible to say something about a child’s developmental potential and talents, it is not possible to say what he will with them That will depend actually on many factors in the future — the quality of his home, friends and school, his personality, health, and nutrition, and the opportunities that he will have FURTHER READING Egan DF, Developmental Examination of Infants and Preschool Children, MacKeith Press, Oxford, 1999 Levene MD, Carey WB, Crocker AC, Developmental-Behavioral Pediatrics, WB Saunders Company, Sydney, 1999 Pitfalls in Developmental Diagnosis 1185 Illingworth RS, The Normal Child: Some Problems of the Early Years and Their Treatment, Churchill Livingstone, London, 1987 Illingworth RS, The Development of the Infant and Young Child: Normal and Abnormal, Churchill Livingstone, London, 1987 Pollack M, Textbook of Developmental Paediatrics, Churchill Livingstone, Melbourne, 1993 Capute AJ, Accardi PJ, Linguistic and auditory milestones during the first two years of life, Clin Pediatr 17:847–856, 1978 Blasco PA, Preterm birth: to correct or not to correct, Dev Med Child Neurol 31:816–822, 1989 Palfrey JS, Singer JD, Walker DK, Butler JA, Early identification of children’s special needs: a study in five metropolitan communities, J Pediatr 111:651–659, 1987 First LR, Palfrey JS, The infant or young child with developmental delay, N Engl J Med 330:478–483, 1994 This page intentionally left blank 68 Feeding Problems in Young Children: A Developmental Perspective Ho Lai Yun INTRODUCTION Feeding and eating serve a range of biological, psychological and social functions in the life of the developing child The most basic function is clearly biological, as the child requires adequate and appropriate nutrition to survive and to thrive physically and mentally However, nurturing is not only nourishing, and feeding is but also one of many ways parents promote children’s growth and development Infant feeding is important in developing and maintaining the emotional relationship between the mother and infant since much of the early interaction between the baby and the mother centers on this activity It has been shown that breastfeeding mothers have a closer and more expressive relationship with their infants during feeding than mothers who bottle-feed Feeding and eating also play an important role in the social life of the child, and are of fundamental significance to the child’s experience of the world and his place in it Meals are usually times when the family is together and provide a focus for family life Furthermore, a great deal of social interaction with non-family members occurs during mealtimes and this context therefore 1187 1188 A Clinical Approach to Medicine serves a wider socializing function Given the central role feeding and eating play in the life of the developing child, it is not surprising that deviations or disturbances in them are not only a problem for the individual child but can cause great anxiety within the family Feeding problems cover a wide spectrum of phenomena of variable significance, ranging from variations of normal behavior such as mild faddiness and pickiness, to conditions of major developmental significance such as failure to thrive Many of these disorders result from a combination of both the child’s own inherent difficulties and parental handling problems In other cases, feeding difficulties may be the expression of general difficulties within the family Thus, when a child presents to the clinician with a feeding or eating problem, adequate management depends on viewing this problem in its wider familial and social context This applies not only to consideration of etiological factors, but also to factors that may be the sequelae of the feeding difficulties, which serve to maintain them (Fig 1) Parents enter the feeding relationship with their children with a set of experiences and expectations, and they make decisions about nutrition and feeding practices for their families Infants and children have their own set of nutritional and caloric needs, as well as certain emotional and developmental requirements These individual characteristics of the infant and caregiver may be in direct conflict with one another; and if FEEDING PROBLEMS Food Refusal Faddiness Pickiness Food Phobias Bad Mealtime Behaviors Colic Diarrhea/Constipation Vomiting / Rumination Failure to Thrive Aspiration Pneumonia Child Abuse & Neglect Poor Parent -Child Interactions Underlying Medical Problems Fig Feeding problems Family Conflicts Behavioral Problems Feeding Problems in Young Children: A Developmental Perspective 1189 problems develop during the course of this feeding interaction, there may be implications for the style and quality of their relationship in other nonfeeding contexts, as well as for subsequent feeding behaviors Mealtimes may therefore be a pleasure or battleground (Fig 2) PARENTAL EXPERIENCES AND EXPECTATIONS Several complex factors interact to influence the attitude of parents towards feeding their children They include the parents’ upbringing and childhood experiences, social and cultural influences, traditional beliefs, peer and family pressure or support, educational and financial status, and their physical and mental health Most of the common problems are related to: lack of parental understanding, parental over-concern or overprotection; parental tension; parental attitudes towards food that cause anxiety for the child; parental projection of their wishes to over-eat or under-eat onto their child; and parental ambivalence towards their children Many parents are inexperienced in parenting small babies They may not have an extended family to support them in such apparently unimportant crises They may also be confused by conflicting and misleading advice from several sources: friends, media, childcare magazines, or even professionals Some parents consider feeding to be the primary means of nurturing their children When they place too great an emphasis on INFANT FEEDING EXPERIENCE INFANT/CHILD Nutritional/ Caloric Needs; Developmental & Emotional Requirements PARENT-CHILD RELATIONSHIP (NON-FEEDING) PARENTS Experiences And Expectations FEEDING INTERACTION FEEDING: PLEASURE or BATTLEGROUND Fig Infant feeding experience 1190 A Clinical Approach to Medicine feeding, they become overly concerned about the quantity, quality, and variety of foods consumed; the regularity of the child’s feeding schedule; and the child’s behavior during feeds They may consciously or unconsciously equate both their ability to feed their child with their own success as parents, and their child’s willingness to eat with his or her love for them Some parents are not responsive to their infant’s feeding signals For example, they may misinterpret infant cues and misread crying after eating as hunger or lack of satisfaction with a meal The parent’s ability to accept the infant’s individual feeding pattern, to use consoling methods other than feeding for non-hunger cries, to wait for the infant to resume sucking after pauses without interfering, and to avoid pushing more on the baby when he or she is satisfied are signs of sensitivity to infant cues Parents may be less sensitive because they are anxious, depressed, or suffering from other mental problems or psychosocial stresses Also, they may have a sense that their baby is vulnerable, be under pressure from a spouse or relatives, or even an intense desire to succeed The frustration and concern that often develop can seriously complicate feedings and result in negative feelings towards the child From the simple beginning of a child’s throwing food, gagging, or refusing to eat, a complex problem between parent and child can develop during feeds Furthermore, these simple beginnings can result in reduced nutritional intake, poor parent-child interactions, and feeding problems that can be exacerbated as the child grows Generally, the most important part of the management of feeding problems is eliciting the parent’s expectations of the child and of themselves as caregivers, identifying the psychosocial stresses they are experiencing, assuring them in their roles as parents, and ensuring adequate supports for them If parents were provided with anticipatory guidance on early feeding scenarios, feeding times would become less challenging to their parenting skills If parents were to relax and enjoy the mealtime interaction and the child’s exploration of foods, acquisition of new behaviors, the common and usually trivial problems that occur during early feeding experiences might disappear so that a reasonable diet and mealtime pattern could evolve naturally for most children However, recommendations can only be followed through by parents who not have significant ambivalence towards their child, that is, both strong feelings of love and anger The concept of parental ambivalence may be rather contentious but it seems to exist The more emotionally healthy parent uses repression to keep the angry feelings out of conscious Feeding Problems in Young Children: A Developmental Perspective 1191 awareness This unconscious anger will often influence and interfere with the parent’s motivation to follow through recommendations to change his or her behavior concerning food and feeding Many requests for child evaluation for food refusal problems are dropped by parents when they are suddenly confronted with their angry feelings towards their children These troubled parents need help to become aware of their unconscious anger, and to accept and cope with their feelings of guilt and shame when this anger is exposed MATERNAL-INFANT RELATIONSHIP PROBLEMS The following types of maternal-infant relationship problems may both cause and present as infant feeding disorders: 1) Impoverished relationship: This is characterized by low verbal contact, little play, little eye contact, and lack of pleasure, warmth and affection 2) Inconsistent relationship: The mother’s responses are irregular and inconsistent both physically and emotionally Due to the lack of consistency, the infant is uncertain of what to expect 3) Indiscriminate relationship: The parent gives high intensity reactions but with poor direction The infant is over-stimulated and his/her real needs are neglected This occasionally occurs in “colicky” infants 4) Interactive mismatch: Typical cases include a burdensome infant with an unresilient mother, an impossible infant with a competent mother, and a normal infant whose parents hold unrealistic expectations of what constitutes normal infant behavior 5) Attachment disorder: In those mother-infant pairs where the relationship will be tenuous, separation or illness at birth may mean that a proper attachment between the mother and infant does not occur Premature infants are about three times as likely to be abused as are term infants This can also happen where the infant is unwanted, where there are overwhelming pressures on the mother, or where the mother is physically or psychiatrically ill NUTRITIONAL AND CALORIC NEEDS OF THE CHILD The most frequently voiced concern about feeding is that children not eat enough or that they eat too limited a variety of foods Each child has 1192 A Clinical Approach to Medicine his own set of nutritional and caloric needs A constitutionally or genetically small child will need less food than the parent expects the child to consume for optimal growth These expectations may be based on the usual daily intake of other siblings, the usual daily intake of the parents themselves, on the expectations of the health workers, or even booklets circulated to new mothers by commercial baby food manufacturers These booklets often give examples of daily diets that are based on what most infants will eat at any specific age There are individual variations in caloric requirements of a child Children who have identical growth and health can have vastly different caloric intakes varying by a factor of two For example, while growing at the same velocity and with the same quality of health, one child may require twice the calories of another The intrinsic growth rate of a child will determine his demand for caloric intake Many children appear to have a “poor appetite” towards the end of the first year of life that often continues until school age This can become apparent quite suddenly and often coincides with the onset of the negativism in the infant Parents will report that their child does not seem to eat enough to sustain his activity At this time, the child requires less food per unit of body surface or weight because the rate of physical growth has decreased, with a concomitant decrease in caloric needs and appetite, and slimming down of his profile If the child is happy, active and growing normally, one can be totally confident about reassuring the parents Unaware of this change in the child’s nutritional requirements, many parents become upset when the child’s appetite tails off They may resort to harsh threats or ineffective cajoling in an attempt to encourage intake, which tends to increase the child’s resistance to authority and to emphasize to the child the parental interest in his food intake The child soon learns to use feeding as an effective tool to gain attention, to retaliate, or to spite his parents DEVELOPMENT OF FEEDING PROBLEMS Three major inter-related developmental areas in young children have significant impact on eating behavior and feeding problems They are: children’s temperamental styles, psychosocial and emotional development of the child, and the development of feeding skills Feeding Problems in Young Children: A Developmental Perspective 1193 Children’s Temperament Historically, it was thought that parents shaped their children’s personalities; that children were born as “lumps of clay” for parents to mold through daily interactions over the course of childhood However, this theory does not explain why some children who are the product of fantastic families have problems, and others, who were born into troubled families, just fine Innate temperamental characteristics probably play an important role in personality development Children are born with a unique combination of temperament characteristics that define an individual’s particular behavioral style These characteristics are derived from constitutional, intrauterine, central nervous system, and postnatal environmental factors Although they are not fixed, an individual’s temperament characteristics are likely to be consistent over time, especially when the interplay between the individual and the environment becomes relatively stable There are nine measurable characteristics of infant temperament: activity level, rhythmicity, approach or withdrawal, adaptability, threshold of responsiveness, intensity of reaction, quality of mood, distractibility, and attention span or persistence The nine temperamental characteristics can be configured into a number of combinations The three most common constellations are seen in children with easy, slow-towarm-up, and difficult temperament styles The “easy” temperament style is characterized by children with regular biological functioning, a positive approach to new stimuli, a high adaptability to change, mild to moderately intense responses, and a predominantly positive mood These children quickly develop regular sleep and eating schedules, adapt easily to new foods, schools, or strangers, accept most frustration with little distress, engage easily with other children, and adjust quickly to new game rules They are indeed a “joy” to parents The “slow-to-warm-up” children show mildly negative responses to new stimuli, slow adaptability after repeated contact, and they tend to need a good bit of time before their various responses shift from negative to positive, before they become comfortable in new situations Although their first encounters with food, people, schools, etc produce distress reactions, these experiences become better tolerated upon repeated exposure 1194 A Clinical Approach to Medicine Children with a “difficult” temperament style have irregular biological functions and negative withdrawal responses and mood expressions They have irregular sleep and feeding patterns, slow acceptance of new foods, and prolonged adjustment periods to new routines, situations, and people They react intensely to everything in the environment and are often described as “colicky” They tend to have both loud and intense crying and laughing Any kind of minimum frustration leads to tantrums and many behavioral difficulties They will stay this way for anywhere from six weeks to six months; some difficult traits will remain for years These temperament characteristics not, in and of themselves, cause problems Rather, it is the “fit” between the child’s temperament and the demands and expectations of the parents and other caregivers that can cause a struggle The question is whether the parents and child complement or antagonize one another, that is the “goodness of fit” between parent and child If there is a good fit, optimal development is likely On the other hand, if parental expectations are not consistent with the child’s temperament, there is a poor fit; the ensuing dissonance results in stress and potential problem behavior When parents understand their children’s unique strengths and weaknesses in their temperamental styles, they can develop strategies to avoid or resolve conflict Given the focused nature of feeding, mealtimes are often times to see children’s temperamental characteristics expressed and to evaluate the “goodness of fit” between parent and the child Feeding struggles can be resolved once incongruities in temperament “fit” between the feeder and the child are mediated For example, parents of infants with irregular biological functions can be counseled that their babies cannot be expected to conform to strict feeding or sleeping schedules Similarly, slow-to-warmup babies may need consistent, gradual and repeated exposure to new foods before they will accept them These babies also not elicit parental interaction and are at risk of failure to thrive When they are hungry, these infants whine a little bit, instead of crying If their parents are preoccupied or are depressed, this minimal response may not be enough to get their attention An understanding of the temperamental characteristics allows the childcare professional to tailor anticipatory guidance based on an individual infant’s unique temperamental style The child’s inherent temperament may not change, but the parent’s expectations and behavioral Feeding Problems in Young Children: A Developmental Perspective 1195 response to the child can be changed to create a better fit and to avoid or lessen the impact of challenges before they arise Psychosocial and Emotional Development of the Child Understanding some of the salient features in the psychosocial development of a child will help parents in adopting a proper approach to feeding their children Feeding provides many opportunities for parents and their child to learn about each other and to test each other’s limits With each spurt of development, tensions are likely to increase between them, and will influence feeding climate During the first 12 months of life, self-regulation is an important determinant of mechanisms of appetite and satiety As common experience shows, most infants are highly skilled letting their parents know when they are hungry, usually by crying lustily, and also letting them know when they are satiated, by falling contentedly to sleep Feeding in the early months, be it breast- or bottle-feeding, should be on a demand basis, and the infant will soon follow a reasonably regular schedule Parents are rarely successful in “training” their baby to follow a strict feeding schedule However, newborn infants who are slow to make the adjustment to oral feedings, especially those born prematurely, may have an inadequate suck that keeps them from taking in enough calories to grow Such infants often require transient tube feedings Immaturity of gastrointestinal motility patterns also may result in excessive spitting Careful attention to feeding cues, setting a regular schedule for erratic feeders, and gradual advancement of feeding times and volumes, will help them to resolve such problems of homeostasis Around months of age, infants become more visually attentive and socially interactive Sights, sounds, objects take on new meaning and they often turn away from the breast or bottle Some parents interpret these exploratory moments as a personal rejection and either terminate feedings inappropriately or begin to wean the child prematurely Parents need reassurance that such a period of refusal is normal and temporary, the baby will eat better in a quiet or darkened room where stimuli and hence distractions are minimal Midline play skills also emerge at about the same time, making it possible for infants to hold their own bottles Some parents take this opportunity to leave the baby alone with feedings However, infants still need the 1196 A Clinical Approach to Medicine comfort, control, and interaction of being held for feedings Bottle-feeding in a supine position should be avoided to decrease the incidence of otitis media, aspiration, or the bottle becoming a comfort object required for sleep The practice of propping the bottle up so that an infant can feed unassisted is also more common in neglected or disturbed parent-child relationships One of the most important issues in the development of a child is his emerging autonomy and independence from his parents Normal children express this individuality by learning how to feed themselves Negativistic or oppositional behavior is a frequent and normal indication of a child’s move from dependence to independence and occurs when they are in the process of discovering how to make their own decisions If this discovery process is continuously thwarted by parents insisting on their own way, or if the negativistic behavior is rewarded by parental attention or other reinforcement, it will be more likely to continue Feeding time can be protracted and tense and preceded by a sense of anxiety in both parents and child If the child’s behavior spills over into sleeping and toileting with tantrums as well, the parents rapidly become exhausted, recriminatory and out of control, and the child more powerful and fractious The situation rapidly becomes intolerable At or months, children begin to be better able to manipulate objects with their fingers They become completely involved in exploring the world with their hands This, of course, becomes the time to introduce finger foods Unless children can participate actively in a feeding, they will feel a real conflict of interest If they can hold onto a piece of food, they can be a participant While they are working at this important new task, they can be fed a whole meal Over the next few months, the child begins to express even more individuality in feeding and their desire to feed themselves will increase As solids are introduced, the child may show strong preferences regarding texture and flavor Their response will depend on their adaptability, the threshold of their sensitivity to new foods, and their initial responses to newness, which are all a reflection of their temperament Refusal of food can be dramatic and messy, and parents may resort to feeding games, bribes, or restraining and force-feeding Meticulous or controlling parents are often upset by the mess of allowing children to try fingerfeeding and instead insist on spooning it all in themselves, which can cause the child to refuse solids It is not surprising to see infant attempts Feeding Problems in Young Children: A Developmental Perspective 1197 to block the spoon during feeding in an effort to take control Parents should understand that allowing finger-feeding practice speeds up development of skillful and neater feeding One strategy is to offer the infant finger foods and avoid spoon-feeding entirely If plastic bibs are not enough, allowing the child to eat naked, or over newspaper or plastic, with a bath afterwards, can make the messiness more tolerable The burst in independence that occurs by the end of first year is likely to set the scene for more feeding difficulties The child’s new-found freedom in walking brings such choices as whether to walk away from his mother or to walk towards her, whether to sit in a highchair or to refuse, whether to cooperate with her or to resist This new sense of autonomy invades all the important events of his day If the parent presses him to eat, he will become all the more determined to have his own way Besides wanting to be more independent during feeds, the child begins to accept food and other caregiving only from the mother as part of a new cognitive awareness of differences Fathers and grandparents may feel hurt or think that the child is getting spoiled and mothers can become exhausted Mothers should insist on at least one other caregiver participating in feedings regularly, if possible, so they become gradually accepted At the same time, the infant also begins to develop the concept of object permanence, partly learned by repetitive games such as peek-aboo The child is learning all about disappearing objects and how to hide and retrieve them, and can be charmed by the game for quite some time The game is fun for parents when played with toys or faces, but it may become less fun when played with food or feeding utensils thrown from the high chair Sometimes, the strong and predictable reactions from the parents make it even more exciting for the child who is rewarded with a response to his normal negativity The most powerful influences on a child’s food preferences are cultural traditions, modeling by family members, especially siblings, and the emotions expressed around foods and mealtimes Parents are advised never to reward a child for eating or to use food as a reward The appropriate strategy to improve eating includes establishing regular mealtime routines, ensuring a pleasant eating atmosphere, providing models of eating a variety of nutritious foods, facilitating multiple exposures to new foods, offering small servings to avoid overwhelming a child, reducing between-meal calories to enhance appetite, and avoiding pressure related to either the type or volume of intake 1198 A Clinical Approach to Medicine By recognizing the importance of allowing the child the freedom of learning and exploring independence, parents should see their child’s resistance less as a personal insult Parents will find it difficult to enforce their own will and should not try to so Even if they succeed, sometimes by pure might, subsequent mealtimes will become emotionally charged and future problems are more likely to arise However, it is equally important for parents to set reasonable limits and rules around feeding in order to help the child to learn to set their own limits and give them a kind of security Mealtime misbehavior, such as getting up and down from the table, playing with food, and fighting with siblings, occur when parents have not established control over the child’s behavior in general A child in the toddler age must learn to separate the rituals of mealtime from the rest of the day Children are likely to tease parents to break their rituals, but observing them is important to the whole family And if children are expected to sit and eat, even for a short time, they will learn the importance of the ritual Getting a child to eat more is not important enough to justify chasing games on the floor, or allowing a toddler to walk around while eating, with a bottle hanging out of his mouth, or holding pieces of food in one hand as he plays with a toy with the other An effective management technique is to serve the child in a high chair or at the table and to terminate the meal calmly when playing with food exceeds eating or there is significant misbehavior, regardless of how much food the child has consumed The quantity of food is not the issue and most children are well-enough established after the first year to survive nutritionally through many bouts of negativism towards food in the second or third year Alternatively, the child may be offered a “second chance” one hour later to eat the same food This will make it more likely that all involved adults will be consistent in setting mealtime limits, because they need not feel they are depriving the child of food The child will soon learn that food is not a plaything and he will become more serious and respectful of mealtimes Development of Feeding Skills The act of feeding is a complex physiological process that depends on two closely inter-related factors: structure and function In infants and young children, the entire process is dynamic because of ongoing growth and development Feeding Problems in Young Children: A Developmental Perspective 1199 Structural integrity of the mouth, pharynx, and the larynx is essential to the development of competent feeding and swallowing skills A child with structural defects of the oropharynx such as cleft palate may have considerable difficulty sucking efficiently Infant anatomy differs from that of adult Anatomical structures change their physical relationship to one another during growth and consequently their function is affected Most growth related changes begin in the third and fourth year, after the development of most feeding skills The maturation of feeding skills, although influenced by anatomical changes associated with growth, is accomplished largely by developmental changes in the central nervous system, coupled with experiential learning Individual temperament, interpersonal relationships, environmental influences, and culture further compound the basic physiological complexity of feeding Oral feeding for the newborn infant is entirely reflexive, under brainstem control Rooting, nipple latching, sucking, and swallowing are some of the primitive feeding reflexes Feeding development begins with the reflexive suck, swallow, and breathe pattern of the newborn Through feeding experience and the process termed encephalization, different sensory inputs are extended past the brainstem to the midbrain, cerebellum, thalamus, and the cerebral cortex These suprabulbar areas interpret the sensory input and exert their higher level of control on the brainstem motor centers As a result, the older infant and young child acquire the ability to evaluate the physical character of the food, manipulate it appropriately, and voluntarily ingest it The sensory information received and the motor output elicited are closely integrated and influence one another In this way, feeding and swallowing gradually change from a reflexive to a volitional process Feeding development is a learned progression of behaviors This learning is heavily influenced by oral sensation, related gross and fine motor development, and experiential opportunities It has also been postulated that a sensitive or critical period exists for optimal learning of feeding skills Oral sensation involves proprioception, touch, pressure, temperature, and taste Mouthing one’s hands, feet, toys, and other inanimate objects provides needed experience for later feeding and facilitates development of mouth and hand function For example, the tongue thrusting (or extrusion) primitive reflex and gag reflex are quite powerful in the first months of life, causing an infant to expel solids placed in his mouth 1200 A Clinical Approach to Medicine These reflexes are modified and diminished as baby brings fingers or toys into the mouth and starts to tolerate more solid foods This may explain why problems arise with the motor-disabled who are incapable of getting limbs and inanimate objects to their mouths These children often develop oral hypersensitivity or defensiveness They may gag when a spoon is placed on their tongue; cry during feeding; pull away as the spoon approaches because of unpleasant past experiences; and refuse to try new taste, texture, or methods of feeding Although feeding depends on control of the mouth and pharynx, related motor development plays a role Stability is needed before the infant can learn mobility Head control and trunk stability provide the necessary gross motor foundation for the fine motor function seen in hands and mouth The precise oral-motor movements needed in feeding occur after the head and trunk have achieved stability, symmetry, and alignment The ability to self-feeding necessitates increasing hand-eye coordination and a fine pincer grasp Until infants develop these abilities from months onwards, they will be unable to feed themselves properly The concept of a “critical” or “sensitive period”, although hypothetical, is relevant to feeding development A critical period refers to a fairly well-delineated period of time during which a specific stimulus must be applied in order to produce a particular action After such a critical period a particular behavior pattern can no longer be learned so readily The “sensitive period” refers to the optimal time for the application of a stimulus After the sensitive period, it is more difficult to learn a specific pattern of behavior This concept offers an explanation for some feeding problems in children Infants with severe gastrointestinal disease, central nervous system dysfunction, or prematurity, may require enteral or parenteral feeding and may be deprived of oral stimulation for a prolonged period For these children, many of the pleasurable sensations usually associated with oral stimulation, such as feeding, mouthing of objects, and thumb-sucking, may be replaced by noxious sensations and experiences such as suctioning, placement of nasogastric tubes, and endotracheal intubation These children may become orally defensive and resistant to oral feedings; food refusal is a frequent outcome Young children usually show a preference for familiar foods over novel ones This “fear” of new tastes and textures is known as “neophobia” Neophobia is a perfectly normal part of any child’s developing relationship to the environment, and may well be essential as it helps avoid Feeding Problems in Young Children: A Developmental Perspective 1201 the ingestion of potentially harmful foods Typically, resistance develops following an episode of choking or nausea after eating, or in association with a traumatic incident It takes more than 10 to 15 tasting exposures to increase the likelihood that a child will eat previously rejected food While innate preferences and aversions clearly exist, food acceptance patterns can be altered or learned They are shaped by three factors: (1) opportunities for repeated exposure to new foods; (2) the social context of meals; and (3) associative learning, either conditioned food preferences or conditioned aversions Parents often not appreciate that their children’s initial rejection of new foods is a normal and transitory phenomenon, which can be reduced by means of repeated exposures Rejection should not be interpreted as dislike of the new food, and hence it should not be removed altogether from the child’s diet, depriving them of the opportunity to learn to like it The problem can easily be overcome if parents repeatedly offer new foods in small quantities in a positive, patient manner, without undue coercion, followed by plenty of praise if the child ingests some Routine family meals teach children about their culture’s rules of cuisine, that is which foods or food combinations their culture finds acceptable and which it does not By watching what others eat and not eat, children learn what foods are “dangerous”, “disgusting”, and which are not The rules of cuisine also dictate which meals are eaten at which times of day and what foods are typically eaten at these meals Importantly, parents’ predisposed beliefs about the anticipated acceptance or rejection of a food vary from culture to culture and can affect the parents’ feeding behavior with regard to that food These expectations shape the feeding interaction between the parent and child and, ultimately, influence the child’s acceptance or rejection of a particular food Children also learn food acceptance patterns through associative conditioning, which is simply the pairing of something in the environment with something else, resulting in a new response When a food is repeatedly associated with a distinctive social context, the child’s preferences can be systematically changed in either a positive or negative direction, depending on the social context employed Social context is the implicit value placed upon that food An example of this is when we eat something and get sick afterwards We invariably assume, rightly or wrongly, that it was that particular food that was responsible What is so remarkable is that people retain these aversions decades later, even when the 1202 A Clinical Approach to Medicine aversions are formed after only one pairing This has been called “one trial learning” For young children with a medical condition, such as gastroesophageal reflux, which leads to vomiting after meals regardless of the type of foods ingested, it is likely that the intense avoiding response will be transmuted into a distinctly maladaptive response to any feeding occasion Similarly, to encourage a child to eat certain food about which he has no strong feelings one way or the other, a non-food reward may be promised, e.g offering to read a favorite story This can also result in a significant negative shift in the child’s attitude to that food The coercive nature of the feeding strategy generates a negative emotion that becomes associated with the food The child may think that if he has to be bribed to eat that food, it cannot be very nice The medical relevance is that if we try to encourage a child to take medicines by offering him a sweet afterwards, we may be virtually guaranteeing that the child will be less likely to accept the medicine without a fuss next time When foods themselves are the reward component for children’s performance of desired behaviors, the pairing may have a positive effect on children’s behavior To reward a child for playing quietly for about one hour without disturbing a busy parent, he is offered an apple at the end of that period The food, about which the child has only a neutral attitude initially, becomes highly valued by the child Again, the social context suggests that food must be valuable or it will not be worth giving as a reward CONCLUSION Feeding problems can dominate the lives of those who feel helpless when denied one of their important parenting roles by a young child who is unable or unwilling to eat Unfortunately, management of these problems is not usually based on an appreciation of the developmental course of normal feeding behavior and appetite regulation Consequently, many young children, whose problem is relatively minor to begin with, go on to develop intractable patterns of behavior that not only cause anxiety and distress to their parents, but also may well have adverse consequences for their growth and health A proper analysis of feeding problems must not only take into account of the overt behavior, and the psychological causes and correlates of that behavior, but also certain developmental and biological character- Feeding Problems in Young Children: A Developmental Perspective 1203 istics of the child Infant feeding problems must be viewed in a developmental perspective, and the individual characteristics of the child and caregiver should be taken into account when assessing possible precipitating and perpetuating factors Comprehensive preventive and treatment programs involving a team of diverse specialists should be developed to bring a range of expertise to bear on the subject FURTHER READING Carey WB, Understanding Your Child’s Temperament, Macmillan, A Simon and Schuster Macmillan Company, New York, 1997 Skuse D, Identification and management of problem eaters, Arch Dis Child 69:604–608, 1993 Harris G, Booth IW, The nature and management of eating problems in pre-school children, in Cooper PJ, Stein A (eds.), Feeding Problems and Eating Disorders in Children and Adolescents, Harwood Academic Publishers, Melbourne, pp 61–84, 1992 Wolke D, Skuse D, The management of infant feeding problems, in Cooper PJ, Stein A (eds.), Feeding Problems and Eating Disorders in Children and Adolescents, Harwood Academic Publishers, Melbourne, pp 27–59, 1992 Illingworth RS, Lister J, The critical or sensitive period, with special reference to certain feeding problems in infants and children, J Pediatr 65:839–849, 1964 Birch LL, Development of food acceptance patterns, Dev Psychol 26: 515–519, 1990 Brazelton TB, Feeding: Pleasure or battleground?, in To Listen to a Child, Addison–Wesley Publishing Company, pp 93–105, 1984 Rudolph CD, Diagnosis and management of children with feeding disorders, in Hyman P, DiLorenzo C (eds.), Gastrointestinal Motility Disorders in Children, Academy Professional Information Services, New York, pp 33–53, 1994 Stevenson RD, Allaire JH, The development of normal feeding and swallowing, Pediatr Clin North Am 38:1439–1453, 1991 10 Finney JW, Preventing common feeding problems in infants and young children, Pediatr Clin North Am 33:775–789, 1986 11 Hammer LD, The development of eating behavior in childhood, Pediatr Clin North Am 39:379–394, 1992 12 Stein MT, Common issues in feeding, in Levine MD, Carey WB, Crocker AC (eds.), Developmental-Behavioral Pediatrics, 3rd ed., WB Saunders, Philadelphia, pp 392–396, 1999 13 Satter E, The feeding relationship: problems and interventions, J Pediatr 117:S181–189, 1990 14 Watt M, Behavioral problems with feeding children, J Pediatr Obstet Gynaecol 12:16–23, 1988 This page intentionally left blank Renal Medicine This page intentionally left blank 69 A Clinical Approach to Glomerulonephritis Woo Keng Thye INTRODUCTION The term glomerulonephritis refers to an inflammation of the kidneys Every year, about 650 new patients are diagnosed with end stage renal failure (ESRF) in Singapore The most common cause for ESRF in Singapore is diabetic nephropathy, which accounts for 42% of all patients Glomerulonephritis (GN) accounts for 29% and is the second most common cause Fifteen years ago, GN was the most common but nowadays with early detection and measures to retard progression to ESRF, it has fallen to second place In many Western countries, Membranous GN is the most prevalent form of GN, accounting for about 35% In Asian countries, Mesangial Proliferative GN is the most common (30%), as was the case in Singapore in the 1970’s and early 1980’s.1 The high incidence of Mesangial Proliferative GN was attributed to infection in these countries IgA nephritis which used to be an uncommon cause of Nephrotic 1207 1208 A Clinical Approach to Medicine Syndrome (9%) is now becoming more common too (15%) However we are now seeing more patients with Minimal Change (30%) and Focal Global Sclerosis (FGS) (19%) not responding to steroids or prednisolone, meaning that they probably have Focal and Segmental Glomerulosclerosis (FSGS), which is less responsive to conventional therapy What this implies is that the true incidence of FSGS is not at 9% but is probably more Our low incidence of FSGS is not in keeping with the incidence in Western countries The incidence of Mesangio-Capillary GN and Crescenteric GN is low (2%) About 20 years ago, Mesangio-Capillary GN was common in the West and it was related to infection; now it is uncommon The epidemiology of GN follows a racial and geographical distribution which is influenced by the environment (infection) and the foodstuff we ingest (allergens).1 The major clinical syndromes are: 1) 2) 3) 4) asymptomatic hematuria and proteinuria; acute nephritic syndrome; nephrotic syndrome; and rapidly progressive glomerulonephritis ASYMPTOMATIC HEMATURIA AND PROTEINURIA Asymptomatic hematuria and proteinuria is the most common presenting sign for a wide variety of GN In the Singapore context, this is the usual presentation for IgA nephritis, the most common form of GN occurring in Singapore.2 Patients with such urinary abnormalities are often referred by their general practitioners following a routine investigation for some unrelated complaints Such cases are also detected on community health surveys or in the course of screening of national service registrants, for example at the Central Manpower Base as in the case of Singapore Surgeons, too, often refer patients with asymptomatic hematuria after they have been shown to have normal intravenous pyelogram and cystoscopic examination History One should ascertain that the patient is truly asymptomatic Enquire for a history of gross or macroscopic hematuria, dysuria or frequency of micturition, which may point to a diagnosis of hemorrhagic cystitis A history of A Clinical Approach to Glomerulonephritis 1209 nocturia, backache, passage of stones, edema or recurrent sore throat may provide useful clues to the underlying basis of the urinary abnormalities If the patient has episodes of gross hematuria, determine if there is a relationship to upper respiratory tract infection, fever or exercise as IgA nephritis is associated with synpharyngitic hematuria, i.e gross hematuria occurring simultaneously with sore throat Always ask for a history of systemic illness Tuberculosis, Systemic Lupus Erythematosus and Henoch–Schonlein purpura may present with urinary abnormalities A family history of nephritis, hypertension and diabetes mellitus may be important In a married woman, enquire into a past history of pre-eclampsia Physical Examination In the general examination look for pallor, sallowness, presence of edema and the rash of Henoch–Schonlein purpura or Systemic Lupus Erythematosus Examine the abdomen for ballotable kidneys or renal masses, which may suggest polycystic kidneys or a renal tumor Always check the blood pressure; examine the fundi and listen for a renal bruit In most cases with asymptomatic hematuria and proteinuria the physical examination is usually normal; nevertheless a complete physical examination is mandatory to exclude any obvious underlying cause for the urinary abnormality Investigations 1) An abnormal full blood count may be the first clue to SLE and tuberculosis 2) Urine Microscopy a) RBC count is usually variable and may be anything from 5–10 to 100–300 per high power field b) WBC count: if pyuria is present, exclude urinary tract infection by doing a urine culture For sterile pyuria, tuberculosis has to be excluded c) Casts: RBC casts point to a glomerulonephritis Granular casts associated with more than a gram of proteinuria per day denotes a more severe lesion d) Albumin may vary from 1ϩ to 3ϩ 1210 A Clinical Approach to Medicine 3) Quantitation of total urinary protein (TUP) in 24 hours Normally this should not exceed 0.15 gm In our experience, a TUP of more than gm generally denotes a more severe glomerular lesion on renal biopsy, i.e the presence of glomerular scarring (glomerulosclerosis) 4) Blood urea, serum creatinine and creatinine clearance should be documented 5) Anti-nuclear factor (ANF) should be done when one suspects SLE together with Anti-DNA and serum complement Mild microscopic hematuria (Ͻ 10 RBC/high-power field (hpf )) in the absence of significant proteinuria is of little prognostic significance In our experience, renal biopsies of this group of patients usually reveal only mild glomerulonephritis which generally has a good prognosis Sometimes on follow-up, patients may develop gross hematuria which may be precipitated by respiratory tract infections or exercise Such patients on biopsy usually have IgA nephritis Proteinuria of gm or more is an indication for a renal biopsy Biopsy is performed under ultrasound guidance Clinical Course Most patients with asymptomatic hematuria and proteinuria have a benign course as they are likely to have mesangial IgA nephritis, which has a favourable prognosis in most cases No treatment is required for most of these patients and all they require is reassurance They could be followed up by their general practitioners and have their blood pressure, urine microscopy, serum creatinine and urinary protein checked once a year It is important to treat any existing hypertension as uncontrolled hypertension often leads to renal impairment in patients with IgA nephritis In those patients with IgA nephritis with significant glomerulosclerosis especially in the presence of severe proteinuria, the prognosis is guarded Patients with crescents on biopsy have a poorer long-term prognosis On long-term follow-up, some patients may develop gross hematuria precipitated by upper respiratory tract infections or exercise They may have colicky loin pain due to clot colic These patients require reassurance, rest and plenty of fluids as well as antibiotics for the respiratory tract infections Those who develop edema or the nephrotic syndrome will require diuretic therapy In those with mild diffuse mesangial proliferative GN A Clinical Approach to Glomerulonephritis 1211 with the nephrotic syndrome, a 12-week course of prednisolone therapy starting at 60 mg/day or mg/kg body weight and tailing off by 12 weeks may induce a remission in about 50% of cases These are patients with selective proteinuria Hypertension, when it occurs, must be treated aggressively as uncontrolled hypertension can lead to rapid deterioration of renal function, culminating in ESRF Currently, the indications for combination therapy with dipyridamole and low dose warfarin in our Department of Renal Medicine are the presence of any one of the following parameters: proteinuria Ͼ gm/day; hypertension; renal impairment; glomerulosclerosis Ͼ 20% on renal biopsy; presence of even a single crescent; medial hyperplasia of blood vessels on biopsy Our department’s guidelines for treatment of patients with IgA nephritis with asymptomatic hematuria and proteinuria consist of control of systemic hypertension, use of ACE inhibitor and or Angiotensin II Receptor Antagonist (ATRA) for glomerular hyperfiltration, dipyridamole and low dose Warfarin, low protein diet (0.8 gm/kg bw/day) to reduce macromolecular flux of high protein diet as well as to reduce afferent vasodilation in glomerular hyperfiltration and control of serum cholesterol to prevent lipid induced glomerulosclerosis On the whole, most patients with asymptomatic hematuria and proteinuria due to IgA nephritis run a benign course, except for about 30% (usually associated with glomerulosclerosis and heavy proteinuria) who develop renal failure over a period of 10 years These patients would ultimately require renal transplantation or dialysis In other words, IgA nephritis is not always a benign disease, especially in Singapore, where we have large numbers of people with the disease It is therefore an important cause of ESRF Clinical Trials in IgA Nephritis The use of Persantin and low dose Warfarin in IgA Nephritis is now accepted as Level I evidence and support Grade A recommendation.3 Since ACE inhibitors decrease ACE activity, ACE inhibitor therapy in patients with IgA nephritis would be expected to reduce renal injury in these patients We have shown that ACEI therapy does lead to decreased proteinuria and retardation of the progression of renal failure in IgA nephritis In our study we also showed that Angiotensin II Receptor 1212 A Clinical Approach to Medicine Antagonist (ATRA) is as effective as ACEI in decreasing proteinuria and preserving renal function It has been postulated that ACEI/ATRA (ACE inhibitor/Angiotensin receptor antagonist) may decrease proteinuria in patients with glomerulonephritis by its action on the Glomerular Basement Membrane We performed a study to examine the relationship between the response of patients with IgA Nephritis (IgA Nx) to ACEI (Enalapril)/ATRA (Losartan) therapy by decreasing proteinuria and its effect on the Selectivity Index (SI) in these patients Forty one patients with biopsy proven IgA Nx entered a control trial with 21 in the treatment group and 20 in the control group The entry criteria included proteinuria of gm or more and or renal impairment Patients in the treatment group received ACEI (5 mg)/ATRA (50 mg) or both with monthly increase in dosage In the control group, hypertension was treated with atenolol, hydrallazine or methyldopa After a mean duration of therapy of 13 Ϯ months, in the treatment group there was no significant change in serum creatinine, proteinuria or SI but in the control group, serum creatinine deteriorated from 1.8 Ϯ 0.8 to 2.3 Ϯ 1.1 mg/dL (p Ͻ 0.05) Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders) and the other 11 did not (non-responders) Among the responders, SI improved from a mean of 0.26 Ϯ 0.07 to 0.18 Ϯ 0.07 (p Ͻ 0.001) indicating a tendency towards selective proteinuria This was associated with improvement in serum creatinine from mean 1.7 Ϯ 0.6 to 1.5 Ϯ 0.6 mg/dL ( p Ͻ 0.02) and decrease in proteinuria from mean of 2.3 Ϯ 1.1 g/day to 0.7 Ϯ 0.5 g/day (p Ͻ 0.001) After treatment, proteinuria in the treatment group (1.8 Ϯ 1.6 g/day) was significantly less than in the control group (2.9 Ϯ 1.8 g/day) (p Ͻ 0.05) The post-treatment SI in the responder group (0.18 Ϯ 0.07) was better than that of the non-responder group (0.33 Ϯ 0.11) (p Ͻ 0.002) Eight out of 21 patients in the treatment group who had documented renal impairment had improvement in their renal function compared to in the control group (2 ϭ 4.4, p Ͻ 0.05) Of the patients in the treatment group who improved their renal function, normalized their renal function Our study suggest that ACEI/ATRA therapy may be beneficial in patients with IgA Nx with renal impairment and non-selective proteinuria as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria and improvement in renal function ACEI/ ATRA therapy probably modifies pore size distribution by reducing the A Clinical Approach to Glomerulonephritis 1213 radius of large nonselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine Individual antiproteinuric response to ACEI/ATRA therapy varies depending on ACE gene polymorphism as those with the DD genotype respond better to the antiproteinuric effect of ACEI/ATRA therapy Yoshida in a study examining the role of the deletion polymorphism of the ACE gene in the progression and therapeutic responsiveness of IgA nephropathy using the ACEI lisinopril reported that the ACEI lisinopril significantly decreased proteinuria in the DD genotype patients but not in the II or ID genotype Similar findings have also been reported by Moriyama ACUTE NEPHRITIC SYNDROME The features are edema with gross hematuria (smoky urine) and frequent association with hypertension Sometimes the symptoms are complicated by encephalopathy and congestive heart failure This condition may be caused by bacteria, parasites, viruses, systemic lupus erythematosus, Henoch–Schonlein purpura and Guillain–Barre syndrome Post streptococcal glomerulonephritis which classically presents as the nephritic syndrome is better referred to as Post Infectious GN because apart from streptococci, other bacteria and viruses can be the causative agent It affects children principally, but no age is exempt There is usually a latent period of 10 to 21 days The urine characteristically shows a rusty or smoky hue Mild renal impairment is common Serum Complements (CH50 and C3) are usually low but normalize after to weeks Treatment is usually symptomatic: generally bed rest is recommended during the acute phase Restrict fluids and salt if edema is present Treat accompanying hypertension and heart failure A course of Penicillin is given if throat swab grows streptococci Dialysis may be required in some instances to tide the patient over the acute renal failure which may complicate the course of a few patients For the majority of patients, this is a benign disease, with children faring better than adults Glassock5 reported a 99% 5-year and a 97% 10-year survival for children whereas adults have 95% 5-year and a 90% 10-year survival Potter6 in a series of 534 patients from Trinidad followed up for 12 to 17 years reported only deaths from chronic renal failure Both those patients had persistent urinary abnormalities Of the surviving 1214 A Clinical Approach to Medicine patients, 3.6% had urinary abnormalities and another 3.6% had hypertension All had normal serum creatinine The bad prognostic features in this disease are persistent nephrotic syndrome, hypertension, renal impairment and crescents These bad prognostic features however, as we shall see later, are true for most forms of GN NEPHROTIC SYNDROME Nephrotic Syndrome is a clinical entity of multiple causes characterised by increased glomerular permeability manifested by massive proteinuria of more than gm per day associated with edema and hypoalbuminemia of less than 30 gm Very often, there is also associated hypercholesterolemia and hypertriglyceridemia and lipiduria Any glomerular lesion may be associated, at least temporarily, with heavy proteinuria in the nephrotic range Causes of Nephrotic Syndrome • • 80% due to GN 20% due to miscellaneous causes 1) Diabetes mellitus 2) Amyloidosis 3) Precipitating causes of renal vein thrombosis (RVT) a) nephrotic syndrome (hypercoagulable state) b) renal amyloid gives rise to thrombosis of intrarenal veins c) hypernephroma gives rise to obstruction and RVT d) trauma of renal veins e) severe dehydration especially in infants suffering from gastroenteritis RVT is a complication of Nephrotic Syndrome and not a cause of Nephrotic Syndrome 4) Malignancy: Hodgkin’s Disease, bronchogenic carcinoma, cancer of the breast, bowel, leukemias, myeloma 5) Infections: Hepatitis B and C, Malaria, syphilis, leprosy 6) Drugs: Trimethadione, penicillamine, phenindione, gold, mercury, bismuth, captopril, NSAIDS 7) Autoimmune Disease, SLE, Cryoglobulinemia, Thyrotoxicosis 8) Congenital Nephrotic Syndrome A Clinical Approach to Glomerulonephritis 1215 Causes: Congenital syphilis, cytomegalovirus infection, mercury poisoning, maternal tuberculosis 9) Miscellaneous: Prophylactic inoculation (smallpox, polio, tetanus), bee stings, pollen allergy MINIMAL CHANGE DISEASE Young children are especially affected with a peak from 2–4 years Minimal Change accounts for 60–70% of all idiopathic nephrotic syndrome in children and 10–30% in adults In Singapore this is also the commonest lesion in adults (30%) Hypertension and renal impairment are uncommon complications and microscopic hematuria is rare Shaloub7 considers this disease a disorder in T cell function with abnormal lymphokine production Focal Global Sclerosis (FGS) accounts for 20% of nephrotics in adults in Singapore Clinically, FGS behaves like Minimal Change, is steroid responsive and has a good prognosis Treatment consists of a three months’ course of prednisolone In those who fail to respond or where they have frequent relapses, cyclophosphamide or cyclosporine A may induce long-lasting remissions This is a disease with a good prognosis even though the relapse rates are high Depending on a patient’s response to prednisolone and his frequency of relapses various categories have been described Primary responders, non-relapsers form 38% If a patient has less than relapses in the first months of the initial response he is a primary responder, infrequent relapser (19%) If he had or more relapses in months, he is a primary responder, frequent relapser (42%) Patients who not respond to steroids following an initial response (secondary non-responder) form 5%.8 In a study among adults, Cameron9 showed that 18% responded with early loss of proteinuria but 70% of them relapsed, 63% repeatedly A small number, after repeated relapse and remission, acquired steroid unresponsiveness They displayed focal glomerulosclerosis on renal biopsy The use of cytotoxics is recommended in this group Of adults with Minimal Lesion, 50–60% will remit for years or more Those who fail to respond to Cyclophosphamide can be given a course of Cyclosporine A for months to a year, or Mycophenolate Mofetil (MMF) (0.75 gm to gm twice daily) for months A patient with Minimal Lesion has an excellent long-term prognosis if he has minimal glomerular lesion on light microscopy, foot process 1216 A Clinical Approach to Medicine fusion on electron microscopy, absence of immunoglobulins on immunofluorescence (IMF), and complete remission following a course of steroids Even so, multiple relapses will still occur FOCAL & SEGMENTAL GLOMERULOSCLEROSIS (FSGS) There is a slight preponderance of males with a peak at 20–30 years accounting for 10–20% of idiopathic nephrotic syndrome The incidence of FSGS is rising in most countries.10 In Singapore it is now about 15% About 70–90% present as the Nephrotic Syndrome; hypertension may be an associated feature The majority of patients with this form of nephritis experience a progressive decline in GFR; hypertension and persistent proteinuria Initially patients present with asymptomatic proteinuria but often they ultimately become nephrotic Initial studies reported little benefit with treatment Nowadays with treatment, response range from 30–50% (include partial response) High dose prednisolone (1 mg/kg bw a day) for first months, then 30 mg for 3rd month, and thereafter reduce gradually to 10 mg and maintain till end of months Those who not respond to prednisolone should have cyclosphosphamide at mg/kg bw a day together with prednisolone (30 mg/day) for months, then reduce and maintain for another months In those who fail cyclophosphamide they could be given cyclosporine A at mg/kg bw a day for months, then mg at 4th month, mg at 5th month, mg at 6th month, and maintain There may be a potential role for FK 506 (0.1 to 0.2 mg/kg bw a day) or MMF MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS It occurs in about 25% of idiopathic nephrotic syndrome among adults in Singapore but appears to be a much less common cause of nephrotic syndrome in Western countries IgA nephritis accounts for about 8% of nephrotic syndrome seen in Singapore and is therefore an uncommon cause of nephrotic syndrome The long-term evolution of this type of nephritis is not well understood This discussion excludes IgA nephritis, which has been dealt with A Clinical Approach to Glomerulonephritis 1217 earlier, but it includes IgM nephropathy, IgG and the IMF negative group Patients with this lesion who become nephrotic and develop focal and segmental sclerosis have a higher incidence of developing chronic renal failure (CRF) Only 30% of those with nephrotic syndrome experience complete remissions with steroid They are usually the ones with mild mesangial proliferation with no focal and segmental sclerosis In those patients therefore who have mild proliferation of the mesangium with no evidence of focal and segmental sclerosis and negative immunoglobulin staining on IMF, a trial of steroid therapy should be offered as they have a good chance of achieving remission Habib11 in fact considered such patients as part of the spectrum of Minimal Change GN Waldher12 reported that more than 50% of patients with Mesangial Proliferative GN were steroid-resistant, 70% with associated focal and segmental sclerosis There is a need for controlled therapeutic trials in patients with this form of nephritis In our experience, those with selective proteinuria tend to respond to steroids and failing that cyclophosphamide Those who fail cyclophosphamide can be offerred cyclosporine A or MMF MEMBRANOUS GLOMERULONEPHRITIS Hypertension and azotemia are late features of the disease Microscopic hematuria is common but gross hematuria is a rare feature Renal vein thrombosis is secondary to the glomerulopathy rather than the cause of it This disease runs an indolent and slowly progressive course with remissions and exacerbations of the nephrotic syndrome Children have a better prognosis, with less than 5% CRF after years and a 90% 10-year survival Adults however have a less benign course; 25% achieve spontaneous remission with another 25% spontaneous partial remission (less than gm proteinuria) Cameron’s series13 had a 75% 5-year and 50% 10-year survival Even patients with partial remission have a better outlook than those who have no response at all A controlled trial with high dose alternate-day prednisolone in the USA has reported a reduction in proteinuria and progression of CRF.14 However, if there is already abnormal GFR, steroid therapy is not of much use We would offer a months course of prednisolone therapy and failing that cyclophosphamide There is a potential role for other agents 1218 A Clinical Approach to Medicine like chlorambucil (0.15–0.2 mg/kg bw/day),15 cyclosporine A (5 mg/kg bw/day) and FK 506 (0.1–0.2 mg/kg bw/day)16 and MMF MESANGIOCAPILLARY GLOMERULONEPHRITIS (MCGN) All age groups are involved, especially those aged 5–15 years It occurs in 5–10% of children with the nephrotic syndrome Fifty percent have associated upper respiratory tract infection and 40% have high antistreptolysin O titer (ASOT) This type of nephritis has a relentless but slowly progressive course The bad prognostic features are low GFR, hypertension, persistent nephrotic syndrome and the presence of diffuse crescents on renal biopsy For Type I MCGN (Subendothelial Deposits) the 5-year and 10-year survival are 80% and 60% respectively For Type II MCGN (Dense Deposit Disease) the respective survival rates are poorer, 60% and 45% at and 10 years Other series reported a poorer prognosis in the presence of nephrotic syndrome with 40% survival at 10 years, compared to 85% at 10 years for patients with no nephrotic syndrome But even in the patients with nephrotic syndrome, the occasional remission has been reported In general, however, those with Type II disease have a poorer outlook For the moment there is no clearly established form of treatment McEnery17 reported the beneficial effects of continuous low dose prednisolone whereas Kincaid-Smith18 reported 3-year survival of 82% using a combination regimen of cyclophosphamide, persantin and warfarin (Melbourne Cocktail) in an uncontrolled trial We would advocate a months course of prednisolone and failing that cyclophosphamide Failing that, try cyclosporine or MMF MANAGEMENT OF NEPHROTIC SYNDROME General Treatment 1) Diuretic Treatment These are the major agents in treatment: a) Frusemide can be used alone Increase the dose till diuresis occurs Kϩ supplements are required A Clinical Approach to Glomerulonephritis 1219 2) 3) 4) 5) 6) b) Spironolactone should be avoided if serum Kϩ is high or patient has renal impairment c) Hydrochlorothiazide has a synergistic action with frusemide and spironolactone We usually use a combination regimen of all diuretics as they have synergistic actions Treatment of hypertension Treatment of infections Use the appropriate antibiotics Diet: The patient requires a high protein, low salt diet with fluid restriction Infusion of Naϩ-free albumin induces diuresis but its benefit is evanescent Use ACE inhibitor or ATRA to reduce intra-glomerular hypertension (hyperfiltration) and limit protein loss in urine Specific Treatment 1) Investigate and try to elucidate the cause of Nephrotic Syndrome and if possible remove or treat it 2) Check through list of causes and investigate accordingly In all patients, always exclude SLE Do anti-nuclear factor (ANF), anti-DNA, and serum complement A patient with membranous GN should be screened for hepatitis B antigen and antibody Treatment with Steroids and Cytotoxic Agents Primary Treatment to induce remission: 1) Minimal change GN and lupus nephritis respond well to a course of prednisolone starting at 60 mg or m/kg bw/day and reducing gradually over a period of months For those who fail to respond to prednisolone or who are frequent relapsers, cyclophosphamide (2 mg/kg bw) for months is advocated Those who fail cyclophosphamide can be given a course of cyclosporine A at mg/kg bw for months with reduction over the next months and maintain up to year 2) Mild diffuse mesangial proliferative GN may respond to prednisolone, failing that, try cyclophosphamide, cyclosporine or MMF 1220 A Clinical Approach to Medicine 3) Membranous GN may respond to a course of prednisolone for a period of months, failing that, try cyclophosphamide, cyclosporine or MMF 4) Focal and segmental glomerulosclerosis may respond to prednisolone and cyclophosphamide for months If no response, try cyclosporine or MMF 5) Newer agents include FK 506 (0.1–0.2 mg/kg bw/day)16 and mycophenolate mofetil (MMF) (0.75–1 gm twice daily)19 for months Persantin and Warfarin Plus Regimen (P and W ϩ Regimen) All patients who fail to respond to steroids and cytotoxics should be offered P and W ϩ regimen, which would help to retard progression to ESRF.20 1) Persantin (dipyridamole) — anti-platelet and anti-PDGF, 75–100 mg tds with low dose warfarin (anti-thrombotic), to mg (INR Ͻ 1.6) to retard progression of renal failure 2) Treat hypertension 3) ACE Inhibitor to reduce intra-glomerular hypertension and retard progression of renal failure 4) Angiotensin Receptor Antagonist (ATRA) to reduce intra-glomerular hypertension (Losartan) and retard progression of renal failure 5) Restricted protein diet (0.8 gm/kg bw) to decrease afferent arteriolar vasodilation and hyperfiltration 6) Treat high lipids and hypercholesterolemia as cholesterol is toxic to mesangial cells Rapidly Progressive Glomerulonephritis (Crescenteric Glomerulonephritis) This is a clinical syndrome of rapid and progressive decline in renal function, usually resulting in end stage renal failure in weeks to months, where there is extensive and exuberant proliferation of epithelial cells of Bowman’s space In clinical practice, this condition is diagnosed when a patient has a rapid decline in renal function (acute renal failure), usually with oliguria, hematuria, hypertension in the presence of normal sized or enlarged kidneys A renal biopsy will show extensive crescents of 50% or more A Clinical Approach to Glomerulonephritis 1221 Preceding flu-like illness is found in 50% of patients Hypertension is often mild Urine microscopy shows many RBC with RBC casts Serum complements (CH50, C3 and Clq) are often normal Fibrin degradation products are often present and anti-streptolysin titer is increased in 30% of patients Treatment consists of plasmapheresis with steroids and cyclophosphamide ideally administered prior to the onset of oliguria A quadruple regimen with heparin, prednisolone, cyclophosphamide and anti-platelet agents (dipyridamole) has been used with success, but caution should be exercised when using heparin A low dose continuous heparin regimen during the acute phase to avoid hemorrhage and then switch over to warfarin therapy is safer A better alternative is to use pulse therapy with methyl prednisolone (0.5 gm IV daily for days) followed by plasmapheresis Other measures include restriction of salt and water, treatment of hypertension and supportive dialysis Patients with 50–80% crescents on biopsy have less than 30% 5-year and less than 10% 10-year survival Those with 80% crescents have an 8% 5-year and less than 5% 10-year survival REFERENCES Woo KT, Chiang GSC, Glomerulonephritis in Singapore (1987–1997), Medicine of the Americas 1(I), 30–341, 2000 Woo KT, Lau YK, Choong HL, Zhao Y, Tan HB, Cheung W, Yap HK, Chiang GSC, IgA nephropathy: Effects of clinical indices, ACE/ ATRA therapy and ACE gene polymorphism on disease progression, Nephrology, 7: S166–172, 2002 Woo KT, Lee GSL, Pall AA, Dipyridamole and low-dose warfarin without cyclophosphamide in the management of IgA nephropathy, Kidney Int 57(1), pp 348–349, 2000 Woo KT, Lau YK, Wong KS, Chiang GSC, ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis, Kidney Int 58:2485–2491, 2000 Glassock RJ, Adler SG, Ward HJ, Cohen AH, Primary Glomerular Diseases, in: Brenner BM, Rector FC (eds.), The Kidney, WB Saunders Company, Philadelphia, pp 1182–1279, 1991 Potter EV, Lipschultz SA, Abidh S et al., Twelve to seventeen year follow up of patients with poststreptococcal acute glomerulonephritis in Trinidad, N Engl J Med 307:725–729, 1982 Shalhoub RJ, Pathogenesis of lipoid nephrosis: A disorder of T cell function, Lancet 2:556–560, 1974 1222 A Clinical Approach to Medicine Cameron JS, The long-term outcome of glomerular diseases, in Schrier RN and Gottschalk CW (eds.), Diseases of the kidney, 2nd ed., Little Brown, Boston, pp 1895–1958, 1992 Cameron JS, The problem of focal segmental glomerulosclerosis, in: Kincaid–Smith P, d’Apice AJF, Atkins R (eds.), Progress in Glomerulonephritis, New York, John Wiley and Sons, pp 209–228, 1979 10 Haas M, Spargo BH, Conventry S, Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: A 20-year renal biopsy study, Am J Kidney Dis 26:740–750, 1995 11 Habib R, Levy M, Gubler MC, Clinicopathological correlation in the nephrotic syndrome, Paediatrician 8:325, 1979 12 Waldher R, Gubler MC, Levy M, Broyer M, Habib R, The significance of pure diffuse mesangial proliferation in idiopathic nephrotic syndrome, Clini Nephrol 10:171–179, 1978 13 Cameron JS, The natural history of glomerulonephritis, in: Black D, Jones NF (eds.), Renal Disease, Blackwell Scientific Publishers, London, pp 329–382, 1979 14 Collaborative Study of the Adult Idiopathic Nephrotic Syndrome, A controlled study of short term prednisolone treatment in adults with membranous nephropathy, N Engl J Med 301:1301–1306, 1979 15 Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S et al., A 10 year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy Kidney Int 48:1600–1604, 1995 16 Mc Cauley J, Shapiro R, Ellis D, Igdal H, Zakis TA, Starzl TE, Pilot trial of FK 506 in the management of steroid resistant nephrotic syndrome, Nephrology, Dialysis and Transplantation 8:1286–1290, 1993 17 McEnery PT, McAdams AJ, West CD, Membranoproliferative Glomerulonephritis: improved survival with alternate day prednisolone therapy, Clin Nephrol 13:117–124, 1980 18 Kincaid–Smith P, The natural history and treatment of mesangiocapillary glomerulonephritis, in: Kincaid–Smith P, Mathew TH, Becker EC (eds.), Glomerulonephritis Morphology, Natural History and Treatment, Part I, John Wiley and Sons, New York, pp 591–609, 1973 19 Briggs WA, Choi MJ, Scheel PJ Jr Successful mycophenolate mofetil treatment of glomerular disease, Amer J Kidney Disease 31:213–217, 1998 20 Woo KT, Current Therapeutic Strategies in Glomerulonephritis, Ann Acad Med Singapore 28:272–278, 1999 70 Urinary Tract Infection Choong Hui Lin Urinary tract infection (UTI) refers to the presence of microorganisms in the urinary tract, causing a host response It should be differentiated from colonization though colonization precedes infection Transient introduction of bacteria into the urinary tract probably occurs in the healthy, especially sexually active women UTI may present as asymptomatic bacteriuria, urethritis, cystitis or acute pyelonephritis in women In men, they often present as acute prostatitis, chronic prostatitis and pyelonephritis In both sexes, predisposing conditions such as obstructive uropathy from congenital anomalies, vesicoureteric reflux, renal calculi, stricture formation and tumors have to be excluded UTI is very common, second only to respiratory tract infections Severity may range from mild to severe associated with septicemia, pyonephrosis and abscess formation Unless there is an underlying anatomic abnormality, urinary tract infection is not likely to cause serious renal disease UTI may be classified as complicated or uncomplicated A UTI is described as uncomplicated when it occurs without the presence of physiologic or anatomical abnormalities, not due to instrumentation and is 1223 1224 A Clinical Approach to Medicine community acquired These occur usually in women as acute cystitis and acute pyelonephritis At least 25–30% of women between the age of 20–40 years have had at least one infection An infection is labeled complicated when there are structural or functional abnormalities present in the urogenital tract Infections in men have been often labeled as complicated as infection rate in men is much lower (as much as 50 times less) than women and is usually accompanied by some predisposing factor A search for a cause is initiated after the first infection in the man while in woman presenting for the first time with cystitis or easily treatable acute pyelonephritis, investigations into the cause is not necessary Young healthy men may suffer from an uncomplicated UTI due to acute prostatitis Factors which suggest a complicated infection include: the male sex, elderly, nosocomial infection, pregnancy, indwelling catheter, recent instrumentation, anatomic abnormality of the urinary tract, previous childhood infection, recent antibiotic use, symptoms persisting for more than days at the time of presentation, diabetes mellitus or immunosuppression SIGNS AND SYMPTOMS Symptoms of frequency, urgency, dysuria, strangury and suprapubic pain suggest a lower tract infection There may also be cloudy or foul-smelling urine or gross hematuria In lower tract involvement, there is usually no fever Upper tract symptoms usually include loin pain associated with a positive renal punch and the patient is febrile Lower tract symptoms may be present In males, symptoms suggesting prostatitis include a sensation of rectal irritation, scrotal pain and pain referred to the front of the thighs Examination might reveal a tender prostate MICROBIOLOGICAL SPECTRUM AND ANTIBIOTIC SUSCEPTIBILITY Most UTI’s are caused by gram-negative organisms In uncomplicated infections from the community, E coli is the major causative pathogen in 70–95% and Staph saprophyticus in 5–20%.1 From urinary isolates in 1998 in Singapore General Hospital (SGH), E coli accounted for 34%, Klebsiella sp 16%, Enterococcus 15% and Pseudomonas 9%.2 In a hospital setting, Urinary Tract Infection 1225 Table Antibiotic Susceptibility of E coli2 Ampicillin Cephalexin Ciprofloxacin Ceftriaxone Gentamicin Amikacin Co-trimoxazole Nitrofurantoin Nalidixic acid 33% 57% 48% 94% 90% 96% 49% 82% 65% nosocomial and more complicated infections are seen A study of admissions for urinary tract infection in SGH showed positive cultures in only 41.4% yielding E coli (56.4%), Klebsiella (14.5%), Candida (12.7%) and Enterococcus (7.3%) reflecting the tertiary nature of the institution.3 Eight out of 150 ‘O’ E coli serotypes responsible for 80% of infections are considered uropathogenic They have certain characteristics including increased adherence to uroepithelium by increased expression of P, F and S fimbriae, hemolysin and aerobactin production Certain relationships have been identified Staph saphrophyticus is commonly found in infections involving sexually active young women, Proteus infections in boys aged 1–12 years and in recurrent stone disease, and Strep fecalis in infections from elderly men with prostate problems Antibiotic use should take into consideration the high resistance shown in E coli isolates Table shows the antibiotic susceptibility in E coli isolates in 1998 It is important to remember that nitrofurantoin and nalidixic acid are not useful agents in impaired renal function as they rely on urinary concentration to deliver adequate drug to the urine However, nitrofurantoin is extremely useful in prophylaxis in normal renal function in women as there does not seem to be in increase in resistance This drug can also be used in pregnancy and for prophylaxis DIAGNOSIS The diagnosis is usually made on history and examination alone Treatment of simple cystitis is usually started without the benefit of cultures though it would be ideal to have one performed prior to starting 1226 A Clinical Approach to Medicine treatment In the case of isolated cystitis in women, cultures are probably not necessary unless there is no response to treatment or when relapse occurs If pyelonephritis is suspected, a specimen for urine culture should be obtained before starting treatment In the collection of a urine sample, the importance of proper midstream collection cannot be over-emphasized Contamination is common if patients are not properly instructed The patient should be able to pass at least 150–200 ml of urine during the procedure In women, it is necessary to clean the periurethral area by washing with water or wiping from front to back with moist gauze wet with saline or tap water Antiseptics should not be used In men, the foreskin should be retracted and the periurethral area cleaned In women, the labia should be parted during collection and in men the foreskin remain retracted.4 A midstream sample is collected after the urine flow is started The initial part of the stream is allowed to drain for a few seconds after which the collection container is passed under the stream without stopping the urine flow Urine may also be collected via catheter or suprapubic puncture, which is more laborious and less pleasant to perform The presence of epithelial cells on microscopy suggests contamination The following are recommended guidelines for diagnosis based on urinary cultures:5 a) Asymptomatic females (supervised collections): • Two consecutive positive clean-catch midstream urine (MSU) specimens revealing 105/ml or more colonies in the urine with the same organism in all three cultures • Two consecutive positive clean-catch midstream urine (MSU) specimens revealing ϫ 104/ml or more colonies in the urine with the same organism in all three cultures if the organism is of the same serotype (E coli), species (Proteus), phage type (Staphylococci) • Single urethral catheter specimen revealing 105/ml or more colonies in the urine Lower counts require repeat collection • Single suprapubic bladder puncture revealing any number of colonies Small numbers with organisms suggestive of skin contaminants such as Staph epidermidis or diphtheroids should be repeated b) Symptomatic males and females • Preferably two consecutive clean-voided specimens or presence of pyuria and bacteria in urinary sediment Urinary Tract Infection 1227 c) Asymptomatic males: • Two consecutive clean-voided specimens revealing 105/ml or more colonies in the urine with the same organism in both • Three consecutive positive clean-catch midstream urine (MSU) specimens revealing less than 105/ml or more colonies in the urine with the same organism in all three • Single urethral catheter specimen or suprapubic bladder puncture, as in asymptomatic females With a positive gram-negative culture of more than 105 cfu/ml, there was true infection in 92% of cases compared with 74% if there were only 103 cfu/ml to 105 cfu/ml in bacteremic pyelonephritis For males, consecutive specimens with 105/ml or more colonies of the same organism would suffice If the counts are lower, three consecutive specimens should be taken The above takes into consideration the work of Kass, who in 1956 introduced the method of quantitating bacteria to distinguish contamination from true infection.6 A lower threshold of significance is used when: 1) fastidious organisms such as chlamydia, mycobacterium are cultured; 2) collection was by urinary catheter or suprapubic aspiration; or 3) the patient is symptomatic with a single organism cultured Negative cultures are common with recent use of antibiotics In practice, suprapubic bladder puncture is seldom performed If allowed to stand for more than hours at room temperature, growth of contaminants may make diagnosis difficult It is recommended that the specimen be refrigerated at 4–10ЊC if specimens cannot reach the culture laboratory in hours Dipslides containing agar media are now available and are convenient to use when collection is done after office hours Pyuria is supporting evidence and can be readily seen on urine microscopy Most symptomatic bacteriuric patients had 10/ml or more in unspun urine.7,8 Urine specimens from patients with UTIs usually contain more than to WBCs per high power field However, up to 50% of patients with significant bacteriuria not have pyuria To ensure consistency, it has been recommended that variabilities in results for urine microscopy be avoided by standardizing the initital urine volume, resuspension volume, method of centrifuging and use of a hemocytometer or a slide with grid lines for counting.9 A test for leukocyte esterase is now commonly incorporated into diagnostic sticks Leukocyte esterase is an enzyme found in neutrophil 1228 A Clinical Approach to Medicine granules This reacts with an agent on the dipstick pad to give a color change The test has a positive predictive value of 50% and a negative predictive value of 92% In this method, the presence of pyuria from contamination cannot be differentiated from pyuria originating from the urinary tract However, with microscopy, epithelial cells if seen, highly suggest contamination There may be no obvious pyuria if urinary flow has been increased with increased fluid intake The nitrite test is the most common chemical test for bacteria This tests for the presence of bacteria that can convert nitrate to nitrite A positive test confirms the presence of bacteria while a negative one does not CLINICAL SYNDROMES Acute Cystitis/Urethritis Uncomplicated cystitis occurs frequently in women Urinary frequency, dysuria and suprapubic discomfort are characteristic of cystitis although vaginitis has to be excluded Gross hematuria occurs in up to one-third of patients with cystitis This is related to the short urethra, proximity of the anus to the urethral opening and sexual activity Nearly 90% of community acquired UTI are due to E coli and other Gram-negative bacteria such as Proteus and Klebsiella Staphylococcus saprophyticus account for about 10% It is thought that colonization of the vaginal introitus with fecal flora (predominantly E coli) is the initiating step leading to colonization of the urethra and ascending infection to cause urethritis and cystitis and subsequent pyelonephritis Sexual intercourse may assist migration Chlamydia, Neisseria, or herpes simplex infection in young sexually active women may cause the symptoms of acute cystitis History of a new or multiple sex partners may point to a sexually transmitted disease There may be accompanying vaginitis and vaginal discharge Dysuria without frequency and urgency suggests vaginitis rather than cystitis in the presence of vaginal symptoms Trichomonas and Candida are common causes of vaginal infection These have to be treated accordingly Treatment of acute cystitis starts with advising the patient to increase her fluid intake Ideally, a urine culture should be taken This is especially indicated in repeated or relapsing infections or those unresponsive to treatment Urinary Tract Infection 1229 Usual first line therapies include: a day course of bactrim tabs (160 mg trimethoprim/800 mg sulphamethoxazole) bd or ciprofloxacin 250 mg bd, day course of other antibiotics such as nitrofurantoin 50–100 mg tds, amoxycillin 500 mg tds, cephalexin 500 mg qds, cefuroxime 250 mg bd.10 In principle, one should give the cheapest and least toxic drug first Single dose therapy is acceptable treatment though less effective than multi-day regimens The following have been tested: bactrim tabs (320 mg trimethoprim/1.6 g sulphamethoxazole), trimethoprim 400 mg, amoxycillin g, nitrofurantoin 200 mg, cephalexin g, kanamycin 500 mg, ciprofloxacin 500 mg and cefuroxime 500 mg It appears more effective in young women with cure rate of 90% rather than in women older than 40 years with cure rate of only 46%.11 The disadvantage is that this dose will not be able to eradicate the vaginal reservoir that a 3–5 day course can Patients who have recurrent attacks should probably be treated for at least days and single dose therapy reserved for the isolated incidents These are not suitable as treatment for complicated infections or where there is a relapse, neurogenic bladder, presence of calculi or obstruction, in males or in children In women, it is usually not necessary to investigate the occasional cystitis Women who are still symptomatic after the initial course should have a urine culture performed If positive, the treatment should be guided by antibiotic sensitivities If negative and pyuria is present, chlamydia infection is suspected especially if the woman is sexually active and should be treated with doxycycline If culture is negative and there is no pyuria, treatment with urinary analgesic would suffice Uncomplicated cystitis may occur in men, though much more uncommon than in women Risk factors predisposing are thought to include intercourse with an infected female partner, homosexuality and lack of circumcision In men, a minimum of a seven-day course is recommended with a fluoroquinolone, bactrim or trimethoprim so as to cover for occult prostatitis.12 Urine culture is advisable before treatment Nitrofurantoin should not be used as there is poor tissue penetration into the prostatic bed Radiological assessment by intravenous urogram should be performed in men even after one infection so to exclude a structural lesion Recurrent infections In women with recurrent cystitis, uropathogenic E coli with increased adherence to the uroepithelium may be the cause Non-secretors of blood 1230 A Clinical Approach to Medicine group H antigen produce other glycosylated lipids, which act as receptors for fimbria of uropathogenic E coli Patients with a positive P antigen status may be more prone to recurrent disease Diaphragm and spermicide use alter vaginal flora by increasing the vaginal pH, leading to colonization with more pathogenic flora Women should be advised on perineal hygiene such as wiping from front to back to avoid fecal contamination of the periurethral area after micturation or passing motion Sexually active couples should be advised to wash before intercourse as well as after and the lady to pass urine within 15 after intercourse There should be adequate lubrication either through the use of surgical lubricants or prolonged foreplay to avoid small tears and lacerations which encourage bacterial adherence Post-coital prophylactic antibiotics (bactrim half a tablet, nitrofurantoin 50 mg, cephalexin 250 mg) appear most useful to patients who can associate the onset of symptoms with sexual intercourse Prophylaxis is given if there are or more infections per year If there are no structural abnormalities, this should be given for at least months An intravenous urogram (IVU) should be performed with recurrent infections or a single episode of pyelonephritis to exclude a structural problem such vesicoureteric reflux where treatment of infection is crucial in preventing ongoing renal damage and obstruction If present, prophylaxis should continue for years from the last infection Vaccination for prevention of recurrent infection has been studied but is not in widespread clinical use.13,14 Cranberry products have been shown to reduce the recurrence of lower urinary tract infections by approximately 20%.15 Recent research has demonstrated that proanthocyanidins found in cranberries have potent antiadhesion properties.16 In young men, recurrence suggests prostatitis or an upper tract abnormality and should be treated with a 4- to 6-week regimen of fluoroquinolone or trimethoprim-sulphamethoxazole combination Acute Pyelonephritis The patient with acute pyelonephritis has systemic complaints such as fever, chills and rigors, nausea, vomiting, leukocytosis with pain localizing to the costovertebral angle This is a more serious infection often associated with septicemia and shock The infection is usually an ascending one The bacterial spectrum is similar to that in acute cystitis Unless there is significant vomiting, many patients can be treated as an Urinary Tract Infection 1231 outpatient with oral antibiotics Oral fluoroquinolones, trimethoprimsulphamethoxazole combination and cephalosporins such as cefuroxime may be used Hospitalization is usually required if there is significant systemic symptoms which require intravenous therapy Recommended first line intravenous antibiotics 10,17 include: a) Ampicillin 500 mg 6-hourly with gentamicin mg/kg body weight 8-hourly This provides coverage for enterocci as well although ampicillin is no longer useful in E coli infections due to resistance in Ͼ 45% of isolates Aminoglycosides continue to be useful agents because of good concentration in renal tissue and there are now recommendations for daily dosing;18 b) First or second generation cephalosporin with aminoglycoside; c) Ceftriaxone g/day is commonly used because of the convenience of once a day dosing; and d) Ciprofloxacin 200 mg bd also achieve high concentrations in the kidney It is good practice to obtain blood cultures before commencing therapy as 12% of patients hospitalized for acute pyelonephritis may have bacteremia and it confirms the offending organism where urine cultures may be contaminated or negative One expects to see improvement in symptoms within 48 hours Otherwise, renal abscess and obstruction must be excluded by ultrasound scanning A switch can be made to oral antibiotics when the patient has been afebrile for 24 hours if he/she has been started on intravenous therapy The antibiotic chosen then can be guided by urine cultures Treatment should be for 14 days though it is permissible to stop after 10 days in a mild illness Some studies have advocated duration as short as days with combinations such as gentamicin and ciprofloxacin A follow-up intravenous urogram is advised Relapses This implies continuing infection with the same organism within weeks They should be retreated If there is another relapse then a 6-week course Follow-up cultures should be performed to ensure eradication Prostatitis In men, acute prostatitis or acute flares of chronic prostatitis is common and the patient may complain of perianal or rectal pain, pain referred to 1232 A Clinical Approach to Medicine Table Evaluation of Prostatic Fluid VB1 The first voided 10 ml of urine represents the urethral flora VB2 EPS Midstream sample represents infection in bladder or above Specimen is collected after massage represents prostatic infection Urine collected after massage flushes out prostatic secretions in the urethra Useful especially if there are no EPS VB3 To localize the infection to the prostate, the EPS or VB3 must have a colony count 10 times higher than VB1 and VB ϭ voided bladder; EPS ϭ expressed prostatic secretions the scrotum and upper thighs with accompanying dysuria and frequency There may also be hemospermia E coli is the most common organism One should exclude prostatic calculi, benign prostatomegaly and cancer of the prostate and obstruction In chronic prostatitis, there may be bacteriuria without symptoms Prostatic massage is not done in acute prostatitis because of acute pain It is recommended for confirmation if there is little prostatic symptoms The patient should not have had antibiotic therapy for one month and have not ejaculated for days.19 The method of Meares and Stamey is used.20 The significance of each of the specimens collected is listed in Table Acute prostatitis should be treated for weeks to prevent chronicity In the inflammed state, antibiotics can cross the prostatic bed easily Ampicillin and gentamicin can be used initially before cultures are back This should be followed up with bactrim, ciprofloxacin or erythromycin (or other drugs of the same group) depending on the culture result Chronic prostatitis should be treated for 4–12 weeks If there is a relapse, then he should be retreated and prophylaxis instituted for years The Prostate Specific Antigen is often raised in prostatic infection and may be used for monitoring of successful treatment, especially if there are no symptoms Asymptomatic Bacteriuria The significance of covert (asymptomatic) bacteriuria would depend on the circumstances in which it occurs The prevalence is shown in Table The decision to treat or not to treat depends on the consequences or natural history Urinary Tract Infection 1233 Table Prevalence of Covert Bacteriuria Population Prevalence (%) Infants School children (6–18 yrs) girls boys 1, Boys Ͼ Girls Sexually active women Nuns (Ͻ 45 yrs) Pregnant women Elderly (Ͼ 65 yrs) men women 1.2 0.03, higher in the uncircumsised 3–10 0.6 5–6 10 20 The truly asymptomatic child has been the subject of much debate and children often cannot complain and present with non-specific symptoms such as fever, poor feeding and lethargy In the presence of an abnormal urinary tract such as vesicoureteric reflux (VUR), therapy should be given as there is a risk of scarring and subsequent renal deterioration Children less than years of age should be treated as there is a high incidence of VUR In the older child with a normal urinary tract, there is doubtful therapeutic benefit For schoolgirls with covert bacteriuria, 30% clear spontaneously Reinfections are common whether treated or not The parents and child should be questioned closely for symptoms and if symptomatic, should be treated Follow-up of growth, blood pressure, urine culture, serum creatinine and radiological investigation has been recommended for recurrent bacteriuria The truly asymptomatic non-pregnant woman is generally thought not to require treatment This is either self-limiting or eradicated by antibiotics given for other conditions These women should be questioned closely as to whether they really have symptoms The pregnant patient will be discussed below COMPLICATED UTI This refers to those categories of patients or associated conditions where failure of therapy because of relapse or persistence of infection is common They need more attentive follow-up The categories are listed in Table Although E coli is still the predominant, the percentage drops to around 20–54%.21 1234 A Clinical Approach to Medicine Table Classification of Complicated UTI21 1) Structural abnormalities • Obstruction, diversion procedures, external drainage • Calculi • Infected cysts, Medullary sponge kidney • Vesicoureteric reflux, neurogenic bladder • Fistula • Renal abscess 2) Metabolic/Hormonal abnormalities • Diabetes mellitis • Chronic renal failure • Pregnancy 3) Impaired host responses • Neutropenia • Steroid therapy • Congenital or acquired immunodeficiency syndromes 4) Unusual pathogens • Yeast • Mycoplasma • Resistant bacteria SPECIFIC PATIENT POPULATIONS The Elderly Bacteriuria without symptoms is common in the geriatric population Recurrence rate of bacteriuria is high even when eradicated Reinfection was common with increasingly resistent organisms As the elderly are more susceptible to adverse effects of antibiotic therapy, treatment should be withheld unless symptomatic In a study on ambulatory elderly women, mortality was not shown to be increased with treatment However, if a patient is to undergo urinary tract instrumentation or surgery, the bacteriuria should be eradicated Symptomatic infections should always be treated Elderly patients are more likely to have bacteremia and hypotension Choice of drug therapy is as discussed above in younger populations Care should be exercised in the use of aminoglycosides because of its associated nephro- and ototoxicity Obstruction such as by prostatomegaly in men and malignant disorders in women should be excluded Post menopausal women who have recurrent cystitis should consider the use of oral hormone replacement therapy or intravaginal estrogens Urinary Tract Infection 1235 Catheter-Related Indwelling catheters are implicated in up to 70% of hospital-acquired UTI’s Prophylactic antimicrobial agents reduce risk of bacteriuria but resistant organisms appear They can be used for short-term catheterization Intermittant self-catheterization is now recommended for neurogenic bladders In a local study in spinal cord injury, 78% were admitted to the rehabilitation unit with indwelling catheters With adequate bladder training using voiding and intermittant self catheterization, indwelling catheters could be avoided in 97%.22 Wherever possible, especially in the younger patient, indwelling catheters should not be used If not possible, strict adherence to practices for proper bladder catheter care is necessary.23 Bacteriuria is not treated unless the patient is symptomatic Instead, a high fluid intake to promote urine flow, regular and complete bladder emptying should be encouraged Diabetics The majority of UTI’s in diabetics are asymptomatic There is a higher incidence of bacteriuria in diabetic women Once established, urinary tract infections are more severe with a high incidence of upper tract involvement and with fungal organisms Poor control, the autonomic bladder and instrumentation are predisposing factors When asymptomatic bacteriuria is found, it should be treated Renal Transplant Recipients Early (less than months post-transplant) cases of bacteriuria are usually related to the surgery and catheterization of the urinary tract This is reduced with the use of prophylactic antibiotics such as half a tablet of bactrim, which is also used for prophylaxis of Pneumocystis carinii pneumonia Urinary tract infection in the transplant patient in the early post transplant period is frequently asymptomatic and associated with overt pyelonephritis and bacteremia Asymptomatic bacteriuria should be treated In the late post-transplant period, the incidence does not differ much from the general population A search should be instituted for reflux in the graft urinary tract or other urological abnormality Bacteriuria should be treated and prophylactic therapy instituted if reflux is present 1236 A Clinical Approach to Medicine Treatment for symptomatic infection follows the same principles as previously discussed though the physician must be aware of the higher risks of fungal infections Pregnancy Pregnancy itself does not lead to an increase in bacteriuria but it permits urinary colonization established prior to pregnancy to lead to symptomatic infection Physiological changes of pregnancy leads to dilatation of the renal tract, reduction in urinary peristalsis and urinary stasis The studies of Kass and others demonstrate that 20–40% of women with bacteriuria detected early in pregnancy will develop acute symptomatic infection later in pregnancy, and only 1–2% without bacteriuria does so The rate of prematurity increases to 20–50% in symptomatic urinary tract infection (UTI) Other increased risks reported are that of intrauterine growth retardation, low birth weight and fetal mortality Treating pregnant bacteriuric patients lowers the incidence of symptomatic UTI by 80–90%.24 Routine screening has therefore been recommended for bacteriuria in pregnancy It has been recommended that the best time to start screening for bacteriuria is in the 16th gestational week This is because the highest rates were detected between the 9th to 17th weeks and the best time to obtain the highest number of bacteriuria-free gestational weeks best yield appears to be at 16 weeks.25 Antibiotics safe to use in pregnancy include amoxycillin, nitrofurantoin, cephalexin Co-trimoxazole is to be used with caution because of possible terogenecity in early pregnancy and hyperbilirubinemia in the neonate when given in the third trimester Many still recommend 7-day course with the above drugs with the usual doses as first-line therapy Failures to single dose therapy must be treated with a conventional course When the infection is eradicated, monthly follow-up cultures are recommended till term Fungal Cystitis This is common with catheterized patients, diabetic or immunosuppressed If confined to the lower tract, they usually respond to intravesical instilation of Amphoteracin 15 mg in distilled water after emptying the bladder If the patient is able to cooperate, the catheter may be removed and the patient instructed not to pass urine for hours Urinary Tract Infection 1237 Otherwise, keep the catheter clamped and released only after hours A repeat culture should be taken a week later SUMMARY The treatment of urinary tract infection varies depending on the clinical scenario Not all cases of symptomatic bacteriuria need to be treated However where the natural history leads to upper tract involvement and bacteremia or in the presence of an abnormal urinary tract, treatment should be started Antibiotic susceptibility patterns change with time and first-line treatment must take into consideration this factor as well as cost of hospitalization, administration of drug therapy as well as subsequent relapse and retreatment REFERENCES Hooton T, Stamm W, Diagnosis and treatment of uncomplicated urinary tract infection, Infect Dis Clin North Am 11(3):551–581, 1997 Antibiogram of urinary isolates, in: Microbiology Lab Singapore General Hospital; 1998 Tan HK, Choong HL, Woo KT, Admissions for urinary tract infection to Singapore General Hospital, in: Chapter of Physicians’ 16th Annual Combined Scientific Meeting; 1996 Whitworth JA, Current concepts in the management of urinary tract infection, Ann Acad Med Singapore 11(1):64–68, 1982 Byungse S, Narins RG, Kunin C, Urinary tract infection — important diagnostic procedures, in: Diagnostic Techniques in Renal Disease, Churchill Livingstone, New York, pp 346–347, 1992 Kass EH, Finland M, Asymptomatic infections of the urinary tract, Trans Assoc Am Physicians 69:56–63, 1956 Little P, Urinary white cell excretion, Lancet 1:1149, 1962 Stamm WE, Measurement of pyuria and its relation to bacteriuria, Am J Med 75(Suppl 1B):53–58, 1983 Pappas PG, Laboratory in the diagnosis and management of urinary tract infections, Med Clin North Am 75(2):313–325, 1991 10 Use of Antibiotics in Urinary Tract Infection, in: Use of Antibiotics in Adults, Singapore, pp 46–64, 2000 11 Cardenas J, Quinn EL, Rooker G, Bavinger J, Pohlod D, Single-dose cephalexin therapy for acute bacterial urinary tract infections and acute urethral syndrome with bladder bacteriuria, Antimicrob Agents Chemother 29(3):383–385, 1986 1238 A Clinical Approach to Medicine 12 Stamm WE, Hooton TM, Management of urinary tract infections in adults, N Engl J Med 329(18):1328–1334, 1993 13 Nayir A, Emre S, Sirin A, Bulut A, Alpay H, Tanman F, The effects of vaccination with inactivated uropathogenic bacteria in recurrent urinary tract infections of children, Vaccine 13(11):987–990, 1995 14 Schmidhammer S, Ramoner R, Holtl L, Bartsch G, Thurnher M, Zelle–Rieser C, An Escherichia coli-based oral vaccine against urinary tract infections potently activates human dendritic cells, Urology 60(3):521–526, 2002 15 Stothers L, A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women, Can J Urol 9(3): 1558–1562, 2002 16 Howell AB, Cranberry proanthocyanidins and the maintenance of urinary tract health, Crit Rev Food Sci Nutr 42(3 Suppl):273–278, 2002 17 Gilbert DN, Moellering RC, Sande MA (eds.), The Sanford Guide to Antimicrobial Therapy, Antimicrobial Therapy Inc., Hyde Park, Vermont, USA, 1999 18 Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH, Once-daily dosing of aminoglycosides: review and recommendations for clinical practice, J Antimicrob Chemother 39(6):677–686, 1997 19 National Guideline for the Management of Prostatitis, in: London: Association for Genitourinary Medicine (AGUM), Medical Society for the Study of Venereal Disease (MSSVD), 2002 20 Meares EM, Stamey TA, Bacteriologic localization patterns in bacterial prostatitis and urethritis, Invest Urol 5(5):492–518, 1968 21 Nicolle L, A practical guide to the management of complicated urinary tract infection, Drugs 53(4):583–592, 1997 22 Menon E, Tan E, Urinary tract infection in acute spinal cord injury, Singapore Med J 33(4):359–361, 1992 23 Rubin RH, Tolkof–Rubin NE, Cotran RS, Urinary Tract Infection, pyelonephritis and reflux nephropathy, in: Brenner BM, Rector FC (eds.), The Kidney: Pathogenesis of Renal Disease, 4th ed WB Saunders Co., Philadelphia, pp 1369–1429, 1991 24 Andriole VT, Patterson TF, Epidemiology, natural history, and management of urinary tract infections in pregnancy, Med Clin North Am 75(2):359–373, 1991 25 Patterson TF, Andriole VT, Detection, significance, and therapy of bacteriuria in pregnancy Update in the managed health care era, Infect Dis Clin North Am 11(3): 593–608, 1997 71 Renal Hypertension Wong Kok Seng INTRODUCTION Renal hypertension refers to hypertension that is secondary to an underlying renal disease This may be due to a renal parenchymal disease or renal vascular disease However it is sometimes difficult to discern if renal parenchymal disease is the cause of the hypertension or if it co-exists with essential hypertension It is also important to realize that renal artery stenosis does not equate renal vascular hypertension as one may have renal artery stenosis without hypertension Therefore the co-existence of hypertension and renal disease does not prove that the hypertension is caused by renal disease Primary renal disease is uncommon in patients with hypertension (probably around 4%) but hypertension is common in all types of renal disease and becomes more prevalent as the renal function deteriorates About 60% of patients with glomerular disease have hypertension and about 33% of patients with chronic pyelonephritis have hypertension at presentation 1239 1240 A Clinical Approach to Medicine RENAL HYPERTENSION — DETECTION AND ASSESSMENT The presence of proteinuria in a patient with hypertension provides an early clue to the possibility of an underlying renal disease In these patients, adequate investigation and effective treatment would retard the progression to end stage renal failure Onset of hypertension in the elderly would suggest the possibility of renal vascular hypertension and this is part of the atherosclerotic disease that also affects the peripheral, coronary and cerebral vasculature Clinical History Table lists the clues in the clinical history that suggest an underlying renal disease These may be useful in selecting patients for further investigation Onset of hypertension before age 20 years suggests the possibility of chronic pyelonephritis as it is the most common cause of hypertension in such young patients A family history of renal disease may indicate the need to exclude the possibility of adult polycystic kidney disease, Alport’s syndrome or other hereditary renal disease Accelerated or resistant hypertension should rouse the possibility of renal vascular hypertension Worsening of renal function after therapy with angiotensin converting enzyme inhibitors would suggest that severe renal vascular disease is present In fact, one should consider the possibility of occult renal vascular disease when therapy with angiotensin converting enzyme Table Clues in the Clinical History Suggesting Renal Hypertension 1) Onset of hypertension before age 30 years but without a family history of hypertension 2) Recent onset of significant hypertension after age 50 years 3) Known history or family history of renal disease 4) Symptoms of underlying renal disease, e.g polyuria, nocturia, dysuria, gross hematuria 5) Accelerated hypertension 6) Resistant hypertension 7) Symptoms of vascular disease (cardiac, cerebral, peripheral) 8) Worsening of renal function after therapy with angiotensin converting enzyme inhibitors 9) Recurrent (flash) pulmonary edema Renal Hypertension 1241 inhibitors gives rise to a significant rise in serum creatinine (greater than 50 mol/L) within to 14 days of commencing treatment Physical Examination A full physical examination is essential and the fundi, heart and peripheral pulses need to be examined in order to assess the severity of cardiovascular complications The cardiovascular system is examined, particularly for heart size and for evidence of arterial disease in the carotid, renal and peripheral vasculature Examination of the optic fundi will revealed the degree of microvascular disease Table shows the clinical clues that suggest the presence of renal hypertension Large palpable kidneys suggest the presence of polycystic kidneys disease Features of systemic disease, such as diabetes or systemic lupus erythematosus, may be obvious An abdominal or epigastric systolic bruit is relatively common in elderly patients and has a low predictive value for renal vascular disease On the other hand, the presence of the continuous or systolic-diastolic abdominal bruit would strongly indicate renal vascular hypertension Initial Investigations Routine investigations in a patient with hypertension include urinalysis for blood or protein as well as a microscopic examination of the urine Blood chemistry will include measurements of potassium, urea, creatinine, fasting glucose and total cholesterol If urinary abnormalities or elevation of urea and creatinine are noted, a 24-hour urine collection for measurement of proteinuria and creatinine clearance should be performed An ECG should also be performed Table Findings on Physical Examination Suggesting Renal Hypertension 1) 2) 3) 4) 5) Edema (peripheral or pulmonary) Palpable kidneys (e.g polycystic kidney disease) Signs of uremia Abdominal bruits Features of vascular disease (e.g carotid or femoral bruits, reduced or absent peripheral pulses) 6) Severe hypertensive retinopathy (grade or 4) 1242 A Clinical Approach to Medicine When the clinical history, physical examination and initial investigations suggest the possibility of renal hypertension, further investigations must be carried out to confirm or rule out this possibility as well as to reach a definitive diagnosis Specialized Investigations Renal ultrasound This is non-invasive and readily performed and is the best method for the diagnosis of polycystic kidney disease It will indicate if the kidneys are reduced in size or have increased echogenicity and thereby suggesting chronic renal parenchymal disease It will show if the kidneys are of unequal length If the inequality is greater than 1.5 cm and is accompanied by other indicators of renal vascular disease, further investigations for renal vascular disease are indicated Duplex ultrasound Color-coded duplex ultrasonography is another non-invasive method to obtain blood flow profiles in the main renal arteries and intrarenal vessels It allows a direct visualization of the renal vasculature while assessing blood flow velocity and pressure waveforms Technical improvements in the current machines have practically overcome problems due to obesity and bowel gas This technique can be used to screen for renal artery stenosis and allows for non-invasive follow-up of patients after interventions, even after placement of stents Intravenous urogram The rapid sequence intravenous urogram has been the traditional test to confirm or exclude renal vascular disease However, it carries a 15% falsepositive and 25% false-negative rates, and its use is now increasingly replaced by isotope renography or intravenous digital subtraction angiography Nevertheless the intravenous urogram is very useful in the diagnosis of chronic pyelonephritis with renal scarring and this is the most common cause of hypertension in patients aged below 20 years Renal Hypertension 1243 Table Criteria for the Captopril Challenge Test Method: 1) The patient should maintain a normal salt intake and receive no diuretics 2) If possible, all antihypertensive medications should be withdrawn weeks prior to the test 3) The patient should be seated for at least 30 minutes; a venous blood sample is then drawn for measurement of baseline plasma renin activity 4) Captopril (50 mg diluted in 10 mL of water immediately before the test) is administered orally 5) At 60 minutes, a venous blood sample is drawn for measurement of stimulated plasma renin activity Interpretation A positive test requires: 1) Stimulated plasma renin activity of 12 ng/mL/hr or more and; 2) Absolute increase in plasma renin activity of 10 ng/mL/hr or more and; 3) Increase in plasma renin activity of 150% or more, or 400% or more if baseline plasma renin activity is less than ng/mL/hr From Muller FB, Sealey JE, Case DB et al Am J Med 80:633, 1986 Captopril challenge test This is based on the fact that peripheral plasma renin activity is elevated in most patients with functionally significant renal vascular disease and is further augmented by blocking of the renin-angiotensin system The test is simple to administer and involved the measurements of plasma renin activity before and sixty minutes after oral administration of 50 mg captopril The criteria for the performance and interpretation of the captopril challenge test is as listed in Table Isotope renogram This is an alternative and widely used method for the diagnosis or renovascular hypertension The original technique of using 131I-hippuran to compare renal blood flow in affected and unaffected kidneys gave a high incidence of false positives and has fallen into disfavor The captoprilenhanced renogram is preferred for identification of functionally significant renal artery stenosis Measuring 99Tcm-diethylenetriaminepenta acetic acid (DTPA) uptake and/or 131I-hippuran uptake before and 60 minutes perform this after a 25 mg oral dose of captopril When functionally significant renal artery stenosis is present, the reduced DTPA 1244 A Clinical Approach to Medicine uptake indicates a fall in glomerular filtration rate while the delayed hippurate secretion indicates a prolongation of the mean parenchymal transit time Using a variety of diagnostic criteria, the captopril-enhanced renogram is used to identify functionally significant renovascular hypertension with a high degree of specificity and sensitivity Renal angiography This is the “gold standard” for the identification and localization of renal arterial lesions It is invasive and carries the risk of radiocontrast-induced acute renal failure Increasingly, this technique is used for percutaneous transluminal angioplasty and should not be used only to confirm a suspected renal artery stenosis Spiral CT angiography This technique utilizes the continuously overlapping transaxial images obtained by means of a rotating X-Ray tube, with the scanning time within a single-breath hold of the patient A three-dimensional reconstruction of the renal vasculature is obtained This allows for visualization of the whole vascular tree with sensitivity and specificity varying from 90–99% However, the amount of contrast medium used is high and thereby limits its use in patients with pre-existing renal insufficiency Magnetic resonance angiography This technique is non-invasive and allows for direct visualization of proximal renal artery lesions It can be used in conjunction with a gadoliniumbased contrast and does not carries the risk of nephrotoxicity Two different imaging methods can be used to diagnose renal artery stenosis with a sensitivity and specificity of 90–100% Renal vein renin ratio This is an invasive technique involving bilateral catherization and sampling from each renal vein as well as the adjacent vena cava above and below the origin of the renal vein With the advent of non-invasive tests such as those using captopril stimulation of the renin system and improved methods of imaging the renal vasculature, sampling of renal vein renin has fallen into disfavor Renal Hypertension 1245 Renal biopsy This is an invasive procedure and is undertaken in patients with hypertension and suspected renal disease These patients will usually have proteinuria and the renal function may be impaired The renal biopsy is also useful in determining whether renal impairment in patients with accelerated hypertension is a consequence of renal damage from hypertension itself, or whether an underlying primary renal disease gives rise to the accelerated hypertension HYPERTENSION IN RENAL PARENCHYMAL DISEASE Mechanisms of Hypertension Several mechanisms are believed to account for hypertension in renal parenchymal disease Decreased renal sodium and water excretion leading to extracellular volume expansion is of major importance Several lines of evidence support this For example, administration of sodium chloride expands the intravascular space and aggravates the blood pressure in patients with renal failure; and diuretics are effective in the blood pressure in patients with renal failure At the other end of the spectrum, end stage renal failure patients who receive aggressive ultrafiltration at dialysis will lower their blood pressure towards normal in most instances The renin-angiotensin system is also activated especially in patients with renal insufficiency Increased sympathetic tone also plays a role as the norepinephrine levels and the rate of sympathetic nerve discharge is raised in such patients Hyperfiltration Mechanism of Renal Injury Glomerular hypertension (Fig 1) in the most likely mechanism by which hypertension leads to progressive renal damage Systemic hypertension is one of these factors that increase glomerular capillary plasma flow rate or hydraulic pressure The high systemic pressure is transmitted into the glomerulus and damages glomerular cells and leads to progressive sclerosis This in turn sets off a vicious cycle by aggravating systemic hypertension, which leads to further glomerular sclerosis 1246 A Clinical Approach to Medicine Fig Pivotal role of glomerular hypertension in the initiation and progression of structural injury (Anderson S, Brenner BM; Q J Med 70:185, 1989) Treatment Lifestyle measures These measures include smoking cessation, weight reduction, exercise, and dietary salt and saturated fat restriction While there is not direct evidence to demonstrate that these measures reduce the overall risk of cardiovascular disease, they are likely to be beneficial The importance of dietary salt restriction in patients with hypertension and renal disease cannot be overemphasised Although in itself unlikely to obviate the need for anti-hypertensive therapy, salt restriction potentiates the blood pressure-lowering effects of many antihypertensive agents, especially the ACE-inhibitors Drug therapy The authors of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended that therapy to reduce blood pressure be instituted in all Renal Hypertension 1247 those with diastolic blood pressure above 90 mm Hg diastolic or systolic blood pressure above 140 mm Hg systolic This recommendation is applicable to patients with renal disease Blood pressure should be controlled to 130/85 mm Hg with whatever anti-hypertensive therapy that is necessary In patients with proteinuria greater than g/day, the target blood pressure should be lower than 125/75 mm Hg (Fig 2) ACE-inhibitors have produced impressive results in patients with in patients with renal insufficiency as well as in patients with proteinuria greater than g/day Unless contraindicated, they should receive an ACE-inhibitor to control the hypertension as well as to slow the progression of renal failure In most cases, a diuretic is also administered for synergistic effects However, ACE-inhibitors should be used with caution in patients with serum creatinine above 265 mol/L or mg/dL In the first months of therapy with an ACE-inhibitor, there may be a transient decrease in glomerular filtration rate If the serum creatinine rises 88 mol/L or mg/dL above baseline levels, the creatinine and potassium levels should be re-checked after a few days If the patient is Patient with hypertension and renal disease (abnormal urinalysis, serum creatinine) 24-hour urine protein and creatinine clearance Lifestyle measures and dietary salt restriction (< 100 mmol/day) < 1g protein/day and a target BP 130/85 mmHg > 1g protein/day and a target BP 125/75 mmHg Fig Treatment of patients with hypertension and renal disease 1248 A Clinical Approach to Medicine euvolemic and the serum creatinine remained persistently high, we need to consider the possibility of renal artery stenosis and the ACE-inhibitors need to be discontinued The most important action is to slow progression of renal failure is to lower the blood pressure to target level All classes of anti-hypertensive drugs are effective and in many cases, several anti-hypertensive drugs may be needed to lower blood pressure to target level RENOVASCULAR HYPERTENSION Renovascular hypertension can be treated in one of ways — medical, surgical, and angioplasty In the younger patient with renal artery stenosis due to fibromuscular dysplasia, this is amenable to angioplasty with or without surgery In the older patient with stenosis that is atheromatous in origin, angioplasty and/or surgery may improve but not cure the hypertension, and medical treatment needs to be continued Some patients are deemed to be poor candidates for revascularization and have to remain on medical treatment Medical Treatment The main indications for medical treatment are listed below: 1) advanced age; 2) poor surgical risk; 3) technical difficulties in performing renal revascularization or angioplasty; 4) irreversible atrophy of kidney distal to the stenosis; 5) doubtful significance of the lesion of renal artery stenosis; 6) hypertension of long duration suggesting pre-existing essential hypertension; or 7) patient’s choice The aim is to lower blood pressure so as to delay the progression of renal failure Sodium restriction to less than 100 mmol per day is recommended as sodium retention and concomitant volume expansion is an important component in the hypertension of such patients Calcium antagonists are quite effective in the treatment of patients with renovascular hypertension as they have direct arteriolar vasodilatory effects Another benefit is the favorable effect on renal function in Renal Hypertension 1249 comparison to ACE-inhibitors Beta-blockers are also useful, due in part to their ability to inhibit renin secretion — most patients with renovascular hypertension have high renin levels Invasive Treatment The potential advantages of invasive treatment of renovascular hypertension include cure for the hypertension, or improved control of high blood pressure; improvement and preservation of renal function However, it carries the potential disadvantage of rare but immediate and lifethreatening complications Percutaneous transluminal renal angioplasty PTRA has become a common invasive therapy for renovascular hypertension It has become popular for the following reasons — low cost, short hospitalization, low mortality and morbidity, readily available in most hospitals, and can be used in patients who are poor surgical risks The success of PTRA is judged by its ability to normalize blood pressure or at least improve control of hypertension, improve renal function, and to widen the stenosis Renal artery stenting Poor technical results from PTRA have led to the current interest in renal artery stent placement Stents are composed of metallic wire with the unexpanded stent mounted on the uninflated balloon of an angioplasty catheter Once positioned across the lesion, the balloon is inflated and the stent is expanded and deployed Over several weeks, endothelization occurs with the renal stent covered with intima Surgical treatment Surgical treatment for renovascular hypertension includes nephrectomy, aortorenal bypass and other techniques for the surgically difficult aorta Nephrectomy or partial nephrectomy is rarely required as the preservation of renal function is an important goal in the treatment of such patients The benefits of surgery need to be appraised with regards to its effect on blood pressure control, improved renal function and better patient survival 1250 A Clinical Approach to Medicine Recently, more centers are performing surgical revascularization to preserve renal function in patients with severe atherosclerotic arterial occlusive disease These patients are at high risk because of age and associated coronary, cerebrovascular, or peripheral vascular disease CHOICE OF THERAPY It has become more common to treat patients with atherosclerotic renal artery stenosis by invasive therapy Various randomized trials that compared invasive with conservative therapy uniformly demonstrated that blood pressure control and renal function are not very different whether an invasive or a conservative approach is taken as the first step in the management of a patient with renal artery stenosis Nevertheless, it would be prudent to restrict balloon angioplasty to those whose hypertension persists despite treatment with three or more drugs, or who have progressive occlusive renovascular disease as indicated by an increase in the serum creatinine HYPERTENSION IN DIALYSIS PATIENTS The prevalence of hypertension increases as the renal function declines About 80–90% of patients have significant hypertension by the time they reach end-stage renal failure The pathogenesis of hypertension in dialysis patients is multifactorial Many of these patients have volumedependent hypertension, especially in those with large interdialytic weight gain Salt ingestion plays an important role as it gives rise to thirst and increase fluid intake The renin-angiotensin system is also important in the pathogenesis of hypertension in some patients with end-stage renal failure In these patients, the blood pressure does not decrease but actually increases during dialysis The management is directed towards correcting volume overload in patients with volume-dependent hypertension Body weight should be reduced by ultrafiltration during dialysis to dry weight Dry weight is defined as the weight below which further fluid removal would produce hypotension This approach controls hypertension in a large number of patients If antihypertensive medication is required, it should be tailored to the patient’s need and associated medical conditions The ACE-inhibitors Renal Hypertension 1251 are useful as non-volume dependent hypertension in these patients is renin-mediated HYPERTENSION IN RENAL TRANSPLANT PATIENTS Post-transplant hypertension is common and is a significant risk factor for accelerated atherosclerosis and premature coronary disease It increases the risk of allograft failure and aggravates the deterioration of allograft function The etiology of post-transplant hypertension is multifactorial In the immediate post-transplant period, it may be due to delayed graft function or the onset of acute rejection In the late post-transplant period, other causes of hypertension such as cyclosporine toxicity, recurrent disease, chronic rejection or transplant renal artery stenosis should be considered Apart from transplant renal artery stenosis, the management of posttransplant hypertension is largely medical Calcium antagonists are the most commonly used antihypertensive drugs in these patients They reduce blood pressure effectively and attenuate both cyclosporine- and endothelin-induced vasoconstriction Most clinicians prefer to use calcium antagonists of the dihydropyridine class as they are least likely to affect the hepatic P450 microsomal system Therefore adjustment of the dose to control blood pressure is least likely to affect cyclosporine blood levels Other clinicians, however, utilize calcium antagonists of the nondihydropyridine class to reduce cyclosporine dosage needed to achieve immunosuppressive blood levels while controlling blood pressure This approach mandates the monitoring of cyclosporine levels whenever the dose of these non-dihydropyridine blockers is altered ACE-inhibitors have been shown to slow the progression of chronic renal failure but the value of ACE-inhibitors for the treatment of hypertension in renal allograft recipients has not been established The administration of ACE-inhibitors after renal transplant requires caution and close monitoring is required for adverse effects such as acute renal failure, hyperkalemia and anemia Nevertheless, most transplant recipients tolerate ACE-inhibitors rather well and such therapy may reduce proteinuria and preserve renal allograft function Angiotensin II receptor blockers with their potent antihypertensive effect, good safety and tolerance profile and beneficial glomerular effects, could also be potentially useful in transplant patients 1252 A Clinical Approach to Medicine REFERENCES Raine AEG, Ledingham JGG, Secondary hypertension, in: Weatherall DJ, Ledingham JGG, Warrell DA (eds.), Oxford Textbook of Medicine, Oxford University Press, pp 2544–2553, 1996 Mann J, Allenberg JR, Christine Reisch, Dietz R, Weber M, Luft FC, Renovascular hypertension, in: Cameron S, Davison AM, Grunfeld J, Kerr D, Ritz E (eds.), Oxford Textbook of Clinical Nephrology, Oxford University Press, pp 2096–2117, 1992 Smith MC, Dunn MJ, Hypertension associated with Renal Parenchymal Disease, in: Schrier RW, Gottschalk CW (eds.), Diseases of the Kidney, Little, Brown and Company, pp 1333–1365, 1997 van Jaarsfeld BC, Krijnen P, Pieterman H et al., The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis, N Engl J Med 342:1007–1014, 2000 72 Diabetic Nephropathy Grace Lee and Woo Keng Thye Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in many countries in the world including the United States, most of Europe, Japan, New Zealand, Malaysia and Singapore In Singapore, diabetic nephropathy accounted for 50% of the new patients starting on dialysis in 2001, with the majority having Type diabetes (91%) This represented a 44.7% increase over the year 1997, where 34.2% of the new ESRD patients had diabetic nephropathy The observed increase in the incidence of diabetic nephropathy is related to several factors Firstly, there has been an increase in the incidence of diabetes mellitus and in Singapore, the National Health Surveys conducted in 1992 and again in 1998 showed the prevalence of diabetes increased from 8.6% to 9.0% The increased prevalence is probably a result of changes in lifestyle with a greater tendency towards more obesity and also aging of the population Secondly, treatment of hypertension and coronary artery disease has improved allowing the diabetic patients (especially the Type diabetics) to live long enough to develop nephropathy Hence, as our population ages, we can expect to see more elderly patients with diabetic nephropathy and cardiovascular disease requiring dialysis 1253 1254 A Clinical Approach to Medicine Once initiated on dialysis, the survival of the diabetic patient is dismal, with less than 20% surviving for more than years Therefore, it becomes imperative that we find treatment that can effectively delay or prevent the progression of renal disease in diabetes DIAGNOSIS Natural History The epidemiology for Type diabetes has been more clearly studied that Type diabetes since the time of clinical onset is usually known Between 25–45% of patients will develop diabetic nephropathy and the peak onset is between 10–15 years after the development of the disease Patients who not have proteinuria after 20–25 years have a reduced risk of developing overt renal disease of about 1% per year Patients with Type diabetes were traditionally thought to have a lower risk of developing diabetic nephropathy but recent data suggest that the renal risk is similar in both Type and disease Clinical Features The mode of presentation depends on the stage of the renal disease Mogensen described five stages of progressive diabetic nephropathy in Type diabetes (Table 1) and patients with Type diabetes have been Table Stages of Nephropathy in Type Diabetes Stage I II III IV V Clinical Term (Onset) Clinical Features Initial stage (at diagnosis) Early renal involvement (1.5–5 years) Incipient nephropathy (5–15 years) Overt nephropathy (10–20 years) Transient albuminuria related to hyperglycemia Normoalbuminuria End-stage renal disease (20ϩ years) Persistent microalbuminuria Hypertension (Ϯ) 1) Macroalbuminuria 2) Hypertension 3) Declining renal function Edema, ↓ serum albumin, associated complications e.g retinopathy, neuropathy, cardiac and vascular disease Dialysis required Diabetic Nephropathy 1255 shown to follow a similar course Stage I occurs at clinical onset of the diabetes and is associated with glomerular hyperfiltration, renal hypertrophy and albuminuria due to the uncontrolled hyperglycemia When the diabetes comes under metabolic control, the patient enters Stage II where the transient albuminuria disappears and the hyperfiltration and hypertrophy resolve After to years, 25–45% of the patients will enter Stage III or incipient diabetic nephropathy with the reappearance of persistent microalbuminuria (Table 2) Without intervention, the patient progresses to Stage IV or overt diabetic nephropathy with the classical diagnostic triad of macroalbuminuria (urine dipstick positive for protein), hypertension and declining renal function Stage V defines end-stage renal failure In most instances, patients with Type diabetes are usually asymptomatic and the presence of renal disease is detected through routine monitoring of the urine for albumin In contrast, patients with Type diabetes frequently have renal disease in the form of macroalbuminuria and/or renal impairment or chronic renal failure at the time of initial diagnosis Most patients with overt diabetic nephropathy have the nephrotic syndrome with odema, hypoalbuminemia and heavy proteinuria and this is accompanied with hypertension that is often difficult to control There are several differences between Type and diabetes While microalbuminuria is predictive of progressive renal disease in 80% of patients with Type diabetes, only 20% of patients with microalbuminuria develop progressive renal disease in Type diabetes This is probably because the microalbuminuria in Type diabetes is more reflective of a generalized vascular disease rather than specific renal disease, and Table Definition of Albuminuria Type Normoalbuminuria Microalbuminuria (Dipstick negative) Macroalbuminuria (Dipstick positive) Albumin/Creatinine Ratio (g/mg) 24-hour Collection (mg/24 h) Ͻ30 30–300 Ͻ30 30–300 Ͼ300 Ͼ300 Measurements should not be performed in the following situations which may temporarily increase urinary albumin excretion: after exercise or excessive protein intake, congestive cardiac failure, hematuria, uncontrolled hypertension or diabetes or urinary tract infection 1256 A Clinical Approach to Medicine explains the observed increased cardiovascular risk in patients with microalbuminuria Hypertension is also more prevalent in Type diabetes where 70% of the patients will have hypertension during the incipient stage compared to only 25% of patients with Type diabetes The presence of retinopathy is more strongly associated with nephropathy in Type diabetes with about 90% of patients having retinopathy compared to 55–65% of patients with Type diabetes Investigations The investigations are targeted at: 1) confirming the presence of albuminuria (with a 24-hour urine albumin excretion), 2) the assessment of renal function (serum creatinine and creatinine clearance); and 3) the exclusion of other non-diabetic renal disease Even if the diagnosis of diabetic nephropathy is clinically obvious, it is prudent to exclude the following non-diabetic renal diseases: 1) multiple myeloma (urine for Bence–Jones protein, Erythrocyte sedimentation rate, total protein and albumin); 2) collagen vascular disease (Antinuclear antibody), and 3) renal stone disease and other obstructive uropathy (ultrasound examination of the kidneys) In most cases, the diagnosis of diabetic nephropathy is made on clinical features without the need for a renal biopsy However, when features suggestive of a non-diabetic renal disease are present (Table 3) the patient would require referral to the nephrologist for further evaluation, which could include a renal biopsy Table Features Suggesting Non-diabetic Renal Disease Proteinuria without retinopathy Nephropathy within years of diagnosis in type diabetes Renal failure without significant proteinuria Gross or microscopic hematuria Rapid decline in renal function Sudden onset of nephrotic syndrome SCREENING FOR RENAL DISEASE Diabetic patients with microalbuminuria are at risk of developing progressive renal disease and screening (Fig 1) identifies those who will benefit from early intervention Screening of urine albumin excretion (UAE) should be performed annually in all Type diabetics and also Diabetic Nephropathy 1257 Type diabetes: Start at years after diagnosis Type diabetes: Start at diagnosis Routine urinalysis for protein – for protein No Repeat in year + for protein Overt nephropathy Quantitate proteinuria, begin treatment Test for urine albumin/creatinine ratio > 30 µg/mg Yes Repeat urine albumin/creatinine ratio twice within 3- month period No of tests > 30 µg/mg? Yes Incipient nephropathy Initiate treatment Fig Annual screening for microalbuminuria in diabetes mellitus annually after years of diagnosis and in all Type diabetics It is important when measuring the UAE to ensure that the patients not have the conditions listed in Table that may invalidate the test TREATMENT Retarding the progression of renal disease in diabetes requires a multipronged approach comprising of: 1) excellent glycemic control; 2) the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs); 3) excellent blood pressure control; 4) dietary protein restriction; and 5) control of hyperlipidemia There are several recent reviews on the treatment of diabetic nephropathy.1–3 Glycemic Control Studies have clearly demonstrated that excellent glycemic control can prevent the development of incipient diabetic nephropathy (microalbuminuria) and progression to overt nephropathy (macroalbuminuria) in type diabetes The evidence is less conclusive for Type diabetes In 1993, the Diabetes Control and Complications Trial (DCCT) convincingly demonstrated that intensive insulin therapy effectively delays 1258 A Clinical Approach to Medicine the onset of diabetic microvascular disease, including nephropathy, in Type diabetes.4 Patients in the intensive therapy arm received insulin in the form of a external insulin pump or by three or more daily insulin injections aiming for a target HbA1c of 6.05% As the primary end-point of the study was retinopathy, most of the enrolled patients (1441 patients) had mild renal disease with either no albuminuria or microalbuminuria (incipient nephropathy) Although less than 5% of the patients managed to maintain the target HbA1c, intensive therapy reduced the development of incipient nephropathy by 39%, overt nephropathy (macroalbuminuria) by 54% and renal impairment by 60% There was a two- to three-fold increase in severe hypoglycemia in the intensive therapy group For Type diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) enrolled 3867 patients who were assigned to intensive therapy of either a sulphonylurea or insulin, or conventional therapy with diet alone.5 The HbA1c was maintained at 7.0% in the intensive therapy group and the follow-up period was 10 years There was a 25% risk reduction in the aggregate microvascular end-points in the intensive therapy group, with a 67% risk reduction of a 2-fold increase in plasma creatinine There was no difference for any of the aggregate end-points between the sulphonylureas and insulin therapy suggesting that both therapies were equally effective This was also true for metformin that was used in a subgroup of obese patients While excellent glycemic control is important in the early stages of nephropathy, its effectiveness on preservation of renal function is less clear in patients with established overt diabetic nephropathy with macroalbuminuria In fact, with worsening renal function, patients with overt nephropathy are at risk of developing hypoglycemia because insulin is metabolized in the proximal renal tubules of the kidney and reduced metabolism prolongs the half-life of insulin The dose of insulin may have to be reduced while those on oral hypoglycemic agents should avoid longacting sulphonylureas (such as chlorpropamide and glibenclamide) and biguanides such as metformin (because of the risk of lactic acidosis) Practical recommendations 1) Intensive insulin therapy should be administered in all Type diabetics with normo- and microalbuminuria (incipient nephropathy) In Type diabetics, sulphonulyureas, metformin and insulin therapy have been Diabetic Nephropathy 1259 found to be equally effective 2) The target HbA1c level is below 7.0% 3) Patients with overt nephropathy and impaired renal function are at increased risk of hypoglycemia and should use short-acting sulphonylureas and avoid metformin ACE Inhibitors and Angiotensin Receptor Blockers (ARB) Blockade of the renin-angiotensin system with either an ACE inhibitor or ARB has been shown to delay the progression of diabetic nephropathy and this effect appears independent of its blood pressure lowering properties In addition to being a potent vasoconstrictor, Angiotensin II has also many effects at the cellular level, including the stimulation of growth factors and cytokines that can lead to cell proliferation and collagen synthesis and the ability to increase glomerular permselectivity Hence the ability to block the effects of angiotensin II by both the ACE inhibitors and ARBs helps explain the superiority of renal protection provided by these agents compared to other anti-hypertensive medications ACE inhibitors have been shown to delay the progression from microalbuminuria (incipient nephropathy) to macroalbuminuria (overt nephropathy) and also retard the progression of renal disease in overt nephropathy in Type diabetes The evidence for ACE inhibitors in Type diabetes is less conclusive as most of the trials concentrated on the easily definable Type diabetes The Collaborative Study Group Trial was a large placebocontrolled trial using captopril in patients with Type diabetes and overt nephropathy (urinary albumin levels Ͼ 500 mg/day).6 There were 409 patients who were followed up for 2.7 years and there was a 50% reduction in the composite end-point of doubling of the serum creatinine, ESRD or death for the captopril group There have also been studies to show ACE inhibitors can decrease progression to overt nephropathy in patients with Type diabetes and microalbuminuria with or without hypertension The ARBs have been more extensively investigated in Type diabetes and are similarly able to delay progression of renal disease in hypertensive patients with either incipient or overt nephropathy Three recent large placebo-controlled trials examined the renoprotective effects of an ARB on the hypertensive Type diabetic with either micro- (incipient nephropathy) or macroalbuminuria (overt nephropathy).7–9 One trial enrolled patients with incipient nephropathy and found that after 2.7 years of follow-up patients treated with the ARB were less likely to develop overt nephropathy 1260 A Clinical Approach to Medicine The two other trials studied patients with overt nephropathy and similarly found that patients treated with an ARB had a reduced risk of developing the primary composite end-point which was a doubling of the serum creatinine, development of ESRD or death More indirect support for the use of ARBs in Type diabetes comes from the recently concluded Losartan Intervention For Endpoint reduction in hypertension study (LIFE) where the ARB, losartan significantly reduced cardiovascular morbidity and mortality when compared to the control group using atenolol.10 Should normoalbuminuric patients receive prophylactic ACE inhibitors or ARBs? Although there is a study that demonstrated a reduced risk of developing incipient nephropathy when enalapril was used in Type diabetics with no hypertension or albuminuria, there is currently no recommendation to treat all diabetics prophylactically with either an ACE inhibitor or ARB Reducing proteinuria Apart from achieving the target blood pressure (discussed in the following section on Blood Pressure), the reduction of proteinuria should be a goal in itself Proteinuria has long been regarded as just a marker of renal disease but more recently, there has been an increasing body of evidence to suggest that proteinuria may cause renal injury through the nephrotoxic effects of the proteins Studies have shown that patients with the greatest reduction in proteinuria have the best preservation of renal function over time A practical target would be to reduce the proteinuria by at least 50% from the baseline value Combination therapy in the form of an ACE inhibitor and ARB have shown greater reduction in blood pressure and proteinuria than the individual agents used singly in patients with Type diabetes Sodium restriction enhances the antiproteinuric effects of the ACE inhibitors and ARBs and sodium intake should be limited to less than 90 mEq/day ACE gene polymorphism The ACE gene comprises of a deletion (D) allele and an insertion (I) allele The D allele is characterized by higher circulating and tissue ACE levels and as this may result in higher levels of Angiotensin II, it is a potential risk factor The DD genotype has been associated with declining renal Diabetic Nephropathy 1261 function and greater risk of progression to ESRD in Type diabetic nephropathy There is also a higher prevalence of the DD genotype in patients with Type diabetes on dialysis While these findings suggest that the DD ACE genotype may be a risk factor for progressive renal disease in Type diabetes, there is firm evidence that it predicts the development of nephropathy Side effects The ACE inhibitors and ARBs have two potential side effects: (1) the development of acute, reversible (if detected early) renal failure in patients with bilateral renal artery stenosis or those who are dehydrated; and (2) the development of severe hyperkalemia Close monitoring of the serum creatinine and potassium should be performed on initiation and when increasing the dose of the ACE inhibitor or ARB, especially in patients with impaired renal function Before initiating therapy it must be ensured that the patient is not dehydrated, does not have a renal bruit and potassium supplements or potassium sparing agents should be discontinued Practical recommendations 1) All patients with diabetes (Type or 2) with a) hypertension, b) microalbuminuria regardless of blood pressure, or c) overt nephropathy should be started on therapy An ACE inhibitor is the treatment of choice in Type diabetes and an ARB in Type diabetes If the ACE inhibitor cannot be tolerated because of cough, an ARB can be substituted 2) The goal is to reduce proteinuria by at least 50% from the baseline level 3) Combination therapy in the form of an ACE inhibitor and ARB can be considered to achieve the goal for proteinuria reduction and/or blood pressure (see below) 4) An abnormal serum creatinine is NOT a contraindication to initiating either an ACE inhibitor or ARB However, close monitoring of the serum creatinine and potassium should be performed at initiation, with each dose increase and at regular intervals (Fig 2) 1262 A Clinical Approach to Medicine BEFORE intiating ACE inhibitor/ARB ensure: No dehydration No renal bruit Stop K+ supplements and K+ sparing agents Correct hyper K+ if present Start ACE inhibitor/ARB (low dose in patients with abnormal Cr) Check Cr and K+ 3–7 days later Cr ↑ 30% baseline Cr ↑ < 30% baseline K+ normal DISCONTINUE MEDICATION Increase dose of ACE inhibitor/ARB Investigate for renal artery stenosis Recheck Cr and K+ ~ 2– weeks K+ ↑ > normal limit Maintain dose Correct K+ Continue to increase dose till target BP/proteinuria achieved Maintain checks on Cr and K+ at regular intervals (3 – monthly) Cr: creatinine, K+ : potassium Fig Initiating a patient on an ACE inhibitor or ARB Blood Pressure Control Blood pressure control is the cornerstone of preserving renal function in virtually all forms of renal disease and diabetes is no exception There have been two recent excellent reviews on the treatment of hypertension in patients with diabetes.11,12 Target blood pressure The glomerulus of the kidney functions optimally at a blood pressure of 80 mmHg and it is therefore not difficult to understand how a high systemic blood pressure can damage the delicate structures of the kidney In fact, the current blood pressure goals are much lower than the previously accepted target of a blood pressure below 140/90 mmHg Some studies using ACE inhibitors and/or ARBs in normotensive patients with renal disease have demonstrated that blood pressure can be further reduced Diabetic Nephropathy 1263 resulting in significant reduction in proteinuria This suggests that our definition of normotension may actually be too high in patients with renal disease and target blood pressures may need to come down further In 2003, the JNC VII (Joint National Committee on Detection, Evaluation, and treatment of High Blood Pressure) recommended that all patients with diabetes or chronic kidney disease should have a target blood pressure of Ͻ130/80 mmHg Antihypertensive agents It has been observed from clinical trials that an average of 3.2 different antihypertensive agents is required to achieve the recommended target blood pressure In patients with blood pressures of more than 15/10 mmHg above goal, at least two antihypertensive agents would be required A step-care approach to achieve the goal blood pressure and reduction in proteinuria is detailed in Fig However, it must be BP > goal Proteinuria > goal ACE inhibitor for type diabetes ARB for type diabetes Thiazide* (Loop diuretic with renal impairment) Combination ARB/ACE inhibitor Long acting calcium blocker (preferably non-dihydropyridine) ) -Blocker Others — methyldopa, hydralazine, minoxidil Refer to nephrologist *use fixed-dose combinations to allow more compliance Fig Step-care approach to achieve blood pressure and proteinuria goals 1264 A Clinical Approach to Medicine remembered that lowering of the blood pressure is more important that the type of antihypertensive agent used Initial therapy should be an ACE inhibitor in Type diabetes and an ARB in Type diabetes The precautions when initiating therapy discussed in the previous section should be observed If the blood pressure goal is not achieved, the second drug should be a diuretic in the form of a thiazide (hydrochlorothiazide up to a maximum of 25 mg/day) in patients with normal renal function or a loop diuretic in patients with renal impairment As the blood pressure in diabetic patients is frequently salt sensitive, the diuretics assist through increased urinary sodium excretion Furthermore, the use of an ACE inhibitor or ARB in combination with a diuretic has also been shown to result in a further reduction in proteinuria (an additional desirable effect) The next step would be to use a combination of ACE inhibitor and ARB (with diuretic) as studies in both Type diabetes and nondiabetic renal disease have shown that a combination of the two agents can more effectively reduce blood pressure and proteinuria than either agent used singly The third-line drug would be a long-acting calcium channel blocker (CCB), e.g diltiazem, amlodipine Although the dihydropyridine CCBs are powerful antihypertensive agents, there has been concern about their cardiovascular safety in patients with Type diabetes Furthermore, studies have also shown that the short-acting dihydropyridine CCBs may actually increase proteinuria in both Type and diabetes They should, therefore, not be used as monotherapy However, several authors have suggested that a combination of a CCB and ACE inhibitor may be superior to either alone and in practical terms, a CCB is often necessary to achieve the target blood pressure Subsequent add-on therapy would include a -blocker followed by other agents such as methyldopa, hydralazine or minoxidil A -blocker should not be used in combination with a non-dihydropyridine CCB in elderly patients and those with conduction abnormalities While much emphasis has been placed on achieving the blood pressure goals, care has to be observed in the elderly patients as many will have cardiovascular disease associated with reduction in both cerebral and renal autoregulation Blood pressure should be slowly lowered in this group of patients and monitored both in the sitting and upright positions to account for orthostatic hypotension Diabetic Nephropathy 1265 Dietary Protein Restriction Although there have been many studies examining the effect of reduced dietary protein intake on the progression of renal disease, there is no conclusive evidence of the benefit of a low protein diet in patients with diabetes Moreover, with the additional fat and carbohydrate restrictions imposed on the diabetic patient, both compliance and malnutrition may become problems However, most authors would recommend a moderate protein restriction of 0.8 g/kg body weight/day in diabetic patients with nephropathy.1 Treatment of Hyperlipidemia Hyperlipidemia is frequently associated with diabetes, especially Type diabetes Most commonly, the lipid abnormalities include an elevated total cholesterol and triglycerides and low HDL (high-densitylipoprotein) cholesterol The hyperlipidemia is worsened by renal failure and responsible for the excessive cardiovascular disease in diabetic patients with ESRD Hyperlipidemia may directly contribute to the development of glomerulosclerosis and studies have shown that oxidized LDL (low-density-lipoprotein) cholesterol causes mesangial cell proliferation at low doses and is cytotoxic at high doses It is therefore prudent in diabetic patients with renal disease who are all at high risk of cardiovascular disease to adopt the NCEP ATP III (National Cholesterol Education Programme Adult Treatment Panel III) guideline of a target LDL-cholesterol of less than 100 mg/dL Treatment with an HMG-CoA reductase inhibitor has been shown to reduce proteinuria in patients with Type diabetes HMG Co-A reductase inhibitors can effectively reduce cholesterol but in patients with renal disease, there is an increased risk of drug-induced myopathy This risk is increased if the HMG Co-A reductase inhibitor is combined with cyclosporine, gemfibrozil or other lipid-lowering agents Hence, when initiating a patient with renal disease on an HMG Co-A reductase inhibitor, the patient should receive a reduced dose and be monitored closely for myopathy after initiation Summary A summary of the therapeutic recommendations is presented in Table 1266 A Clinical Approach to Medicine Table Therapeutic Strategies in Diabetic Nephropathy (Types and 2) Treatment Stages of Diabetic Nephropathy I II III Glycemic control Maintain excellent glycemic control Target HbA1c Ͻ 7.0% ACE inhibitor and/or ARB Only if hypertension is present BP Control Excellent BP control; Ͻ 130/80mmHg Sodium restriction Protein restriction Hyperlipidemia control IV V Watch for hypoglycemia with worsening renal function STRONGLY For RECOMMENDED control Type diabetes — ACEi of BP Type diabetes — ARB Sodium intake of Ͻ 90mEq/day to achieve BP and proteinuria goals 0.8g/kg BW/day Target LDL cholesterol level Ͻ 100 mg/dL ACEi — ACE inhibitor, BP — blood pressure, BW — body weight INDICATIONS FOR REFERRAL TO NEPHROLOGIST The diabetic patient should be referred to the nephrologist in the following circumstances: 1) when non-diabetic renal disease is suspected (Table 3); 2) when target blood pressure or reduction in proteinuria cannot be achieved; and 3) when the patient develops progressive chronic renal failure (creatinine ~ 350 mol/L) requiring preparation of renal replacement therapy REFERENCES Ismail N, Becker B, Strzelczyk P, Ritz E, Renal disease and hypertension in non-insulindependent diabetes mellitus, Kidney Int 55:1–28, 1999 Diabetic Nephropathy 1267 Mogensen CE, Cooper ME, Diabetic renal disease: from recent studies to improved clinical practice, Diabet Med 21:4–7, 2004 Remuzzi G, Schieppati A, Ruggenenti P, Nephropathy in patients with type diabetes, N Engl J Med 346:1145–1151, 2002 The Diabetes Control and Complication Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med 329:977–986, 1993 UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type diabetes, (UKPDS 33) Lancet 352:837–853, 1998 Lewis EJ, Hunsicker LG, Bain RP, Rohde RE, The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy, N Engl J Med 329:1456–1462, 1993 Parving HH, Lehnert H, Brochner–Mortensen J, Gomis R, Anderswn S, Arner P, The effect of irbesartan on the development of diabetic nephropathy in patients with type diabetes, N Engl J Med 345:870–878, 2001 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis LB, Ritz E, Atkins RC, Rohde R, Raz I, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type diabetes, N Engl J Med 345:851–860, 2001 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, Effects of losartan on renal and cardiovascular outcomes in patients with type diabetes and nephropathy, N Engl J Med 345:861–869, 2001 10 Lindholm LH et al for the LIFE study group, Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 359:1004–1010, 2002 11 Arauz–Pacheco C, Parrott MA, Raskin P, The treatment of hypertension in adult patients with diabetes, Diabetes Care 25:134–147, 2002 12 Bakris GL, Williams M, Dworkin L, Elliott J, Epstein M, Toto R, Tuttle K, Douglas J, Hseuh W, Sowers J for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group, Preserving renal function in adults with hypertension and diabetes: a consensus approach, Am J Kidney Dis 36:646–661, 2000 This page intentionally left blank 73 Contemporary Management of Renal Failure A Vathsala INTRODUCTION Renal failure is characterized by progressive deterioration in the physiological functions of the kidney leading to accumulation of toxic substances in the blood and to alterations in functions of various hormones These effects lead to a clinical syndrome associated with fatigue, anorexia, weight loss, nausea, vomiting, pruritus, pericarditis, hypertension, fluid overload and neurological disturbances, which if untreated, culminates in coma and death due to end-stage renal failure (ESRF) Though historically, the term renal failure referred primarily to the later stages in its development including chronic renal failure (CRF) and ESRF, it has become increasingly apparent that these later stages can be prevented or delayed with appropriate interventions initiated at the earlier stages Thus, recently, the scope of management of chronic renal disease has been extended to include chronic kidney damage from its earliest stages in addition to CRF and ESRF This article proposes a schema for the holistic management of chronic renal disease that begins with identifying patients who have chronic renal disease, evaluating the cause, 1269 1270 A Clinical Approach to Medicine • • • • • • • • • Screen Individuals at Risk for Kidney Disease for • Renal Damage • Reduced Renal Function Evaluate Primary Cause of Kidney Disease Severity of Renal Disease • Emergent Conditions • Acute Reversible Factors Complications of Renal Failure Treat Primary Kidney Disease Retard Progression of Renal Failure Complications of Renal Failure Prepare for End Stage Renal Failure End Stage Renal Failure and Its Complications Fig Schema for management of chronic kidney disease severity and complications of renal failure, retarding the progression of renal failure, optimizing preparation for and timely initiation of ESRF therapy and its management in adults DEFINITION A definition of chronic renal disease has been recently devised by the National Kidney Foundation (NKF, USA), and is based on the presence of chronic renal damage and on the level of kidney function.1 The presence of structural, functional or pathological abnormalities of the kidney or abnormalities in the composition of the blood, urine or in imaging tests of the kidney, persisting for more than months is deemed as evidence for chronic renal damage Glomerular filtration rate less than 60 mL/min/1.73 m2, with or without other evidence for renal damage for more than months is also deemed evidence for chronic renal disease Given that renal damage is progressive in nature, the NKF has also established a framework for defining the various stages of chronic renal disease, based on the degree of renal functional impairment (Table 1) Management of Chronic Kidney Disease 1271 Table Stages of Chronic Renal Disease Stage Description GFRa mL/min/1.73 m2 High Blood Pressure or Laboratory Abnormality Symptoms Kidney damage with normal or ↑ GFR Kidney damage with mild ↓ GFR Moderate ↓ GFR Severe ↓ GFR Kidney failure у 90 Sometimesb Sometimes 60–89 Possible Sometimes 30–59 15–29 Ͻ 15 or dialysis Mild Moderate Severe Possible Mild Moderate aGFR — Glomerular Filtration Rate to instances where patients may have symptoms and signs due to nephrotic syndrome, urinary tract symptoms, tubular syndromes etc Adapted from K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification.1 bRefers Based on these definitions and stages, it is readily apparent that, the vast majority of patients become symptomatic from chronic renal disease when they have already lost more than 50% of their renal function This reiterates the need for screening of at-risk individuals as the first step in approaching the problem of chronic renal disease SCOPE OF CHRONIC RENAL DISEASE In the USA, it has been estimated that nearly 21% of the population may have some form of renal disease or are at risk for renal disease: 4.6% have moderate to severe reduction in renal function or are on dialysis, 6.3% have evidence of early kidney damage with normal to mildly decreased renal function and at least 10% of the population are at risk for renal disease.1 Among the various causes of ESRF, glomerular diseases such as diabetic nephropathy (Range: 22– 44% in Asia) and glomerulonephritis (Range: 10– 42% in Asia) are the leading causes worldwide Vascular disease including hypertensive nephrosclerosis is the third leading cause (Range: 5–19% in Asia), while tubulo-interstitial diseases such as “chronic pyelonephritis” and vesicoureteric reflux, toxic nephropathy, analgesic nephropathy, urinary tract obstructive disorders such as 1272 A Clinical Approach to Medicine obstructive uropathy as well as cystic diseases are less common causes Of particular concern is the increasing incidence of ESRF in Singapore and in the rest of Asia; whereas in 1995, there were 403 new cases of ESRF starting dialysis in Singapore, in 2000, there were 513 new cases of ESRF starting dialysis, a nearly 20% increase (Singapore Renal Registry, 2001, unpublished) SCREENING FOR CHRONIC RENAL DISEASE Screening for chronic renal disease in adults is contingent on firstly identifying patients at risk for chronic renal disease and secondly performing the necessary screening tests on these patients to identify those with chronic renal damage and/or decreased renal function At Risk Populations The following categories of patients are at risk for renal disease and should be screened for renal damage: • • • • • • • • • • • diabetes hypertension older age (у 60 years) family history of chronic kidney disease autoimmune diseases systemic infections urinary tract disorders neoplasia those with exposure to drugs toxic to the kidney those with recovery from acute renal failure those with reduced kidney mass Screening Tests Patients at risk for chronic renal disease should be screened for markers of renal damage and level of renal function Proteinuria is a hallmark of renal damage; as normal individuals excrete minimal quantities of protein in the urine, persistent proteinuria (Ͼ 1ϩ on dipstick), if detected on two consecutive tests, is suggestive of renal damage and indicates the need for further evaluation Once detected, a positive urine dipstick for Management of Chronic Kidney Disease 1273 protein should be confirmed with a quantitative protein assessment Spot urinary measurements of protein/creatinine ratios are an accurate estimate of urinary protein excretion rate This test is performed by measuring protein and creatinine concentration (in mg/dL) in a spot urine specimen; the protein concentration is divided by the creatinine concentration and the unit-less number (the protein/creatinine ratio) equals the 24 hour urine protein excretion rate (normal values are Ͻ 0.15, equal to Ͻ 0.15 g protein/day) While a serum creatinine value above the normal reference range for that laboratory is indicative of reduced renal function, its measurement alone has been deemed inadequate The usual method of estimating renal function or glomerular filtration rate (GFR) in clinical practice has been timed urine collection for creatinine clearance However, due to the tendency of timed urine collections to overestimate GFR and their cumbersome nature, various prediction equations have been used to assess GFR instead As these equations have acceptable accuracy among western populations, the NKF (USA) guidelines accept these prediction equations as surrogate markers for GFR, making timed urine collections for creatinine clearance redundant Nevertheless, as these prediction equations were largely obtained from larger-sized western populations, their accuracy in estimating GFR in the smaller-sized Asian population is unestablished Timed creatinine clearance will estimate GFR more accurately in at risk Asian populations Other laboratory tests that are markers of renal damage include: • • • microhematuria; other abnormalities on examination of urine sediment, e.g pyuria, red blood cell casts etc; and imaging studies such as Ultrasonography, Intravenous Pyelography, CT scan, Magnetic Resonance Imaging, Nuclear Medicine scans Thus patient groups at risk for renal disease as listed above should undergo urine protein, urine sediment and blood creatinine measurements to confirm the presence of chronic renal disease In those with abnormalities detected on screening, proteinuria should be confirmed and quantitated by urine protein/creatinine ratios and renal function estimated with creatinine clearance and the stage of renal disease classified as in Table The speed of further assessment and management obviously is based on the presence of symptoms and severity of renal disease — more 1274 A Clinical Approach to Medicine symptomatic and more severe disease requires more rapid assessment and management In the absence of evidence of renal disease on initial screening of at-risk individuals, the screening should be repeated annually EVALUATION OF CHRONIC RENAL DISEASE After identifying patients with chronic renal disease, the next steps in the evaluation are to firstly establish the cause and to secondly, to establish its chronicity and severity A full history, physical examination and various diagnostic tests are useful in the evaluation (Table 2) As laboratory tests to evaluate cause of renal disease can be quite extensive, investigations should be tailored to the individual patient Importantly, during the course of evaluation of patients with renal disease, the chronicity and severity of renal disease should be established Chronicity is favored by the presence of symptoms of renal failure, anemia, elevated parathyroid hormone and small kidneys on ultrasound/or increased renal parenchymal echogenicity The evaluation should assess the severity of renal failure; emergent conditions requiring urgent dialysis or other treatment as well presence of acute reversible factors, which, upon correction, would result in reversal of acute renal dysfunction (Table 3) should be identified and appropriately managed Part of the evaluation of chronic renal disease includes an assessment of the manifestations and complications of renal failure These manifestations are more prominent with increasing severity of chronic renal disease and contribute significantly to its morbidity (Figure 2) Chronic renal disease, once diagnosed, invariably progresses over time to CRF and eventually to ESRF The interval of progression to CRF and ESRF is variable and is affected by the cause of renal disease and by other factors Diabetic nephropathy, glomerulonephritis and polycystic kidney disease are generally associated with a faster rate of decline in renal function than tubulo-interstitial diseases and hypertensive nephrosclerosis In diabetics, worse glycemic control is associated with a faster decline in GFR; furthermore, regardless of cause of renal disease, those with more proteinuria, lower serum albumin, higher blood pressure and smoking also experience a faster decline Finally, patients with chronic renal disease progress rapidly to ESRF if they experience renal insults that cause acute renal dysfunction Thus, optimal treatment of Management of Chronic Kidney Disease 1275 Table Evaluation of Primary Cause of Renal Disease Medical history Drug history Family history Physical examination • Diabetes • Hypertension • Previous renal problems including urinary abnormalities, stones, difficulty micturition, dysuria, urgency, gross hematuria, urinary tract obstruction • Previous auto-immune disease • Previous serious systemic infections or renal failure • Previous failed/normal urinary examinations: • Insurance examination • Pre-employment checks etc • Other screening for urine abnormalities • Pregnancy: hypertension, pre-eclampsia, recurrent abortions • Previous pelvic surgery • Hepatitis • Non Steroidal Anti-Inflammatory Agents (NSAIDS) • COX2 Inhibitors • Traditional herbs or medications • • • • • • • • • • • Laboratory confirmation of renal disease • • • • • • • • Kidney failure, or urinary abnormalities Diabetes Hypertension Polycystic kidney disease Urinary abnormalities Blood pressure (postural drop?) Uremic fetor, asterexis Skin: rash, scratch marks, vasculitis, stigmata of embolic disease, gouty tophi Assess volume status: • Jugular venous pressure • Crepitations in lungs • Edema Cardiomegaly, gallop rhythm Abdomen: • Organomegaly • Renal bruits • Flank tenderness • Palpable masses Peripheral vascular disease Peripheral neuropathy Joints: Arthritis (auto-immune disease, gout) Digital rectal examination (prostate) in men Urine protein/creatinine ratio (or Urine albumin/ creatinine ratio) or 24-hour urinary protein Urine microscopy Serum creatinine 24-hour creatinine clearance 1276 A Clinical Approach to Medicine Table (Continued) Laboratory evaluation of cause of renal disease Other tests • Urine phase contrast microscopy • Ultrasound kidneys/Intravenous pyelography/ CT scan/MRI/Nuclear medicine studies • Fasting glucose/HbA1C • Anti nuclear factor/Double stranded DNA etc • Serum complement levels (CH50, C3, C4) • Anti neutrophil cytoplasmic autoantibody • Anti glomerular basement membrane antibody • Serum/Urine immunoelectropheresis for myeloma • Cryoglobulins • Hepatitis B Surface Antigen, Anti-HCV, HIV • Eosinophiluria • Renal biopsy • Electrocardiogram • Chest radiograph • Fasting lipids chronic renal disease in its early stages includes treatment of the primary disease, retardation of progression of renal failure by ameliorating risk factors for progression and preventing acute declines in renal function, and most importantly educating and counseling patients on these measures (Table 4) While the treatment of primary renal disease per se, is beyond the scope of this chapter, excellent glycemic control (HbA1C target Ͻ 7%) clearly reduces the risk of progression of diabetic nephropathy in both Type I and Type II diabetes.2,3 Two other measures, namely excellent blood pressure control and renoprotection with Angiotensin Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARB) have been shown to retard progression of renal disease and should be implemented in all patients as part of the holistic management of chronic renal disease Blood pressure control The majority of patients with chronic renal disease have hypertension and the level of blood pressure is directly proportional to progression; thus strict blood pressure control would be expected to retard progression Management of Chronic Kidney Disease 1277 Table Assessment for Severity of Renal Disease Symptoms of renal failure • • • Laboratory evaluation • of severity of renal • disease • • • Renal emergencies • • • • • • Acute reversible • factors Nausea, vomiting Oliguria, nocturia, polyuria Dyspnea, orthopnea, edema Urea/Electrolytes/Glucose Full Blood Count Calcium/Phosphate Total Protein/Albumin Parathyroid Hormone Rapidly rising serum creatinine Fluid overload, especially pulmonary edema Severe hyperkalemia Severe metabolic acidosis Encephalopathy: Coma, seizures etc Pericarditis Pre-renal causes: • Volume depletion/Hypotension • Severe congestive heart failure • Renal causes: • Acute glomerulonephritis (Crescenteric change) • Acute tubular necrosis (Vasomotor nephropathy) due to: • Sepsis • Nephrotoxic agents • Acute interstitial nephritis • Angiotensin-converting enzyme inhibitors/ Angiotensin II Receptor blockers/ Radiocontrast agents • Rhabdomyolysis • Cholesterol emboli • Post-renal causes: Urinary tract obstruction • Renovascular: • Accelerated hypertension • Stenosis/Thrombosis of renal failure The Modification of Diet in Renal Disease (MDRD) study evaluated the impact of different levels of blood pressure control on rate of GFR decline in non-diabetic renal disease.4 As patients with higher levels of proteinuria experienced the greatest benefits from the lower blood pressure (BP Ͻ 125/75 mm Hg), these lower target blood pressure levels are recommended for patients with proteinuria Ͼ g/day These lower target blood pressure levels are also recommended for all diabetics regardless of level of proteinuria.5 For patients with non-diabetic renal 1278 A Clinical Approach to Medicine Neurological • Fatigue, malaise, irritability • Cognitive dysfunction • Day-night sleep reversal patterns • Drowsiness • Cramps • Restless legs • Seizures • Peripheral/autonomic neuropathy • Coma Respiratory • Pleuritis, pleural effusions • Uremic lung Gastro-intestinal • Anorexia, nausea and vomiting • Stomatitis • Gastritis • Ulceration • Pancreatitis Musculoskeletal • Bone pains • Renal osteodystrophy • Osteomalacia • β2 Amyloidosis and Carpal tunnel syndrome • Gout Metabolic • Elevated Parathyroid Hormone • Relative Erythropoietin deficiency • Derangements in Insulin, Glucagon, Thyroid Stimulating Hormone, Luteinizing Hormone, Follicle Stimulating Hormone, Prolactin, Growth Hormone Other • Thirst • Uremic foetor • Impotence, diminished libido, Infertility in women Skin • Pruritus • Hyperpigmentation Cardiovascular • Hypertension and Left ventricular hypertrophy • Fluid overload, especially pulmonary edema • Myocardial dysfunction/cardiomyopathy • Ischemic heart disease • Uremic pericarditis • Accelerated atherosclerosis Hematologic • Anemia due to • Relative erythropoietin deficiency • Shortened red blood cell survival • Gastrointestinal bleeding • Iron deficiency • Impaired iron utilization/ Anemia of chronic disease • Uremic inhibitors of erythropoiesis • Leukocyte dysfunction and Immune deficiency • Coagulopathy • Platelet dysfunction • Impaired Von Willebrand factor release Fig Manifestations of chronic renal disease disease and proteinuria Ͼ 1g/day, guidelines for target blood pressures have been less stringent at 130/85 mm Hg.6 However more recent guidelines by various bodies recommend an even lower BP target of 130/80 mm Hg in patients with chronic renal disease with proteinuria Ͻ g/day.7 All anti-hypertensives can be used in patients with chronic kidney disease, though dihydropyridine calcium channel blockers (e.g Amlodipine) should not be used alone in patients with chronic kidney disease due to their association with faster decline in renal function.8 On the average, to anti-hypertensives may be needed to control blood pressure to the desired levels suggested above Reno-protection While any anti-hypertensive drug appears to be equally effective in reducing blood pressure, ACEI and ARB theoretically confer an Management of Chronic Kidney Disease 1279 Table Early Treatment of Chronic Renal Disease Treat underlying disease • • • Monitor renal • function • • Retard progression • of renal failure • Treat and prevent reversible factors • • • • Educate and counsel • • Control blood glucose strictly in diabetics Control blood pressure Primary disease (glomerulonephritis etc) Urea, electrolytes and creatinine Urine protein/Creatinine ratio Creatinine clearance Control blood pressure • Ͻ 130/80 mm Hg for those with proteinuria Ͻ g/day • Ͻ 125/75 mm Hg for those with proteinuria у g/day and diabetics Angiotensin converting enzyme inhibitors/ Angiotensin receptor blockers Control blood glucose strictly in diabetics Correct: • Volume depletion/hypotension • Heart failure Treat: • Sepsis • Urinary tract obstruction • Vascular stenosis/thrombosis • Acute interstitial nephritis • Uncontrolled hypertension Stop/avoid: • Nephrotoxic agents • Radiocontrast agents • Agents causing rhabdomyolysis (Statins, Colchicine etc.) Regarding disease, severity, treatments and prognosis Refer Dietician, Pharmacist, Psychologist, Social worker additional reno-protective effect in patients with renal disease by ameliorating intra-glomerular hypertension and reducing proteinuria; they may also be beneficial in reducing angiotensin II mediated cell proliferation and fibrosis Several large studies have demonstrated the effects of ACEI to lower blood pressure, decrease proteinuria and slow the progression of renal failure to a greater extent than other anti-hypertensive agents in patients with non-diabetic and diabetic renal disease, making these drugs the preferred choice for treatment of high blood pressure in these patients.9,10 Recent studies have also demonstrated the efficacy of ARB to reduce proteinuria and delay progression of renal failure in Type II diabetics with various stages of nephropathy.11 Though similar evidence for ARB’s in non-diabetic renal disease are currently lacking, 1280 A Clinical Approach to Medicine ARB’s may have similar effects to that of ACEI and may be particularly useful for patients unable to tolerate the latter because of cough Combined use of ACEI and ARB has been advocated by some to reduce proteinuria and control blood pressure, however, they should be used cautiously in combination in patients on non-cardio-selective  blockers When used in patients with chronic renal disease, both ACEI and ARB’s are associated with transient increases in serum creatinine (due to their hemodynamic effects) and hyperkalemia and should be used with caution in patients with serum creatinine greater than 265 mol/L or mg/dL A rise in serum creatinine Ͼ 88 mol/L following ACEI/ARB therapy has been suggested as an indication to exclude renal artery stenosis and discontinuation of ACEI/ARBs Patients with hyperkalemia (serum Kϩ Ͼ 5.5 mmol/L) respond to dietary potassium restriction or addition of a diuretic; failing this ACEI/ARB doses may need to be reduced In addition to pharmacologic therapy, sodium intake should be restricted to less than 100 mmol/day so as to improve blood pressure control as well as ameliorate fluid overload As hypertension in renal failure occurs frequently in relation to fluid overload, fluid restriction and treatment with high dose, loop diuretics is often necessary to optimize therapy Other measures that are often instituted with the diagnosis of chronic renal disease are dietary protein restriction and control of hyperlipidemia Though protein restriction has been shown to retard progression of renal failure, this requires intensive nutritional counseling to prevent malnutrition.4 Thus modest protein restriction diet consisting of 0.8 g protein/kg/ body weight/day of high biologic value protein can be instituted when the creatinine clearance is less than 25 mL/min As patients with renal failure have a high incidence of hyperlipidemia with elevations in total and low density cholesterol and triglycerides, treatment with dietary intervention and pharmacologic therapy is likely to reduce risk for cardiovascular disease as in the general population, though this may not have any renoprotective effects.12 LATE COMPLICATIONS OF CHRONIC RENAL DISEASE Appropriate management of the later stages of chronic renal disease including treatment of complications of renal failure such as anemia and secondary hyperparathyroidism; timely initiation of dialysis can Management of Chronic Kidney Disease 1281 Table Treatment of Late Stages of Chronic Renal Disease Monitor complications of renal failure Treat complications of renal failure • • • • • • • Prepare for end-stage renal failure • • • • • • • • • • Hemoglobin, Iron status Serum calcium, Phosphate, Alkaline phosphatase Serum parathyroid hormone Serum albumin Exclude other causes of anemia • Gastrointestinal bleeding • Iron/vitamin deficiency • Thalassemia Correct anemia • Iron/vitamin deficiencies • Recombinant erythropoietin Prevent and treat hyperparathyroidism • Phosphate binders • Calcium carbonate or calcium acetate • Active vitamin D analogues Fluid overload with diuretics Acidosis with bicarbonate supplements Hyperlipidemia with statins or fibrates Evaluate suitability for • Renal transplantation • Hemodialysis • Peritoneal dialysis Refer transplant or dialysis coordinator Refer psychologist, social worker Do serology for Hepatitis B, Anti HCV, HIV Consider tissue typing, vascular mapping Refer surgeon Consider timely initiation of dialysis significantly reduce the morbidity associated with CRF (Table 5) Recombinant Erythropoietin (rEPO) has significantly facilitated the management of anemia of renal failure At doses of 80 to 120 units/kg/week in divided doses and in the presence of adequate iron stores, rEPO administration reverses the anemia of renal failure, improves appetite and reduces hospitalization rates in patients with renal failure Current recommendations for treatment of anemia aim for target hemoglobin levels of 11 and 12 g/dL in pre-menopausal females and males/post menopausal females respectively.13 However, financial and logistical considerations frequently limit the use of rEPO in pre-dialysis patients and patients often receive only enough rEPO to remain asymptomatic and transfusion-independent 1282 A Clinical Approach to Medicine Nevertheless, with progression of renal disease, accumulation of uremic toxins and symptoms of fluid overload worsen; conservative measures become inadequate and the patient requires renal replacement therapy to treat ESRF As early dialysis has been suggested to reduce hospitalization and morbidity, current recommendations suggest a strategy of “timely” initiation of dialysis when the creatinine clearance is between 9–14 mL/min/1.73 m2 with incremental dialysis being administered as residual renal function diminishes.13 However, in Asia, socioeconomic considerations often prevent early initiation of dialysis, and the majority of patients start dialysis when serum creatinine is greater than 900 mol/L (or 10 mg/dL) and earlier only if symptoms of uremia and fluid overload supervene RENAL REPLACEMENT THERAPIES An integrated and individualized management is the ideal approach for treatment of ESRF and each patient must be educated regarding the options for renal transplantation, hemodialysis or peritoneal dialysis The choice of one modality over another for any individual patient is based on medical suitability, the availability of these options as well as socioeconomic and cultural circumstances The presence of multiple underlying co-morbidities may prompt some patients to opt for conservative management without renal replacement therapy and these patients will require the necessary social and psychological support In the holistic management of renal failure, every patient needs to be evaluated medically, financially and psychosocially and prepared appropriately with a view towards the timely initiation of renal replacement therapy of ESRF Renal Transplantation Generally, renal transplantation (RTX), with kidneys obtained from live or cadaveric donors, is the ideal form of treatment for many categories of patients with ESRF as it is the most successful in reversing the metabolic consequences of uremia Patients with underlying systemic malignancy, severe cerebrovascular or cardiovascular disease, significant liver disease, and serious infections are excluded from consideration for RTX Additional criteria such as age or minor coronary artery disease or cerebrovascular disease are occasionally imposed in some countries due to Management of Chronic Kidney Disease 1283 lack of adequate donor kidneys for RTX For patients suitable for RTX, family members (live-related and emotionally related) are counseled and those willing to be considered for renal donation are evaluated to exclude systemic disease as well as diseases that may pose a risk for renal deterioration after uninephrectomy (example: baseline renal dysfunction, hypertension and diabetes) In the immunological evaluation of a live-related donor, the donor with the best tissue match is given preference as RTX between Human Leukocyte Antigen (HLA) identical siblings still yields the best long-term results However, with newer immunosuppressive drugs, live donor RTX even across HLA mismatched donor-recipient pairs also yields excellent results and matching alone need not be a consideration for live donor RTX After ensuring compatibility between donor and recipient, and screening for infections that may be transmitted to the recipient with RTX, the most suitable donor undergoes evaluation of renal vascular anatomy to confirm suitability If a suitable donor is available, the pre-ESRF patient can undergo pre-emptive RTX, prior to the need for dialysis Those without a suitable live-donor are started on dialysis and placed on a waiting list for a cadaveric RTX Live donor uninephrectomy was in the past performed through a flank incision; currently, the surgery can be performed via a laparoscopic approach, a method which does away with the flank incision and reduces post-operative hospitalization Cadaveric kidneys are harvested from patients declared brain dead following cerebrovascular accident or trauma Criteria for selection of recipients for cadaveric RTX vary between different countries but are generally based on HLA matching, waiting period on dialysis, pre-sensitization and other medical considerations Surgical preparation for the potential recipient for RTX is straightforward; native nephrectomy is unnecessary unless in the presence of an infected/obstructed native kidney Live donor kidneys are transplanted immediately after harvest, while cadaveric kidneys are preserved either with cold or machine perfusion for up to 48 hours; transplantation requires anastamoses of donor renal vessels to recipient iliac vessels with implantation of the donor ureter into the bladder with a neocystostomy Life-long immunosuppression is required to prevent rejection of the allograft in the majority of patients Standard immunosuppression in many centers is with cyclosporine (CsA), azathioprine and corticosteroids, with CsA doses adjusted to levels Newer agents include tacrolimus (FK506) as a substitute for CsA, mycophenolate as a substitute for azathioprine, 1284 A Clinical Approach to Medicine interleukin receptor antagonists and sirolimus, the latter, a calcineurin inhibitor-sparing agent With the introduction of these newer immunosuppressants into clinical practice in recent years, the choice of therapy is varied and can be tailored to the individual, based on immunological risk and other clinical factors Induction protocols using anti-lymphocyte preparations may be especially useful in high-risk candidates such as re-transplants and those with sensitization Acute rejection episodes which occur in 10–40% of transplants (based on risk and regimen used) can be treated with high dose corticosteroid pulse therapy or anti-lymphocyte preparations such as anti-CD3 monoclonal antibody (OKT3) with successful reversal in over 90% of cases With current immunosuppressive protocols, short and long-term results of renal transplantation are excellent: one-year graft survival rates for recipients of live donor and cadaveric transplants are 96.4% and 87.9% respectively at our center under CsA immunosuppression and compare favorably with the 93% and 87% one-year graft survivals respectively reported from the Registry of the United Network of Organ Sharing, UNOS.14 The importance of HLA match is still evident with 93% threeyear graft survival for HLA identical sibling transplants versus 87% and 86% for those receiving one haplotype and live unrelated transplants respectively Nevertheless, results of live donor transplants are still superior to that of cadaveric transplants, supporting the continued use of living donors as the preferred modality of renal replacement therapy With improving immunosuppressive protocols, graft loss due to acute rejection is becoming less frequent and patient death with graft function is of increasing importance.14 As cardiovascular mortality and sepsis remain the leading causes of death in RTX, the challenge for the future is to further reduce mortality in RTX with optimal immunosuppressive and disease management strategies Hemodialysis Though RTX is the ideal form of renal replacement therapy, most ESRF patients not have a suitable live donor and need dialysis to sustain life Dialysis is a process by which the solutes diffuse between the blood and dialysate across a semi-permeable membrane down a concentration gradient; waste products such as urea, creatinine, and phosphates diffuse from the blood into the dialysate while bicarbonate and calcium from the Management of Chronic Kidney Disease 1285 dialysate diffuse back into the blood In hemodialysis (HD), diffusion occurs between the blood and the dialysate through the hollow fibers of an artificial semi-permeable membrane comprising the hemodialyzer A permanent vascular access is needed to provide delivery of blood at flow rates of 200 to 350 mL/min to the hemodialyzer The preferred access is a radiocephalic or brachiocephalic arteriovenous fistula in the non-dominant hand, a procedure in which the radial or brachial artery is anastamosed to the cephalic veins After surgical creation of a fistula, the venous limbs of the fistula dilate and the vessel walls becomes arterialized under the influence of systemic arterial pressures thereby permitting repeated needling and the high blood flow rates required for HD In patients with inadequately developed superficial veins, an arterio-venous access can be created using a graft made of synthetic material such as polytetrafluoroethylene The graft can then be needled directly and repeatedly to provide the necessary blood flow for HD Access infection and failure due to the occurrence of stenosis or thrombosis are major causes of morbidity and hospitalization in HD patients In patients without a permanent vascular access, temporary access can be secured using a catheter placed in the internal jugular, subclavian or rarely the femoral vein Their use is also complicated by infections and vascular stenosis, such that timely creation of a permanent vascular access in anticipation of its future use is crucial in the management of HD patients The three components of the HD apparatus are the hemodialyzer, the HD machine and the dialysate Standard hemodialyzers are made from hollow fibers comprised of cellulose, substituted cellulose or other synthetic materials such as polysulfone, polyacrylonitrile and polymethylmethacrylate and provide surface areas between 0.8 m2 to 2.0 m2 for dialysis After the first use, a hemodialyzer can be rinsed free of blood, cleansed and sterilized for reuse for up to uses for the same patient The HD machine itself consists of a blood pump, a dialysate mixing and delivery system and appropriate safety monitors to detect pressures, blood and air leaks and ion conductivities within the extracorporeal circuit In a typical circuit, blood is moved from the arterial limb of the patient’s vascular access to the blood compartment of the hemodialyzer with the aid of a blood pump; a heparin pump permits the continuous infusion of heparin into the patient for anticoagulation of the circulating blood The dialysate delivery system mixes the bicarbonate-based dialysate concentrate with treated water to its final dilution, heats it to body 1286 A Clinical Approach to Medicine temperature and delivers it to the dialysate compartment of the hemodialyzer circuit at rates of 500 mL/min As the flow of blood and dialysate are in countercurrent directions, concentration gradients between the blood and dialysate are maximized, thereby permitting maximal cross diffusion of solutes across the dialyzer membrane In addition to solute exchange, fluid removal is an important component of the dialysis procedure and is achieved by application of transmembrane pressure to the blood in the dialysis circuit, thereby permitting ultrafiltration of blood via hydrostatic pressure Following transit through the hemodialyzer, the purified blood is returned to the patient through the venous limb of the vascular access The HD procedure is generally performed over a 1/2 to 1/2 hour period times a week Goals of dialysis are to normalize some electrolytes and ions such as potassium and hydrogen ions, remove uremic toxins and make the patient euvolemic by the end of the dialysis Adequate dialysis when delivered to a patient with adequate nutrition is associated with lower hospitalization rates and lower morbidity and mortality Thus for each patient, adequacy of HD is periodically assessed during a single dialysis by monitoring the delivered dose of dialysis with urea kinetic modeling; based on this, and other parameters such as lean body weight, residual renal function and dietary protein intake, dialysis can be individualized by prescribing the appropriate duration of dialysis and type of dialyzer to be used Though HD is a safe procedure, and is the most common modality of renal replacement therapy for ESRF in Asia, complications unique to the procedure occur as a result of the intensive nature of the procedure Intradialytic hypotension may occur due to absolute volume depletion, fluid shifts between extracellular and intracellular compartments and changes in osmolality or cardiac arrythmias Anaphylactoid reactions may occur due to complement activation by dialyzer membranes upon exposure to blood usually with the first use of dialyzer or due to exposure to ethylene oxide-altered proteins, when ethylene oxide has been used to sterilize the dialyzer Dialysis associated neutropenia and hypoxaemia can be related to the first use syndrome The need for anticoagulation during HD often increases the risk for bleeding Overall mortality for HD patients is dependent on age and presence of co-morbid risk factors such as diabetes and cardiovascular disease For 20- to 29-year-olds prevalent on hemodialysis in the USA in 1999, annual Management of Chronic Kidney Disease 1287 death rate was 50.7 per 1000 patient years at risk in comparison to the death rate of 224.8 per 1000 patient years for those between age 60–64 years (proportionately higher with age) These results are in contrast to the death rates of 8.3 and 61.4 per 1000 patient years, respectively, in the USA, for transplanted patients in the same age groups Five year survival for the entire cohort of patients entering a HD program between 1991 and 1995 in Singapore are comparable at 85.2% (Choong HL, personal communication) As with RTX, the leading causes of death in dialysis patients are cardiac or infectious in origin with cerebrovascular disease, malignancy and hemorrhage comprising the remainder.15 Peritoneal dialysis Peritoneal dialysis (PD) is an alternative form of dialysis in which exchange of toxins and solutes occurs between the blood and the dialysate across the peritoneal membrane lining the peritoneal cavity During the procedure, to 2.5 L of sterile peritoneal dialysate is instilled into the peritoneal cavity by gravity and allowed to dwell for a period of time Toxins diffuse from plasma to the dialysate during the dwell period and are removed with the dialysate when the dialysate is drained out of the peritoneal cavity, after which fresh dialysate is instilled into the cavity In Continuous Ambulatory Peritoneal Dialysis (CAPD), the patient manually performs the exchanges to times a day and is fully ambulant during the dwell periods In Automated Peritoneal Dialysis (APD), a machine called a cycler performs a scheduled number of exchanges during the night, freeing the patient from having to multiple exchanges during the daytime The preference for PD over HD is often based on medical and nonmedical factors Patients who prefer the convenience of a home-based dialysis procedure or those who stay far from a HD facility may opt for PD for non-medical reasons Others who are unable to tolerate HD for various reasons such as significant cardiac disease, extensive vascular disease or those in whom vascular access is problematic are, in fact, better medically suited for PD Nevertheless, there are some contraindications to PD, including the presence of either intra-abdominal adhesions that could limit dialysate flow, uncorrectable mechanical defects such as a diaphragmatic or other irreparable hernia, severe inflammatory bowel or diverticular disease The physiology of PD is not significantly different from that of HD Toxins, solutes and fluid move between the blood and dialysate through 1288 A Clinical Approach to Medicine the processes of diffusion and ultrafiltration and transport of smaller molecules is more efficient than that of larger molecules However, unlike in HD, the peritoneal membrane permits the transport of larger molecules and proteins to diffuse and lead to protein losses through the dialysate Fluid removal is achieved in PD through osmotic ultrafiltration The dialysate in PD contains the osmotically active substance, glucose, in high concentrations (1.25%, 2.5%, 4.25%); the osmotic pressure generated by the glucose then draws water from the blood across the peritoneal membrane into the dialysate, thereby effecting fluid removal Glucose absorption from the dialysate does occur and may predispose to obesity and hypertriglyceridemia in PD patients in general and increase insulin requirements in diabetic patients in particular Newer dialysates such as those containing amino acids or Icodextrins may ameliorate problems of malnutrition and inadequate ultrafiltration occurring with PD using the conventional glucose-based dialysates The apparatus for PD is simple and includes dialysate solutions, the peritoneal access catheter and a transfer set that is used to connect the access device to the peritoneal dialysate bags Peritoneal access catheters are inserted surgically into the abdomen through a subcutaneous tunnel with the catheter tip placed in the pelvis Dialysate bags are connected to the peritoneal access catheter through a special transfer set that minimizes the risk for peritonitis The transfer set currently used in Singapore uses a twin bag system, which has yielded a peritonitis rate of one episode every 38 months (Chew STH, personal communication), comparable to the peritonitis rate of in 45 months reported in other centers Adequacy of PD can be measured using urea and creatinine clearances and studies have demonstrated an association between greater urea clearance and a decreased relative risk of death Thus after initiating PD, peritoneal membrane transport characteristics and adequacy of dialysis are measured and dialysis schedules modified to individualize and optimize PD prescription Peritoneal dialysis is a simple technique that is easy to perform and has the advantages of portability, fewer dialysis-related symptoms and does not require anticoagulation However, and despite the simplicity of PD techniques, the major problem with this modality is peritonitis Peritonitis occurs generally as a result of transmigration of bacteria from the skin into the abdominal cavity and is defined as a cloudy dialysate effluent associated with a dialysate white blood cell count greater than 100/mm.3 Concomitant symptoms of abdominal pain are usually present, Management of Chronic Kidney Disease 1289 though fever is less common Though infections with the usual organisms such as Staphylococcus epidermidis or aureus usually respond to intraperitoneal antibiotics, those due to other organisms such as Pseudomonas aeruginosa, while less common, are less responsive to antibiotic therapy and may require catheter removal and even lead to peritoneal fibrosis and failure Other complications of PD are pericatheter leaks, catheter malfunction due to catheter migration or omental wrapping, hernia development and exit site infections Transfer from PD to HD may become necessary in those receiving inadequate dialysis or ultrafiltration and in those developing technical problems due to the procedure One year death rate on PD for 20–29 year olds and 60–64 year olds, prevalent on PD in USA in 1999, is reported as 56.1 and 284.0 per 1000 patient years respectively, the excess risk in comparison to HD being attributed to the higher incidence of cardiovascular deaths in the former.15 CONCLUSIONS With the increasing numbers of patients with chronic renal disease, its contemporary management has shifted from that of treatment of CRF and ESRF to its early diagnosis and retardation of progression REFERENCES K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification, Am J Kidney Dis 39 (Suppl 1):S14–S266, 2002 The Diabetes Control and Complications Trial Research Group, The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, NEJM 329:977–986, 1993 UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type diabetes, BMJ 317:703–713, 1998 Peterson JC, Adler S, Burkart JM et al., Blood pressure control, proteinuria, and the progression of renal disease: The Modification of Diet in Renal Disease Study, Ann Intern Med 123:754–762, 1995 Hansson L, Zanchett A, Carruthers SG, Bahlof B et al., Effects of intensive blood pressure lowering and low-dose aspirin in patientswith hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomized trial The HOT Study Group, Lancet 351:1755–1762, 1998 The Sixth Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure, Arch Int Med 157:2413–2416, 1997 1290 A Clinical Approach to Medicine The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC report Chobanian AV, Bakris GL, Black HR, Cushman WC et al., National Heart, Lung, and Blood Institute Joint Naitonal Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee JAMA 2003 May 21;289(19):2560–2572 Agodoa LY, Appel L, Bakris GL, Beck GJ et al., African American Study of Kidney Disease and Hypertension (AASK) Study Group Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial, JAMA 285:2719–2728, 2001 Jafar TH, Scmid CH, Landa M et al., Angiotensin-converting enzyme inhibitors and the progression of nondiabetic renal disease: a meta-analysis of patient-level data, Ann Intern Med 135:73–87, 2001 10 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy, NEJM 329:1456–1466, 1993 11 Brenner BM, Cooper ME, de Zeeuw D, Keane WF et al., The RENAAL Study Investigators Effects of losartan on renal and cardiovascular outcomes in patients with type diabetes and nephropathy, NEJM 345:861–869, 2001 12 Levey AS, Controlling the epidemic of cardiovascular disease in chronic renal disease: Where we start? Am J Kidney Dis 32(5):853–906, 1998 13 NKF DOQI Clinical Practice Guidelines, Am J Kidney Dis 30 (Suppl 2): S15–S240, 1997 14 Cecka JM, The UNOS scientific renal transplant registry, in: Cecka JM, Terasaki PI (eds.), Clinical Transplants 1999, UCLA Tissue Typing Laboratory Los Angeles, California, USA, pp 1–21, 2000 15 US Renal Data System, USRDS 2001 Annual Data Report, Atlas of End-Stage Renal Disease in the United States National Institutes of Health, National Institute of Diabetes and Diabetes and Kidney Diseases, Bethesda MD 483–507, 2001 Respiratory Medicine This page intentionally left blank 74 Approach to the Patient with Respiratory Disease Philip Eng Respiratory diseases are a major cause of morbidity and mortality all over the world In the primary care setting, upper respiratory tract infections are the most common reason why patients consult their doctors Lung cancer is the second most common type of cancer in Singapore, with dismal 5-year survival rates of 14% Pneumonia is the third most common cause of death in Singapore and is often the end result of many chronic debilitating diseases like cerebrovascular disease and cancer Principal causes of death in Singapore: 1) 2) 3) 4) 5) cancer; ischaemic heart disease; pneumonia; cerebrovascular disease; and injuries 1293 1294 A Clinical Approach to Medicine Most common Cancers in Singapore: Male 1) Lung 2) Colorectal 3) Stomach Female 1) Breast 2) Colorectal 3) Lung RAPID EVALUATION In the initial evaluation of a patient with suspected respiratory disease, a detailed history is the cornerstone The only exception is when one is dealing with a critically ill patient where rapid assessment and control of the ABCs, i.e airway, breathing and circulation, must take precedence Examples are those with problems of: • • • Airway, e.g apnea, stridor; Breathing, e.g respiratory distress due to severe pneumonia; and Circulation, e.g hypovolemic shock from bleeding, septic shock Once this is done, history taking usually involves relatives, colleagues and bystanders in this setting Clinical examination is also more complicated as there is a need to verify that all the devices e.g central venous catheters, endotracheal tube … etc are in the right place and functioning properly In this modern era where many patients seek to undergo routine health screening, one must also be mindful of the fact that there are patients who are totally asymptomatic, yet have abnormal CXR findings leading to more sinister diagnoses like lung cancer HISTORY In the history taking, certain symptoms may point to a respiratory disorder but this is not invariable The most common symptom of respiratory disease is shortness of breath or dyspnea Dyspnea that is unrelated to exertion is commonly due to asthma This symptom can be brought on by cold, emotion, stress or upper respiratory tract infections In asthma, the dyspnea is usually but not invariably accompanied by wheezing Also, the symptoms are rapidly relieved by inhaled short acting beta agonists like Salbutamol Symptoms of mild asthma may also resolve spontaneously Approach to the Patient with Respiratory Disease 1295 Dyspnea can also be due to other organ dysfunction Severe anemia, sepsis and metabolic acidosis are common non-cardio-respiratory causes of shortness of breath The more common situation, however, is to try to differentiate it from cardiac disease Cardiac dyspnea is usually due to congestive heart failure and is effort related and relieved by rest Orthopnea, paroxysmal nocturnal dyspnea and bilateral ankle edema, if present helps clinch the diagnosis Orthopnea is the sensation of shortness of breath when lying down and is a classic symptom of left ventricular failure as the venous return increases in the supine position, aggravating pulmonary congestion Paroxysmal nocturnal dyspnea is explained by the same mechanism This is not invariable as there are some reasons why respiratory patients may get short of breath in the supine position Some examples are morbid obesity, diaphragmatic paralysis and patients with severe chest wall disease, e.g kyphoscoliosis In contrast, some patients experience dyspnea when adopting the standing position (platypnea) If desaturation is documented, this is called orthodeoxia The classic cause of this is anatomical pulmonary arteriovenous malformation (ϩ/Ϫ Hereditary Hemorraghic Telangiectasia), or functional ones due to the hepatopulmonary syndrome related to liver cirrhosis Wheezing is another common symptom or sign seen in patients with respiratory disease e.g Chronic Obstructive Pulmonary Disease (COPD) and asthma It is best described as a high pitched sound best heard during expiration caused by turbulent airflow through narrowed airways Features in the history suggestive of asthma are young age (Ͻ 50), non-smoking status, past history or family history of atopy (asthma, allergic rhinitis, eczema) The patient is usually totally well between episodes As described above, the wheezing and shortness of breath in asthma is also unrelated to exertion unlike in COPD Tumors, notably carcinoid, mucoepidermoid cancer, anaphylactic reactions, tracheobronchitis, e.g due to Sarcoidosis, Wegener ’s, Tuberculosis, Aspergillus, can also cause wheezing Rarer causes of wheezing are acute pulmonary embolism and herpes simplex tracheobronchitis in those with the Acute Respiratory Distress Syndrome (ARDS) In unilateral wheezing in a child, the diagnosis of an inhaled foreign body must always be entertained Chronic cough (Ͼ months) is another classic symptom found in respiratory patients Chronic cough in patients with normal CXR is usually 1296 A Clinical Approach to Medicine due to one of the following: smoking, ACE inhibitors, cough variant asthma, post nasal drip syndrome and gastroesophageal reflux disease About 15% of patients on ACE inhibitors complain of chronic cough Chronic cough is much rarer in patients using angiotensin receptor antagonists Hemoptysis is another symptom suggestive of respiratory disease The character of hemoptysis may help differentiate the cause Pink frothy hemoptysis is suggestive of acute pulmonary edema Hemoptysis going on for years is suggestive of a long-standing process like bronchiectasis or arteriovenous malformations Massive hemoptysis is usually due to active tuberculosis, bronchiectasis or mycetoma Streaky hemoptysis of recent onset for weeks is always worrying for lung cancer, especially if it happens in a middle-aged male smoker It is important to rule out “pseudohemoptysis”, i.e bleeding that is not from the lower respiratory tract Gastrointestinal bleeding is characterized by blood mixed with food particles The acidic nature of the fluid, confirmed on litmus, points towards a gastric origin Another source for confusion is bleeding from the post-nasal space and upper airway In Singapore, one has to consider nasopharyngeal cancer, especially if there is unilateral epistaxis, decreased hearing or rhinorrhea Chest pain due to respiratory disease is extremely varied It should be noted that the lung parenchyma and the visceral pleura not have pain fibers Chest wall pain due to a fractured rib is exquisitely tender whereas that due to pleurisy varies with respiration Pleural effusion and lung cancer involving the chest wall gives a dull ache Sometimes, the chest tightness due to asthma can be mistaken for chest pain It is important also not to miss the searing pain characteristic of the initial presentation of herpes zoster of the intercostal nerves Hoarseness of voice can be due to left recurrent laryngeal nerve palsy, which is usually due to compression by aortopulmonary mediastinal lymph nodes from metastases from primary lung cancer Other causes include tuberculous lymph nodes, sarcoidosis and lymphoma Infrequently, tuberculous laryngitis can present like an acute febrile illness with prolonged hoarseness of voice Snoring is another symptom of respiratory disease, and is usually reported by the person’s spouse Accompanying daytime somnolence, headaches and nocturnal choking all help point towards obstructive sleep apnea Approach to the Patient with Respiratory Disease 1297 SMOKING HISTORY A smoking history is extremely important in the evaluation of a patient not just confined to those with respiratory disease Smokers are predisposed to develop cancers of the lung, larynx, esophagus, pancreas In addition, they are at risk for coronary artery disease, peripheral vascular disease, COPD and cerebrovascular accidents Cigar smokers are also at similar risk It is also important to realize that passive smokers are also predisposed to developing lung cancer and the data is best established in nonsmoking spouses of smokers The risk is also dose dependent, i.e it depends on the number of sticks smoked per day and the number of years smoked The new marketing strategy of the tobacco industry of “light cigarettes” with less tobacco content per stick is targeted at those who are less informed The data shows that those who use such cigarettes tend to take deeper inhalations to achieve the same “kick” The smoking prevalence in Singapore has somewhat stabilized over the past years at 15% but what is alarming is that there has been a 20-fold rise in female smokers aged 18–24 over the past 16 years from 0.4% to 8% in 2001 It is notable that in many developed countries in the world today including the US, UK, Sweden and Finland, female smoking rates are about even with male smokers and hovering at about 28% Oblivious to such is the alarming increase in smoking prevalence in Asian countries like Japan, Korea and China, which tobacco industries have now turned their attention to HIV The most common opportunistic infection in patients with the Human Immunodeficiency Virus (HIV) is oral candidiasis Indeed, in patients who are not known to be immunosuppressed by cancer or chemotherapy or prolonged antibiotics, it would be unusual to find oral candidiasis unless he is harboring the HIV virus The most common life threatening opportunistic infection in patients with the Human Immunodeficiency virus (HIV) is the Pneumocystis Carinii Pneumonia (PCP) PCP remains a relatively common index presentation in patients subsequently found to have the HIV The more common risk factors for HIV in Singapore are sexual promiscuity in heterosexuals, followed by homosexuals and intravenous drug abusers This history must be sought for in all cases who present with a community acquired pneumonia where there are risk factors for acquiring the HIV 1298 A Clinical Approach to Medicine OCCUPATIONAL HISTORY An awareness of common occupation-related disease is important for diagnosis A history of working in a sand quarry should immediately alert one to the possibility of silicosis Occupation on board a ship as an electrician should make one think of asbestos as this was a popular material for electrical insulation more than 30 years ago However, the most common cause of occupation-related lung disease today is occupational asthma The list is endless, but common ones include the use of glutareldehyde in health care workers, flour amongst bakers, soldering flux, and isocyanate A continuously updated list on the Asmanet website (http:// asmanet.com) currently includes more than 361 occupational agents shown to be involved in occupational asthma CLINICAL EXAMINATION There are few clinical signs that are specific to respiratory disease In the examination, one must be observant to the fact that many clues lie outside the chest Clubbing can be due to respiratory disease like idiopathic pulmonary fibrosis, lung cancer, bronchiectasis and other suppurative lung disease All patients with clubbing must be examined for features of hypertrophic pulmonary osteoarthropathy (HPOA) This is usually evident as tenderness over the distal end of long bones like the radius/ulna or the tibia/fibula and is usually seen on X-rays as periostitis In such patients it is mandatory to a CXR to rule out lung cancer, e.g squamous cell carcinoma Even if lung cancer is proven, evidence of HPOA is not a criteria for inoperability Other causes of clubbing include cyanotic congenital heart disease, atrial myxoma, infective endocarditis, liver cirrhosis, thyrotoxicosis, inflammatory bowel disease and congenital Cervical lymphadenopathy is another important sign as it can be a sign of metastatic lung cancer Other causes include tuberculosis, sarcoidosis, chronic lymphocyctic leukemia, lymphoma and metastatic cancer from the gastrointestinal tract (especially if the deep cervical lymph node is involved) In patients with chronic respiratory disease, one must examine and look for features of complications, i.e chronic respiratory failure, cor pulmonale, polycythemia due to chronic hypoxia and cyanosis due to Approach to the Patient with Respiratory Disease 1299 increased concentrations of reduced hemoglobin Cor pulmonale can be demonstrated by evidence of loud P2, right parasternal heave and ankle edema Evidence of chronic hypoxia include irritability and tachycardia Ventilatory failure as manifested by severe hypercapnia may result in vasodilation, bounding pulse, asterexis, and sweating Stridor is a very important sign that should never be missed It is best described as the death rattle because death is imminent unless efforts are taken to correct it immediately The best way to pick up stridor is to auscultate over the neck area and compare it with the breath sounds In true stridor, the breath sounds are decreased and there are added sounds especially during inspiration best heard over the throat Common causes are upper airway obstruction from tumors like laryngeal cancer, acute epiglottitis, laryngospasm, foreign bodies, post extubation glottic edema, tracheal strictures, bilateral vocal cord paralysis and neuromuscular dysfunction Breath sounds are important as they are a clue to the function of the respiratory system Expiratory phase can be prolonged in those with obstructive airway disease Diminished breath sounds are a clue to very severe obstruction Crepitations or rales or crackles on auscultation indicate that there is fluid in the alveoli, usually due to acute pulmonary edema or pneumonia Occasionally these disappear when the maneuver is repeated after coughing, indicative of minor atelectasis Basal crepitations, which sound like “velcroe”, are indicative of idiopathic pulmonary fibrosis It is important to differentiate crepitations from pleural rub as the latter is heard both during inspiration and expiration Pleural rub is a sign of pleural inflammation, often seen in parapneumonic effusions Percussion is an important part of the physical examination of the respiratory system Abnormal unilateral resonance is commonly found in pneumothorax whereas bilateral hyperresonance is found in COPD Dullness is found in underlying consolidation, atelectasis and pleural effusion although it is classically stony dull in the latter RADIOGRAPHIC DIAGNOSIS In the approach to the patient with respiratory disease, a standard PA CXR is the most important investigation Clinical diagnostic algorithms emanate from pattern recognition of the most obvious CXR abnormality In the evaluation of patients with abnormal mediastinal masses, the clue lies in the localization of the mass except in the case of lymphomas 1300 A Clinical Approach to Medicine and aortic aneurysm, which can occur anywhere in the mediastinum Superior mediastinal masses are usually due to retrosternal thyroid goiters and thymomas whereas anterior mediastinal masses are usually due to teratomas, thyroid goitres and thymomas Middle mediastinal masses are usually either bronchogenic cysts, pericardial cysts, pericardial fat and hiatus hernia Posterior mediastinal masses are usually either diaphragmatic hernia and neurogenic tumors In the evaluation of patients with lung infiltrates , the most important step is to determine the distribution as upper lobe infiltrates are usually due to silicosis, tuberculosis, ankylosing spondylitis, histiocytosis X and aspergillosis Lower lobe infiltrates are commonly due to idiopathic pulmonary fibrosis, asbestosis, bronchiectasis and aspiration pneumonia Causes of diffuse miliary nodules (Ͻ mm) include miliary tuberculosis, disseminated histoplasmosis, previous Varicella pneumonia, silicosis, and pulmonary alveolar microlithiasis If the pattern is that of diffuse nodules (up to cm) , then others like disseminated adenocarcinoma, septic infarcts due to bacteremia and sarcoidosis enter into the differential diagnoses The pattern of metastatic carcinoma is usually that of diffuse nodules, especially in the peripheries and bases of varying sizes compared to septic infarcts where the nodules tend to be more similar sized Bilateral hilar adenopathy is usually due to sarcoidosis, silicosis and lymphoma In silicosis, the pattern is classically that of eggshell calcification with upper lobe fibrosis In the approach to a slowly resolving/non-resolving pneumonia, one must always think of aspiration, bronchoalveolar cell carcinoma, obstructed bronchus (due to tumor or foreign body), mechanical complications e.g empyema or lung abscess, inappropriate antibiotics, e.g tuberculosis or multi-resistant organisms, e.g Burkholderia pseudomallei, penicillin resistant streptococcal pneumonia REFERENCES Global Initiative for Asthma, Global strategy for Asthma Management and Prevention, National Institutes of Health, 2002 Cancer Incidence in Singapore 1993–1997, Singapore Cancer Registry, 2000 Hospital Statistics, Ministry of Health 2001, www.moh.gov.sg 75 Asthma Tan Keng Leong EPIDEMIOLOGY Asthma is a common disorder that is encountered in clinical practice Worldwide, epidemiological studies in both children and adults suggest that asthma is largely under-diagnosed and consequently, under-treated In Singapore in the year 2000, bronchitis, emphysema and asthma as a group accounted for 0.7% of total deaths and was the 9th principal cause of death Although rising trends in mortality from asthma in the 1970’s and/or 1980’s have been reported in a number of countries, including Hong Kong, New Zealand, England and Wales, France, Italy and the United States, there was no evidence of a temporal increase in asthma mortality from 1976 to 1995 among adults in Singapore The local prevalence rate of adult asthma based on a cross-sectional population-based sample study in 1992 was 2.4% in men and 2.0% in women Marked ethnic differences exist, with Malays and Indians having higher asthma mortality and morbidity rates than Chinese in Singapore Data from local prevalence studies indicate that the proportion of children under 14 years diagnosed with asthma have increased from 5% in 1967 to 20% in 1994 1301 1302 A Clinical Approach to Medicine DEFINITION Asthma is defined as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night and in the early morning These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment Airflow inflammation produces four forms of airflow limitation: acute bronchoconstriction, swelling of the airway wall, chronic mucus plug formation, and airway remodeling CLINICO-PATHOLOGIC FEATURES OF ASTHMA The classic triad of symptoms associated with asthma consists of cough, dyspnea and wheezing However, it is not unusual for one or more of these typical symptoms to be absent, or for asthmatics to present with other symptoms such as chest tightness, chest discomfort, phlegm production or hyperventilation syndrome Similar respiratory symptoms may also be seen in various other disorders including left ventricular failure, bronchiectasis and chronic obstructive pulmonary disease Asthma may present as chronic cough, especially at night, with exercise or with viral illness Dyspnea and/or wheezing are the common symptoms of airflow obstruction Eliciting the nature of the dyspnea may aid in differential diagnosis In non-asthmatic chronic airflow limitation, the dyspnea is usually chronic and progressive Episodic dyspnea or cough, on the other hand, is more typical of asthma Variable airflow obstruction and airway hyperreactivity are typical of asthma Asthma is a chronic inflammatory disorder of the airways with recurrent exacerbations Symptoms may be precipitated or aggravated by upper respiratory tract infections, inhalant allergens, cigarette smoke, exercise, occupational exposure to triggers, drugs (e.g aspirin, Asthma 1303 non-steroidal anti-inflammatory drugs) and pets Exposure to allergens and respiratory (viral) infections are the main factors responsible for causing exacerbations of asthma and/or the persistence of symptoms Inflammation, airway remodeling and altered neural control of the airways are responsible for both recurrent exacerbations of asthma and more permanent airflow obstruction During an exacerbation of asthma, contraction of airway smooth muscle, edema, and hypersecretion tend to close the smaller (noncartilaginous) airways To compensate, the patient breathes at a higher lung volume to increase outward retraction of the airways, thereby helping to maintain their patency The more severe the airflow limitation, the higher the lung volume must be to keep the airways open The combination of hyperinflation and advanced airflow limitation in an asthma exacerbation also increases the work of breathing Bronchial biopsy specimens in patients with mild asthma reveal significant collagen deposition beneath the epithelial basement membrane, in addition to the inflammation The presence of the subepithelial basement membrane fibrosis suggest that progressive airway fibrosis may ensue in long-standing asthma, especially when anti-inflammatory therapy is inadequate Long-standing asthma may progress to chronic airflow limitation The physical examination of the respiratory system may be normal as the airway obstruction in asthma is variable and often reversible either spontaneously or with treatment The clinical findings of widespread wheezing are characteristic of asthma although they are not specific for the diagnosis Wheezing may be absent in severe asthma exacerbations Physical signs, which may be present during an exacerbation of asthma, include tachypnea, difficulty speaking, reduced ribcage expansion and hyperresonance, activity of accessory muscles, pulsus paradoxus, drowsiness and central cyanosis With worsening airflow obstruction, hyperinflation results in the loss of cardiac dullness and increase in the anteroposterior diameter of the chest Among the common obstructive pulmonary disorders, there exist some similarities in their pathophysiologic features and clinical presentations Overlap among these disorders is common The importance of differentiating asthma, emphysema and chronic bronchitis lies in the different approaches to treatment and prevention, particularly in light of the major advances in the last decade and differences in prognosis 1304 A Clinical Approach to Medicine DIAGNOSIS The diagnosis of asthma is based on appropriate clinical history and evidence of reversible airflow obstruction To establish a diagnosis of asthma, the clinician should determine that episodic symptoms of airflow obstruction are present, airflow obstruction is at least partially reversible and alternative diagnoses are excluded A clinical diagnosis of asthma is often prompted by compatible symptoms such as episodic dyspnea, wheezing and chest tightness Favorable symptomatic response to bronchodilator therapy, seasonal variability of symptoms, nocturnal symptoms, exacerbation of symptoms on exposure to stimuli such as aeroallergens, exercise, cold air, air pollutants, upper respiratory tract infection, or strong odours, a positive family history of asthma and a personal or family history of atopic diseases aid in supporting the diagnosis A detailed past and present occupational history is essential in the evaluation of individuals exposed to occupational agents known to cause asthma The diagnosis of asthma is established by demonstrating reversible airway obstruction Variability greater than 20% in serial FEV1 or peak expiratory flow (PEF) suggests the diagnosis of asthma DIFFERENTIAL DIAGNOSIS In the evaluation of a patient with new-onset asthma, particular attention should be paid to atypical presenting features such as hemoptysis, weight loss, clubbing or airflow obstruction that does not reverse with bronchodilators Atypical presenting features should prompt consideration of alternative diagnoses In children, foreign body aspiration and viral bronchiolitis may mimic asthma Upper airway obstruction by tumour or laryngeal edema, bronchiectasis and pulmonary embolism can occasionally be confused with asthma Transmission of expiratory wheezing from the upper airway can mimic asthma on auscultation of the chest Clinical differentiation between upper and lower airway obstruction may sometimes be difficult In upper airway obstruction, the clinical clue is maximal wheezing over the laryngeal (neck) area Persistent wheezing localized to one area of the chest raises the suspicion of endobronchial disease such as Asthma 1305 tumor, foreign body aspiration or stricture Vocal cord dysfunction, a condition due to functional (non-organic) causes can also masquerade as asthma The condition is characterized by paradoxical adduction of the vocal cords during inspiration and definitive diagnosis is established by visualization of the vocal cords by laryngoscopy during an attack Late-onset asthma occurring in association with vasculitis and marked eosinophilia should raise the possibility of the diagnosis of Churg–Strauss syndrome In travelers to and foreign workers from filarial endemic areas who present with paroxysmal cough and wheezing worse at night, low-grade fever and eosinophilia, the diagnosis of tropical pulmonary eosinophilia should be considered Asthma is prevalent in all age-groups while in general, chronic obstructive pulmonary disease (COPD) is a disease of older patients COPD (that is not secondary to congenital alpha1-antitrypsin deficiency) commonly presents in the 5th decade of life In the older-aged patients, COPD and heart failure should be considered in the differential diagnosis Smoking history is valuable in distinguishing non-asthmatic from predominantly asthmatic obstruction In symptomatic COPD, there is usually a history of at least 20 pack-years of cigarette smoking PULMONARY FUNCTION TESTS In patients with suspected airflow obstruction, pulmonary function tests are essential for the diagnosis, assessment of severity of disease and monitoring of response to treatment Although asthma can often be diagnosed on the basis of symptoms, measurements of lung function, especially the reversibility of lung function abnormalities, greatly enhance the diagnostic confidence Spirometry is helpful in the diagnosis of asthma, the assessment of its severity and in the monitoring of the progression of asthma and response to therapeutic intervention Spirometry, unlike peak flow measurement, differentiates the physiologic pattern of airflow obstruction from pulmonary restriction A reduction in the ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (VC) from the predicted range is diagnostic of airflow obstruction The severity of airflow obstruction is classified on the basis of FEV1, expressed as a percent of predicted values An increase in FEV1 of at least 200 mL and 12% after bronchodilator administration indicate bronchial reversibility At least a 12% improvement in FEV1 1306 A Clinical Approach to Medicine either spontaneously, after inhalation of bronchodilator, or in response to a trial of glucocorticosteroid therapy, favors a diagnosis of asthma Bronchoprovocation testing is another strategy for diagnosing asthma in patients with normal lung function The provocative stimuli used include inhaled methacholine, exercise, inhaled histamine and hyperventilation of cold and dry air While a positive test result (indicating bronchial hyper-responsiveness) is not entirely specific for asthma, a negative bronchoprovocation challenge has a very high negative predictive value in excluding asthma In primary health care settings, peak expiratory flow (PEF) meters are relatively inexpensive and may be helpful in the diagnosis of asthma A 15% or greater improvement in PEF following inhalation of bronchodilator or in response to a trial of corticosteroid therapy is supportive of the diagnosis of asthma A diurnal variation in PEF of more than 20% is diagnostic of asthma However, in mild intermittent asthma or in severe asthma, the variability in PEF may not be present CHEST RADIOGRAPH The chest radiograph is usually normal in patients with asthma The chest radiographic features of airway obstruction include hyperinflation manifesting as depression and flattening of the diaphragm on the posteroanterior film and increase in the retrosternal airspace on the lateral chest radiograph In patients presenting with clinical features suggestive of new-onset asthma, chest radiograph is valuable in excluding alternative diagnosis OTHER TESTS An elevated eosinophil count and serum immunoglobulin E (Ig E) may indicate the presence of atopy However, markedly elevated eosinophil percentages (Ͼ 15%) should prompt consideration of alternate diagnosis such as drug reactions, parasitic infections, and syndromes of pulmonary infiltrates with eosinophilia High Ig E levels (Ͼ 1000 ng/mL) in association with asthma and central bronchiectasis suggests the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) Measurements of the allergic status (e.g skin prick test or specific Ig E in serum) aid in the identification of risk factors so that appropriate environmental control measures and allergen avoidance measures can be recommended Asthma 1307 TREATMENT Under diagnosis and under treatment are major contributors to asthma morbidity and mortality Long-term preventive treatment is the cornerstone of good asthma control Patient education is an essential part of the overall management of asthma The goals of management in asthma are to achieve and maintain control of symptoms, prevent asthma exacerbations, maintain pulmonary function as near to normal levels as possible, maintain normal activity levels (including exercise), provide optimal pharmacotherapy with minimal or no adverse effects, prevent the development of irreversible airflow limitation and prevent asthma mortality Asthma severity is classified by the presence of clinical features prior to commencing treatment and/or by the amount of daily medication needed for optimal control (Table 1) The severity of asthma is subdivided into four steps: Intermittent, Mild persistent, Moderate persistent and Severe persistent Short-acting inhaled beta2-agonists taken as needed to treat symptoms (reliever medication) are usually sufficient therapy for intermittent asthma Persistent asthma, either mild, moderate, or severe, is controlled with daily anti-inflammatory therapy (preventer medication) Inhaled corticosteroids are the most potent inhaled anti-inflammatory agent currently available Inhaled corticosteroids should be given to patients with persistent asthma (i.e needing reliever medication one or more times a week) In patients with persistent asthma, inhaled corticosteroids have been shown to improve asthma control and reduce mortality from asthma Early intervention with inhaled corticosteroids can improve asthma control and normalize lung function, and may prevent irreversible airway injury A stepwise approach to pharmacologic therapy is recommended Pharmacologic therapy is usually initiated at a higher level at the onset to establish prompt control and then stepping down Response to therapy is monitored clinically and with serial measurements of lung function (spirometry or peak expiratory flow) If control is sustained for at least months, a gradual stepwise reduction in treatment may be attempted to identify the minimum therapy required to maintain control Discontinuation of long-term preventive treatment with inhaled steroids should be attempted with great caution After stopping inhaled steroids, patients are at an increased risk of severe 1308 A Clinical Approach to Medicine Table Classification of Asthma Severity by Clinical Features and Current Daily Medication Current Treatment Step Step 1: Intermittent Clinical features on current therapy Step 2: Mild Persistent Step 3: Moderate Persistent Level of severity Step 1: Intermittent Symptoms Ͻ once a week Brief exacerbations Nocturnal symptoms not Ͼ 2x a month Normal lung function Intermittent Mild persistent Moderate persistent Step 2: Mild persistent Symptoms Ͼ once a week but Ͻ once a day Nocturnal symptoms Ͼ twice a month but Ͻ once a week Normal lung function Mild persistent Moderate persistent Severe persistent Step 3: Moderate persistent Symptoms daily Exacerbations affect activity and sleep Nocturnal symptoms Ͼ once a week 60% Ͻ FEV1 Ͻ 80% predicted 60% Ͻ PEF Ͻ 80% of personal best Moderate persistent Severe persistent Severe persistent Step 4: Severe Severe persistent persistent Symptoms daily Frequent exacerbations Frequent nocturnal symptoms FEV1 Ͻ 60% predicted PEF Ͻ 60% of personal best Severe persistent Severe persistent Asthma 1309 asthma and fatal asthma relapse If control is not achieved, prior to stepping up drug therapy, it is important to review patient’s inhaler technique, compliance and environmental control such as avoidance of allergens or other trigger factors Short-acting inhaled beta2-agonists taken as needed are used in the treatment of acute asthma symptoms and exacerbations and in the prevention of exercise-induced bronchospasm Increasing use of short-acting beta2-agonists for acute asthma symptoms indicates inadequate control of asthma and the need for increasing anti-inflammatory therapy Regularly scheduled, daily use of short-acting beta2-agonist is not recommended Increasing use of beta2-agonist has been associated with increased risk for death or near-death in patients with asthma Nocturnal symptoms may be controlled with long-acting inhaled beta2-agonist or sustained-release theophylline In persistent asthma, the addition of a long-acting inhaled beta2-agonist to inhaled steroids results in better asthma control and reduction in severe exacerbations when compared with doubling the dose of inhaled steroids In asthmatics with symptoms not controlled with 400–800 mcg of inhaled budesonide or equivalent, long-acting inhaled beta2-agonist may be added Alternatives to longacting inhaled beta2-agonist for add-on treatment to inhaled steroids in persistent asthma include oral sustained release-theophylline, leukotriene modifier, or long-acting oral beta2-agonist Management of acute asthma exacerbations includes inhaled beta2agonist to provide prompt relief of airflow obstruction, increasing the dose of inhaled corticosteroids, initiating systemic corticosteroids for moderateto-severe exacerbations to suppress and reverse airway inflammation and oxygen to relieve hypoxemia The management of acute asthma in the hospital setting is outlined in Fig Addition of ipratropium to an aerosolized solution of beta2-agonist in adults has been shown to cause additional bronchodilatation, particularly in those with severe airflow obstruction and to reduce hospitalizations Asthmatics, particularly those with moderateto-severe persistent asthma and those with a history of severe exacerbation, should be provided with a written action plan to guide self-management during acute asthma excerbations Asthma self-management plans are costeffective and have been shown to lead to significant reductions in morbidity and patients’ need for medical services Self-management plans based on either peak flow or symptoms are of similar efficacy Patient education should aim to improve understanding, compliance, skills and self-management Review of patient technique in using 1310 A Clinical Approach to Medicine Initial Assessment History, physical examination Oxygen saturation, PEF, ABG Other tests as indicated Initial Treatment Continuous inhaled short-acting beta2-agonist by nebulization (e.g Salbutamol 5mg every 20 minutes for 1hour) Oxygen (keep oxygen saturation 90%) Systemic corticosteroids (e.g prednisolone 40mg immediately and for 7–10 days) Repeat Assessment Symptoms, physical examination, oxygen saturation, PEF Other tests as indicated Moderate Episode Moderate symptoms, accesory muscle use PEF 60%–80% predicted /personal best Inhaled beta2-agonist and inhaled anticholinergic hourly Consider glucocorticosteroids Good Response Response sustained 60 minutes after last treatment Normal physical examination PEF >70% No distress Oxygen saturation >90% Severe Episode Severe symptoms at rest, chest retraction PEF < 60% predicted/personal best No improvement after initial treatment Inhaled beta2-agonist and inhaled anticholinergic oxygen Systemic glucocorticosteroids Consider s/c, i/m or i/v beta2-agonist Consider i/v methylxanthines Consider i/v magnesium Incomplete Response History of high risk patient Mild to moderate symptoms PEF 45 mmHg pO2 < 60 mmHg Admit to Intensive Care Consider intubation and mechanical ventilation deteriorate Fig Management of acute asthma in hospital medications and drug delivery devices is mandatory Patients should also be advised to avoid or control allergens, irritants or other factors that worsen their asthma Rhinitis, sinusitis and gastroesophageal reflux should be treated when present Annual influenza vaccinations are recommended for patients with persistent asthma Asthma 1311 OCCUPATIONAL ASTHMA Occupational asthma is defined as a disease characterized by variable airflow limitation and/or airway hyper-responsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace The term “work-related asthma” has been used for cases of pre-existing asthma, which are aggravated by the working environment Two types of occupational asthma are distinguished by whether they appear after a latency period Sensitizer-induced asthma is characterized by a variable time during which “sensitization” to an agent present in the worksite takes place Irritant-induced asthma occurs without a latent period after substantial exposure to an irritating dust, mist, vapour or fume Reactive airways dysfunction syndrome (RADS) is a term used by some to describe irritant-induced asthma caused by short-term, highintensity exposure Occupational asthma is the most common occupational respiratory disease in Singapore In Singapore, occupational asthma is a legally notifiable industrial disease under the Factories Act and a compensable occupational disease under the Workmen’s Compensation Act It is a condition associated with disability in the workplace and may still be largely under-reported More than 250 agents capable of causing occupational asthma have been reported Substances that cause occupational asthma are classified either as high molecular weight allergens or low molecular weight compounds High molecular weight agents that cause occupational asthma include laboratory animal allergens, flour, detergent enzymes and fish and seafood protein Examples of low molecular weight agents include acid anhydrides, metals, isocyanates, western red cedar, amines, colophony and antibiotics The most common causative agent in Singapore is isocyanates Other common causative agents include solder flux, welding fumes and wood dust A detailed occupational history and a knowledge of the common causative agents and association with various occupations and industries are helpful in identifying possible causative agents Work-relatedness may be suspected based on the history demonstrating improvement when away from work and onset of symptoms during working periods The diagnosis of occupational asthma is established by demonstrating the presence of asthma, relationship between the asthma symptoms 1312 A Clinical Approach to Medicine PEFR (L/min) and work, and exposure to a specific causative agent Serial peak expiratory flow rate monitoring during periods at work and away from work is a useful tool in documenting work-relatedness and has been found to be both sensitive (86%) and specific (89%) for the diagnosis of occupational asthma (Fig 2) The gold standard for the diagnosis of occupational asthma is a positive specific bronchial provocation test to the causative agent It may not be necessary to require a specific bronchial provocation test to diagnose or confirm every case of occupational asthma Besides the time and expense that is required from the patient and the investigating doctor, there are risks involved as well Indications for specific bronchial provocation testing include: 1) to document new causative agents; 2) to distinguish between multiple known agents; and 3) to provide objective evidence in a difficult case or where it is not possible to a serial peak expiratory flow rate monitoring (e.g in a patient who has already left employment) It has been recommended that all workers confirmed to have occupational asthma be permanently transferred to a job with totally no exposure to the causative agent It may also be possible to substitute the offending agent with a safer one Improved local exhaust ventilation and enclosure of specific processes may also be helpful With irritant-induced asthma, the use of personal protective equipment may lower exposures to levels that not induce bronchospasm With sensitizer-induced asthma, however, the worker should be precluded from further exposure to the sensitizing agent It may be necessary to completely remove the worker from 450 400 350 300 250 200 150 100 50 maximum mean minimum At work Off-work At work 13 10 16 19 days 22 25 28 31 34 Fig Serial peak expiratory flow rate (PEFR) monitoring in a worker with occupational asthma Note the PEFR improvement at home and deterioration at work Asthma 1313 the workplace because even exposure to minute quantities of the offending agent may induce bronchospasm Prevention of additional cases of occupational asthma should be considered in all work places in which cases are diagnosed Protection of workers by the use of appropriate ventilation systems, respiratory protective equipment, and education about appropriate procedures should be recommended REFERENCES Ng TP, Adult asthma prevalence, morbidity and mortality and their relationships with environmental and medical care factors in Singapore, Asian Pac J Allergy I 17:127–135, 1999 National Asthma Education Program Expert Panel Report Guidelines for the diagnosis and management of asthma, Office of Prevention, Education and Control, National Heart, Lung and Blood Institute, National Institutes of Health, US Dept of Health and Human Services, Public Health Service, Bethesda, NIH Publication No 97–4051, 1997 Global initiative for asthma, Global strategy for asthma management and prevention National Institutes of Health National Heart, Lung and Blood Institute, 2000 Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI, Asthma in the workplace, Marcel Dekker Inc., New York, 1993 Chan-Yeung M, Assessment of asthma in the workplace, Chest 108:1084–1117, 1995 Lee HS, Chee CB, Clinical update on occupational asthma, Ann Acad Med Singapore 30:546–550, 2001 Kor AC, Lee HS, Chee CB, Wang YT, Occupational asthma in Singapore, Singapore Med J 42:373–377, 2001 This page intentionally left blank 76 Chronic Obstructive Pulmonary Disease Loo Chian Min INTRODUCTION Chronic bronchitis and emphysema are two distinct diseases characterized by chronic airflow limitation They are often present in combination and are collectively termed as chronic obstructive pulmonary disease (COPD) COPD is one of the leading causes of death worldwide, ranking fourth or fifth in developed countries It has been increasing in prevalence and mortality, and is projected to be the third leading cause of death worldwide by 2020 In Singapore, bronchitis, emphysema and asthma as a group account for 0.8% of total deaths and is the eighth principal cause of death Although there are similarities between COPD and asthma, it is important to differentiate them as treatment and prognosis differ DEFINITION COPD is a disease state characterized by airflow limitation that is not fully reversible Airflow limitation is usually progressive and associated 1315 1316 A Clinical Approach to Medicine with an abnormal inflammatory response of the lungs to noxious particles or gases Chronic bronchitis is defined clinically as the presence of a chronic productive cough on most days, for a minimum of months, for at least consecutive years, in a patient in whom other causes of chronic cough have been excluded Emphysema is defined anatomically as abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis Airway obstruction due to other specific etiologies, like bronchiectasis and obliterative bronchiolitis, is not classified as COPD Figure shows the relationship between emphysema, chronic bronchitis and asthma It may sometimes be difficult to differentiate asthmatics with partially reversible airway obstruction from COPD with airway hyperreactivity This group of patients is sometimes classified as COPD Fig Venn diagram showing the relationship between emphysema, chronic bronchitis and asthma It is possible for asthma, chronic bronchitis or emphysema to have no airway obstruction There is a subset of asthma that is difficult to differentiate from COPD and is sometimes classified as COPD (see text) COPD 1317 Table Risk Factors for COPD Host factors Genes e.g alpha-1 anti-trypsin deficiency Airway hyper-responsiveness Lung growth Environmental factors Tobacco smoke Occupational dust and chemicals e.g coal Air pollution Socioeconomic status Infections RISK FACTORS Evidence concerning risk factors for COPD came from epidemiological studies that identified associations rather than cause-effect relationship As such, much is still unknown regarding risk factors and development of COPD Table shows the risk factors for developing COPD Tobacco smoke is by far the most important risk factor for developing COPD In fact, diagnosis needs to be carefully considered in a nonsmoker who has been labelled with COPD However, not every smoker will develop COPD It is believed that genetic predisposition is important for the development of COPD Alpha1 anti-trypsin deficiency a well studied gene abnormality that causes emphysema Other candidate genes like gluthatione S-transferase P1, micosomal epoxide hydrolase, tumor necrosis factor ␣ are still under investigation Occupations like coal and gold miners and farmers have been shown to be associated with higher risk of developing COPD The exact role of air pollution, airway hyperresponsiveness, socioeconomic status and infection is still unclear PATHOGENESIS The pathogenesis of COPD is still not fully understood Data are mainly obtained from animal models and in vitro studies Three mechanisms are thought to be important in the pathogenesis of COPD: 1) airway inflammation; 2) imbalance of proteinases and anti-proteinases in the lung; and 3) oxidative stress Noxious gases and particles are thought to cause lung inflammation There is increased production of proteinases as well as oxidative injury 1318 A Clinical Approach to Medicine These are normally counteracted by anti-oxidants and antiproteinases However, there seems to be an imbalance in these counter mechanisms in some patients If repeated damage cannot be adequately repaired by the body, chronic bronchitis or emphysema may develop This is indeed simplified as the actual mechanism is complex and there is a lot of interplay between the different mechanisms How other environmental and host factors affect the pathogenesis is unclear The main inflammatory cells that are found in airways of COPD are CD8 T lymphocytes, macrophages and neutrophils, producing mediators like interleukin 8, tumor necrosis factor-␣, leukotriene B4, etc In contrast, the inflammatory cells (eosinophils, CD4 T lymphocytes, activation of mast cells) found in asthma are different from that of COPD It is because of different inflammatory response that occurs in these conditions The best example of proteinase-anti-proteinase imbalance is that of ␣-1 anti-trypsin deficiency In this genetic disorder (rare in Singapore), ␣-1 anti-trypsin, which inhibits a number of proteinases like neutrophil elastase, is deficient As a result, these individuals are at higher risk of developing emphysema There is data to suggest that imbalance in these enzymes may either be due to over production of proteinases or under production of anti-proteinases There is now evidence to suggest that oxidative stress is important in the development of COPD There is overproduction of oxidants with respect to anti-oxidants Markers of oxidative stress like nitric oxide (NO) and hydrogen peroxide are found to be increased in breaths of COPD patients PATHOPHYSIOLOGY AND CLINICAL CORRELATION The pathological changes in COPD are correlated with the physiological abnormalities and clinical features Physiological abnormalities usually develop in the following order: • • • • • • • mucous hypersecretion; ciliary dysfunction; airflow limitation; lung hyperinflation; gas exchange abnormalities; pulmonary hypertension; and cor pulmonale COPD 1319 Chronic inflammation leads to goblet cell hyperplasia, which causes increased mucous production Chronic inflammation also causes squamous metaplasia that leads to ciliary dysfunction At this early stage of disease, patient may only have cough and increased sputum production Irreversible narrowing of peripheral airways (small bronchi and bronchioles) occurs in COPD due to remodeling (fibrosis and narrowing) This is the main cause of airflow limitation in COPD Two other causes are loss of elastic recoil of the lung and small airway collapse The former is due to parenchymal destruction; the reduced elastic recoil reduces the driving pressure in the alveoli during expiration Small airways collapse when their alveolar attachment and support are lost, causing early airway closure during expiration Hyperinflation of the lungs occurs due to inadequate emptying As airway obstruction worsens, patient will begin to experience increasing dyspnea Reversible airway obstruction may be contributed by smooth muscle contraction and airway inflammation As not every part of the lung is equally affected, the distribution of ventilation and perfusion will be heterogeneous Ventilation-perfusion mismatch will then occur, contributing to gas exchange abnormalities As more alveoli and interstitium are destroyed, there will be a loss of vascular bed and reduced surface area for gas exchange These also contribute to gas exchange abnormalities in later stages of COPD Eventually pulmonary hypertension develops secondary to chronic hypoxia and loss of vascular bed Cor pulmonale occurs when there is right heart failure secondary to pulmonary hypertension, with the patient experiencing fluid retention CLINICAL FEATURES The cardinal feature of COPD is dyspnea This is the first presentation in most COPD patients In contrast to asthma where dyspnea is episodic, COPD tends to have progressive dyspnea with periods of exacerbation Exertional dyspnea is a common complaint and usually begins when a patient is in his sixties This may be present for many years before the patient seeks medical attention In the early stage, patient often notices dyspnea only on strenuous activities It may be the only symptom in early COPD This gradually progresses with time and eventually dyspnea is noticeable even with minimal exertions In late stages, dyspnea may be present at rest, with severe limitation of activities Wheeze may be 1320 A Clinical Approach to Medicine noticed by patients and may be present in the absence of acute exacerbation This can be confused with asthma Cough productive of mucoid sputum are frequent associations However, purulent sputum should alert the doctor to possible concomitant respiratory infection Orthopnea, paroxysmal nocturnal dyspnea and leg swelling are non-specific symptoms The first symptoms could occur in later stages of COPD All the symptoms could also be present in cor pulmonale secondary to pulmonary hypertension or concomitant coronary heart disease with congestive cardiac failure Weight loss and poor appetite are also common in the late stages of COPD A history of tobacco abuse is present in most patients with COPD One has to be careful in diagnosing COPD in a person without a smoking history Other causes of COPD, e.g occupational exposure, should also be sought for In earlier stages, physical examination may be unremarkable Nicotine stains of the finger nails may be present as clues to tobacco abuse In later stages, hyperinflation of the chest wall may be present with use of accessory muscles of respiration Purse lip breathing, retraction of intercostal muscles and paradoxical abdominal movement may be present during respiratory distress Cyanosis may be seen in severe hypoxemia Asterixis can be present in those with respiratory failure Bounding pulse and conjunctival hyperemia are signs of carbon dioxide retention There will be raised jugular venous pressure and ankle edema in patients with cor pulmonale However, ascites and anarsarca are relatively uncommon Percussion of the lungs will show increased resonance due to air trapping and hyperinflation Lung auscultation frequently just reveals decreased breath sounds with prolonged expiratory phase Rhonchi may be heard in some patients, especially during an acute exacerbation Loud pulmonary second sound may be present on cardiac auscultation in patients with pulmonary hypertension and heart sounds are frequently distant INVESTIGATIONS Pulmonary Function Studies Spirometry is central in the diagnosis, severity grading and follow-up of COPD All suspected COPD patients should have spirometry performed to confirm airflow limitation An obstructive pattern as demonstrated by reduced FEV1 / FVC with varying decrease of FEV1 is expected FEV1 is easily performed, has less variability and has more accurately predictable COPD 1321 Table NHLBI/WHO Classification of Severity of COPD Stage Characteristics 0: At risk Normal spirometry Chronic symptoms: cough, sputum 1: Mild COPD FEV1 / FVC Ͻ 70% FEV1 у 80% predicted ϮChronic symptoms 2: Moderate COPD FEV1 / FVC Ͻ 70% 30% р FEV1 Ͻ 80% predicted 2a: 50% р FEV1 Ͻ 80% predicted 2b: 30% р FEV1 Ͻ 50% predicted ϮChronic symptoms 3: Severe COPD FEV1 / FVC Ͻ 70% FEV1 Ͻ 30% predicted, or, FEV1 Ͻ 50% predicted ϩ respiratory failure or cor pulmonale normal values that other parameters of airway dynamics like peak flow or airway resistance Bronchodilator challenge should also be performed to assess for airflow reversibility which occurs in asthma but not in COPD A change in FEV1 of 12% and 200 ml is significant by American Thoracic Society (ATS) criteria FEV1 has been shown to correlate with mortality from COPD in previous studies Table shows a classification of severity of COPD adopted by NHLBI/WHO Total lung capacity (TLC) is increased in COPD consistent with hyperinflation Residual capacity (RV) and RV/TLC ratio are both increased, demonstrating air-trapping in this disease Diffusing capacity is reduced in more severe emphysema due to interstitial destruction and loss of alveolar capillaries Chest Radiograph A chest radiograph should be performed in the initial assessment of a new undiagnosed COPD patient or in an existing COPD patient with acute respiratory symptoms In frontal and lateral chest radiographs, features of hyperinflation like low flattened diaphragm, increased retrosternal airspace and a long narrow heart can be seen Hyperlucent lungs with reduced vascular shadowing and hyperinflation are features of emphysema Bullae may be seen and represents local disease In pulmonary hypertension, prominent hilar vascular shadows may be present 1322 A Clinical Approach to Medicine CT Thorax CT thorax has no role in the routine management of COPD Arterial Blood Gas Measurements Arterial blood gas (ABG) results may be normal in early stages of COPD As the disease progresses, worsening hypoxemia occurs This is later followed by hypercapnia and compensatory metabolic alkalosis Blood gas abnormalities can also occur during acute exacerbations NATURAL HISTORY AND PROGNOSIS OF COPD The natural history of COPD is well-studied It is generally slowly progressive, with many patients remaining asymptomatic for many years Symptoms usually begin when patients are in their fifties or sixties The exception to this is ␣1 antitrypsin deficiency, where emphysema occurs 10–20 years earlier The following factors have been shown to be associated with poorer prognosis: • • • • • • advanced age; low FEV1; tobacco smoking; hypoxemia; hypercapnia; and pulmonary hypertension or cor pulmonale Studies have differing survival rates and this is related to patient selection criteria MANAGEMENT Acute Exacerbation Acute exacerbation is suspected when symptoms like dyspnea, cough and sputum are increased In the assessment of COPD exacerbation, it is important to try to identify and correct precipitating factors: • • • • infection; cigarette smoking; air pollution; and allergen exposure COPD 1323 However, a precipitating factor may not be found in up to one-third of patients Also, one must not forget that other concomitant medical conditions like heart failure, pneumonia, pneumothorax, pulmonary embolism, etc may mimic a COPD exacerbation In the assessment of an acute exacerbation, it is very important to ascertain the baseline functional status, arterial blood gas and spirometry measurements They form the basis for comparison and are important for subsequent management of the patient Table gives a summary of the history, physical findings and investigations of patient with acute COPD exacerbation There is increase in breathlessness that is frequently accompanied by more cough and sputum Fever and purulent sputum indicate an infective exacerbation Wheeze may not always be present Other associated symptoms include poor appetite, reduced exercise tolerance and malaise Drowsiness may indicate acute carbon dioxide retention Physical examination frequently shows tachypnea and use of accessory muscles of respiration Fever and wheeze may be present Raised jugular venous pressure and ankle edema are present in heart failure Investigations will depend on the severity of exacerbation None may be necessary during a mild exacerbation In a more severe exacerbation, relevant investigations will help in the assessment as well as aid treatment of these patients Spirometry during an acute exacerbation is usually not required and often does not add information that affects management Indications for hospital admission include: • • • • • • • • • marked worsening of symptoms; severe baseline COPD; poor response to initial treatment; old age; significant comorbidities; new arrhythmias; hemodynamic instability; respiratory failure; and poor home support Indications for ICU admission include: • • worsening hypoxemia while on high FiO2; worsening respiratory acidosis and hypercapnia despite treatment; 1324 A Clinical Approach to Medicine Table Assessment of COPD Exacerbation History 1) Baseline status 2) Severity of new or worsening symptom 3) Response to any prescribed treatment 4) Number of previous hospitalizations 5) Fever and purulent sputum 6) Wheeze 7) Home oxygen therapy 8) Usual medication Sign 1) Mental status 2) Tachypnea/ability to speak & converse 3) Fever 4) Wheeze 5) Raised JVP and edema 6) Cyanosis 7) Use of accessory muscles of respiration 8) Paradoxical chest wall or abdominal movement 9) Hemodynamic instability Investigations • Full blood count • Urea, creatinine, electrolytes • Arterial blood gas Findings It is important to ascertain baseline functional status, arterial blood gas and spirometry as a basis for comparison This has to be compared to the baseline of each patient A big increase indicates a more severe exacerbation Patients who are not responding to treatment tend to have a more severe exacerbation Patients requiring frequent hospitalization for COPD exacerbation are at higher risks Fever and purulent sputum indicate infection Wheeze is not related to severity or cause of exacerbation, and may not be present This indicates a more severe baseline COPD and allows comparison of severity of hypoxemia Gives an indication of baseline and present starting bronchodilator dose and frequency Findings Drowsiness indicates a severe exacerbation and possible acute hypercapnia Gives an indication of severity of dyspnea Respiratory rate Ͼ 30/min indicates severe exacerbation Suggests the presence of infection Wheeze may be absent Indicates right heart failure Indicates severe hypoxemia Frequently present in an exacerbation Present in severe exacerbation Needs admission to intensive care unit Findings Raised white cell suggests infection Polycythemia may be present in chronic hypoxemia Useful baseline Important to assess for hypokalemia in frequent 2-agonist or diuretic use Assess both oxygen and ventilation Respiratory acidosis indicates a severe exacerbation COPD 1325 Table (Continued) Investigations • Pulse oximetry • Serum theophylline level • Sputum gram stain and culture • Chest radiograph • Electrocardiogram • • • • Findings It is a useful non-invasive means of checking oxygenation but it does not give information on the level of carbon dioxide It is useful for patients treated with theophylline as it has low therapeutic index It is useful if a respiratory tract infection is suspected It helps to assess for alternative diagnosis It helps to assess for cardiac ischemia, arrhythmia and right heart hypertrophy severe respiratory distress that is not responding to initial therapy; hemodynamic instability; life-threatening arrhythmia; and impaired mental status Mild exacerbations may be managed as an outpatient but more severe ones require hospitalization Table summarizes the management of acute exacerbation of COPD Bronchodilator therapy Inhaled bronchodilator therapy remains the cornerstone of treatment Combined short-acting 2-agonist and anti-cholinergic are frequently used although 2-agonist alone may be used initially There is presently no strong evidence that combining both drugs improve outcome Inhalation via spacer or nebuliser may be used although dyspneic patient may prefer nebuliser therapy Frequency and/or dose need to be increased from baseline Methylxanthines Routine use of methylxanthines is not warranted in acute exacerbation of COPD Aminophylline or theophylline may be considered in severe exacerbation that is not responding to first line treatment 1326 A Clinical Approach to Medicine Steroids Glucocorticoid therapy has been shown to be beneficial in the treatment of an acute COPD exacerbation A course of up to 14 days therapy with 30–40 mg daily of prednisolone may be used There is no role for inhaled steroids in the treatment of acute exacerbation of COPD Antibiotics Antibiotics are only indicated in the presence of bacterial infection Purulent sputum alone is sufficient for commencement of antibiotic therapy Sputum culture may be useful to guide antibiotic therapy if positive Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis are the most common bacteria involved It may also be considered in patients with severe exacerbations Adjunct therapy Oxygen therapy is useful to correct hypoxemia However, oxygen therapy needs to be controlled as some patients may develop hypercapnia and acute respiratory acidosis Reassessment of arterial blood gas after 30 minutes of oxygen therapy is useful Oxygen therapy may be monitored using pulse oximetry or arterial blood gas The later is indicated when hypercapnia needs to be monitored Adequate nutrition and hydration should be maintained Tube feeding and intravenous hydration may be necessary in a dyspneic patient There is no study to show that mucolytics or routine chest physiotherapy is useful in acute exacerbation of COPD Chest physiotherapy may be considered in patients who produce Ͼ 25 ml of sputum a day or when atelectasis is present Mechanical ventilation Invasive or non-invasive mechanical ventilation may be indicated in severe exacerbation Non-invasive positive pressure ventilation (NIPPV) has been shown to improve patient outcomes in acute exacerbation of COPD Selection of patient is important for a successful outcome Invasive mechanical ventilation is necessary for those who fail NIPPV, or in those who are too ill for NIPPV However, before this is instituted, it is important to consider the risk and benefit of mechanical ventilation COPD 1327 Table Management of Acute Exacerbation of COPD Bronchodilator therapy • Inhaled short-acting 2-agonist, e.g salbutamol • Inhaled anti-cholinergic, e.g ipratropium bromide • Delivery either through spacer or nebulizer • They may be combined • Routine use of methylxanthines is not warranted Glucocorticoid • Intravenous hydrocortisone or methylprednisolone Antibiotics • Antibiotic is indicated only when there is evidence of bacterial infection, clinical or laboratory • Antibiotic choice: -lactam, -lactam ϩ -lactamase inhibitor, new generation macrolides, doxycycline, newer generation fluoroquinolones Adjunct therapy • Controlled supplemental oxygen • Chest physiotherapy only if there is atelectasis or sputum production Ͼ 25 ml • Nutrition • Hydration Mechanical ventilation • Indicated when ventilation cannot be sustained by patient, worsening gas exchange despite treatment The main concern in a severe COPD patient is whether he will become ventilator dependent Unfortunately, there is no foolproof way of predicting such an outcome Degree of airway obstruction does not accurately predict ventilator dependence and should not be used alone for making a decision on whether to institute mechanical ventilation Other considerations include social and cultural factors, comorbid conditions, baseline performance status, patient and family wishes or expectations, and quality of life Stable COPD The aims of treatment of stable COPD are to: 1) 2) 3) 4) 5) control symptoms; improve quality of life; improve exercise tolerance; prevent exacerbations; prevent and treat complications; 1328 A Clinical Approach to Medicine 6) prevent progression of disease; and 7) reduce mortality Most of the treatment options address the first points, but only smoking cessation and oxygen therapy had been able to prevent progression of disease and reduce mortality from COPD Treatment should be stepwise and gradually increased depending on the disease severity Both pharmacological and non-pharmacological components of treatment should be addressed Bronchodilators Bronchodilator therapy is the main pharmacological treatment of COPD Short-acting inhaled 2-agonists are given as necessary in patients who have mild COPD with few or intermittent symptoms Those patients with moderate COPD with regular symptoms should be given regular inhaled anticholinergics and/or short-acting 2-agonists Long-acting 2-agonists may be added in patients who not respond to the above treatment and theophylline However, studies have not consistently shown these agents to be beneficial in stable COPD Methylxanthines Long-acting theophylline may be added if symptoms are not well controlled on regular inhaled bronchodilators Its mode of action in COPD is unknown It only has a mild bronchodilator effect Its main effect could be improvement in diaphramatic function Glucocorticoids Large studies have not shown that chronic inhaled glucocorticoids improve lung function or quality of life in stable COPD However, inhaled glucocorticoids may be considered in these subsets of COPD patients: • • those who exhibit positive bronchodilator response in spirometry, i.e 200 cc and 12% improvement in FEV1 (ATS criteria) or 15% increase in FEV1 alone (European Respiratory Society criteria); those who had significant improvement in spirometry (200 cc and 15% increase in FEV1 by ATS criteria) after a trial of weeks of 0.5–1 mg daily of prednisolone or 2–3 months of moderate to high dose of inhaled glucocorticoids; and COPD 1329 • those with FEV1 Ͻ 50% with frequent exacerbations requiring antibiotics or glucocorticoids In this group, treatment should be discontinued if no improvement is noted after an adequate trial of treatment Vaccination Influenza vaccination has been shown to reduce mortality and serious illness in COPD patients by 50% It is recommended every autumn in temperate countries However, it is uncertain whether influenza vaccination should be routinely advised in the Singapore context as there is no local seasonal change and the epidemiology of influenza in Singapore is unknown Pneumococcal vaccination using 23-valent vaccine may reduce mortality and morbidity in COPD patients Others Alpha1 antitrypsin augmentation may be prescribed for patients with proven ␣1 antitrypsin deficiency There is presently no evidence that respiratory stimulant, mucolytics, antioxidants or prophylactic antibiotics is beneficial in COPD Vasodilator therapy has not been shown to be effective in pulmonary hypertension secondary to COPD Chronic use of antitussives is also not recommended in COPD The non-pharmacological aspect of COPD management needs to go hand-in-hand with pharmacological treatment To date, only oxygen therapy and smoking cessation have been shown to retard disease progression and improve mortality in indicated patients with COPD Oxygen Long-term home oxygen therapy is indicated in chronically hypoxemic patients with stable COPD Although supplemental oxygen may be prescribed during an acute exacerbation, its need should be reassessed when patient has become stable and reached his baseline Only when the patient continues to be hypoxemic should long-term oxygen therapy be advised Table shows the criteria for long-term home oxygen therapy Oxygen should be used for more than 15 hours a day and titrated to PaO2 у 60 mmHg or SaO2 у 90% Long-term use improves survival, pulmonary hemodynamics, exercise capacity, mental alertness and lung 1330 A Clinical Approach to Medicine Table Criteria for Long-Term Home Oxygen Therapy Assessment must be made when patient is clinically stable and on appropriate therapy PaO2 р 55 mmHg or SaO2 р 88% (with or without hypercapnia) PaO2 р 56–59 mmHg or SaO2 р 89% with either of the following: 1) Pulmonary hypertension 2) Edema due to heart failure 3) Hematocrit Ͼ 55% PaO2 — arterial oxygen partial pressure, SaO2 — arterial oxygen saturation mechanics For these patients, titration can be performed for exercise and sleep although empiric increment by 1–2 litres per minute is also acceptable There is currently no evidence that oxygen use for hypoxemia during sleep or exercise without daytime resting hypoxemia improves survival Smoking cessation Smoking cessation is recommended for all COPD patients who continue to smoke Physicians should routinely inquire about smoking habits and provide advice on the effects of tobacco for those who continue to smoke These patients should be assessed for readiness and encouraged to quit smoking on every clinic visit Those who are ready should either be referred to dedicated smoking cessation clinics or be counseled on smoking cessation techniques Patient should be encouraged to set a quit date rather than reducing gradually Nicotine replacement therapy (NRT) and slow-release bupropion have been shown to be effective in smoking cessation Formulations of NRT include transdermal patch, intranasal device, inhaler, lozenges and gum There were concerns regarding the use of NRT in patients with cardiovascular disease but studies have shown it to be safe in these patients as the delivered nicotine dose is much less than that of cigarettes Second-line drugs in smoking cessation include nortriptyline and clonidine, but they should be used with care and by experienced physicians The safety of drugs for smoking cessation has not been studied in pregnancy Pregnant smokers should be given psychosocial intervention and routine use of pharmacotherapy cannot be recommended in this group of patients COPD 1331 Pulmonary rehabilitation Pulmonary rehabilitation is a multidisciplinary and multimodality program that aims to achieve and maintain maximum level of independence and functioning in a patient with chronic lung disease Although it has been widely studied in COPD, its efficacy in other chronic lung diseases has not been well investigated It has been shown to improve exercise endurance and capacity, quality of life, health-related cost, reduce dyspnea and hospitalization It has no effect on physiological parameters like lung function and gas exchange COPD patients often follow a vicious cycle where dyspnea leads to inactivity, which leads to skeletal muscle atrophy, which leads to increased dyspnea and further physical inactivity Pulmonary rehabilitation is an intervention to break this cycle All patients who are with dyspnea should be referred for pulmonary rehabilitation Patients should be assessed prior to entering a program to ensure there are no contraindications like unstable comorbid conditions or dyspnea due to non-COPD causes A program usually lasts 4–8 weeks Central to a program will be exercise training, which consists of both strengthening and endurance exercises The program is individually tailored to the patient’s requirements Exercises are gradually increased and patients are taught to continue with their own exercises even when the program is completed Other components of pulmonary rehabilitation include education, dietary advice, smoking cessation, psychological counseling and self management skills Table shows the various team members of a pulmonary rehabilitation program Table Members of a Pulmonary Rehabilitation Program Team member Component Physician Team leader Provide medical input, interpret exercise test, evaluate outcome Physiotherapist Exercise training, teach breathing techniques, chest therapy as needed Nurse Coordinate activities, organize program, patient education Psychologist Counseling, smoking cessation, stress management, teach relaxation techniques Pharmacist Educate drug usage and supervise delivery devices Dietician Occupational therapist Dietary advice Vocational and activities-of-daily-living (ADL) counseling 1332 A Clinical Approach to Medicine Education Patient education is important in any chronic disease Although there are no studies to show that it improves outcome, it is certainly helpful in improving the ability to cope with the illness The scope of education will depend on social and cultural factors Education should include the following topics: • • • • • nature of the disease and complications; medication use, including inhaler techniques; how to cope with symptoms; recognition and treatment of exacerbations; and end of life issues and advanced directives Mechanical ventilation Long-term mechanical ventilation may be necessary in advanced COPD when it becomes impossible for patients to maintain adequate gas exchange Depending on the degree of compromise, patients may need continuous or partial ventilatory support The latter is usually achieved with nocturnal NIPPV Studies on long-term continuous ventilator support have shown good survival However, quality of life is definitely affected Whether this is a viable option depends on the cultural and social background, home and family support of the patient Bullectomy Bullae are defined as abnormally dilated airspaces of Ͼ cm in diameter within the lung parenchyma The reason for bulla formation is unknown but is thought to be due to ball-valve effect where obstruction of airway leads to progressive air-trapping and dilatation of distal airspaces that are already damaged by emphysema Giant bulla that causes compression of the adjacent lung tissue may be excised if it is thought to contribute to dyspnea Careful selection of patient is necessary CT thorax, radionuclide ventilation-perfusion scan and lung volume measurements by plethysmography and inert gas dilution is necessary for evaluation Poorer results of surgery occur in patients where bullae occupy less than onethird of the hemithorax, and in those with diffuse emphysema or chronic bronchitis COPD 1333 Lung volume reduction surgery (LVRS) Lung volume reduction surgery is a palliative surgical procedure for selected patients with pulmonary emphysema It has been shown to improve dyspnea, quality of life, exercise tolerance and lung mechanics Improvement in gas exchange is not consistent among studies Longterm follow-up studies have not shown any reduction in mortality in COPD The mechanisms of improvement are hypothesised to be improved lung elastic recoil, improved respiratory muscle function, and correction of ventilation-perfusion mismatch Patient eligibility must be carefully assessed and pulmonary rehabilitation before surgery is compulsory Patients should have significant dyspnea despite maximum medical therapy, pulmonary emphysema with minimum airway hyperreactivity, and predominantly upper lobe disease with lower lobe compression Recent data shows that patients with very low FEV1 and diffusing capacity have high mortality after LVRS Lung transplant is indicated in this group of patients instead Surgery may be performed via median sternotomy, bilateral thoracotomy or video-assisted thoracoscopy Approximately one-third of both upper lobes are resected in this procedure to allow the lower parts of the lungs to expand and restore normal pulmonary mechanics Studies show that improvement in lung function may last for 2–3 years before deteriorating again It may be used as a bridge to lung transplantation Lung transplantation Lung transplantation is appropriate in patients with end-stage COPD that is unresponsive to medical treatment Indication for lung transplantation in COPD include dyspnea of class by New York Heart Association classification, FEV1 Ͻ 25% predicted, PaO2 Ͻ 60 mmHg, PaCO2 Ͼ 45 mmHg, secondary pulmonary hypertension, rapid decline in lung function or repeated life-threatening exacerbations The inclusion and exclusion criteria are complex and patients need to be carefully evaluated and selected Patients who are suitable for lung transplant have poorer pulmonary physiology than those who are eligible for LVRS Data from the United Network of Organ Sharing in USA suggests that lung transplantation after years may not confer survival benefit for end-stage COPD Either single or bilateral sequential lung transplant may be performed for COPD Common complications after lung transplantation 1334 A Clinical Approach to Medicine are operative mortality, acute and chronic rejection, and opportunistic infections At present, the main problem in lung transplantation worldwide is the shortage of donor organs SUMMARY Chronic obstructive pulmonary disease (COPD) usually comprises of various degrees of both chronic bronchitis and emphysema It is characterized by chronic airflow limitation that is not fully reversible The main cause of COPD is tobacco smoking It has a progressive course with gradually worsening lung function and symptoms There are exacerbations that tend to become more frequent as the disease progresses The cardinal symptom is dyspnea Other possible associated symptoms are coughing, sputum, reduced exercise tolerance and wheezing It can sometimes be confused with asthma Relevant investigations in the assessment of COPD include chest radiograph and spirometry Arterial blood gas assessment may be necessary in the later stages of COPD Management should include both pharmacological and non-pharmacological treatment Inhaled bronchodilators (short-acting 2-agonist and anticholinergic) are the form of treatment A step-wise approach should be adopted in the pharmacological treatment A short course of systemic steroid improves outcome in an acute exacerbation Antibiotic is only indicated if bacterial infection is suspected A trial of inhaled steroids in chronic COPD treatment may be given if indicated Smoking cessation should be advised for current smokers Pulmonary rehabilitation has been shown to improve quality of life, dyspnea score and exercise tolerance of symptomatic COPD However, it does not alter the course of the disease Longterm oxygen therapy, when indicated, reduces mortality in severe COPD Lung volume reduction surgery and lung transplantation are only useful in selected patients with end-stage COPD on maximal medical therapy REFERENCES National Heart, Lung and Blood Institute/World Health Organisation, Global Initiative for Chronic Obstructive Lung Disease, Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, NHLBI/WHO Workshop Report, NHLBI Publication Number 2701, March 2001 American Thoracic Society, Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease, Am J Respir Crit Care Med 152:S84–S96, 1995 COPD 1335 Siafakas NM, Vermeire P, Price NB, et al., Optimal assessment and management of chronic obstructive pulmonary disease (COPD): The European Respiratory Society Task Force, Eur Respir J 8:1398–1420, 1995 The COPD Guideline Group of the Standards of Care Committee of the BTS, BTS guidelines for the management of chronic obstructive pulmonary disease, Thorax 52(suppl 5):S1–S28, 1997 Fiore MC, Bailey WC, Cohen SJ, et al., Treating Tobacco Use and Dependence, Clinical Practice Guideline U.S Department of Health and Human Services, Public Health Service, Rockville, MD June 2000 American Thoracic Society, Pulmonary rehabilitation, Am J Respir Crit Care Med 159(5 Pt 1):1666–1682, 1999 Medical Research Council, Report of the Medical Research Council Working Party, Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema, Lancet 1(8222):681–686, 1981 Nocturnal Oxygen Therapy Trial Group, Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial, Ann Intern Med 93:391–398, 1980 Yusen RD, Lefrak SS, Evaluation of patients with emphysema for lung volume reduction surgery, Semin Thorac Cardiovasc Surg 8:83–93, 1996 10 Sciurba F, Early and long-term functional outcomes following lung volume reduction surgery, Clin Chest Med 18:259–276, 1997 11 National Emphysema Treatment Trial Research Group A randomized trial comparing lung volume reduction surgery with medical therapy for severe emphysema New Engl J Med 348:2059–2073, 2003 12 Trulock EP, Lung transplantation, Am J Respir Crit Care Med 155:789–818, 1997 This page intentionally left blank 77 Sleep Disorders Anne Hsu This chapter is a major revision of the previous one that the chapters on Sleep-disordered Breathing and Sleep Disorders have been merged onto this chapter The subject of sleep disorders is too vast to be covered in one chapter, hence the aim here is to provide an overview of sleep disorders The more common sleep disorders will be reviewed briefly but many disorders are beyond the scope of this overview The knowledge of sleep, sleepiness and sleep disorders has advanced dramatically over the last decades Although sleep medicine has become established as a specialty field, it is important for medical students, the general practitioners, the internists and public health authorities to appreciate the prevalence of sleep disorders, and the consequences of sleepiness and sleep disorders This knowledge will serve to enhance the lives, both qualitatively and quantitatively, of patients and will also have a significant impact on the socioeconomic burden and the medicolegal aspect To name a few of the socioeconomic impact of sleepiness and sleep disorders identified by the USA National Commission on Sleep Disorders Research:1 • The official final determination of cause of the Exxon Valdez, Bhopal, Challenger, Chernobyl accidents was fatigue-related impairment of judgment and performance in the workplace 1337 1338 A Clinical Approach to Medicine • • 40 million Americans suffer from chronic sleep disorders 95% of these are undiagnosed and untreated In 1990, 200 000 motor vehicle accidents in the USA were due to falling asleep at wheels The direct cost of sleepiness and sleep disorders to the American public was US$15.9 billion Indirect costs may have added another US$150 billion FUNCTIONAL ANATOMY OF SLEEP AND CLINICAL CORRELATES We spend our lives in three different states of being: wakefulness; nonREM (rapid eye movement) sleep; and REM sleep Each state has its own distinct neuroanatomic, neurophysiologic, and neuropharmacologic mechanisms and behavioral features The neuronal system that controls this sleep-wake cycle is found in the brainstem, hypothalamus and basal forebrain with the relay nuclei nested in the thalamus and the target organ in the cortex The electrophysiologic expression of wakefulness is desynchrony of the electroencephalogram (EEG) by activation of the midbrain reticular neurons, which directly excite thalamocortical projection During sleep, distinct stages of REM sleep and non-REM sleep alternate in a well-organised fashion REM sleep originates in the brainstem2 and is characterized by rapid eye movements (Fig 1), the hallmark of REM sleep, dream content and muscle atonia The EEG is desynchronized The ponto-geniculo-occipital spike activity, seen in phases in REM, may eventually reach the cortical areas and trigger off fragmentary imagery, which we recognise as dreams Muscle atonia occurs in all skeletal muscles except for the ocular and diaphragmatic muscles Hence, significant hypoventilation occurs, and this can occur profoundly in patients with diaphragmatic dysfunction such as those with chronic obstructive pulmonary disease and those with diaphragmatic paralysis Neurophysiologic and behavioral features of more than one state may occur simultaneously, resulting in bizarre and important clinical syndromes.3 REM sleep intrusion into wakefulness accounts for the symptoms of narcolepsy, such as cataplexy, sleep paralysis and hypnogogic hallucinations In cataplexy, a strong emotion, such as laughter, triggers off REM sleep atonia, thereby causing paralysis Non-REM sleep intrusion into wake occurs as micro-sleep periods that interrupt the wakefulness Sleep Disorders 1339 Fig This 30-second epoch of a standard polysomnogram shows obstructive apnea occurring during REM sleep The vertical line corresponds to arousal with brief termination of the preceding obstructive event that has lead to oxyhemoglobin desaturation to a nadir of 61% Channel abbreviations are as follows: C3-A2, C4-A1, O2-A1 ϭ EEG; LOC-A2, ROC-A2 ϭ left, right oculogram; EMG ϭ chin EMG; ECG ϭ electrocardiogram; Sp02 ϭ oxyhemoglobin saturation via pulse oximeter; Airflow ϭ via nasal thermistor; Thoracic, Abdominal ϭ chest, abdominal movements; Sound ϭ records snoring in this case; Position ϭ body position; leg/L, leg/R ϭ left, right leg EMG state, hence causing automatic behavior The most prominent dissociated state arising from REM sleep is REM sleep behavior disorder (RBD) The muscle tone of the wakefulness state persists even during REM sleep The preservation of the motor tone in patients with RBD may result in vigorous and injurious motor activity as they can act out their dreams CLASSIFICATIONS OF SLEEP DISORDERS The International Classification of Sleep Disorders lists 84 known sleep disorders4 classified under dyssomnias, parasomnias, medical/psychiatric sleep disorders and proposed sleep disorders Dyssomnias are disorders that produce either difficulty initiating or maintaining sleep or excessive sleepiness Parasomnias are disorders of arousal, partial arousal, and sleep stage transition Sleep disorders associated with medical or psychiatric 1340 A Clinical Approach to Medicine disorders are not primarily sleep disorders but are medical or psychiatric conditions that have either sleep disturbance or excessive sleepiness as a major feature of the disorder Proposed sleep disorders are for disorders for which there is insufficient information available to confirm the unequivocal existence of the disorders A more useful and practical diagnostic classification is classifying sleep disorders into the following four categories: 1) 2) 3) 4) insomnia; hypersomnia; disorders of sleep/wake cycle; and parasomnias or movement disorders associated with sleep or partial arousal INSOMNIA Insomnia is the most common of all sleep-related complaints A 1991 study found that 36% of Americans reported having insomnia.5 Although local data shows that the prevalence of insomnia is lower, there is an increasing trend over the last 1–2 decades A survey reported in 1986, of clinics in Singapore showed that 8% of patients had insomnia and a subsequent study revealed that 25% of the 612 elderly people in the community had sleep difficulties.6 The prevalence of insomnia in a Singapore community was 15% reported in 19967 and in an unpublished survey, the Insomnia Tracking Study, completed in early 2002 indicated that this has risen significantly The morbidity of insomnia includes impairment of quality of life and cognitive function; and increased motor vehicle accidents, work absenteeism, healthcare use and risk of depression.1,5,8 Insomnia is a symptom, and not a disorder in and of itself It is often the symptom of many underlying medical, psychiatric, and psychological conditions and may be the presenting symptom of other primary sleep disorders It could be transient, lasting several nights in response to a precipitating factor; short-term if it is less than weeks; and chronic if it persists beyond weeks Untreated short-term insomnia places the individual at risk for a more chronic psychophysiological or conditioned insomnia, which becomes difficult to treat and hence better managed by a sleep specialist or a psychiatrist The primary cause of chronic insomnia is rarely immediately apparent and the likelihood of more than cause is significant The Sleep Disorders 1341 two most frequent causes of chronic insomnia are anxiety and depressive disorders It is important to establish the cause as specific therapy such as anxiolytics, antidepressant, treatment of sleep apnea can than be instituted with good outcomes Sedative-hypnotic treatment has a role, particular in short-term insomnia and may serve to prevent the development of chronic insomnia Effective agents include the benzodiazepines and the newer non-benzodiazepines A combination of behavioral and pharmacological therapy is often effective for chronic insomnia.9 Sleep hygiene (Table 1) should be reviewed A good sleep history and sleep diary is often diagnostic and few insomniac patients require polysomnographic study for other suspected primary sleep disorders such as sleep apnea, sleep state misperception and periodic leg movements Periodic Leg Movements Periodic leg movements of sleep (PLMS) is a frequent cause of insomnia or excessive daytime sleepiness in elderly patients Stereotyped movements of the limbs occur periodically, predominantly in the legs during sleep It is not myoclonic and is identical to the Babinski response where there is extension of the toes and dorsiflexion of the ankle There could be flexion of the knees or hips It lasts from 0.5 to seconds and is shown on the Table Sleep Hygiene Tips • Maintain regular wake time regardless of the hours of prior sleep • Avoid excessive time in bed Get out of bed if you have not fallen asleep or don’t feel sleepy after 30 minutes Go to another room but go back to bed when you feel sleepy • Sleep only as much as you need for refreshment Avoid getting too much sleep The quality of our sleep is more important than quantity • Use the bed only for sleeping and sex • Make your bedroom a pleasant place to sleep, e.g use a comfortable bed with clean linen, keep your bedroom quiet and dark or dim • Develop a bedtime routine Do things that give you a sense of security, relaxation and comfort Reserve the hour before bedtime for quiet activities Read a “light” novel or watch a relaxing TV program; not finish office work or discuss family finances with your spouse, for example • Eat a light snack before bedtime if hungry • Do not watch the clock • Avoid nicotine, caffeine, and alcohol • Exercise regularly and early (before pm) in the day • Avoid naps, except if shift worker 1342 A Clinical Approach to Medicine electromyogram of the anterior tibial muscle as a burst of muscle activity causing arousal during non-REM sleep The average interval between jerks is 20 to 40 seconds These movements occur in clusters that last several minutes At least bursts per hour i.e PLMS index of on the polysomnography, are required for a diagnosis PLMS occurs in majority of patients with restless leg syndrome (RLS) and forms a component of it RLS may not occur in all cases of PLMS It is characterized by irresistible leg movements accompanied by a creeping unpleasant sensation deep in the limbs typically occurring at rest and relieved with movements It affects at least 5% of the general population but seems to pose less of a problem in Singapore RLS and PLMS have been observed in pregnancy, chronic renal failure, peripheral neuropathy, iron deficiency anemia and hypothyroidism, although it can occur in healthy people Both can disrupt sleep and hence treatment with Clonazepam, Sinemet or opioids at bedtime may be necessary HYPERSOMNIA Sleepiness is the normal consequence of sleep deprivation or the use of hypnotics A very common cause of sleepiness in our modern society is “voluntary” sleep deprivation This societal sleep deprivation is due to many factors: shift work, air travel allowing rapid time zone shifts, 24-hour TV, stock exchanges and information technology When sleepiness is excessive or inappropriate especially in the absence of “voluntary” sleep deprivation, it often indicates a clinical disorder termed as hypersomnia or daytime hypersomnolence or excessive daytime sleepiness (EDS), which is the result of many sleep disorders The well-documented consequence of sleep loss is impairment of performance with respect to judgement, reasoning, learning and reaction time particularly at tasks involving sustained attention.10 Falling asleep on the job and behind the wheel have resulted in grave consequences and in some fields, e.g internship, legislation has been developed restricting duty hours.11 The following common sleep disorders with hypersomnia as a key feature will be discussed: 1) 2) 3) 4) Obstructive Sleep Apnea Narcolepsy Idiopathic hypersomnia Periodic hypersomnia Sleep Disorders 1343 Obstructive Sleep Apnea Obstructive sleep apnea (OSA) is the most common sleep disorders encountered in the Sleep Disorders Unit in Singapore General Hospital and in many Sleep Centres worldwide Sleep-related disordered breathing consist of breathing disorders that occur only during sleep such as obstructive sleep apnea and central sleep apnea, as well as breathing disorders which can have significant worsening during sleep (such as chronic alveolar hypoventilation, Table 2) Prevalence of OSA OSA is very prevalent in the general population The largest and most often quoted population survey to date found the prevalence of OSA, to be 24% and 9% in middle-aged adult males and females respectively.12 Of these, not all are associated with symptoms and the investigators concluded that 4% of males and 2% of females in the middle-aged workforce of the USA have clinically important degree of sleep apnea, i.e OSA syndrome (OSAS) defined as OSA with excessive daytime sleepiness There is less prevalence data in Asia compared to the Western population A recent community-based study of sleep apnea among middle-age men in Hong Kong showed similar OSAS prevalence of 4.1%.13 The prevalence of Table Etiology of Chronic Ventilatory Failure “DRIVE” PROBLEMS • Primary alveolar hypoventilation • Structural defects: CNS tumor, bulbar poliomyelitis, Arnold–Chiari malformation, cerebrovascular accident • Metabolic: severe metabolic alkalosis, uremia, hemodialysis • Cheyne-stokes respiration associated with severe left ventricular dysfunction “PUMP” PROBLEMS • Neuromuscular disorders • Neuropathic processes, such as motor neuron disease • Neuromuscular junction disorders, such as myastehnia gravis and Eaton–Lambert syndrome • Myopathies, such as muscular dystrophy and acid maltase deficiency • Restrictive abnormalities, such as kyphoscoliosis “MIXED” DISORDERS • Myxoedema • Chronic obstructive pulmonary disease • Obesity-hypoventilation syndrome 1344 A Clinical Approach to Medicine OSAS amongst medical inpatients in Singapore General hospital was 20%, 30% and 12% for Chinese, Malays and Indians respectively.14 Another outpatient hospital-based study conducted in the same hospital reported an extrapolated population prevalence of 15% for OSAS.15 Pathogensis and sequaela of OSA (Fig 2) OSA is characterized by repetitive upper airway, from the pharynx to the larynx, collapse during sleep Unlike the trachea and bronchi, whose patency is maintained by cartilaginous support, the patency of the upper airway depends critically on the action of its dilator muscles Sleep predisposes one to narrowing and, in susceptible persons, collapse of the upper airway by reducing the tone of the upper airway muscles and their reflex response to the sub-atmospheric airway pressures generated during inspiration The pathogenic factors that lead to instability of the upper airway patency during sleep include: 1) the size of the channel, which is related to the adjacent soft tissue, e.g tonsillar structures and “preset” skeletal structures; and 2) the compliance of the airway wall, which is related to the neuromuscular function, e.g in bulbar palsy or myasthenia gravis Fig Pathophysiology of Obstructive Sleep Apnea (OSA) * Key symptoms of OSA Sleep Disorders 1345 The risk factors for OSA include: 1) Obesity 2) Older age 3) Male gender The male to female ratio is 3:1.16 In women, OSA increases markedly after 55–65 years; after menopause.17 4) Familial and genetic risk.18 Children of subjects with OSA tend to inherit similar craniofacial abnormalities, which may subsequently predispose them to the development of OSA 5) Race Thus far, most epidemiological studies on OSA have involved mainly Caucasians The limited data on other racial groups including African-Americans, Hispanics and Asians gave higher prevalence compared to the Caucasian population.15,19,20 6) Alcohol and sedatives predisposes one to upper airway closure Smoking causes upper airway inflammation 7) Specific medical conditions include hypothyroidism, acromegaly, Down’s syndrome and all neuromuscular dysfunction affecting the upper airway muscles, e.g bulbar poliomyelitis Loud habitual snoring and excessive daytime sleepiness are the two key symptoms of OSA When complete obstruction of the airway develops, however, the snoring is interrupted by periods of silence lasting 10 seconds to a couple of minutes This coincides with the complete cessation of airflow During these episodes of apnea, futile respiratory efforts continue and oxyhemoglobin desaturation develops until a brief awakening or arousal terminates the apnea (Fig 1) Hence the airway patency is restored These events are usually accompanied by a generalized startle response, snorting and gasping After a few deep breaths, the patient returns to sleep, only to have the cycle of events repeated as many as few hundreds times through the night Clinical features of OSA Symptoms During Sleep 1) Loud habitual snoring A local study,15 similar to other published studies, showed that snoring is the most common presenting symptom The snoring is interrupted by apnoeic episodes associated with snorting or gasping Some patients are awaken with snorting or with feeling of choking 1346 A Clinical Approach to Medicine 2) Abnormal motor activity during sleep Patients or their bed partners may complain of excessive tossing and turning during sleep 3) Sleep disruption Patients are often unaware of the frequency and intensity of arousals from sleep Some may complain of insomnia 4) Oesophageal reflux 5) Nocturia and enuresis due to increased secretion of atrial natriuretic peptide in response to reflex pulmonary vasoconstriction during apneic episodes; increased venous return and increased intraabdominal pressure associated with respiratory efforts against a closed upper airway 6) Heavy sweating at night Daytime Symptoms 1) Excessive daytime sleepiness This is the chief clinical consequence of OSA This is thought to be related to the fragmentation of sleep by recurrent arousals, the loss of deeper levels of sleep and the effects of hypoxemia on the cerebral function Many studies have documented the debilitating effects of sleep deprivation in patients with OSA: poor vigilance, cognition, memory, impaired school and work performance, changes in personality and sexual problems, “sleep drunkenness” (disorientation and morning confusion) and, perhaps most worrying of all, a significant increase in driving accidents.21,22 Sleepiness scale can be used to subjectively quantify sleepiness and one of the common scales used is the Epworth Sleepiness Scale23 (Table 3) This is a simple, self-administered questionnaire, which can provide a measurement of the subject’s general level of daytime sleepiness 2) Morning headaches due to hypoxemia, with or without hyerpcapnia 3) Dry throat on waking up 4) Loss of hearing Loud habitual snoring may lead to hearing impairment for both the snorer and his or her bed partner after many years Physical examination Evaluation of the following should be done: 1) Upper airway patency Crowding of the oropharynx due to large adenoids or tonsils, elongated soft palate, edematous reddish uvula or large tongue Sleep Disorders 1347 Table Epworth Sleepiness Scale24 Situation • • • • • • • • Chance of dozing (score to 3) Sitting and reading Watching television Sitting, inactive in a public place As a passenger in a car for an hour without a break Lying down to rest in the afternoon when the circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in traffic ϭ would never doze, ϭ slight chance of dozing, ϭ moderate chance of dozing, ϭ high chance of dozing A score of Ͼ 10 is considered as abnormal 2) Craniomandibular abnormalities such as micrognathia or retrognathia 3) Obesity The body mass index and the neck circumference should be measured A measurement of Ͼ 40 cm15 for the latter is significant 4) Associated syndromes or conditions OSA may coexist with other respiratory disorders (the so-called “overlap” syndrome), namely, obesity hypoventilation syndrome and chronic obstructive pulmonary disease The Pickwickian syndrome, which describes an obese, hypersomnolent individual with polycynthemia and leg edema, has often been considered to be synonymous with the OSA syndrome It, however, more closely describes a patient with the obesity-hypoventilation or the “overlap” syndrome, rather than obese individuals with OSA alone Neuromuscular disorders such as myasthenia gravis, myotonia dystrophica and poliomyelitis can be the contributory factor of OSA Other conditions associated with OSA are acromegaly and hypothyroidism 5) Complications of OSA Numerous reports have suggested that OSA are linked to systemic hypertension, pulmonary hypertension, increased risks of arrhythmias, ischemic heart disease, stroke and premature death.24–27 It is estimated that a third of OSA patients have systemic hypertension and conversely a third of hypertensive patients have OSA 1348 A Clinical Approach to Medicine Objective evaluation of OSA Attended full night polysomnography (Fig 1) has been established by consensus28,29 as the accepted test for the diagnosis and determination of the severity and treatment of OSA The polysomnography (PSG) consists of the evaluation of a minimum of seven parameters, including electroencephalogram, electro-oculogram, chin electromyogram, electrocardiogram, airflow, respiratory effort and oxygen saturation Body position during sleep must be documented Leg movement recording is desirable, but optional Trained personnel must be in constant attendance and be able to intervene A minimum of hours sleep recording is required Unattended portable sleep studies are not recommended for the routine assessment of OSA Currently, there are no established rules for the assessment of the severity of OSA The apnea-hyponea index (AHI), which is the number of apneas or hyponeas per hour of sleep, and the minimum oxygen saturation during sleep are often used in the analysis of results of the PSG to grade the severity of the condition There are a few tests that can objectively measure excessive daytime sleepiness Multiple sleep latency test is the preferred study as it is a standardized and well-validated measure of physiologic sleepiness.30 This test is discussed later Management of OSA Indications for the treatment of OSA are: 1) to alleviate excessive daytime sleepiness (EDS); and 2) to reduce the potential cardiovascular and neurocognitive morbidity and premature mortality associated with OSA While the data is still emerging for the latter indication, treatment is warranted for EDS as this can be disabling There is strong evidence in support of reduction in driving accidents with CPAP therapy for OSA.22 Therapeutic measures for OSA are: 1) Continuous positive airway pressure (CPAP) 2) Surgery As OSA is mainly a problem of multilevel upper airway collapse, this has to be well addressed for a successful surgical outcome This well explains why tracheostomy is completely effective, though not well accepted, and uvulopalatopharyngoplasty by itself has relatively low efficacy for treatment of OSA Sleep Disorders 1349 3) Oral appliances 4) Behavioral such as attain an ideal body weight, avoid sedatives or alcohol or smoking and sleeping on sides The most consistently efficacious, safe therapy and therefore the most commonly recommended, is CPAP therapy CPAP mechanically splints open the entire upper airway, hence is universally effective regardless of the site of obstruction However, the major disadvantage is that it is not curative for OSA, i.e lifelong usage is generally expected Narcolepsy Narcolepsy is not a rare disease.31 It affects up to in every 1000 individuals in North America, making it relatively as common as Parkinson disease or multiple sclerosis It is known that there are many instances of symptomatic patients who are not diagnosed as narcolepsy for between 10 to 40 years Men and women are equally affected and its onset occurs in the second or third decade of life It is a primary sleep disorder characterized by excessive daytime sleepiness In addition, patients with narcolepsy can have abnormal manifestations of REM sleep, such as cataplexy, hallucination on falling asleep or waking up and sleep paralysis.31 A patient can have sleepiness and electrophysiological evidence of narcolepsy, but without the other features This condition is called monosymptomatic narcolepsy Some patients can develop cataplexy years later Patients have a irresistible tendency to sleep This has given rise to the term “sleep attacks” Despite many catnaps, patients with narcolepsy not sleep any more hours than normal people Abnormal drowsiness (apart from sleep episodes) is the cause of poor job performance, scholastic failure, family disruption and anti-social behavior Automatic behavior is the result of ongoing drowsiness punctuated by microsleep Cataplexy is a symptom unique to narcolepsy It is episodic weakness without any loss in consciousness and occurs in all voluntary muscles in the body, except the eye muscles and diaphragm, and can last for minutes Laughter is the most common emotion that brings on the weakness It could be mild enough to cause buckling of knee, jaw dropping, head dropping or dysarthria The marked weakness could cause the patient to fall It is this history that distinguishes cataplexy from transient ischemic attacks, myasthenia gravis, periodic paralysis, syncope and atonic seizure 1350 A Clinical Approach to Medicine Sleep paralysis and hypnagogic hallucinations are terrifying experiences for the patient during the onset of sleep or upon waking up The hallucinations of narcoleptic patients are dream-like, visual events with auditory and tactile perceptions or a feeling of levitation They differ from dreams in that there is no theme or story, e.g a static image (a hallucination of someone standing over the bed) is present The etiology of narcolepsy remains unknown although there seems to be a genetic component32 as over 90% of narcoleptics have HLA-DR2 or HLA-DQ1 Recent studies also indicate the nacroleptics have deficiency in the hypothalamic neuropeptide hypocretin.33 Objective evaluation of narcolepsy Patients should have an overnight polysomnography followed by a multiple sleep latency test The former excludes other forms of sleep disorders and the latter demonstrates sleep onset REM (the electrophysiological signature of narcolepsy) in or more tests with an average sleep latency of five minutes or less HLA typing supports, but does not determine, the diagnosis of narcolepsy as up to 30% of the general population without narcolepsy may have the same HLA type.32 The measurement of cerebrospinal fluid concentrations of hypocretin as a new diagnostic tool may be a promising application.33 Management of narcolepsy There is no cure for narcolepsy The hypersomnia in these patients responds well to stimulant medication, such as amphetamines and newer drug, Modafinil; with little evidence of tolerance, dependence, or abuse Naps of between 15 to 20 minutes are refreshing for these patients and they can cut down on the dosage of stimulant medication The ancillary symptoms of cataplexy, hypnagogic hallucinations, and sleep paralysis respond to antidepressants, a REM suppressant Many patients with narcolepsy are poorly tolerant of irregular wake/sleep patterns, including shift-work Idiopathic Hypersomnia This condition is characterized by hypersomnia and naps without cataplexy or REM sleep abnormality Sleepiness dominates the patient’s life Sleep Disorders 1351 The diagnosis is made based on normal overnight polysomnography and multiple sleep latency test Treatment is with stimulant medication Peroidic Hypersomnia These are uncommon, but are well-defined conditions of episodic hypersomnia that typically occur weeks or months apart The Kleine–Levin syndrome is one such example and it is characterized by excessive sleepiness associated with hyperphagia and hypersexuality The symptoms begins in young, adolescent boys and its etiology is unknown Menstrual hypersomnia is another form of periodic hypersomnia, which strikes in the days preceding menstruation The onset is soon after menarche and may disappear after pregnancy PARASOMNIAS Parasomnias are defined as unpleasant or undesirable behavioral phenomena, which occur during sleep.34 They are initially attributed to psychiatric disorders but recent clinical and ploysomnographic analysis has revealed that they are in fact the result of a large number of completely different conditions, most of which are diagnosable and treatable These disorders are manifestation of central nervous system activation usually transmitted through skeletal muscle or autonomic nervous system channels And the behavior may result in injury or violence to self or others They can be classified as: 1) Arousal disorders, including confusional arousal, sleepwalking and sleep terrors which are common in children Treatment with medication or hypnotherapy is often effective 2) Sleep-wake transition disorders, including rhythmic movement disorders, sleep starts, sleep talking and nocturnal leg cramps 3) Parasomnias associated with REM sleep, including nightmares, sleep paralysis, impaired sleep-related penile erections and REM sleep behavior disorder (RBD) RBD was predicted by animal experiments (bilateral perilocus ceruleus lesions) in 1965 and were subsequently identified in humans.35 In RBD, there is absence of REM atonia and this permits “acting out of dreams”, often with violent, injurious behavior The patient might dream that he was rescuing his wife from 1352 A Clinical Approach to Medicine attackers and, in the process, actually hit and injure her whilst sleeping next to her RBD is more common in the elderly Although it can occur in otherwise healthy people, there is a higher prevalence of central nervous disorders such as Parkinson’s disease The administration of Clonazepam at bedtime suppresses these attacks Other parasomnias such as nocturnal seizures, sleep bruxism, enuresis and sleep-related abnormal swallowing syndrome Nocturnal seizures may be misdiagnosed because of their tendency for bizarre behaviors, exclusively nocturnal timing, and clustering in time.36 DISORDERS OF THE SLEEP/WAKE CYCLE The sleep-wake pattern of humans follow a circadian rhythm The impact of circadian disorders is on the alertness, concentration and performance of the individuals during the time when they have to be awake Circadian disturbances can be triggered off by: 1) intrinsic factors, i.e malfunction of the biologic clock per se Primary circadian dysrhythmia include: delayed sleep phase syndrome, advanced sleep phase syndrome, non 24-hour sleep phase and the irregular sleep phase syndrome 2) extrinsic factors, i.e due to environmental effects upon the underlying clock The societal revolution in the last century has given rise to steady erosion of the circadian rhythm in shift workers and air/space travelers Jetlag occurs when the body is transported rapidly to a new time zone while the internal circadian clock remains at the home time and it takes a while for the body clock to adjust to the new time zone These secondary circadian disorders such as shift work and jetlag are usually apparent upon simple questioning of the patients The primary disorders may be much more difficult to diagnose, as they may masquerade as other disorders such as hypersomnia, insomnia, substance abuse, or psychiatric conditions Identification of these disabling disorders is important, as treatment exist Several agents can manipulate circadian rhythms They are phototherapy (using bright light) for shift workers and jetlag; chronotherapy for delayed sleep phase syndrome; melatonin, which synchronizes the circadian rhythm and facilitates sleep, for jetlag and advanced sleep phase syndrome Sleep Disorders 1353 EVALUATION OF SLEEP DISORDERS Clinical A detailed sleep history and focused physical examination should be performed The latter include evaluation of the oronasomaxillofacial and neck region, cardiopulmonary, neurologic and psychiatric examinations Supporting information from roommates, family members or care-givers is usually required for a complete and accurate assessment of sleep behaviors Sleep/wake diaries completed by the patient or observer over weeks may be helpful Laboratory Studies It is recommended that patients who required sleep studies be referred to the sleep specialist as these tests are complex and are best tailored to the specific clinical situation Polysomnography (PSG) The technology used for the diagnosis of sleep disorders employs standard electrophysiologic recording systems which allows sleep to be accurately quantified, sleep stages to be fully characterized and the analysis of sleep-related events The basic PSG consists of electroencephalogram, electro-oculogram, chin electromyogram, electrocardiogram, respiratory parameters (at least, airflow) and anterior tibialis electromyogram Multiple respiratory parameters, including respiratory effort, oxygen saturation and airflow, must be monitored to evaluate sleep disordered breathing Other parameters may be monitored as clinically indicated, such as multiple channel electroencephalogram for parasomnias, esophageal sensors for upper airway resistance syndrome or reflux, or penile tumescence for erectile function Multiple sleep latency test (MSLT) The MSLT is a standardized and well-validated measure of quantifying daytime sleepiness30 and in differentiating the subjective complaints of “sleepiness”, “fatigue” and “tiredness” The MSLT consists of four to five 20 minute-nap opportunities scheduled at 2-hour intervals in the 1354 A Clinical Approach to Medicine day It quantitates sleepiness by standard electrophysiological test that measures how quickly a subject falls asleep on sequential naps by measuring the latency between ‘lights out’ and sleep onset A mean latency of minutes or less indicates severe daytime sleepiness The MSLT also identify the abnormal occurrence of REM sleep during a nap and the number of naps during which REM sleep appears is noted as well As many factors can affect sleep latency and REM sleep during the daytime, proper interpretation requires a preceding night PSG to measure the quality and quantity of night sleep prior to the MSLT Actigraphy This is a more objective way of analyzing the sleep/wake pattern compared to sleep diaries completed by patients An actigraph is a small wrist-mounted device that records the activity plotted against time, usually for to weeks The data collected is transferred into a computer where the software displays activity versus time demonstrating the rest/activity pattern This information compliments the subjective sleep log obtained concurrently LEGAL ASPECTS OF SLEEP AND ALERTNESS Sleep disorders and lack of alertness can cause various legal problems It is a vexing question whether a person who causes harm while sleep-walking is criminally liable The association between daytime sleepiness and accidents is well-known It is becoming increasingly apparent that various drugs, including sedatives, tranquilizers and hypnotics, seriously affect a person’s ability to drive or operate heavy machinery as much if not more than alcohol does When a driver falls asleep at the wheel, the court may convict him of a driving offence on the grounds that he should have pulled off the road when he began to feel drowsy However, such sleep may be totally unpredictable and it occurs in microsleep Due to sleep deprivation regardless of the cause, short microsleeps occur during periods of wakefulness They take the form of short 1- to 10-second bursts of Stage or sleep, enough to result in an accident that the person is not aware of This typically results in frequent automobile accidents especially along highways, driving on the wrong side of the road and ignoring traffic signals These attacks are difficult to distinguish from automatism, which is associated with partial complex seizures, or absence seizures, transient Sleep Disorders 1355 global amnesia or simple day-dreaming The concept of microsleep and its implication is not well-known among doctors and the public CONCLUSION Sleep disorders medicine has exponentially evolved over the past few decades Although there remains many intriguing issues to be resolved, it is timely that doctors and the public be more aware of this field of medicine and certainly, it should be a core subject well taught in the medical undergraduate school REFERENCES National Commission on Sleep Disorders Research, Report of the National Commission on Sleep Disorders Research, Sup of Docs., U.S Government Printing Office, DHHS Pub Washington, DC, 1992 Douglas NJ, White DP, Pickett CK, Respiration during sleep in normal man, Thorax 37:840–844, 1982 Mahowald M, Schenck C, Status dissociates — a perspective on states of being, Sleep 14:67–79, 1991 Diagnostic Classification Steering Committee, Thorpy MJ, Chairman, International Classification of Sleep Disorders : Diagnostic and coding manual, Rochester, MN: American Sleep Disorders Association, 2000 The Gallop Organisation Sleep in American, National Sleep Foundation Los Angeles, California, pp 1–30 Kua EH, Depressive disorder in elderly Chinese people, Acta Psychiatr Scand 81(4):386–388, 1990 Yeo BK, Perera IS, Kok LP, Tsoi WF, Insomnia in the community, Singapore Med J 37(3):282–284, 1996 Roth T, The relationship between psychiatric diseases and insomnia, Int J Clin Pract Suppl 116:3–8, 2001 Walsh JK, Mahowald MW, Avoiding the blanket approach to insomnia, Postgraduate Med 90:211–224, 1991 10 Monk TH (ed), Sleep, Sleepiness and Performance, John Wiley and Sons, Chichester, 1991 11 Leung L, Becker CE, Sleep deprivation and house staff performance, Update 1984–1991, J Occupational Medicine 12:1153–1160, 1992 12 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S, The occurrence of sleepdisordered breathing among middle-aged adults, N Engl J Med 328:1230–1235, 1993 1356 A Clinical Approach to Medicine 13 Ip MSM, Lam B, Lauder IJ, Tsang KWT, Chung KF, Mok YW et al., A community study of sleep-disordered breathing in Middle-aged Chinese Men in Hong Kong, Chest 119:62–69, 2001 14 Tan YK, Khoo KL, Low JAYH, Wong ZW, Theng CTS, Ong YY et al., Ethnicity, Obstructive Sleep Apnea and Ischaemic Heart Disease, Ann Acad Med, Singapore, 28:214–216, 1999 15 Puvanderan K, Goh KL, From snoring to sleep apnea in a Singapore Population, Sleep Research Online 2(1):11–14, 1999 16 Strohl KP, Redline S, Recognition of obstructive sleep apnea, Am J Respir Crit Care Med 154:279–289, 1996 17 Guilleminault C, Quera-Salva MA, Partinen M, Jamieson A, Women and the obstructive sleep apnoea syndrome, Chest 3:983–988, 1988 18 Guilleminault C, Partinen M, Hollman K, Powell N, Stoohs R, Familial aggregates in obstructive sleep apnea syndrome, Chest 107:1545–1551, 1995 19 Kripke DF, Ancoli-Israel S, Klauber MR, USA population estimates for sleepdisordered breathing: high rates in minorities, Sleep Res 24:268, 1995 20 Ong KC, Ckerj AA, Comparison of the severity of sleep-disordered breathing in Asian and Caucasian patients seen at a sleep disorders centre, Respir Med 92:843–848, 1998 21 Naegele B, Thouvard V, Pepin JL, et al., Deficits of cognitive executive functions in patients with sleep apnea syndrome, Sleep 18:43–52, 1995 22 Findely L, Smith C, HopperJ, Dinnen M, Suratt P, Treatment with nCPAP decreases automobile accidents in patients with sleep apnea, AJRCCM 161:857–859, 2000 23 Murry WJ, A new method of measuring daytime sleepiness: the Epworth Sleepiness Scale, Sleep 14:540–545, 1991 24 Roux F, D’Ambrosio C, Mohsenin V, Sleep-related breathing disorders and cardiovascular disease, Am J Med 108(5):396–402, 2000 25 Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S et al., Association of sleepdisordered breathing, sleep apnea, and hypertension in a large community-based study Sleep Heart Health Study, JAMA 283(14):1829–1836, 2000 26 Kessler R, Chaouat A, Weitzenblum E, Oswald M, Ehrhart M, Apprill M, Kreiger J, Pulmonary hypertension in the obstructive sleep apnea syndrome: prevalence, causes and therapeutic consequences, Eur Respir J 9(4):787–794, 1996 27 Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AF, Sleep-disordered breathing among patients with first-ever stroke, J Neurol 247(1):41–47, 2000 28 Standards of Practice Committee of the American Sleep Disorders Association, Practice parameters for the use of portable recording in the assessment of obstructive sleep apnea, Sleep 17:372–377, 1994 Sleep Disorders 1357 29 Indications for Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee, Practice Parameters for the Indications for Polysomnography and Related Procedures, Sleep 20:406–422, 1997 30 American Sleep Disorders Association, The clinical use of multiple sleep latency test, Sleep 15:268–276, 1992 31 Aldrich MS, The neurobiology of narcolepsy-cataplexy, Progr in Neurobiology 41:538–541, 1993 32 Practice parameters for the use of stimulants in the treatment of narcolepsy, Standards of practice committee of the American Sleep Disorders Association, Sleep 17:348–351, 1994 33 Overeem S, Scanmmell TE, Lammers GJ, Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy, Curr Opin Nuerol 15(6):739–745, 2002 34 Schenck CH, Hurwitz, TD, Mahowald MW, REM sleep behavior disorder: a report on a series of 96 cases and a review of the literature, J Sleep Res 2:224–231, 1993 35 Mahowald MW, Schenck CH, REM sleep parasomnias, in: Kryger MH, Roth T, Dement WC (eds.), The Principles and Practice of Sleep Medicine, 3rd ed., WB Saunders Philadelphia, pp 724–741, 2000 36 Mahowald MW, Schenck CH, Parasomnia purgatory — the epileptic/nonepileptic interface, in: Rowan AJ, Gates JR, (eds.), Non-epileptic Seizures, ButterworthHeinemann, pp 123–139, 1993 This page intentionally left blank 78 Lung Cancer Constance Lo and Philip Eng INTRODUCTION Lung cancer remains the number cancer in males and number cancer in females (after breast and colorectal cancer) in Singapore to date This is despite the decreasing prevalence of lung cancer since the mid-1980s The age-standardized rate of lung cancer is 54 and 17 per 100 000 per year for males and females respectively.1 Epidemiology of Lung Cancer The age-adjusted incidence of lung cancer among men exceeds by twofold that of women The peak incidence is at age 70–79 Lung cancer is the leading cause of cancer mortality in most countries.2 The varying rates of incidence rates correlates well with cigarette smoking habits prevalent at least 10 years prior Much of the geographical and cultural variations in lung cancer incidence can be at least partially attributed to the variations in smoking habits, including age when the habit was picked up, type of cigarettes smoked and duration of smoking 1359 1360 A Clinical Approach to Medicine Lung cancer is largely felt to be a “preventable” disease There is a strong etiologic link between lung cancer and cigarette smoking, being implicated in Ͼ 85% of lung cancer cases Tobacco smoke is a potent cocktail of carcinogens, including polynuclear aromatic hydrocarbons, N-nitrosamines, aromatic amines, and other organic (benzene, acrylonitrile) and non-organic compounds (arsenic, acetaldehyde) Increases in lung cancer are seen 20–30 years after a parallel increase in cigarette smoking.3 The risk of developing lung cancer increases with both the duration of smoking and the number of cigarettes smoked While manufacturing companies have the touted lower tar content and the use of filters to reduce lung cancer risk among smokers, changes in smoking patterns (for example, deeper inhalations) reduce this theoretical advantage Other forms of tobacco smoke, in the form of pipe and cigar smoking are also linked to lung cancer Although smoking cessation reduces the risk of developing subsequent lung cancer among smokers, the risks still remain elevated above non-smokers, even up to 40 years of abstinence Environmental tobacco smoke also has the same carcinogenic composition of mainstream smoke, and involuntary smoking is associated with an increased risk of lung cancer Other environmental agents incriminated in the causation of lung cancer include radon, asbestos, arsenic, nickel chromium and combustiongenerated carcinogens In developing countries, exposure to the fumes from cooking stoves and fires has been associated with elevated lung cancer risk Lung cancer is known to complicate diffuse fibrotic lung disease While lung cancer also frequently complicates chronic obstructive lung disease, this association may arise from a common etiology: cigarette smoke Finally, genetic and dietary factors clearly influence the development of lung cancer, as ultimately, only approximately 10–15% of lifetime smokers develops lung cancer, and 10–15% of patients with lung cancer are non-smokers Studies have suggested a protective association between lung cancer and increased fruit and vegetable consumption In addition, other micronutrients have been suggested to decrease lung cancer risk, including vitamin C and selenium Lastly, the tendency for familial aggregation of lung cancer suggests an inheritable tendency This may be secondary to inherited variations in carcinogen metabolism and DNA repair Lung Cancer 1361 Signs and Symptoms More than 90% of patients with lung cancer will have symptoms at presentation The symptoms are diverse, and arise from: 1) the primary tumor; 2) regional/intrathoracic spread; 3) distant metastasis; and 4) paraneoplastic syndromes Symptoms The common symptoms are: • • • • • Cough Wheeze or stridor Hemoptysis Dyspnea Chest pain Symptoms arising from the primary tumor depend on its location Central tumors (in the mainstem, lobar and proximal segmental bronchi) are associated with cough, hemoptysis, wheezing, and dyspnea secondary to central airway obstruction with post-obstructive pneumonitis Although cough is the most common presenting symptom in lung cancer, it is often difficult to distinguish the cough due to chronic bronchitis (in the smoker) versus that due to lung cancer Suspicious features of cough in a chronic smoker are a change in the character of the cough, a change in the quality and quantity of expectoration, and hemoptysis Although bronchitis is the most common cause of hemoptysis, the incidence of bronchogenic carcinoma varies from 19–29% Bronchoscopic series also show that lung cancer can occur in up to 9% of patients with hemoptysis and an unsuspecting chest radiograph The indications for bronchoscopic airway examination in patients with hemoptysis and a normal chest X-Ray include: age over 40 years, a significant smoking history and male sex.4,5 Conversely, tumors arising in the distant airways (peripheral tumors) tend to have less cough, and present with chest wall pain Intrathoracic extension Symptoms from intrathoracic extension may be from direct extension of the tumor or lympthatic spread This may cause symptoms from compression of vascular structures (superior vena caval obstruction), 1362 A Clinical Approach to Medicine nerve invasion (recurrent laryngeal, and phrenic nerves, brachial plexus involvement and sympthathetic nerve involvement), visceral (pericardium, diaphragm and esophagus) , and chest wall involvement (pain) One study showed that lung cancer is one of the commonest causes of metastatic carcinoma of unknown primary The most common site of distant metastasis from lung cancer the bones, the liver, adrenal glands, intraabdominal lymph nodes, brain, spinal cord and skin Paraneoplastic Symptoms • • • • • • Loss of appetite and weight Hypertrophic osteoarthropathy Hypercalcemia Ectopic ACTH Secretion Syndrome of Inappropriate ADH Secretion Lambert–Eaton Syndrome Other Symptoms Clearly within any individual tumor stage, and adverse prognosis was seen with concomitant systemic symptoms of anorexia, weight loss and fatigue This is thought to be a reflection of a subgroup with more extensive disease Asymptomatic It is the occasional individual who has a chest X-Ray done for other reasons, e.g pre-employment or health screening, where a solitary pulmonary nodule is the only presentation This presents the best, though rare, scenario for a curative resection Diagnostic Tests for Lung Cancer • • • • • • • Sputum cytology Lymph node biopsy (fine needle aspiration cytology and excision biopsy) Closed pleural biopsy and thoracentesis Percutaneous lung biopsy (peripheral lesions) Bronchoscopy (proximal lesions) Thoracoscopy Thoracotomy (rarely) Lung Cancer 1363 A variety of techniques are available to confirm a diagnosis of lung cancer The diagnostic procedure of choice depends on the patient’s disease presentation, and specimens for histology or cytology may be obtained from either the primary tumor or from secondary sites of involvement, as for example, lymph nodes, and skin nodules Central tumors may be assessed by sputum cytology, (which has a lower yield of 20–30%) or flexible fibreoptic bronchoscopy, which yields as high as 90% when the tumor is visible endoscopically) Peripheral lung lesions may be sampled by bronchoscopic lung biopsy or transthoracic needle aspiration biopsies Pleural effusions should be sampled by repeated pleural aspirations, with a view to thoracoscopy after consecutive negative samples Peripheral lung nodules may also be sampled by thoracoscopic lung biopsies Finally, patients with a nodule that is suspicious for malignancy and limited disease should be considered for excision biopsy and lobectomy should lung cancer be confirmed CLASSIFICATION OF MALIGNANT LUNG TUMORS IN 1999, the World Health Organization (WHO) revised its classification of lung and pleural tumors.6 A discussion of the changes is beyond the scope of this chapter, and the reader is requested to refer to the article for its details Bronchogenic carcinoma is derived from epithelial tissue, and histological classification is based on light microscopy The most common subtypes of bronchogenic carcinoma are squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell lung cancer Currently, adenocarcinoma has surpassed squamous cell carcinoma as the most frequent histologic subtype, representing approximately 31% of lung cancers, with squamous cell at 30%, large cell at 9%, and small cell at 18%.7 The important clinical question is in differentiating small cell lung cancer from non-small cell lung cancer, as, traditionally, reasonable results may be obtained with chemotherapy in the former cell type STAGING OF NON SMALL CELL LUNG CANCER The International System for Staging Lung cancer by Mountain8 is currently the most widely used staging system This classification regroups the 1364 A Clinical Approach to Medicine TNM subsets based on survival in a contemporary time frame The stage of disease at presentation is thus a strong prognostic factor in survival Primary Tumor Tx T0 T1s T1 T2 T3 T4 Primary tumor cannot be assessed or tumor proven by the presence of malignant cells in sputum or bronchial washings, but not visualized by imaging or bronchoscopy No evidence of primary tumor Carcinoma in situ Tumor Ͻ cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than lobar bronchus Tumor with any of the following: Ͼ cm in widest dimension; involves main stem bronchus Ͼ cm from carina; invades visceral pleura; associated atelectasis or obstructive pneumonitis that extends to hilar but does not involve entire lung Tumor of any size that directly invades any of the following: chest wall, diaphragm, mediastinal pleura, parietal pericardium, or tumor in main stem bronchus Ͻ cm distal to carina but without involvement of carina, or associated atelectasis or obstructive pneumonitis of entire lung Tumor of any size that invades: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina, or tumor with malignant pleural or pericardial effusion, or with satellite tumor nodules within the ipsilateral primary tumor lobe of the lung Regional Lymph Nodes Nx N0 N1 N2 N3 Regional Lymph nodes cannot be assessed No regional lymph node metastases Metastases to ipsilateral peri bronchial or hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor Metastases to ipsilateral mediastinal lymph nodes and/or subcarinal lymph nodes Metastases to contra lateral mediastinal lymph nodes Lung Cancer 1365 Distant Metastases Mx M0 M1 Presence of metastases cannot be assessed No distant metastases Distant metastases Stage Grouping Carcinoma in situ IA IB T1N0M0 T2N0M0 IIA IIB T1N1M0 T2N1M0 T3N0M0 IIIA T3N1M0 T1N2M0 T4N0M0 T2N3M0 T2N2M0 T4N1M0 T3N3M0 IIIB IV T3N2M0 T4N2M0 T4N3M0 T4N3M0 Any T, Any N, M1 MANAGEMENT OF NON-SMALL CELL LUNG CANCER Surgical Treatment Surgery with curative intent remains the cornerstone for early lung cancers (stage IA and IB, IIA and IIB, and selected patients with IIIA) Patients with good performance status and locally advanced disease (Stage IIIA) may benefit from pathologic down staging with neoadjuvent chemo radiotherapy prior to surgical resection.9,10 Standard resection techniques are lobectomy, bilobectomy or pneumonectomy Limited resections with wedge resections and segmentectomy appear to have a higher incidence of recurrence when compared with standard lobectomy.11 Other lung sparing surgical procedures include bronchial and sleeve operations Preliminary assessment of resectable lung cancers includes a complete history, physical examination, and computerized tomogram of the chest to assess the tumor and mediastinum The importance of mediastinal lymph node status in overall prognosis cannot be 1366 A Clinical Approach to Medicine underscored and is a powerful prognostic indicator Surgery as a sole modality of treatment in patients with greater than N2 disease is poor.12,13 Mediastinal nodal enlargement seen on computerized tomogram of the chest has a reported sensitivity and specificity of 64% and 62% respectively, using a short axis diameter of cm.14 Because of this low specificity, enlarged lymph nodes should be biopsied for accurate staging before curative surgery is precluded.15 Bone scans should be performed on the finding of elevated serum calcium, or elevated alkaline phosphatase and brain scans in the event of symptoms or localizing signs Medical evaluation of the patient’s respiratory status includes pre-operative spirometry A patient with a pre-operative FEV1 (forced expiratory volume in one second) of greater than litres, can be expected to tolerate a pneumonectomy.16,17 Other techniques to predict post-operative pulmonary complications include quantitative perfusion lung scanning18 and exercise testing.19,20 Metastatic Disease Radiotherapy Radiotherapy may be used in radical and palliative settings Radical radiotherapy aims to provide local control of the tumor in patients with clinical Stage I and II disease who are medically in-operable due to comorbid problems, for example, ischemic heart disease In contrast, palliative radiotherapy is indicated for metastatic disease to the brain, bones, spinal cord, superior vena caval obstruction and endobronchial obstruction Chemotherapy Cisplatinum based chemotherapy has been showed to improve survival outcome in patients with metastatic disease when compared to best supportive care At one year, 10% more patients receiving palliative chemotherapy would be alive compared to the supportive care group.21 However, it is clear that much of this data was gleaned from trials where only patients with good performance status (ECOG Ͻ 2) are included Hence, the decision whether or not palliative chemotherapy is to be useful should only be made following a lengthy discussion with the patient on the relative risks, benefits and costs involved Lung Cancer 1367 Interventional bronchoscopy for malignant airway occlusion A variety of endoscopic techniques have evolved to relieve malignant major airway occlusion This includes neodymium:yttrium-aluminiumgarnet (Nd:YAG) laser resection for malignant exophytic lesions, implantation of tracheobronchial airway stents for extrinsic airway compression and brachytherapy, which allows local irradiation to a tumor following bronchoscopic placement of an after loading catheter Malignant pleural effusion Management of malignant pleural effusion is entirely palliative There is no doubt that tube thoracostomy followed by pleurodesis is the best approach in most patients with malignant pleural effusion Intermittent thoracocentesis results in frequent recurrences and possibility of iatrogenic pleural space infection Efforts continue in the quest for the best pleurodesing agent Bleomycin, tetracycline and talc slurry remain the agents to instil via tube thoracostomy Pleurodesis may also be performed under direct vision using talc poudrage via thoracoscopic approach (video assisted thoracoscopy, medical thoracoscopy), and is frequently reserved for the young and fitter patients, yet its cost-effectiveness remains controversial Malignant pericardial effusion The approach to malignant pericardial effusion is mainly surgical with options of pericardial window or pericardiectomy In the critically ill patient with cardiac tamponade and hypotensive, bedside pericardiocentesis with ultrasound guidance in the ICU setting is life-saving Small Cell Lung Cancer Small cell lung cancer accounts for 20–25% of all cases of bronchogenic carcinoma Small cell lung cancer is an aggressive disease with a short symptom period preceding diagnosis Nevertheless, at the time of diagnosis, 70% of patients already frequently have metastatic disease Without treatment, survival may be as short as 6–12 weeks for such patients.22 Small cell lung cancer is commonly staged according to the 2-stage system developed by the Veterans Administration Lung Cancer Study 1368 A Clinical Approach to Medicine Group The essence of the 2-stage classification is the ability to encompass the disease within radiation portal Hence, limited stage disease is defined as tumor confined to the ipsilateral hemithorax and its regional lymph nodes (hilar or mediastinal), with or without ipsilateral supraclavicular lymph node involvement Extensive disease is defined as disease beyond the confines of the ipsilateral hemithorax, and includes metastatic disease and pericardial disease As the majority of patients present with metastatic disease, staging includes chest radiographs, computerized tomography of the chest, liver, adrenals and head, and bone scans Routine bone marrow aspirates and biopsy in staging is not recommended outside research protocols Common sites of dissemination include the bone, liver, the central nervous system, lymph nodes and pleura Treatment Chemotherapy remains the cornerstone in the management of small cell lung cancer, given 1) at the time of diagnosis, small cell carcinoma is frequently a systemic neoplasm, and 2) the chemosensitive nature of small cell lung cancer The treatment scenario can be divided into limited-stage, extensive-stage and relapsed disease Limited-stage disease Limited-stage disease is treated with curative intent with chemotherapy and radiation therapy, with approximately 20% of patients achieving a cure Combination regimens using chemotherapy and radiotherapy are employed in the treatment of limited stage disease Popular chemotherapeutic protocols include 1) Etoposide and Cisplatin (EP) 2) Cyclophosphamide, doxorubicin, vincristine (CAV), and 3) Cyclophosphamide, doxorubicin and etoposide (CAE) The most commonly used regimen is EP, as it has the most favorable toxicity profile The addition of thoracic radiotherapy (to control local disease has a modest advantage in survival23,24 and should be considered early, while weighing against the overall treatment toxicity The overall response rate is 80–90%, with a 2-year survival rate of 20–40%.25 Lung Cancer 1369 Extensive disease Chemotherapy remains the mainstay of extensive stage disease, with regimens similar to limited stage disease Routine thoracic irradiation is not prescribed and its role is relegated to palliation of symptomatic sites The overall response rate is 50–70%, with 2-year survival of 5–10% Recurrent disease Following successful chemotherapy, most patients experience relapse and die within years The prognosis for recurrent small cell lung cancer is poor, with median survival of 4–5 months when treated Salvage protocols depend on the previous chemotherapeutic regimen, its response, and the duration of response Prophylactic cranial irradiation Patients with limited disease achieving a complete remission should be considered for prophylatic cranial irradiation, which reduces the occurrences of brain metastases.26 Surgery for small cell lung cancer Surgery in not considered standard treatment in the management of small cell lung cancer, as studies have not shown a survival advantage with the addition of surgery in limited-stage disease There has been some interest, however, in patients that present with a solitary pulmonary nodule In historical series of patients who present with a solitary pulmonary nodules that is subsequently found to be small cell following resection, impressive 5-year survival reached 40–53%.27 Surgery was often combined with post-operative chemotherapy Hence, this encouraging result has revived the controversial role of surgery in the management of very small cell lung (T 1-2, N0 tumors) The Solitary Pulmonary Nodule (SPN) The optimal management of an isolated pulmonary opacity seen on plain chest X-Ray is not an unusual clinical dilemma On the one hand, the resection of malignant nodules provides the best opportunity for cure, with 5-year cure rates as high as 80% with stage I lesions.28 This should be 1370 A Clinical Approach to Medicine weighed against the risks of an unnecessary thoracotomy for benign lesions A solitary pulmonary nodule is defined as a well-circumscribed spherical lesion that is completely surrounded by normal lung tissue, and is not associated with adenopathy or atelectasis The size is variable, but is generally agreed to be less than cm in diameter The causes of the solitary pulmonary nodule can be divided into malignant and benign causes Examples of common causes of solitary pulmonary nodules are as follows: Malignant Primary bronchogenic carcinoma Solitary pulmonary metastasis Bronchial carcinoid Pulmonary sarcoma Benign Granulomas: tuberculosis, histoplasma, coccidiodomycosis Harmatoma Abscess Pulmonary arteriovenous malformations Pulmonary sequestration Pulmonary infarcts Bronchogenic cysts Wegener’s granulomatosis Rheumatoid nodule Amyloid Echinococcal cyst The majority of solitary pulmonary nodules (Ͼ 50%) have a benign etiology.29,30 Malignant causes account for 20% of cases, and to up to 40% in certain surgical series.31,32 Factors that predict benignity include: 1) Radiographic stability A nodule that has remained stable in size over duration of years is likely to be benign, and no further investigations beyond annual chest radiographs are necessary.33 It cannot be emphasized enough that the first step in the evaluation of SPN is a review of previous chest X-Rays 2) Calcification pattern Characteristically, calcification in a difuse, laminated or central pattern favors a benign process Harmatomas tend to have a popcorn calcification pattern Eccentric or stippled calcification, is seen in both benign and malignant lesions Predictors of malignancy The presence of spiculation and irregularity on the nodule edge seen on both the plain X-Rays and computed tomographic studies is suggestive of Lung Cancer 1371 a malignant nodule In addition, larger nodules (e.g Ͼ cm), and advanced age tend to favor a malignant nodule.34 While cavitation of a nodule is seen in both benign and malignant nodules, cavitory nodules with a wall thickness Ͼ mm were more likely to be malignant (84% malignant), compared with Ͻ mm (95% benign).35 Histological diagnosis may be obtained by transthoracic needle aspiration, bronchoscopic biopsy, thoracoscopy and thoracotomy Screening for Lung Cancer The five-year survival for patients with lung cancer, at 7–13%36,37 is an appalling figure At the time of presentation, the majority of patients have advanced disease beyond curative surgery.41 The idea of earlier detection of bronchogenic carcinoma via screening methods is an appealing concept The most celebrated trials involving lung cancer screening were in the 1970s by the Mayo Clinic,38 John Hopkins39 and Memorial Sloan–Kettering Hospitals.40 In the Memorial Sloan–Kettering Lung project and, and John Hopkins Lung project, subjects were randomized to receive annual chest X-Rays (control group), or annual chest X-Rays with four monthly sputum cytology (screened group) No significant differences were found between the two groups with regards to overall cancers detected, number of late stage cancers and number of resectable cancers The Mayo Lung project had a slightly different protocol, the subjects first undergoing a prevalence screen comprising a chest radiograph and sputum cytologic examination Only patients found to be cancer-free were subsequently randomized to a control group, who received standard recommendation comprising annual chest X-Rays and sputum cytology, with no efforts at enforcing compliance, or the experimental group, who received four monthly chest X-Rays and sputum cytology The Mayo Lung Project found the proportion of early stage and resectable cancers to be higher in the experimental group Overall mortality between the two groups, however, did not reach statistical significance Much more recently, the Early Lung Cancer Action Project (ELCAP) looked at the use of low radiation dose computer tomography (low dose CT) in people at high risk of lung cancer They reported that low dose CT can greatly improve the possibility of detecting non small calcified nodules and thus of lung cancer when compared with CXR.41 This sensitivity has to be weighed against a high rate of false positive results, and high financial 1372 A Clinical Approach to Medicine cost Moreover, a reduction in mortality has not been demonstrated with low dose CT screening Other screening tools under evaluation include autoflorescence bronchoscopy, and monoclonal antibodies to detect neoplastic changes in the sputum of high-risk patient groups With ongoing enthusiasm into developing the ideal screening method for lung cancer, we should not neglect the role of primary prevention in reducing lung cancer mortality Efforts should continue in discouraging the smoking habit and facilitating smoking cessation REFERENCES Chia KS, Lee HP, Seow A, Shanmugaratnam K, Trends in Cancer Incidence in Singapore 1968–1992, Singapore Cancer Registry Report No 2, 1996 Miller BA, Ries LAG, Hankey BF et al (eds.), SEER Cancer statistics review: 1973–1990, Nat Cancer Institute NIH Pub No 93-2789, 1993 Advisory Committee to the Surgeon General of the US 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RW, Kosiuk JP, Templeton PA, Shepard JA, Bronchogenic carcinoma: analysis of staging in the mediastinum by CT and correlative lymph node mapping and sampling, Radiology 182:319–323, 1992 15 Dales RE, Stark RM, Raman S, Computerized tomography to stage lung cancer Approaching a controversy using meta-analysis, Am Rev Respir Dis 141:1096–1101, 1990 16 American College of Physicians, Preoperative pulmonary function testing, Ann Intern Med 112:793–794, 1990 17 Dunn WF, Scanlon PD, Preoperative pulmonary function testing for patients with lung cancer, Mayo Clin Proc 68:371–377, 1993 18 Markos J, Mullan BP, Hillma DR, Musk AW, Antico VF, Lovegrove FT, et al., Preoperative assessment as a predictor of morbidity and mortality after lung resection, Am Rev Resp Dis 139:902–910, 1989 19 Bechard D, Wetstein L, Assessment of exercise oxygen consumption as pre-operative criterion for lung resection, Ann Thorac Surg 44:344–349, 1987 20 Smith TP, Kinasewitz GT, Tucker WY, Spillers WP, George RB, Exercise capacity as a predictor of post-thoracotomy morbidity, Am Rev Resp Dis 129:730–734, 1982 21 Non-small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: a meta-analysis in patients from 52 randomized clinical trials, BMJ 311:899–909, 1995 22 Souhami RL, Law K, Longevity in small cell lung cancer: a report to the lung cancer subcommittee of the United Kingdom Co-ordinating Committee for Cancer research, Br J Cancer 61:584–589, 1990 23 Kotalik J, Yu E, Markman BR, et al., Practice guideline on prophylactic cranial irradiation in small-cell lung cancer, Int J Radiat Oncol Biol Phys 50:309–316, 2001 24 Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RT, et al., A metaanalysis of thoracic radiotherapy for small cell lung cancer, New Engl J Med 327:1618–1624, 1992 25 Johnson BE, Bridges JD, Sobczeck M, Patients with limited stage small cell lung cancer treated with concurrent twice daily chest radiotherapy and etoposide/cisplatin followed by cyclophasphamide doxorubicin and vincristine, J Clin Oncol 14:806–813, 1996 26 Kristjansen PE, Hansen HH, Prophylactic cranial irradiation in small cell lung cancer, Lung Cancer 87:161–162, 1995 1374 A Clinical Approach to Medicine 27 Kreisman H, Wolkove N, Quiox E, Small cell lung cancer presenting as a solitary pulmonary nodule, Chest 101:225–231, 1992 28 Lillington GA, Management of solitary pulmonary nodules, Dis Mon 37:271–318, 1991 29 Swenson SJ, Jett JR, Payne WS, Viggiano RW, Pairolero PC, Trastek VF, An integrated approach to the evaluation of the solitary pulmonary nodule, Mayo Clin Proc 65:173–186, 1990 30 Lillington GA, Systemic diagnostic approach to pulmonary nodules, in Fishman AP (ed)., Pulmonary Diseases and Disorders, 2nd ed., McGraw-Hill Book Company, New York NY, 3:1945–1954, 1988 31 Khouri NF, Meziane MA, Zerhouni EA, Fishman EK, The solitary pulmonary nodule assessment, diagnosis and management, Chest 91:128–133, 1987 32 Midthun DE, Swensen SJ, Jett JR, Clinical strategies for the solitary pulmonary nodule, Annu Rev Med 43:195–208, 1992 33 Good CA, Wilson TW, The solitary circumscribed pulmonary nodule: study of seven hundred five cases encountered roengographically in a period of three and one half years, JAMA 166:210–215, 1958 34 Midthun DE, Swensen SSJ, Jett JR, Approach to the solitary pulmonary nodule, Mayo Clin Proc 68:378–385, 1993 35 Woodring JH, Fried AM, Significance of wall thickness in solitary cavities of the lung: a follow up study, Am J Roentgenol 140:473–474, 1983 36 Boring CSS, Squires TS, Tong T, Cancer statistics, CA Cancer J Clin 42:19–38, 1992 37 Bignall JR, Martin M, Smithers DW, Survival in 6068 cases of bronchial carcinoma, Lancet 967:1067–1070 38 Fontana R, Sanderson DR, Woolner LB, Lung cancer screening: the Mayo programme, J Occup Med 28:746–750, 1986 39 Tockman M, Survival and mortality from lung cancers in a screened population: the John Hopkins Study, Chest 89 (suppl):325S–326, 1986 40 Melamed MR, Flehinger RB, Heelan RT, Perchick WA, Martinin N, Screening for early lung cancer: results of the Memorial Sloan– Kettering study in New York, Chest 86:44–53, 1984 41 Henschke CI, McCauley DI, Yankelentz DF, Naidich DP, McGuiness G, Mietiren OS, et al., Early lung cancer action project: overall design and findings from bedside survey, Lancet 354:99–104, 1999 79 Pulmonary Infections Loo Chian Min and Leng Poh Hock The entire respiratory tract extends from the nasal passage to the alveolus and infections can occur anywhere along this route In addition, infections of the sinuses and pleural space contribute significantly to respiratory dysfunction The host response to infection, virulence and load of infecting organisms and sensitivity of the microbe to antibiotics, all determine the overall outcome of a host who has pulmonary infections We shall discuss upper and lower respiratory tract infections, infections of the pleural space and uncommon but life-threatening pulmonary infections in this chapter ACUTE UPPER RESPIRATORY TRACT INFECTIONS Common Cold Etiology Viruses, e.g adenovirus, influenza, parainfluenza and respiratory syncytial virus Transmission is by aerosolized droplets and/or contaminated secretions on fomites and hands 1375 1376 A Clinical Approach to Medicine Clinical features It is usually an acute illness involving the nasopharynx with fever and cough After an incubation period of 12 hours to days, infection develops with local inflammation and submucosal edema and subsequent sloughing of the affected epithelial cells of the nose and pharynx General malaise and myalgia can occur Complications are rare but sinusitis and otitis media can occur Treatment Management is mainly symptomatic with antipyretics and nasal decongestants Antibiotics are not routinely indicated unless clinical symptoms persist and complications of pneumonia, bronchitis or sinusitis occur Randomized controlled clinical trials have shown that neuraminidase inhibitors, e.g zanamivir and ostelmivir, can reduce symptoms of influenza by 1–1.5 days if used within 48 hours of onset of illness Cost and side effects limit their widespread use In addition, amantadine and rimantidine are effective against influenza A Vaccination with inactivated live virus should be considered in patients who are Ͼ 65 years old, have cardiopulmonary disease, diabetes, renal failure, immunosuppression or resident of a chronic care facility Amantadine and rimantadine can be administered simultaneously with the vaccine to prevent influenza Sinusitis Etiology Bacteria: Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, anaerobes, Staphylococcus aureus, Gram-negative bacteria Viruses: Influenza, parainfluenza, rhinovirus virus Others: Actinomyces, Nocardia, Rhizopus and Rhizomucor species Sinusitis can be part of a sinopulmonary spectrum of diseases including ciliary dysmotility syndrome, Wegener’s granulomatosis, cystic fibrosis and diffuse panbronchiolitis Clinical Features These include low-grade fever, malaise, blocked nose, purulent nasal discharge, facial pain, toothache, headache and pain on mastication Examination may reveal discomfort and abnormal transillumination over Pulmonary Infections 1377 the appropriate sinus Purulent secretions through the ostium of the involved sinus may be seen on speculum examination or nasoendoscopy Sinus radiograph may show fluid levels, complete antral opacity or mucosal thickening, although it is not as sensitive as the CT (computed tomogram) scan, especially for the ethmoidal and sphenoidal sinuses A diagnostic antral puncture and culture of the secretions is useful for complicated cases Treatment Antibiotics need to cover both S pneumoniae and H influenzae Amoxycillin, amoxycillin-clavulanate or macrolides are the preferred first line antibiotics Duration of therapy is usually extended for days after resolution of symptoms Nasal decongestants should also be used Complications Rare complications include local and cerebral abscesses, cerebral infarction, meningitis, osteomyelitis, cellulitis, and cavernous sinus thrombosis Pharyngitis Etiology Bacteria: Group A Streptococcus, sexually transmitted diseases (gonorrhea, syphilis, Herpes Simplex virus), chlamydia, Corynebacterium diptheria, Arcanobacterium haemolyticum Viruses: Adenoviruses, Coxsackie viruses, Epstein–Barr virus, retrovirus Clinical features The hallmark is a sore throat, often with associated fever and malaise The presence of membrane suggests bacterial infection and culture for Corynebacterium diphtheriae should be obtained Localized cervical lymphadenopathy is frequent in streptococcal infection and infectious mononucleosis (IMS) Treatment Antibiotics should not be used if the cause of the sore throat is viral in origin However, antibiotics should not be withheld in the severely ill, 1378 A Clinical Approach to Medicine suspected or previous rheumatic fever, recurrent tonsillitis, concomitant laryngitis and stridor A throat swab yielding group A Streptococci is not diagnostic of streptococcal pharyngitis for this may be a normal throat commensal Bacterial infections contribute to a third of cases of pharyngitis Therapy with penicillin or erythromycin is justified for persistent and severe symptoms Ampicillin and its derivatives should be avoided for sore throats, as these are well-recognized to produce a widespread skin rash in IMS Epiglottitis This condition is well-recognized in children It has been described with increasing frequency in adults over the last few years H influenzae is often the offending microbe Clinical features These range from sore throat, cough and dysphagia to rapidly increasing life threatening symptoms of upper airway obstruction and respiratory distress over 1–3 days This can be a cause of acute upper airway obstruction Findings include fever, neck tenderness, stridor and pooling of saliva in the throat The epiglottis should not be visualized unless immediate endotracheal intubation or tracheostomy is available The diagnosis is suggested by lateral radiographs of the neck, which show laryngeal and epiglottic swelling (the “thumb sign”) Treatment Antibiotics active against the likely pathogens, in particular H influenzae should be started immediately Intravenous third generation cephalosporins provide adequate coverage in this situation Facilities for urgent upper airway management should be available at all times Laryngotracheitis In adults larygngotracheitis is usually viral in etiology, although M catarrhalis can be the causative agent Secondary infection of the trachea by S pneumoniae and H influenzae is a complication of viral upper respiratory tract infection Staphylococcus aureus tracheitis can be a sequelae of Pulmonary Infections 1379 herpes virus infection Airway intubation and tuberculosis can lead to tracheitis and airway stenosis Initially there may be a dry cough with retrosternal soreness Beta-agonist aerosols will help wheeze and cough Good hydration and physiotherapy facilitates removal of viscid secretions Appropriate antibiotics should be prescribed Acute Bronchitis Acute bronchitis may occur at the time of or shortly after an upper respiratory infection The etiological agents include viruses, particularly adenovirus or influenza virus in adults, and respiratory syncytial or parainfluenza virus in children; Mycoplasma pneumoniae, H influenzae and S pneumoniae are also involved If the patient has chronic pulmonary disease, then additional bacterial pathogens are usually implicated (e.g Pseudomonas aeruginosa or S aureus in bronchiectasis, H influenzae or M catarrhalis in chronic bronchitis) Clinical features Cough, chest discomfort and dyspnea are the main symptoms A cough productive of blood stained mucopurulent sputum with fever may be present, especially when there is superimposed bacterial infection Wheezes and crepitations may be heard on lung auscultation A persistent cough should arouse the suspicion of infection with Bordetella pertussis Treatment Antibiotics can hasten recovery In general, macrolides, cephalosporins and ampicillin with beta lactamase inhibitor for 7–10 days are useful agents ACUTE INFECTIVE EXACERBATION OF CHRONIC BRONCHITIS Acute infective exacerbation of chronic bronchitis responds to antibiotic therapy, particularly if increased sputum production, dyspnea and sputum purulence are noted Macrolides, amoxycillin-clavulanate and fluoroquinolones are effective therapies 1380 A Clinical Approach to Medicine Bronchiectasis Bronchiectasis refers to destruction of the distal bronchial walls resulting in dilatation and ectasia There is a predisposition to proximal airway involvement in aspergillosis Upper lobe involvement may be seen in mycobacterial infections, allergic bronchopulmonary aspergillosis (ABPA), chronic mycotic infections and cystic fibrosis Etiology Infection: Mycobacterium tuberculosis, measles pneumonia, whooping cough, adenoviruses, mycoplasma and pneumococcal pneumonia Mucociliary clearance defects: Cystic fibrosis, Immotile cilia syndrome, Kartegener’s syndrome Immunoglobulin disorders: Congenital and acquired agammaglobulinemia and hypergammaglobulinemia IgE (Job’s syndrome) Immunologic: Allergic bronchopulmonary aspergillosis (ABPA) Other causes: Chronic bronchial obstruction from benign tumors, foreign body and stenosis; inhalational injury, recurrent aspiration (such as from gastroesophageal reflux), inflammatory bowel disease, sequestrated lung, relapsing polychondritis, post-lung transplantation, chronic granulomatous disease of childhood, alpha 1-antitrypsin deficiency Associated conditions Felty’s syndrome, Yellow nail syndrome (triad of discoloration of nails, leg lymphoedema and pleural effusion), Young’s syndrome (obstructive azoospermia) and Macleod–Swyer–James syndrome Clinical features Those with minimal or focal bronchiectasis may be asymptomatic or have mild symptoms They may present with a cough productive of purulent sputum with or without hemoptysis during infective exacerbations In the severely affected patients, the cough productive of copious purulent sputum is continuous Accompanying features include intermittent fever, anorexia, weight loss, clubbing, arthralgia, hypertrophic pulmonary osteoarthropathy, cyanosis and cor pulmonale Bronchospasm may be present during infective exacerbations, or in cases of ABPA Otherwise the Pulmonary Infections 1381 only sign present is localized or widespread coarse crepitations Specific features of associated conditions mentioned above should be sought for Investigations Chest radiography: Changes relevant to bronchiectasis are tramline shadows (suggestive of bronchial wall edema), cystic lesions with or without air fluid levels (suggestive of saccular bronchiectasis), volume loss, crowding of bronchovascular markings (indicative of damaged or infected areas), evidence of past tuberculosis or mycosis, and pulmonary fibrosis (this may have associated traction bronchiectasis) High resolution CT scan: This has replaced the bronchogram as the diagnostic test because of the ease, availability, and safety factors The specificity and sensitivity are more than 90% Findings include signetring shadows (dilated bronchus with adjacent bronchial artery), bronchial wall thickening, dilated bronchi extending to the periphery, bronchial obstruction from inspissated secretions, consolidative changes during infective exacerbations, volume loss and cystic changes Sputum cultures: Acid-fast bacillus smear and mycobacterial cultures should be obtained to rule out tuberculosis Others: Relevant tests for associated conditions or etiologies such as sinus radiograph, serum immunoglobulins, aspergillus precipitins, skin prick test or specific IgE to aspergillus, barium swallow and bronchoscopy (especially for localized bronchiectasis with volume loss) Complications Hemoptysis can occur, usually during infective exacerbations in up to 50% of patients with bronchiectasis and can be life-threatening Those with diffuse and severe bronchiectasis can progress to respiratory failure Secondary infections with multi-drug resistant bacteria, fungi and atypical mycobacteria can complicate the management In recent years, Burkholderia cepacia has emerged as a respiratory pathogen of increasing importance in patients with cystic fibrosis Its presence is a marker of poorer survival Treatment The key measures are physiotherapy and antibiotics for symptom control and prevention of complications 1382 A Clinical Approach to Medicine Physiotherapy: Postural drainage should be done twice daily, usually on waking up in the morning and before bedtime Cough expectorant and mucolytics appear to be ineffective but humidification, nebulized saline and bronchodilators can be beneficial Antibiotic therapy: A 10 to 14-day course is indicated for a clearly defined infective exacerbation as manifested by increase sputum purulence with or without fever and increased dyspnea Common pathogens encountered are H influenzae, S pneumoniae and S aureus However in those with severe bronchiectasis with recurrent or persistent infection or colonization, coverage for P aeruginosa may be necessary Acute infective episodes may sometimes require hospitalization for intensive therapy, including chest physiotherapy and intravenous antibiotics Nebulized aminoglycosides has also been reported to be useful in patients with cystic fibrosis and severe bronchiectasis with persistent infection Surgery: This is reserved for localized, resectable and symptomatic bronchiectasis or in patients with massive hemoptysis Bronchoscopy is useful in localizing the bleeding pulmonary segment If surgery is elective, a full pulmonary function test is warranted Bronchial artery embolization can be considered if the expertise is available Specific therapies: These include intravenous immunoglobulin replacement for patients with immunoglobulin deficiency, relief of airway obstruction, control of recurrent aspiration, treatment of upper respiratory tract infections such as chronic sinusitis Pneumonia Pneumonia is defined as infection of the lung parenchyma where there is accumulation of secretions and inflammatory cells in the alveolar spaces Despite the advent of potent antibiotics, it is still the third principal cause of death in Singapore The management of pneumonia requires an understanding of the clinical spectrum of pneumonia and an awareness of the current antibiograms in specific settings Classification A useful and practical classification of the types of pneumonia includes reference to the clinical and environmental circumstances under which the pneumonia is acquired and to the prior clinical state of the patient Pulmonary Infections 1383 Initial choice of empiric antibiotic influences mortality and morbidity outcome and is based on the clinical classification of the type of pneumonia (Table 1) and risk stratification of the patient Community Acquired Pneumonia Community acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient not hospitalized or residing in a long-term care facility for more than 14 days It is usually accompanied by symptoms of acute infection, presence of auscultatory findings consistent with pneumonia and new infiltrates on a chest radiograph Etiology The list of pathogens causing community acquired pneumonia and their frequency can differ geographically Knowledge of prevalence and sensitivities of the pathogens can greatly aid initial empiric therapy Streptococcus pneumoniae is the most common CAP pathogen in Singapore and other parts of the world Atypical pneumonia is used to describe pneumonia that have clinical features that are unlike those of the usual bacterial pneumonia Extrapulmonary manifestions are more common Organisms causing atypical pneumonia include: • • • • • Mycoplasma pneumoniae; Legionella species; Chlamydia (TWAR and psittaci strains); Coxiella brunetti (Q fever); and Viruses Burkholderia pseudomallei: Melioidosis is more prevalent in some parts of Southeast Asia, including Singapore, and Northern Australia Sporadic cases found elsewhere are related to travel to these endemic areas Incubation period varies from days to years Transmission occurs by direct inoculation from soil through small cuts or abrasions, inhalation of contaminated dust and ingestion or aspiration of contaminated water Humanto-human transmission is extremely rare Predisposing factors include diabetes, renal disease, alcoholism, and occupations such as rice farming, army and construction Presentation may be acute with fulminant 1384 A Clinical Approach to Medicine Table Clinical Classification of Pneumonia and Common Microbial Causes CAP* NP؉ (includes VAP؉؉) Streptococcus pneumoniae (15–76%) Gram-negative Community bacilli (50–70%): acquired: Klebsiella pneumoniae Peptostreptococci Pseudomonas aeruginosa Peptococcus Escherichia coli, Bacteroides Acinetobacter baumannii fragilis Hemophilus influenzae Melaninogenicus Enterobacter species, Fusobacterium Stenotrophomonas nucleatum maltophilia Legionella pneumophilia Nosocomial: Staphylococcus aureus Gram-positive: Escherichia coli Staphylococcus aureus Klebsiella (including MRSA) pneumoniae Streptococcus pneumoniae Pseudomonas Other streptococci aeruginosa Hemophilus influenzae (3–46%) Mycoplasma pneumoniae (2–14%) (in those Ͻ 40 years old) Aspiration Pneumonia Opportunitic Pneumonia Pneumocystis carinii Fungus: Candida species, Aspergillus species Cytomegalovirus Herpes simplex Nocardia asteroides Actinomyces israelii Mycobacterium tuberculosis complex Mycobacterium avium intracellulare Chlamydia pneumoniae or C psittaci (3–12%) Influenza A (may be complicated by Staphylococcus aureus infection) Legionella pneumophila (0–15%) Staphylococcus aureus (3–14%) Moxarella catarrhalis (1–2%) Klebsiella pneumoniae (3–14%) Burkholderia pseudomallei (in endemic areas) Mycobacterium Anaerobes tuberculosis complex (in endemic areas) Fungi More resistant organisms with VAP *CAP-community acquired pneumonia, +NP-nosocomial pneumonia, ++VAP-ventilator associated pneumonia Pulmonary Infections 1385 septicemia, subacute with fever and localized pneumonia or lung abscess, or chronic, similar to a tuberculous infection Mortality is high in patients with advanced age, septicemia, smoking history and renal or heart failure Relapse is common, even after appropriate antibiotic treatment Clinical features Symptoms and signs (Table 2) are neither sensitive nor specific in defining the etiology of CAP Respiratory symptoms vary but classically include cough, dyspnea, sputum production with or without hemoptysis and pleurisy Clinical signs may be minimal or florid such as cyanosis, tachypnea, confusion and signs of consolidation on chest examination In atypical pneumonia, constitutional symptoms such as headaches, malaise, arthralgia and gastrointestinal tract symptoms may predominate and precede the chest symptoms by several days Marked confusion is seen in patients with any severe pneumonia but is a feature of legionellosis and psittacosis In the elderly, the classic symptoms and signs of pneumonia may be absent, with the only indication being a raised pulse and respiratory rate associated with deterioration in physical or mental state Travel history is important, bearing in mind the epidemiology of the endemic pathogens of each geographical region Investigations Although an early etiologic diagnosis is optimal in the management of CAP, the responsible pathogen is not defined in as many as 50% of patients, despite extensive diagnostic investigations There must be a Table Common Symptoms and Signs in CAP Symptom Fever Cough Purulent sputum production Perspiration Hemoptysis Dyspnea Chest pain and pleurisy Sign Confusion Tachypnoea Dullness to percussion Inspiratory crackles Bronchial breathing Increased vocal resonance Pleural rub 1386 A Clinical Approach to Medicine balance between reasonable diagnostic studies and empiric treatment Table shows the common investigations that are performed for CAP Chest radiograph: This is indicated for all patients with CAP Radiographic abnormalities include consolidation, diffuse or peribronchial infiltrates, but these correlate poorly with the causative organisms Cavitation may occur in tuberculosis, melioidosis, Gram negative bacteria, anaerobic, Staphylococcal or pneumococcal pneumonia and rarely, Legionella infection Parapneumonic effusions may occur in up to 20% of cases and are uncommon in atypical pneumonia Sputum examination: The sputum sample must reflect the bronchial airway secretions and not oropharyngeal secretions for proper interpretation of the specimen Criteria for acceptability of respiratory specimens for bacteriological studies take into account the relative number of polymorphonuclear cells and squamous epithelial cells Sputum culture is neither sensitive nor specific and should be interpreted together with the sputum Gram stain Induced sputum is useful for pneumocystis carinii or Mycobacterium tuberculosis Table Investigations for Community Acquired Pneumonia Blood • Full blood count • Serum urea, creatinine and electrolytes • Liver function test • Arterial blood gas • Blood cultures ( ϫ2, pre-treatment) • Serology (generally not useful in acute diagnosis) Sputum • Gram stain and bacterial culture • Acid-fast bacillus stain and mycobacterial culture Urine • Urine legionella antigen • Urine pneumococcal antigen Imaging • Chest radiograph Others (when indicated) • Pleural fluid assessment • Bronchoscopy with bronchoalveolar lavage Pulmonary Infections 1387 Blood and pleural fluid culture: Blood cultures should be taken from separate sites before initiation of antibiotics in hospitalized patients It has low sensitivity but is highly specific The yield of blood cultures in studies of CAP ranged from 6.7–27% The presence of bacteremia has prognostic significance as the risk of complications increase in Gramnegative bacteremia Pleural effusion with CAP should be aspirated A positive culture or Gram stain is significant since this is a normally sterile site Serological studies: Serological studies are not helpful in the initial evaluation of patients with CAP and should not be routinely performed It may provide data for epidemiological surveillance In such cases, paired serum samples 14 days apart may be used to document a 4-fold rise in antibody titres The presence of cold agglutinins supports the diagnosis of M pneumoniae infection, with a sensitivity of 30–60%, but with poor specificity A Legionella antibody titre of у 1:256 may be used as a criteria for presumptive diagnosis but a convalescent serology should also be sent Melioidosis serology may be useful and can be present in people with previous exposure but no clinical disease A positive culture for B pseudomallei is diagnostic Antigen detection: Antigen detection is useful only in selected instances Direct fluorescent antibody (DFA) staining of respiratory secretions for L pneumophila is difficult, and shows poor results when not performed by experts using only certain antibodies Urinary antigen test is 70% sensitive and 100% specific It detects antigen of L pneumophila serogroup 1, which accounts for up to 90% of cases of legionella pneumonia An immunochromatographic membrane to detect S pneumoniae antigen in the urine is reported to have sensitivity and specificity of 86% and 94% respectively Invasive tests: There are no studies to show that the early use of invasive tests improves outcome of CAP compared to empiric therapy Fibreoptic bronchoscopy is useful in the evaluation of a non-resolving or progressing CAP It is subject to contamination by upper airway flora Quantitative culture of bronchoalveolar lavage (BAL) fluid or protected specimen brush (PSB) specimen is superior to conventional technique It is, however, costly and requires technical expertise Transtracheal aspiration and percutaneous lung biopsy are rarely performed because of higher risks and relatively low yield Invasive testing should be considered for 1388 A Clinical Approach to Medicine those patients in whom etiologies are unknown with non-invasive studies and are not responding to usual antibiotics Complications The list of possible complications is as follows: • • • • • lung abscess; complicated parapneumonic effusion or empyema; respiratory failure; acute respiratory distress syndrome; or septic shock Treatment Supportive measures include adequate hydration and rest, supplemental oxygen or ventilatory support if necessary Chest physiotherapy is not routinely helpful in patients with pneumonia Numerous guidelines have been published for the treatment of CAP Empiric treatment should take into account the epidemiology and antibiotic susceptibility pattern of causative organisms Some guidelines for empiric treatment of CAP are given in Table Risk assessment is an important consideration in the management Patients who are well with no comorbidities may be treated as outpatients, whereas seriously ill, elderly or the very young, those with an underlying respiratory disorder, heart or other systemic disease, immunocompromised hosts and those with unsatisfactory home circumstances should be hospitalized Oral macrolides covers both pneumococcal and atypical pneumonia Doxycyline is the antibiotic of choice for Chlamydia infection Combination therapy with beta-lactams and macrolides is indicated in patients with CAP who are hospitalized to broaden coverage to include the usual CAP organisms and atypical bacteria as well Newer generation fluoroquinolones are useful as single agents as they are active against S pneumoniae, M pneumoniae, Legionella species and Gram-negative bacteria For severe CAP in endemic areas, empiric treatment should include high-dose ceftazidime to cover B pseudomallei Intravenous ceftazidime or imipenem for weeks is the initial treatment of choice for melioidosis This is followed by maintenance therapy with a combination of doxcycline and co-trimoxazole for months to reduce relapse rate Table Guidelines for Empiric Therapy for Community Acquired Pneumonia Singapore (2000) IDSA (2000) ATS (2001) ERS (1998) BTS (2001) Oupatient CAP No modifying factors: Macrolide, or doxycycline Outpatient CAP Macrolide, or doxycycline, or newer G quinolone Outpatient CAP No modifying factors: Newer macrolide, or doxycycline Outpatient CAP Aminopenicillin, or tetracycline, or oral cephalosporin, or newer G quinolone, or oral streptogramins, macrolide Outpatient CAP Amoxycillin or erythromycin Modifying factors: Macrolide, or 2nd G* cephalosporin, or beta-lactam/ beta-lactamase inhibitor ICU**: Macrolide ϩ ceftazidime*** Ϯ Hospitalized CAP Newer G quinolone, or 2nd, 3rd, 4th G cephalosporin ϩ macrolide Hospitalized CAP No modifying factors: iv azithromycin, or or beta-lactam ϩ doxycycline, or newer G quinolone Modifying factors: iv beta lactam ϩ macrolide or doxycycline; or iv newer G quinolone ICU: No risk for pseudomonas: Clarithromycin for those with GI intolerance to erythormycin Hospitalized CAP Hospitalized CAP 2nd, 3rd G Non-severe CAP: cephalosporin, or Oral Amoxycillin beta-lactam/betaor iv ampicillin ϩ lactamase inhibitor, erythromycin or or benzyl-penicillin/ clarithromycin, or amoxycillin iv Ϯ levofloxacin alone macrolide, or 2nd G quinolone Severe CAP: iv amoxycillin/ (ciprofloxacin, ofloxacin), OR newer clavulanate or G quinolone alone cefuroxime or cefotaxime or Pulmonary Infections 1389 Hospitalized CAP General ward: High dose penicillin Ϯ macrolide, or 3rd G cephalosporin or beta-lactam/ beta-lactamase Ϯ macrolide, or newer macrolide, or newer G quinolone Modifying factors: Betalactam (high-dose amoxycillin, cephalosporin, or beta-lactam/beta-lactamase inhibitor) ϩ macrolide or doxycycline, or newer G quinolone Singapore (2000) cloxacillin or clindamycin or vancomycin, or newer G quinolone ϩ ceftazidime IDSA (2000) ATS (2001) iv beta-lactam ϩ iv macrolide or iv quinolone Risk for pseudomonas: iv antipseudomonal beta-lactam ϩ antipseudomonal quinolone (ciprofloxacin), or iv antipseudomonas beta-lactams ϩ iv aminoglycosides ϩ iv macrolides or iv nonpseudomonas quinolone ERS (1998) BTS (2001) ceftriaxone ϩ erythromycin or clarithromycin (Ϯrifampicin), or iv levofloxacin ϩ benzylpenicillin IDSA-Infectious Disease Society of America, ATS-American Thoracic Society, ERS-European Respiratory Society, BTS-British Thoracic Society *G-generation, **ICU-intensive care unit, ***ceftazidime-high dose to cover melioidosis Newer G quinolone: levofloxacin, moxifloxacin, gatifloxacin Newer macrolide: azithromycin, clarithromycin Beta-lactam/beta-lactamase inhibitor: ampicillin-sulbactam, piperacillin-tazobactam 1390 A Clinical Approach to Medicine Table (Continued) Pulmonary Infections 1391 No controlled trial exists to specifically address the issue of duration of treatment The following should be taken into consideration: • • • • • pathogen; coexisting illness; severity of illness; treatment response; and complications Generally, antibiotics for bacterial infection should be continued for 7–10 days, or for more days after fever has settled Pneumonia with parenchyma necrosis should probably be treated for at least weeks Atypical or staphylococcal pneumonia should also be treated for 2–3 weeks Resolution of fever is the first and best indicator of clinical response Complete radiologic recovery may take weeks to months (especially elderly patients) The common causes of treatment failure are: • • • • • incorrect diagnosis: pulmonary embolism, pulmonary edema; resistant organism: penicillin-resistant S pneumoniae; resistant infection: B pseudomallei, M tuberculosis, Legionellosis, S aureus; complication: empyema, abscess, fever related to drug therapy; and underlying disease: lung cancer, cardiac failure, immunodeficiency Nosocomial Pneumonia Nosocomial or hospital-acquired pneumonia is by definition a lung infection that develops in hospitalized patients and was neither present nor incubating at the time of admission This infection develops at least or more days after hospital admission or there is a recrudescence of infection in those who had pneumonia on admission Nosocomial pneumonia is the leading cause of death from hospital acquired infections with an associated mortality of 20–50% It also contributes significantly to the morbidity of hospitalized patients Etiology Table shows the common causative organisms of nosocomial pneumonia The list of common and emerging resistant organisms are as follows: • extended spectrum beta-lactamase (ESBL) Gram-negative bacteria (contributed by prior third-generation cephalosporin usage); 1392 A Clinical Approach to Medicine • • • • • vancomycin-resistant Enterococcus (rare in Singapore); multi-drug resistant Acinetobacter baumanii; Stenotrophomonas maltophilia (related to carbepenem usage); methicillin-resistant S aureus (MRSA); and fluconazole-resistant Candida species Common ESBL Gram-negative bacteria include Klebsiella pneumoniae, Serratia marascens, Citrobacter diversus, Enterobacter species, E coli and Proteus mirabilis The main pathogenesis of nosocomial pneumonia is aspiration of upper respiratory secretions colonized with pathogenic organisms An effective infection control program is important for reducing the prevalence of nosocomial infections Clinical features and investigations Clinical features and investigations are similar to other types of pneumonia although debilitated or very ill patients may not have the classical features of fever, purulent sputum or leucocytosis Treatment Mortality and morbidity of nosocomial pneumonia is much higher than community acquired pneumonia Antibiotic choice depends on antibiogram and epidemiology of causative organisms of the institution Specific antibiotics like anti-pseudomonal penicillins, fluoroquinolones and cephalosporins, aminoglycosides and carbepenems for P aeruginosa; vancomycin for MRSA; ampicillin/sulbactam, fluoroquinolones and carbapenems for Acinetobacter; co-trimoxazole for S maltophilia; carbepenems, fluoroquinolones and aminoglycosides for ESBL bacteria; and amphotericin for fungus, may be necessary Ventilator Associated Pneumonia (VAP) This is a nosocomial pneumonia developing in mechanically ventilated patient more than 48 hours after intubation This is a cause of an increase in ICU morbidity and mortality Table lists some common factors for VAP Many studies have shown the lack of diagnostic accuracy using clinical features of fever, leucocytosis and purulent endotracheal aspirates New or progressive radiographic lung infiltrates should suggest the presence of Pulmonary Infections 1393 VAP Tracheal aspirates, non-bronchoscopic blind catheter lavage or brushing, and bronchoscopic protected specimen brush (PSB) or bronchoalveolar lavage (BAL) are invasive methods to obtain airway secretions directly Treatment is the same as for nosocomial pneumonia Aspiration Pneumonia Acute aspiration of gastric contents into the lung can cause severe chemical pneumonitis resulting in acute lung injury Bacterial infection can set in due to aspiration of anaerobes (especially in those with poor dental hygiene) and Gram-negative colonies (in hospitalized patients) from the upper aereodigestive tract Necrotizing pneumonia, lung abscess, empyema and bronchiectasis are important sequelae Predisposing causes of aspiration pneumonia are shown in Table Initial antibiotic of choice is clindamycin or penicillin with beta lactam For nosocomial Table Risk Factors for Ventilator-Associated Pneumonia Mechanical ventilation of more than days* Reintubation Prior antibiotic administration* Multi-organ dysfunction Thoracic or upper abdominal surgery Duration of hospitalization prior to mechanical ventilation Chronic obstructive lung disease Advanced age Use of positive end-expiratory pressure Intracranial pressure monitoring and/or depressed consciousness Histamine type-2 receptor antagonist Daily ventilator circuit changes Nasal intubation and/or sinusitis Supine head positioning, i.e head of bed not elevated Aspiration of gastric content *associated with antibiotic resistant pathogen Modified from Kollef MH, Silver P, Respir Care 1995;40:1130 Table Predisposing Causes of Aspiration Pneumonia Pregnancy Gastroesophageal reflux Esophageal stricture Tracheoesophageal fistula Vocal cord palsy Reduced conscious level due to anesthesia, drugs, alcohol, stroke, epilepsy 1394 A Clinical Approach to Medicine aspiration pneumonia, antibiotic coverage should include organisms commonly found in the institution, especially Gram-negative bacteria Predisposing causes for aspiration should also be treated Pneumonia due to Opportunistic Infections Pneumonia is a common cause of morbidity and mortality in hosts with all types of immune deficiency The increasing magnitude of this problem is due to the increase in numbers of HIV-infected cases and proliferation of usage of immunosuppressive drugs for organ transplantation, malignancy and autoimmune disorders Etiology The causative organisms involved depend on the type of immunodeficiency (Table 7) Immunodeficiency can be mixed and may vary with the type and stage of the primary disease and treatment course Investigations Early use of invasive procedures such as bronchoscopic sampling, needle aspirates and open lung biopsies may be required Identification of Table Relationship between Type of Immunodeficiency and Causative Organism Type of Deficiency Cause Causative Agents Neutropenia Chemotherapy (early phase) Bacterial infection (especially Gram-negative and S aureus), fungi (especially Aspergillus and Candida spp.), community acquired pneumonia organisms T lymphocyte dysfunction HIV Immunosuppressive drugs like steroids, cyclosporin, late phase of chemotherapy Bacterial infection, fungi, Pneumocystis carinii, herpes viruses, mycobacterium, Nocardia, Toxoplasma gondii, Strongyloides stercoralis, Legionella pneumophila Immunoglobulin(Ig) deficiency Hyposplenia, Ig deficiency Streptococcus pneumoniae, Hemophilus influenzae, Mycoplasma pneumoniae Pulmonary Infections 1395 organisms, e.g Cytomegalovirus in bronchoalveolar lavage, could imply pathogenicity or colonization Correlation with the clinical findings is required Treatment Empiric antimicrobial therapy depends on the clinical setting and the suspected organisms Lung Abscess This is a pus-containing necrotic lesion of the lung parenchyma Bacteria, mycobacteria, fungi and parasitic infections can cause lung abscess Bacterial infection is the most common, in particular the anaerobic bacteria from aspiration in the presence of periodontal disease Other bacteria such as S aureus, K pneumoniae, P aeruginosa, Nocardia and Actinomyces species and less commonly, Legionella sp are also known etiologic agents In endemic areas, Burkholderia pseudomallei and Mycobacterium tuberculosis need to be excluded Bacteremia, especially from line sepsis, can result in multiple nodules with cavities from septic emboli Lung abscesses can occur in malignant lesions, pulmonary infarction and pneumoconiosis Predisposing factors Factors predisposing to the development of lung abscess are malnourishment, poor dental hygiene, recurrent aspiration, diabetes, hematological malignancies, immunocompromised states and renal failure Clinical features Fever, cough productive of purulent or blood-stained sputum which may be foul-smelling (due to the presence of anaerobes) and weight loss are symptoms that may be present for days to weeks The source of sepsis may be evident such as poor oral hygiene and presence of infected vascular access Clubbing may be present in chronic cases Investigations The chest radiograph classically shows a cavitating lesion with an air fluid level Sometimes it can be difficult to differentiate a lung abscess 1396 A Clinical Approach to Medicine from fluid in a cyst or bleb If the lung abscess has ruptured into the pleural space, resulting in an empyema with a bronchopleural fistula, the presentation would then be a hydropneumothorax Sputum Gram stain and cultures should be obtained Bronchoscopic and percutaneous lung aspiration are other means of obtaining samples for Gram stain and culture studies Besides sampling secretions, bronchoscopy may be performed to exclude suspected obstructing lesions Otherwise, routine bronchoscopy for lung abscess is not necessary Complications Rupture of abscess into the airway or the pleural space may cause sudden respiratory decompensation Treatment The majority of lung abscesses respond to antibiotic therapy The initial choice of antibiotics should cover Gram-positive, Gram-negative and anaerobes Empiric choice of a third generation cephalosporin/quinolone with clindamycin or a penicillin/beta-lactam antibiotic is appropriate Antibiotics should be given for at least weeks Surgical resection is considered when there is no clinical response to antibiotics after weeks, there is an abscess rupture, or when the patient cannot mount an immune response and the abscess is deemed resectable Empyema The pleural space is a sterile cavity and pleural infections can occur via direct inoculation, hematogenous seeding or an adjacent lung infection with spillover effect Bacterial pneumonia is the most frequent cause of empyema Other causes are septicemia, trauma, thoracic surgery, perforation of esophagus or lung abscess Causative organisms are S aureus (especially trauma related), anaerobes, Gram-negative bacilli (especially nosocomial acquired) and S pneumoniae and other streptococci Mycobacterium tuberculosis is also a known cause Clinical features These include fever, cough, purulent sputum, dyspnea and pleurisy There is a pleural effusion with decreased chest movement, stony dull percussion note, decreased breath sounds, and decreased vocal fremitus Pulmonary Infections 1397 Investigations Chest radiography, especially the lateral decubitus film, should be obtained The absence of free flowing pleural fluid on the decubitus view indicates loculation and pleural fluid sampling and drainage can be done safely under imaging (ultrasound or CT) guidance Pleural fluid should be analyzed for Gram stain and culture, acid-fast bacillus smear and TB culture, pH, LDH, glucose, total protein, cytology and fungal smear and culture CT thorax is helpful in assessing loculations, identification of associated lesions such as lung abscess, tumor or bronchopleural fistula, and verifying the position of the chest tube Bronchoscopy is indicated if an endobronchial tumor is suspected or a bronchopleural fistula is present Treatment Early diagnosis is important Aspiration of gross pus necessitates early tube drainage and appropriate antibiotics Loculated empyema may need tube positioning under imaging guidance Controlled trials show that instillation of fibrinolytic agents such as urokinase and streptokinase into the pleural space can shorten hospital stay There is some evidence that early intervention with video-assisted thoracoscopy and drainage can improve outcome and reduce morbidity OTHER LIFE THREATENING PULMONARY INFECTIONS Anthrax The threat of bioterrorism has made inhalational anthrax a serious threat to the world community Anthrax, caused by Gram-positive Bacillus anthracis, cause infections via the inhalational, cutaneous or gastrointestinal route The incubation period is several days and can be up to a few weeks An initial flu-like illness consisting of fever, non-productive cough and myalgia is then followed by hemorrhagic mediastinal lymphadenitis Lymphatic obstruction in the lungs predispose to pulmonary edema In addition, the release of exotoxins results in the septic shock syndrome with rapid progression to death Early identification by Gram’s stain and treatment are essential in preventing mortality Intravenous ciprofloxacin is given empirically if B anthracis resistant to penicillin and doxycycline is suspected 1398 A Clinical Approach to Medicine Plague This is a disease spread by rodent fleas and was the cause of “Black Death” during the 14th century Pneumonic plague, caused by inhalation of Yersinia pestis or by hematogenous dissemination, has an acute presentation of cough and hemoptysis, with progression to respiratory failure, stridor and cyanosis This is highly contagious The incubation period is to days The diagnosis is suggested by Gram stain of the sputum or lymph node aspirate which reveal a Gram-negative coccobacillus Intravenous aminoglycoside (gentamicin or streptomycin) is treatment of choice Alternative antibiotics include doxycycline and chloramphenicol Tularemia Pulmonary tularemia, caused by Franciscella tularensis, may spread to humans as a form of zoonosis Exposure to an aerosol of this bacteria from live domestic animals or dead wildlife or hematogenous dissemination from the ulceroglandular form of tularemia can cause pneumonia It presents initially as an atypical pneumonia, with progression to bilateral patchy infiltrates, cavitating lesions and empyema This form of pneumonia is suspected after a careful travel and occupational history is obtained Treatment is effective with IV streptomycin or gentamicin, but not tobramycin MYCOBACTERIAL INFECTIONS Mycobacterium Tuberculosis Tuberculosis (TB) has remained a major public health problem in underdeveloped and developing countries Over the last decade, there has been an increase in incidence of TB worldwide because of the increase in numbers of HIV infected cases In parallel to this phenomenon, there is also a rise in the emergence of multi-drug resistant tuberculosis (MDR-TB) Almost all cases of TB are caused by Mycobacterium tuberculosis, which is one of the mycobacteria belonging to the Mycobacterium tuberculosis complex (Table 8) Transmission is via droplet nuclei expelled when an infected person coughs or sneezes Infectiousness is highest amongst close contact of infected persons with laryngitis, sputum smear-positive or cavitating Pulmonary Infections 1399 Table Classification of Mycobacteria Mycobacterium Tuberculosis Complex (MTC) M tuberculosis, M bovis, M africanum, M microti Nontuberculous Mycobacteria (NTM) Slowly growing organisms E.g M avium complex, M kansasii, M xenopi, M malmoense, M scrofulaceum, M ulcerans, M marinum Rapidly growing organisms E.g M abscessus, M chelonei, M fortuitum pulmonary TB Latent TB is generally non-infectious Incubation period is from weeks to years Ten percent of infected persons with an intact immune system will develop TB disease at some point of their lives Certain conditions such as diabetes mellitus, immunocompromised states including HIV infection, chronic renal failure, malignancy, gastrectomy, malnutrition and silicosis increase the risk that a latent TB infection will progress to a disease state Clinical features Pulmonary TB accounts for 90% of TB cases Mild disease may be asymptomatic and is evident only on a screening chest radiograph Symptom duration at presentation is usually weeks to months with cough, hemoptysis, loss of weight, loss of appetite, fever, night sweats, chills and fatigue Hemoptysis is generally minor but can also be life-threatening Hoarseness usually indicates laryngitis Patients with miliary TB may be very ill and can deteriorate rapidly Although lung parenchymal involvement is most common, patients may present with just a pleural effusion (commonest cause of exudative pleural effusion amongst patients Ͻ 60 years in endemic areas) and less commonly empyema Airway TB has been found at bronchoscopy or post-mortem examination in 15–42% of patients with active pulmonary TB These patients may have been misdiagnosed to have asthma or chronic obstructive airway disease or even bronchogenic carcinoma Airway stenosis may develop many years later despite appropriate antituberculous chemotherapy The incidence of residual airway stenosis range from 12–57% Extrapulmonary disease such as lymphadenitis (especially cervical), osteomyelitis, arthritis, genitourinary infection, meningitis or gastrointestinal involvement may occur with or without the presence of pulmonary infection The possibility of underlying HIV infection should be 1400 A Clinical Approach to Medicine considered, especially in those with atypical chest radiographic findings, extrapulmonary or disseminated disease Investigations There are three main investigations that have diagnostic value They are: 1) Mantoux skin test: A positive reaction of mm or more induration indicates exposure of the immune system to tubercle bacilli In endemic areas, a positive reaction may not be clinically significant for disease occurrence unless the reaction is 15 mm or more with clinical and/or radiological features of TB A strongly positive reaction of 20 mm or more induration is often associated with blistering and intense erythema False negative reactions may occur in severely ill, immunocompromised hosts and patients with sarcoidosis 2) Chest radiograph abnormalities may be the first to indicate the presence of tuberculosis This includes cavitating nodular lesions, fluffy infiltrates or nodules especially in the apical and posterior segments of upper lobe and superior segment of lower lobe; diffuse alveolar infiltrates, miliary shadows, lymph node enlargement, pleural effusion and enlarged cardiac size due to pericardial effusion Atypical appearances such as lower lobe basal segment infiltrates and prominent lymphadenopathy are seen in the immunocompromised host, in particular HIV-infected person 3) Bacteriological examination for smear and culture can be obtained from the sputum collection, laryngeal swab, bronchoscopic sampling (washings, brushings and biopsy), gastric aspirates, pleural fluid (15% positivity) and tissue (80% positivity for caseous granulomas on histology and Ͼ 75% positivity for culture) A series of early morning specimens should be collected on different days for sputum (supervised collection), laryngeal and gastric samples Bronchoscopic sampling may be obtained if there is no sputum or when bronchoscopy is performed to exclude other causes such as bronchogenic carcinoma Smear examination results should be available within 24 hours A positive result in endemic areas should be taken as MTC infection unless proven otherwise However in low prevalence areas, a positive test may be due to NTM and nucleic acid amplification test may be helpful in distinguishing the types of mycobacterial infection Culture results may take between 10 days (for BACTEC Pulmonary Infections 1401 radiometric system) to weeks (for conventional method) Follow-up bacteriologic examinations are recommended for assessing the patient’s infectiousness and response to therapy Documentation of conversion to smear and culture negative sputum should be achieved during treatment The role of nuclei acid amplification (NAA) tests using polymerase (PCR) and ligase (LCR) chain reaction is still not clearly defined Complications Tuberculosis is a chronic inflammatory infection that heals with tissue destruction and fibrosis Significant sequelae includes bronchiectasis, fibrothorax, end-stage lung destruction, severe airway stenosis with associated obstructive complications and lung fibrosis with mycetoma formation, recurrent or massive hemopytsis and respiratory failure Chronic bronchopleural fistula may occur in TB empyema Treatment Tables and 10 show the first- and second-line drugs for tuberculosis therapy respectively The principles of treatment are: • • use the safest, most effective and shortest course of therapy; and ensure patient compliance to treatment When adequate treatment is given, almost all patients will recover and remain well Tuberculosis has to be treated with at least drugs in the initial phase and then at least drugs in the continuation phase for a total of to 24 months depending on the drug regime Those at risk of MDR-TB are individuals with a history of noncompliance with TB treatment, reactivation of past TB, contacts of MDRTB cases, persons from areas where prevalence of MDR-TB is Ͼ 4% and persons whose smears or cultures remain positive after months of TB treatment In Singapore the incidence of MDR-TB is Ͻ 4% Review of drug susceptibility test should always be done within months of initiation of drug therapy Fixed-dose combination drugs such as Rifamate (isoniazid 150 mg and rifampicin 300 mg) may enhance adherence to drug therapy The beneficial effects of corticosteroids have not been well established for TB pleural effusion and airway TB It may be 1402 A Clinical Approach to Medicine Table Antituberculous Therapy for Adults (First-line Drugs) First-line Drugs Main Adverse Effects Isoniazid mg kg day 15 mg kg thrice wk Hepatitis* (increases with age, hepatic disorders and alcohol consumption) Peripheral neuropathy (give pyridoxine for individuals at risk, e.g diabetes mellitus, uremia, malnutrition, malignancy, alcoholic, pregnancy) Rifampicin 10 mg kg day 15 mg kg thrice wk Gastrointestinal (GI) intolerance (most common) Hepatitis* Drug interaction** Rash Flu-like symptoms Hematological abnormalities Pyrazinamide 15–30 mg kg day 50–70 mg kg thrice wk Hepatitis* Rash Arthralgias Hyperuricemia (treat only if symptomatic) GI intolerance Ethambutol Optic neuritis (usually does not occur with 15 mg/kg daily dose for months) GI intolerance 15 mg kg day 25 mg kg thrice wk Streptomycin (intramuscular) 15 mg kg day 25 mg kg thrice wk Ototoxicity (avoid or reduce dose in those Ͼ 60 yrs old) Renal impairment Intermittent regimens should be used with directly observed therapy *hepatic dysfunction is relatively common with these drugs which may be continued unless the enzymes are Ͼ times normal or times above the baseline **rifampicin is a hepatic enzyme inducer, hence dosage of contraceptive pills, corticosteroids, warfarin, anticonvulsants, cyclosporin, theophylline, ketoconazole, oral hypoglycemics and antiarrhythmic drugs have to be increased useful in those with pronounced systemic features, meningitis, adrenal insufficiency and tuberculous pericardial effusion Referral to centres with experts managing tuberculosis such as the Tuberculosis Control Unit in Singapore, is recommended for: 1) Non-adherence to drug therapy This is a major problem worldwide because of adverse reactions and prolonged therapy All patients nonadherent to drug therapy must be placed under directly observed Pulmonary Infections 1403 Table 10 Second-line Antituberculous Therapy in Adults Second-line Drugs Ciprofloxacin Ofloxacin Amikacin Kanamycin Capreomycin Ethionamide Cycloserin Clofazimine Dapsone therapy (DOT) where a health care worker watches the patient swallow each dose of medication 2) Multi-drug resistant TB, i.e TB resistant to at least drugs, e.g isoniazid and rifampicin This is extremely difficult to manage with high mortality and morbidity rates and is as infectious as drug-sensitive TB The second-line anti-TB drugs (Table 10) are less tolerable, costly and a more prolonged course of treatment is required for MDR-TB All these lead to higher non-compliance rates Surgery may have a role in recalcitrant cases 3) Relapse cases because of the possibility of non-adherence to drug therapy and MDR-TB 4) Persistence of symptoms or smear positive after months of therapy Lastly, major research efforts are being made in recent years to develop new vaccines for tuberculosis This renewed interest was prompted by the increasing incidence of MDR-TB worldwide and also the variable protective efficacy of 10–80% by the only currently approved BCG vaccine NONTUBERCULOUS MYCOBACTERIA Nontuberculous mycobacteria (NTM) is also known as environmental mycobacteria and mycobacteria other than tuberculosis (MOTT), Table Most of them are found in natural waters and soil Human to human transmission has not been documented Two group of populations are most likely to be affected: 1) those with structural lung disease; and 2) HIV-infected persons Presentation tends to be subacute in structural lung disease M avium intracellulare is the most common NTM in HIV patients and the clinical course could be acute and disseminated 1404 A Clinical Approach to Medicine Diagnosis of NTM requires a positive culture Treatment is usually prolonged and may require multiple drugs Surgery is an option in localized and poorly responding lesions As treatment of NTM is generally difficult, prolonged and ineffective, it is important to ensure the presence of disease rather than colonization before commencing treatment Also, prophylaxis against NTM (with a macrolide) should be considered in HIV patients with low CD4 counts MYCOSES Table 11 shows the common fungi that infect the lungs They tend to occur in patients with impaired immunity but may also affect previously well individuals Cryptococcosis Cryptococcosis is caused by the encapsulated yeast, Cryptococcus neoformans, which is found in soil, food and animals especially the excreta of pigeons Human infection is acquired through inhalation of aerosolized organisms Conditions that predispose to cryptococcosis are diabetes mellitus and immunocompromised states such as lymphoma, leukemia and corticosteroid ingestion Infection in normal hosts is often characterized by granulomatous inflammation Cryptococcal meningitis has to be excluded in every case These patients present with fever, headache, nausea, anorexia Table 11 Pulmonary Fungal Infections Common (worldwide) Cryptococcosis Aspergillosis Candidiasis Mucormycosis Pneumocystis carinii Uncommon (found in endemic areas) Histoplasmosis* Blastomycosis Coccidioidomycosis Paracoccidioidomycosis Sporotrichosis *In the recent years, sporadic cases of histoplasmosis have been seen here These patients are either from Indonesia or have travelled to endemic areas Pulmonary Infections 1405 and incidental lung infiltrates on the chest radiograph Chest radiographic features include cavitating nodular infiltrates, solitary nodule or mass especially in the lower lobes, occasional hilar adenopathy and pleural effusion Differential radiographic diagnoses include carcinoma and other granulomatous infections e.g tuberculosis and histoplasmosis Organisms can be seen in respiratory secretions, biopsy of lung lesions and cerebrospinal fluid (CSF) by using the Indian ink stain Cryptococcal antigen titers should be routinely done in the serum and CSF, as this may indicate disseminated infection Cryptococcus can also infect the skin, bone and prostate gland Treatment is as follows: 1) Observation only if sputum isolated for C neoformans in a normal host with no chest radiographic and CSF abnormalities 2) Oral fluconazole in those with pulmonary cryptococcosis with negative serum serology and CSF abnormalities 3) Amphotericin with or without flucytosine for disseminated infection 4) Lifelong maintenance with fluconazole is needed for AIDS patients Aspergillosis This can be caused by Aspergillus fumigatus, A niger or A flavus resulting in a spectrum of human diseases: 1) Allergic response in allergic bronchopulmonary aspergillosis 2) Mycetoma (aspergilloma) of the respiratory tract in preexisting lung diseases 3) Chronic necrotizing aspergillosis of lung tissue and tracheobronchial aspergillosis in the immunocompromised host 4) Acute invasive pulmonary aspergillus with systemic hematogenous spread (angioinvasive form) This form most commonly occurs in neutropenic patients 5) Bronchocentric granulomatosis This is a more focal form of aspergillus infection involving the airways It can be seen in asthmatics The mere presence of aspergillus in respiratory secretions is not diagnostic and tissue invasion should be evident However, in patients with hematologic malignancies who have dry cough, hemoptysis, pleurisy, dyspnea, prolonged neutropenia on broad-spectrum antibiotics and pulmonary infiltrates, the presence of aspergillus in the respiratory secretions 1406 A Clinical Approach to Medicine should be treated as a pathogen Pulmonary abnormalities on chest radiograph are that of nodular infiltrates and consolidation with or without cavitation Mortality in this group is high despite adequate treatment with amphotericin Candidiasis Candidiasis is usually caused by Candidia albicans and is more likely to affect the immunocompromised host (especially in hematologic malignancies with prolonged neutropenia), diabetics, patients with burns, renal failure, cirrhosis, prosthesis, catheters and on prolonged antibiotics Lung involvement is uncommon in the normal host Chest radiograph shows patchy or diffuse infiltrates Pulmonary candidiasis is often part of disseminated candida infection as primary lung candidiasis is rare As the oropharynx is colonized with Candida in ill patients, histologic demonstration of tissue invasion is required to prove Candida pneumonia However, the febrile immunocompromised host with positive blood cultures with or without lung infiltrates (on chest radiograph) must be treated The common drugs used for treatment of candidiasis are amphotericin and fluconazole All infected vascular access, catheters and prosthesis must be removed Candida krusei and Torulopsis glabrata are resistant against the azole group of antifungals and hence therapy is best initiated with amphotericin PARASITIC INFECTIONS Parasitic lung infections are uncommon in Singapore Important parasitic infections with pulmonary involvement include falciparum malaria (adult respiratory distress syndrome), amoebiasis (lung abscess), microfilaria Wuchereria bancrofti (tropical eosinophilic lung) and paragonimiasis (eosinophilic pleural effusion) REFERENCES Cifu A, Levinson W, Influenza, JAMA 284:2843–2847, 2000 Bisno AL, Acute pharyngitis, N Engl J Med 344:205–211, 2001 Monto A, Gravenstein S, Elliot M, Colopy M, Schweinle J, Clinical signs and symptoms predicting influenza infection, Arch Intern Med 160:3243–3247, 2000 Tan YK, Khoo KL, Chin SP, Ong YY, Aetiology and outcome of severe community acquired pneumonia in Singapore, Eur Respir J 12:113–115, 1998 Pulmonary Infections 1407 Hui KP, Chin NK, Chow K, Brownlee A, Yeo TC, Kumarasinghe G, Chan TB, Tan WC, Prospective study of the aetiology of adult community acquired bacterial pneumonia needing hospitalisation in Singapore, Singapore Med J 34:329–334, 1993 Lee KH, Hui KP, Tan WC, Lim TK, Severe community acquired pneumonia in Singapore, Singapore Med J 37:374–377, 1996 Clinical Practice Guidelines, Use of antibiotics in adults Ministry of Health, Singapore, 2000 Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ, Practice guidelines for the management of community-acquired pneumonia in adults, Clin Infect Dis 31:347–382, 2000 Niederman MS, et al., Guidelines for the management of adults with communityacquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention, Am J Respir Crit Care Med 163:1730–1754, 2001 10 ERS Task Force Report, Guidelines for management of adult community-acquired lower respiratory tract infections European Respiratory Society, Eur Respir J 11:986–991, 1998 11 British Thoracic Society, British Thoracic Society guidelines for the management of community-acquired pneumonia in adults admitted to hospital, Thorax 56(suppl 4): 1–64, 2001 12 Clinical guidelines on anthrax, botulism, plague and smallpox, Ministry of Health, Singapore, 2001 13 Guidelines on the clinical diagnosis, laboratory investigation, Treatment and prevention of melioidosis, Singapore General Hospital, 1999 14 Colice GL, et al., Medical and surgical treatment of parapneumonic effusions An evidence-based guideline ACCP Consensus Conference, Chest 118:1158–1171, 2000 15 Chin NK, Lim TK, Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic effusions, Chest 111:275–279, 1997 16 Wait M, Sharma S, Hohn J, Dal Nogare A, A randomized trial of empyema therapy, Chest 111:1548–1551, 1997 This page intentionally left blank 80 Acute Respiratory Distress Syndrome J Raghuram and Phillip Eng INTRODUCTION The Acute Respiratory Distress Syndrome (ARDS) continues to exert its toll on patients in the intensive care units worldwide Despite advances, ARDS continues to tax resources in terms of financial and human costs Asbaugh and colleagues1 first described this condition in 1967 when 12 patients presented with severe dyspnea, diffuse bilateral infiltrates on chest radiograph, decreased lung compliance and hypoxemia, which was refractory to supplemental oxygen therapy but responded to positive pressure ventilation Autopsies in of these patients revealed marked edema of both lungs with atelectasis and surfactant deficiency mimicking infant respiratory distress syndrome Subsequently, it was recognized that ARDS affects patients of all age groups and as such, it would be appropriate to refer to it as acute rather than adult respiratory distress syndrome.2 Incidence The true incidence is still controversial This is primarily because the reported incidence varies depending on the diagnostic criteria and 1409 1410 A Clinical Approach to Medicine population studied In the USA it is estimated to range from 3.5 to per 100 000 individuals per year.3,4 A recent survey suggested that patients with ARDS occupy approximately 9% of all ICU beds in the USA.5 Definition Clinical experience indicates that this disease varies in severity from patient to patient It was agreed at the American-European Consensus Conference on ARDS that the term Acute Lung Injury (ALI) be used to represent this wide clinical spectrum of presentation.2 ARDS is being reserved to represent the most severe end of this spectrum The following definitions are widely accepted and utilized by clinicians and researchers currently.2 Acute lung injury (ALI) Represents a constellation of symptoms and signs resulting from acute and persistent inflammation of the lung associated with increased vascular permeability The characteristic features of this syndrome include: 1) acute onset of symptoms and signs; 2) chest radiographic evidence of bilateral pulmonary infiltrates; 3) the ratio of the partial pressure of oxygen (PaO2) to the inspired fraction of oxygen (FiO2), i.e PaO2/FiO2 should be р 300 mmHg regardless of the level of Positive End Expiratory Pressure (PEEP); and 4) no evidence of elevated left atrial pressure, i.e the measured pulmonary capillary wedge pressure (PCWP) should be р 18 mmHg ARDS All the characteristic features of ALI apply except that the degree of hypoxemia associated with ARDS is worse, i.e PaO2/FiO2 р 200 mmHg It is not essential to measure PCWP in all cases of ALI/ARDS unless clinical suspicion of heart failure is high.6 It must be borne in mind that in both ARDS and ALI the degree of hypoxemia does not correlate well with the underlying pathologic changes occurring in the lung Furthermore, severity of hypoxemia does not have a predictable clinical impact on the outcome.7 Acute Respiratory Distress Syndrome 1411 PATHOLOGY Early in the course of this disease, an intense inflammatory response characterized by the presence of large quantities of neutrophils and mesenchymal cells is seen in the interstitium Associated with this there is accumulation of protein-rich fluid within the parenchyma and alveolar space.8 As the disease progresses, proliferation of the Type II pneumocytes occurs replacing the Type I pneumocytes that under normal conditions covers 95% of the alveolar surface This inflammatory process progresses at an unpredictable pace, leading to parenchymal fibrosis and obliteration of the adjacent vascular endothelium by fibrin.9 Hyaline membrane formation, which represents a mixture of debris from cells lining the alveolar surface and fibrin, occurs within the first two days of the onset of the injury to the lung Approximately to 10 days later, collagen deposition by proliferating fibroblasts occur along the alveolar lining with progression of the fibrotic process.10 The extent of involvement of the fibrotic process varies In some patients, this process progresses at an unrelenting pace and leads to permanent irreversible scarring, while in others complete recovery is seen within days The exact reason for this difference is unknown However, the extent of the initial insult, development of nosocomial pneumonia and iatrogenic injury to the lung (e.g oxygen toxicity and barotrauma) may all have a role to play PATHOGENESIS The pathogenesis of ARDS/ALI can be thought of as arising from injury either direct to the pulmonary epithelium and endothelium or indirect secondary to an extra-pulmonary septic or inflammatory focus This eventually leads to loss of function of the alveolar-capillary unit This is histologically described as Diffuse Alveolar Damage (DAD) DAD is defined as endothelial and Type I pneumocyte cell necrosis associated with hyaline membrane and proteinaceous alveolar edema formation There appears to be a temporal sequence of progression of DAD: an exudative phase (1st–3rd day) followed by the fibroproliferative phase (4th–7th day) and eventually the fibrotic phase (after the 1st week) The inflammatory response leading to DAD includes both cellular and humoral factors.2 Neutrophils, monocytes, macrophages and lymphocytes 1412 A Clinical Approach to Medicine being the key players in the cellular response The mechanism by which neutrophils attach to endothelial lining has been the focus of interest recently because if adhesions can be prevented, lung injury can be reduced or eliminated altogether.11 The components of the humoral system include the complement, fibrinolytic and coagulation factors interacting with cytokines, lipid mediators, proteases, nitric oxide and other growth factors.12 These factors are generally thought of as the main effectors of cell injury leading to defects in surfactant metabolism and ultimately ventilation perfusion mismatch.2 Neutrophils together with alveolar macrophages are in part responsible for the orderly removal of cellular debris and repair of the damaged alveolar epithelium.11 This process of repair may become disordered in some patients resulting in an exuberant fibrosis leading to inefficient gas exchange and persistent hypoxemia The reason why acute lung injury resolves in some patients but progresses to extensive fibrosis in others remains unknown The factors that may be responsible for the development of fibrosis are the severity of the initial insult to the lung, persistence of the inflammatory process and the development of microthrombi within the pulmonary microvasculature.10 RISK FACTORS There are currently more than 60 different causes of ARDS identified New therapeutic modalities continue to emerge to treat various disease states Many of these modalities of treatment may result in adverse pulmonary reactions As such, additional risk factors for the development of ARDS are becoming apparent Three prospective studies have shown that ARDS most commonly occurred inpatients with the following conditions.13–15 1) Sepsis syndrome: Bacteremia with systemic manifestations, e.g metabolic acidosis, hypotension 2) Aspiration of gastric contents 3) Near drowning: Immersion injury associated with loss of consciousness, metabolic acidosis or hypothermia 4) Pulmonary contusion: Development of localized infiltrate on chest radiograph within hours of blunt trauma to the overlying chest wall The risk of developing ARDS increases as the number of potential risk factors increase.13,14 Sepsis is very often suspected as the underlying cause of ARDS/ALI and as such many clinicians would begin treatment Acute Respiratory Distress Syndrome 1413 for possible infections immediately when ARDS/ALI is encountered.17 Gram-negative organisms are responsible for most of the cases of ARDS seen in hospitalized patients ARDS developing in patients outside the hospital is most likely due to a viral infection Pneumocystis carinii pneumonia (PCP) was not considered as a risk factor in all studies.13–15 However, the American-European Consensus Conference group decided that pulmonary infections including PCP should be considered as risk factors for the development of ARDS/ALI when the physiologic criteria are met.2 It was also decided that the risk factors be divided into groups: 1) Direct lung parenchymal injury a) aspiration of gastric contents; b) diffuse pulmonary infections; c) near drowning; d) toxic gas inhalation; and e) lung contusion 2) Indirect lung injury a) sepsis syndrome; b) multiple trauma; c) multiple blood transfusion; and d) cardiopulmonary bypass MANAGEMENT In general, managing patients with ARDS involves measures that aid in sustaining cellular physiological functions (i.e gas exchange, organ perfusion and aerobic metabolism).16 As a result the therapy involves largely supportive measures such as mechanical ventilation, positioning patient, judicious use of fluids and vasoactive agents to maintain hemodynamic stability and systemic perfusion and various techniques to optimize oxygen transport and utilization The management of these patients with ARDS/ALI should be aimed at establishing the underlying cause Diagnosing and treating infections are particularly important in this regard Patients with diffuse pulmonary infiltrates and ARDS should undergo bronchoscopy, bronchoalveolar lavage and possibly transbronchial lung biopsy to establish or rule out the presence of an infection Most patients with ARDS/ALI will require positive pressure ventilation to maintain adequate oxygenation Some patients breathing 1414 A Clinical Approach to Medicine spontaneously may be able to achieve sufficient tissue oxygenation and perfusion without mechanical ventilatory support The clinical objectives of mechanical ventilation in ARDS are to: 1) reverse hypoxemia and respiratory acidosis; 2) relieve respiratory distress; and 3) prevent and reverse pulmonary atelectasis and respiratory muscle fatigue Positive End Expiratory Pressure (PEEP) The conventional approach to ventilating patients with ARDS was to use a volume-oriented approach to ventilation to achieve these goals Gattinioni and colleagues have shown that in patients with ARDS, the lung compliance is reduced because much of the dorsal aspects of both lungs are collapsed and not accessible to ventilation.18 The compliance of the aerated ventral portions of the lungs would be close to normal If a volume-oriented approach is used, a lower tidal volume has to be used in order to prevent alveolar distention in the aerated lungs There is evidence of acute lung parenchymal and microvascular injury histologically similar to ARDS in animals that are ventilated with high inflation pressures and tidal volumes.19,20 To avoid ventilator induced lung injury, small tidal volumes with sufficient PEEP should be used to prevent endexpiratory collapse and tidal recruitment of alveolar units The dependent lung regions in ARDS are subject to a superimposed pressure from the weight of the overlying lung resulting in atelectasis during expiration.21 Providing sufficient PEEP to avoid end-expiratory atelectasis in these dependent regions probably results in higher than normal end-expiratory volume in alveoli in non-dependent regions Thus the non-dependent ventral portions of the lungs run the risk of becoming overdistended especially if normal tidal volumes (10–12 mLs/kg) are used Furthermore, the aerated portions of the lungs are small in ARDS even with optimum PEEP.18 For these reasons, it is necessary to use low tidal volumes with optimum PEEP to avoid end-expiratory overdistention Gattinioni has demonstrated that most of the recruitment of atelectatic lung units occurs with PEEP levels of 15 to 20 cm H2O.22 Current recommendations would include the use of PEEP levels of usually 15 to 20 cm H2O and to set tidal volumes of between to mLs/kg In addition to these measures, the adoption of permissive hypercapnia and pressure-limited rather than Acute Respiratory Distress Syndrome 1415 volume-cycled ventilation have been advocated to prevent lung damage resulting from regional overdistention of the lung units related to high ventilatory volumes and reopening of atelectatic lung units with resultant shear injury.23 Amato et al have shown in a prospective randomized controlled trial that these measures, so-called “open-lung approach”, improved oxygenation significantly there was but there was no impact on the survival rate to hospital discharge.24 Permissive Hypercapnia Permissive hypercapnia is a ventilation strategy in which hypoventilation and hypercapnia are allowed so that detrimental rise in alveolar pressure is avoided The PaCO2 is allowed to rise as tidal volume and respiratory rate are adjusted to prevent increase in plateau pressure In general, the resulting respiratory acidosis is treated with intravenous bicarbonate if arterial pH Ͻ 7.2.25 This was introduced initially to reduce the barotraunma in mechanically ventilated patients with obstructive airway disease.26 Permissive hypercapnia may be an inevitable consequence of the “lung protective strategy” that limits airway pressure and volume adopted in ventilating patients with ARDS Several uncontrolled studies initially showed that survival might be improved by adopting permissive hypercapnia.26–28 However, randomized studies have shown that there was no survival advantage to permissive hypercapnia in patients with ARDS.29,30 In adopting permissive hypercapnia, one has to be aware of the consequences of carbon dioxide (CO2) retention Acute elevations in CO2 result in increase in sympathetic activity and cardiac output, impairment of musculoskeletal and central nervous system function.31,32 Therefore, CO2 retention may be detrimental in patients with co-existing raised intra-cranial pressure, significant cardiovascular dysfunction, beta-blockade and autonomic dysfunction Based on the available evidence, permissive hypercania with pressure targeted ventilation may be considered in patients with ARDS developing plateau pressures in excess of 35–40 cm H2O.33 Inverse Ratio Ventilation (IRV) Inverse ratio ventilation (IRV) is another ventilation strategy employed by clinicians to improve oxygenation while attempting to maintain acceptable peak airway pressures in patients with ARDS.34 Commonly this mode of ventilation is combined with pressure controlled ventilation, 1416 A Clinical Approach to Medicine though not always In this mode the inspiratory time is prolonged thus reversing the Inspiratory: Expiratory (I:E) ratio In doing so the mean airway pressure is increased without increasing the peak airway pressure.35 Several hours may be required to achieve the maximal benefits of IRV on gas exchange as recruitment of atelectatic lung units occur with sustained inspiratory pressures.36 IRV has been shown to improve oxygenation in patients with severe ARDS when conventional modes of ventilation have failed.37 However in a recent randomized controlled trial using IRV, no significant improvement in oxygenation was seen.38 Furthermore, IRV is not well tolerated by spontaneously breathing patients As such patients are usually heavily sedated and paralyzed with neuromuscular blocking agents to allow patient-ventilator synchronization This method of ventilation is used when arterial oxygenation cannot be maintained with conventional modes of ventilation when the use of PEEP results in excessive plateau pressure (Ͼ 35 cm H2O) Posture Positional changes in ARDS patients can bring about improvement in the ventilation, perfusion mismatching that is present.39,40 Many patients in the early phase of ARDS improve pulmonary gas exchange remarkably when turned prone.41 In the prone position the weight of the heart rests on the ventral rib cage and sternum This reduces the compressive atelectasis seen in the dorsal regions of the lungs Furthermore, modifications of the chest wall compliance upon proning the patient alters the transalveolar pressure gradient.42 These changes result in improvement in the distribution of ventilation to the dorsal atelectatic lung units In essence the use of the prone position pursues three therapeutic goals: 1) Reduction in FiO2 to prevent oxygen toxicity; 2) Recruitment of atelectatic dorsal lung units; and 3) Improve postural drainage of bronchial secretions.43 Most patients show an improvement in gas exchange within the first hour of adopting the prone position while in others it may take several hours.42 Gas exchange improves in more than 50% of patients turned prone in the early phase of ARDS allowing significant reductions in both FiO2 and PEEP.41 When adopting this strategy, continuous monitoring of intra-arterial blood pressure, cardiac rhythm and pulse oximetry is essential Strict attention should be given to proper positioning of the endotracheal tube and patency of peripheral and central venous catheters during the turning Acute Respiratory Distress Syndrome 1417 process Hypotension, cardiac arrhythmias and hypoxemia are usually transient events These can be minimized by providing FiO2 of 1.0 during the manoeuvre and also by ensuring that the airway is suctioned prior to proning the patient The optimal frequency of switching from supine to prone is yet to be determined In general, switching from positions can be carried out twice a day The relative duration assigned to each position is determined by the gas exchange response.42 Liquid Ventilation This technique of ventilation involves the use of perfluorochemicals, which are biologically inert and non-toxic Amongst the perfluorochemicals, perfluoro-octyl bromide (perflubron) is currently being used in the clinical and experimental settings.44 Perflubron can dissolve 15 times the amount of oxygen per given volume as per the same volume of plasma.45 Carbon dioxide and other gases are also highly soluble in it There are essentially methods of ventilation using perflubron: 1) Total Liquid Ventilation (TLV); and 2) Partial Liquid Ventilation (PLV) In TLV, the entire lung (residual volume and tidal volume) is filled with oxygenated perflubron With the aid of specialized equipment, tidal volume amounts of perflubron is removed from the lungs, pumped through an extracorporeal circuit in which gas exchange is facilitated and subsequently returned to the patient.46 The perflubron facilitates gaseous exchange at the alveolar unit level because of the Extraordinary solubility of oxygen and carbon dioxide in it.45 In PLV, lungs are filled with perflubron up to a volume (20–30 mLs/kg) equivalent to the Functional Residual Capacity (FRC) Conventional mechanical ventilation is continued enabling gas exchange.45 As the fluid evaporates from the lungs, it is intermittently replaced with small amounts (2–8 mLs/kg/hr) to maintain liquid volume equivalent to FRC Clinical experience with this method of ventilation has been encouraging.47 The perflubron recruits alveoli in the dependent regions by providing a PEEP-like effect.48 Pulmonary blood flow is also preferentially redistributed to the non-dependent regions of the lungs thus bringing about an improvement in ventilation-perfusion matching.47 The other potential benefits of liquid ventilation include facilitation of removal of cellular debris, inflammatory mediators and exudative material from the distal airways.49,50 PLV appears to be promising in the 1418 A Clinical Approach to Medicine ventilatory management of patients with ARDS It is currently being evaluated in a large ARDS trial in the USA.44 Extracorporeal Membrane Oxygenation (ECMO) and Extracorporeal Carbon Dioxide Removal (ECCO2R) are two methods of supporting the respiratory system by partially substituting the gas exchange function of the lungs Both these techniques have been evaluated in ARDS patients A fraction of the systemic circulation in both ECMO and ECCO2R is exposed to oxygen across a semi-permeable membrane, which assists in the gas exchange function of the compromised lungs If the oxygenation is the main reason for extracorporeal support then veno-arterial circuit is used In this circuit, blood exiting through a large bore cannula located in central vein is allowed to traverse the extracorporeal circuit and subsequently returned to the aorta.51 If carbon dioxide (CO2) extraction is the main concern, then a veno-venous circuit is employed with an extracorporeal device extracting CO2.52 Despite its clear success in neonates with severe respiratory failure, a large trial comparing ECMO with mechanical ventilation showed no benefit.53,54 A randomized trial comparing ECCO2R with pressure controlled inverse ratio showed no difference in outcome between the two modes of support.55 ECCO2R and ECMO are not recommended for the routine management of ARDS The judicious use of fluids, diuretics and vasoactive agents are important in supporting patients with ARDS Pulmonary edema arises in ARDS as a result of increased vascular permeability.56 Several clinical studies have shown improvement in survival in ARDS patients in whom the pulmonary capillary occlusion pressure is kept low by the judicious use of diuretics and intravenous fluids.57–59 Nevertheless, decreasing the intravascular pressure excessively can compromise the hemodynamic state and lead to renal impairment/failure especially in mechanically ventilated patients with PEEP Therefore it is recommended that ARDS patients be fluid restricted and, if need be, diuresed with careful monitoring of end organ function The use of vasoactive agents, like dopamine, should be considered in attempt to maintain adequate blood pressure especially in the setting of hypotension with euvolemia OPTIMIZATION OF OXYGEN TRANSPORT It has been reported that survivors of ARDS have a significantly higher oxygen delivery (DO2) and oxygen consumption (VO2) than non-survivors.60 Acute Respiratory Distress Syndrome 1419 These patients with ARDS manifest a higher critical oxygen transport concentration below which they may be vulnerable to tissue hypoxia This observation has brought forth the notion that by achieving supranormal patterns in oxygen transport in the critically ill mortality may be reduced Such an approach was thought to reverse or prevent tissue hypoxia, which arises as a result of increased oxygen demand and maldistribution of blood flow.61 Recent studies have shown that if such treatment measures were instituted in high-risk surgical patients during the perioperative period, a significant reduction in mortality can be achieved.62,63 These studies support the notion that VO2 is dependent on DO2 However, this assumption has been challenged and recent randomized prospective trials have failed to show any benefit in terms of morbidity and mortality in patients achieving supranormal values of oxygen transport.64,65 At present attempts at achieving supranormal levels of oxygen transport indices is not recommended for the management of ARDS patients PHARMACOLOGICAL THERAPY Steroids Several anti-inflammatory agents have been used in the treatment of the underlying inflammation in ARDS Corticosteroids, prostaglandin E1 and inhibitors of arachidonic acid metabolism have all been investigated for this purpose Preliminary trials with high-dose corticosteroids in septic patients with ARDS showed possible benefit.66,67 Multicenter placebocontrolled trials in which steroids were given to patients who were at risk of ARDS or in the early phase of ARDS did not show any reduction in the frequency of occurrence of ARDS in the at risk group or improvement in mortality in the ARDS group.68–70 Recent studies have suggested that corticosteroids may have a beneficial role in the fibroproliferative phase of ARDS.71,72 The corticosteroidtreated patients had a significantly lower mortality rate than the placebo-treated group in these trials Interpretation of this result is complicated by the small number of patients enrolled, the fact that half the placebo treated group crossed over to the corticosteroid group and that the incidence of infection in the steroid group was twice as high as the placebo group The use of corticosteroids in late phase ARDS is currently being evaluated in the USA in an ongoing multicenter trial 1420 A Clinical Approach to Medicine Trials have been conducted with other anti-inflammatory agents such as prostaglandin E1,73 ketaconazole,17 ibuprofen,74 N-acetylcysteine75 in patients with ARDS, but none have proven successful in reducing mortality Inhaled Vasodilator Inhaled vasodilators, particularly prostacyclin and nitric oxide (NO) have been administered in patients with ARDS resulting in improvement of the ventilation-perfusion mismatching and ultimately amelioration of hypoxemia.76,77 However, neither of these agents has been shown to improve survival in ARDS Surfactant Abnormalities of surfactant function have been described in patients with ARDS.78,79 Abnormal surfactant function, thought to result from the action of inflammatory mediators on surfactant itself, will lead to collapse of the alveolar units resulting in the creation of shunts Administration of exogenous surfactant has been shown to improve oxygenation in ARDS patients.80 However, in a large multicenter prospective placebo-controlled trial, there was no benefit in 30-day mortality, length of stay in the intensive care unit or the duration of mechanical ventilation.81 Currently, there is no evidence to support the use of exogenous surfactant in patients with ARDS OUTCOME Most patients who die with ARDS so within the first weeks of the illness The cause of the death in most cases would be sepsis syndrome or multi organ dysfunction syndrome rather than respiratory failure.82 Mortality rates of 60–70% were quoted in several studies in the first two decades.13,14 Recent reports have indicated that with current supportive strategies the mortality rate has fallen to approximately 40%.83,84 Predictors of mortality have been identified in a recent trial and these include7: 1) non-pulmonary organ dysfunction occurring between hospital admission and ICU admission; 2) sepsis syndrome; and 3) chronic liver disease Acute Respiratory Distress Syndrome 1421 Many survivors of ARDS can lead a normal life despite a lower health-related quality of life than the general population.85 Lung function studies in survivors have shown that lung mechanics return to normal within the first year after hospital discharge or extubation.86,87 However, reduction in diffusion capacity and exercise induced increment in dead space ventilation (Vd/Vt) persist.86 The severity of the residual pulmonary defect appears to correlate with the severity of the ARDS.88 REFERENCES Ashbaugh DG, Bigelow DB, Petty TL, Levine BE, Acute respiratory distress in adults, 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lung injury, Am J Respir Crit Care Med 156:1120–1128, 1997 86 Elliot CG, Morris AH, Cengiz M, Pulmonary function and exercise gas exchange in survivors of adult respiratory distress syndrome, Am Rev Respir Dis 123:492–495, 1981 87 McHugh LG, Milberg JA, Whitcomb ME, Schoene RB, Maunder RJ, Hudson LD, Recovery of function in survivors of adult respiratory distress syndrome, Am J Respir Crit Care Med 150:90–94, 1994 88 Elliot CG, Rasmusson BY, Crapo RO, Morris AH, Jensen RL, Prediction of pulmonary function abnormalities after adult respiratory distress syndrome, Am Rev Respir Dis 135:634–638, 1987 Rehabilitative Medicine This page intentionally left blank 81 A Clinical Approach to Rehabilitation Medicine Peter A C Lim Rehabilitation medicine is a relatively young specialty in the history of medicine and surgery that nevertheless has become increasingly important as societies everywhere develop This is primarily related to a greater awareness of the benefits of rehabilitation, the driving factors of aging populations with extension of life expectancies, and an increase of traumatic events in a fast-moving modern world The US is generally accepted to be where the most organized and developed rehabilitation or rehabilitative services are available Rehabilitation medicine there had its beginnings in wartime But prior to the Second World War in the 1940s, the high mortality rates from infection and limitations of medical care then often meant little could be done for the victims of serious slash and stab wounds, gunshot injuries and explosions With the availability of antiseptics and antibiotics however, there developed a large patient-base of military survivors with various impairments who needed help returning to optimal functioning and back into the society Of great importance was public consciousness that the injuries were suffered while defending freedom and the homeland, leading to a push for development of services for these worthy veterans 1429 1430 A Clinical Approach to Medicine Many of the principles and techniques of modern rehabilitation medicine came from this period Principles pioneered then such as the desirability of getting patients out of bed quickly to avoid the deleterious effects and hazards of immobility, as well as early ambulation, intensive therapy, and the therapeutic effects of activities like handicrafts are taken for granted nowadays The comprehensive approach to rehabilitation in order to deal with wide-ranging issues from self-care ability to mobility, self-image to vocation, was also established in this era Another tragedy that gave impetus to the development of rehabilitation was the poliomyelitis epidemic of the 1940s and 50s In a similar manner, the demand for something to be done to help the innocent children stricken may have rivaled that to help the heroes of war Techniques in bracing, the use of thermal modalities and therapeutic exercise received much attention, research, experimentation and widespread usage It led to the demand for physicians trained in comprehensive physical, psychosocial, and vocational rehabilitation to lead and direct the restoration efforts The fields of physical therapy, occupational therapy, and orthotics also became areas of interest for many in healthcare The physicians who used physical agents and therapeutics for diagnosis and treatment were initially known as physical therapy physicians, but the term commonly used for them became physical medicine physician in 1944 They worked mainly with occupational or musculoskeletal diseases and injury, but then united with the more inpatient-centered rehabilitation medicine physicians to become one specialty in 1949, recognizing their common approaches and philosophies of care In the US the term for the joint specialty is physical medicine and rehabilitation, and the physician in this field is referred to as the physiatrist In more recent times, rehabilitation medicine has played a leading role in the development of rehabilitation healthcare systems for the disabled and introducing concepts of outcome-oriented research and costeffectiveness It has been involved in the influencing of public policy and awareness towards the use of seatbelts, and safety helmets for motorcyclists Accessibility for the disabled has been championed such as cuts in street curbs, installation of ramps and lifts in public buildings, as have the philosophy of independent-living, civil rights for the disabled, and the value of the individual with a disability or handicap to the society Singapore has acquired developed-country status in the very short period of about 30 years It has one of the highest per-capita gross national A Clinical Approach to Rehabilitation Medicine 1431 Table Increasing Demands for Rehabilitation Services in Singapore Singapore: Then and Now* 1970 2000 Population (mil) Population Growth (%) Life Expectancy (Yrs) Infant Mortality Rate (per 1000 live births) Total Fertility Rate (per 1000 females) 2.1 2.8 65.8 20.5 1.7 78 2.5 3065 1586 Singapore: A Comparison† Singapore Japan UK US Population (mil) 4.1 127.1 60.0 285.7 Per-Capita GNP (US$) 24 664 37 950 23 793 35 277 Life Expectancy (Yrs) 78 80 77 77 Aged у 65 (%) 7.3 17.2 In the year 2030 those aged 65 years and older will comprise 19% of the Singapore population.** *Department of Statistics, Singapore †Asiaweek, September 2001 **Report of the Interministerial Committee on the Ageing of the Population, November 1999 product, and the infant mortality rate, a good indicator of health in general, is one of the lowest in the world However, it has also become one of the fastest aging societies in Asia Along with a low birth rate inadequate to even replace the population, the specter of having to care for increasing numbers of the disabled elderly looms In conjunction with changes in cultural norms such as both the husband and wife working outside the home, smaller families to share the burden, philosophies on expectations and sacrifice, taking care of the disabled parent is often a difficult task Rehabilitation, which focuses on minimizing disabilities and optimizing independence, is one of the solutions The benefits of rehabilitation includes fewer medical complications, a better functional outcome and quality of life, with corresponding lower medical costs IMPAIRMENT, DISABILITY, AND HANDICAP Although these terms are often used interchangeably, awareness of the differences between them is helpful for understanding the 1432 A Clinical Approach to Medicine 60 50 40 30 20 10 under 18 18-24 25-44 45-64 65-69 70-74 75-84 over 85 Fig Relationship between age and activity limitations of different extents There is a strong correlation between age and limitation in functional activity or disability, and this increases significantly past the age of 65 years (Craus LE, Stoddard S Chartbook on disability in the United States: an InfoUse report U.S National Institute on Disability and Rehabilitation Research, 1989) 20 18 A: In and out of bed 16 B: Getting around inside home 14 C: Speech understood 12 D: Getting around outside home 10 E: Hearing normal conversation F: Seeing newsprint G: Up flight of stairs H: Lifting/carrying 10 lb bag I: Walking quarter mile Fig Nature of functional limitations Functional limitation can vary from the relatively mild e.g unable to walk a quarter mile, to as severe as being unable to get in and out of bed (Craus LE, Stoddard S Chartbook on disability in the United States: an InfoUse report U.S National Institute on Disability and Rehabilitation Research, 1989) A Clinical Approach to Rehabilitation Medicine 1433 implications and approaches to management As per the World Health Organization, 1980: Impairment is a loss or abnormality of psychological, physiological, or anatomical structure or function Disability is a restriction or inability due to impairment, to perform a normal activity Handicap is a disadvantage resulting from impairment or disability, limiting or preventing a normal role Where most other medical or surgical specialties focus on the pathology or disease that leads to the impairment, Rehabilitation Medicine’s job extends across the spectrum In a stroke for instance, the rehabilitation physician’s involvement begins with a referral of the patient by the neurologist or neurosurgeon, following which the patient may be taken over for rehabilitation This then includes management of associated risk factors such as hypertension or diabetes (Pathology), the hemiplegia (Impairment) that results from the stroke, inability to walk due to the paralysis (Disability), and inability to get around in a wheelchair in public due to steps or curbs (Handicap) Using the above definitions, it is possible to see that this same stroke survivor may have much residual impairment, yet after rehabilitation not be very disabled This person may have significant residual hemiparesis, but be able to perform all activities of daily living (ADL) independently, using modified techniques or by compensation with equipment such as a wheelchair He or she might still be handicapped though, if there are only stairs to get into a building, a handicap that can be removed by installing a lift This understanding is important from the perspective that the disabled person should be very much a normal part of our society Such a person is not necessarily a burden but is instead capable of valuable contributions to the community, yet not able to so because of environmental or social norms and policy THE REHABILITATION MEDICINE TEAM Because of the far-reaching consequences from an event such as a stroke or spinal cord injury, many deficits and issues need to be addressed and rehabilitation is often a multi-disciplinary team effort: The Rehabilitation Physician who leads the rehabilitation team, is trained in neurological and musculoskeletal assessment and medical management of rehabilitation patients, including complications resulting 1434 A Clinical Approach to Medicine from disabling conditions or injuries, has training in therapeutic exercise, modalities, prosthetics, orthotics, wheelchairs/other assistive equipment, and procedures such as soft tissue injection, urodynamics and electrodiagnosis The Rehabilitation Nurse is involved in direct nursing care of physically impaired patients, assisting with the reacquisition of self-care abilities, teaching in the use of adaptive equipment, and has a major role in patient-family education The Physical Therapist/Physiotherapist works on motor restoration, posture, balance, coordination, mobility and ambulation, application of modalities, chest physiotherapy, and the evaluation of walking aids or wheelchair needs of the patient The Occupational Therapist is involved with self-care and functional activities, upper limb performance, assistive devices and technology, training in use of upper limb prostheses, home environment evaluation, and compensations for visual-spatial and cognitive disorders The Speech Therapist/Pathologist works with speech-language and communication, swallowing and dysphagia, the use of augmentative and alternative communication devices, as well as with cognitive disorders The Medical Social Worker explores patient-family relationships, resources, finances, discharge living situation, assists with vocational issues, liaison activities, provides emotional support and counseling The Orthotist-Prosthetist designs, fabricates and evaluates the orthoses (braces) and prostheses (replacement devices) used in rehabilitation The Psychologist carries out testing of intelligence, memory, cognition, counseling in body image changes, compensations for solving skill deficits, and assists the team to understand patient dynamics, helps resolve conflicts The Dietitian assesses adequacy and suitability of nutrition and hydration, gives recommendations for parenteral feeds, and counsels patient, family, or the rehabilitation team on dietary matters Other Members of the Rehabilitation Team The Kinesiotherapist/Corrective Therapist, uses therapeutic exercise and education, adapts physical activities, fitness programs, and provides driver’s education The Pharmacist helps with patients on multiple medications, for drug efficacy, potential interactions and side-effects The A Clinical Approach to Rehabilitation Medicine 1435 Vocational Counselor assists in developing/attaining realistic vocational goals, including evaluation, counseling, training, liaison services and support The Podiatrist is involved with management and care of diseases/ conditions of the feet and nails, shoe inserts/devices for improving function and protection The Audiologist handles hearing tests, assessment and fitting of hearing aids The Biomedical-engineer designs, evaluates, customizes devices and equipment for the disabled such as wheelchairs, cushions, computers, and environmental control units The Therapeutic Recreation Specialist assesses interests, uses recreational activities to assist in adjustment to disability, increase independence, and reintegration into society The Durable Medical Equipment Vendor helps with knowledge of options available and pricing for devices and equipment, procurement and special orders The Religious Counselor/Representative assists with spiritual aspects, including dealing with and adjusting to serious injury, disease, or dying The Child Life Therapist helps minimize interruption/disruption to the child from the hospitalization by continuation of schooling, and providing age-appropriate explanations of medical procedures needed The Horticultural Therapist uses gardening as therapy, and the raising of flowers/plants for rebuilding self-confidence The Music Therapist uses various forms of music including listening/performing instruments, voice, body-movements, and musical events to help with speech, paralysis, pain and palliation The Dance Therapist uses the psychological/ physical effects of body movements and music REHABILITATION MEDICINE PATIENTS A Rehabilitation Medicine consultation can be requested for assistance with recommending, planning, managing rehabilitation options for the patient, as well as for a prognosis of functional capabilities For example, a patient may only need a few sessions of focused therapies, or may need more comprehensive rehabilitation intervention, or sometimes may not be able to benefit from active rehabilitation Rehabilitation can be inpatient or outpatient in nature, the former being generally more complex, with patients having associated potential for medical instability The need for rehabilitation can result from a disease, injury or process, examples of which include: Neurological events such as cerebrovascular accidents (stroke), spinal cord injury, traumatic or infective brain injury, Parkinson’s disease, Guillain–Barre Syndrome, multiple sclerosis and motor neuron disease 1436 A Clinical Approach to Medicine Musculoskeletal events such as fractures, joint-replacements, upper and lower limb amputation, back injury/surgery, chronic pain, arthritis and other musculoskeletal injuries Others Conditions include: • • • • deconditioning post-surgery, from prolonged immobilization, and from being bed-bound; cardiac rehabilitation post-MI, post-cardiac surgery such as CABG, cardiac valve surgery; respiratory rehabilitation such as in COPD, lung surgery; and cancer rehabilitation, where there are deconditioning states, spinal or cerebral metastatic lesions, pathologic fractures and peripheral nerve invasion/compression INDICATIONS FOR COMPREHENSIVE INPATIENT REHABILITATION In general, a good candidate for comprehensive inpatient rehabilitation in a specialized rehabilitation unit: • • • • is medically stable with acute problems resolved or adequately controlled; has functional deficits in more than only one area, e.g difficulties in communication, swallowing, self-care abilities (eating, grooming, dressing, toileting, bathing; bowel/bladder management), transferring from surface to surface, locomotion Single functional deficit may not require comprehensive rehabilitation; has clear, achievable, rehabilitation goals; and is able to participate in the rehabilitation program from the perspective of cognition, medical condition, and motivation THE REHABILITATION ASSESSMENT The rehabilitation medicine assessment includes elements of the following: History • • risk factors that might need to be monitored and managed while undergoing rehabilitation; premorbid functioning, which is useful to assess current functional deficits and set achievable rehabilitation goals; A Clinical Approach to Rehabilitation Medicine 1437 • • • • social history including family relationships, the home setting, friends and significant-others, occupation, and recreational interests, to determine support systems and overall goals; possible impediments to community reintegration including living environment (e.g lift landing, squatting toilets), family functioning (poor or abusive relationships), and poor social supports; personal and family’s rehabilitation goals, as there needs to be mutual agreement and harmony between expectations and limitations; and discharge plans as this could affect the rehabilitation, e.g in a cancer patient, the appropriate goal might be a very short focused period of rehabilitation rather than a longer stay The remaining life-span might be better spent in the support and comfort of home and family In a demented or non-participating patient whose family has committed to caregiving at home, an inpatient rehabilitation stay might be appropriate for caregiver training, equipment needs assessment/ supply and home-modifications Physical Examination • • • • • • • • cognition and ability to follow directions, including the ability to “carry-over” or retain that which has been taught; affect/mood changes that may need counseling intervention or medications, as these could determine the patient’s ability to participate and hence benefit from active rehabilitation; speech and language functioning; swallowing and dysphagia; sensory deficits including proprioception, that could severely limit functional activities even in the presence of good motor return, and could also lead to accidental injuries; neglect or lack of self-awareness on the affected side, that may result in perception deficiencies, functional difficulties, safety concerns and accidental self-injuries; range of motion limitations, which could impair rehabilitation due to inability to situate the limb or trunk in a functional/optimal position; tone, and spasticity that could restrict movements, be painful, and limit function with potential for injuries from falls during a spasmodic episode; 1438 A Clinical Approach to Medicine • • • • motor strength, both from the perspectives of power (ability to generate a forceful movement) and endurance (ability to repetitively carry out the movement); skin integrity or breakdown, especially in immobile, incontinent patients with insensate skin and cognitive deficits; bowel and bladder functioning; functional issues including ability to feed oneself, dress, toilet, transfer, use a wheelchair or walk Additional Investigations in Rehabilitation • • Urodynamics is a relatively common procedure as many rehabilitation patients have neurogenic bladders, or are in the age group when obstructive pathologies such as prostatic enlargement are common Besides a detailed pressure-volume study of the bladder in response to filling and stimulation, of particular usefulness are measurements such as post-voiding residual urinary volume, input and output monitoring, as well as tests for detrussor-sphincter dyssynergia Electrodiagnosis, which includes the procedures of nerve conduction studies (NCS) and electromyography (EMG) are investigative procedures that may be performed by a rehabilitation physician These studies could help in the determination of diagnosis, e.g a neuropathy versus myopathy, could also be used for determining the extent of injury, and to monitor progress of the condition LEVELS AND LOCATIONS FOR REHABILITATION Inpatient Acute and subacaute comprehensive inpatient rehabilitation Hospital-based Rehabilitation Medicine Unit (e.g SGH, TTSH, CGH departments of Rehabilitation Medicine) Generally, these patients have multiple or complex rehabilitation needs, moderate risk for medical instability, require maximal-minimal assistance with ADL (activities of daily living), physically and cognitively are able to participate and learn They receive 2–3 hours of therapies per day, 5–6 days a week, under direct supervision of a rehabilitation physician A Clinical Approach to Rehabilitation Medicine 1439 Subacute or slow-stream or lower-intensity inpatient rehabilitation Community Hospital (e.g AMKCH, St Luke’s, St Andrew’s, Bright Vision, Westpoint) Patients have minimal risk from medical instability, require maximalminimal assistance with ADL, with cognitive or physical limitations precluding intensive rehabilitation They receive 1–3 hours of therapy per day, 3–5 times per week The doctor, who may not be a rehabilitation physician, sees the patient 1–3 times per week Outpatient Day Rehabilitation Center (e.g various senior citizens health care centers, Salvation Army, Apex, Muhammadiyah, Metta, HWA, SPD, or outpatient programs of acute/community hospitals) Patients are medically stable, require minimal assistance with ADL, and have family support to manage at home Advantages include socialization, peer support, with availability of professional personnel and equipment Therapy sessions are 2–5 times per week A doctor may prescribe the therapies but direct involvement is variable Nursing Homes Selected Nursing Homes (various locations) Patients need extended care, are medically stable, and often require maximal-minimal assistance with ADL These are usually group-type therapies with limited one-on-one attention, with goals of maintenance of functioning Therapy sessions are 1–5 days per week Direct involvement by nursing home doctor is variable, usually monthly Home-based E.g SGH HomeCare, Tsao Foundation or Mt Alvernia Home Care Program, AMKCH Patients cannot safely get to outpatient programs, or endurance is poor and patient is exhausted by the travel itself There is added advantage of teaching in patient’s own surroundings, especially for the cognitively impaired Therapy may be 1–3 times per week, prescribed by a doctor, but amount of direct involvement is variable 1440 A Clinical Approach to Medicine THE MECHANICS OF INPATIENT REHABILITATION Rehabilitation addresses some or all aspects of the following: Management of Immediate Care Issues: In the acute rehabilitation patient particular attention is given to dysphagia, communication, DVT prophylaxis, nutrition, hydration, skin integrity, urinary bladder and bowel management Patient and family involvement are intrinsic to the rehabilitation program Emotional support, and education as to main features of stroke, treatment, and prognosis should be provided Training/Improving Neurological/Musculoskeletal Recovery: As neurological recovery occurs or the musculoskeletal structures heal, rehabilitation aims for functional restoration and includes motor strengthening, sensory reeducation or compensation, balance and posture restoration, coordination drills, and strategies to improve or compensate for visuo-spatial and cognitive deficits Management of Complications: The immobilized, acutely ill patient is at high risk for complications such as skin breakdown, spasticity, contractures, venous thromboembolism, musculoskeletal and neurogenic pain, depression, autonomic dysfunction, reflex sympathetic dystrophy, infections, seizures, falls, malnutrition, cardiac events, recurrent stroke, etc which may need to be managed while on the rehabilitation medicine unit Compensation Strategies: Frequently there are permanent impairments that will require teaching the patient modified techniques or sequences to carry out a routine functional task, e.g dressing in bed instead of standing up, placing the paralyzed arm in the sleeve before the non-paralyzed Equipment can be used to compensate for the impairment including prostheses, orthoses, mobility devices such as wheelchairs and walking aids, electronic environmental control units and computers Discharge Planning: The team, patient and family, will need to work out a plan for destination after discharge, and continuity of care including arrangements for follow-up and subsequent outpatient care A home visit and renovations/modifications may be needed Avocational (recreational) issues are important from the perspective of quality of life and the person’s interests should be assessed Vocational issues are relevant in some patients A Clinical Approach to Rehabilitation Medicine 1441 especially the younger ones and need to be addressed This may involve liaison with the employers, workplace adaptations, and retraining Finally there are many other adjustments that may be needed when a severe disability has occurred including sexuality, issues of self-worth, and identity THE TOOLS OF REHABILITATION In addition to medications, injections and debridement procedures, the rehabilitation physician may also prescribe orthoses, prostheses, and: Therapeutic Exercise Therapeutic exercise increases strength and muscle size, may be isotonic (concentric or shortening exercises, also eccentric or lengthening exercises), isometric (static or non-shortening exercises), or isokinetic (constant velocity or accommodating resistance exercise) The DeLorme Axiom is an important principle in rehabilitation This states that low-repetition, high-resistance exercises produce power, whereas high-repetition, lowresistance exercises produce endurance, and each is incapable of producing results of the other Hence therapeutic exercises usually includes both The concept of specificity training is also well-accepted in rehabilitation, e.g although therapeutic exercises for the muscles of ambulation are important, it is still necessary to work on actual walking to regain this function well Other aspects of therapy include restoring coordination, balance, and posture, exercises in preparation for gait retraining including crutch and cane usage if necessary, and acquiring of wheelchair skills Heat and Cold Modalities Thermal modalities are often used in rehabilitation: Heat Modalities (e.g hot packs, paraffin wax bath, fluidotherapy, infrared radiation, shortwave diathermy, ultrasound for deep heating): Heat has excellent properties including analgesia and sedation that decreases pain, spasms, and aids relaxation It is a general stimulant, and dilates vessels improving blood flow resulting in increasing nutrient inflow and waste removal It causes an increase of capillary permeability 1442 A Clinical Approach to Medicine that may either increase or decrease interstitial fluid and hence edema An important effect is increase of non-elastic tissue extensibility, allowing elongation/stretching of tendons or scars and hence improving range of movement The resultant decrease in joint stiffness increases speed, freedom of movement, and agility Heat increases peripheral nerve conduction velocity and motor nerve transmission, and thus motor function as a whole Cold Modalities/Cryotherapy (e.g ice massage, chemical cold packs, ice towels, ice packs, vapocoolant sprays): Cold modalities also have properties of analgesia/sedation, decreasing pain, spasms, and aiding relaxation The initial superficial vasoconstriction on application decreases superficial bleeding, and subsequent increase in blood viscosity with decreased flow further retards blood loss Decrease in peripheral nerve activity from cold may reduce spasticity Lowering of joint tissue and fluids temperature decreases activity of jointdamaging enzymes Hydrotherapy Hydrotherapy in a swimming pool or whirlpool tub allows for delivery of hot or cold treatment modalities The physical effects of buoyancy, hydrostatic pressure, surface tension, and turbulence create an ideal environment for therapeutic exercise, such as muscle strengthening, balance, range-of-motion activities, and reduced-weight ambulation Both thermal properties and hydrostatic pressure improves circulation and reduces edema Pressure, fluidity, and turbulence are useful for the treatment of open wounds and skin problems, including debridement, removal of dressings, and application of medications or skin lubricants Water is also a relaxing medium in general, producing psychological benefits Therapeutic Electricity, etc Electrical Stimulation can decrease spasticity with direct stimulation of spastic or antagonistic muscles Muscle irritation, spasm and pain may respond to high-frequency intermittent stimulation Use of electrical stimulation to increase circulation and nutrition to denervated muscle is A Clinical Approach to Rehabilitation Medicine 1443 controversial as it retards atrophy, but may interfere with peripheral nerve regeneration It decreases edema by improving muscle-pumping action that increases circulation, and accelerates wound healing by retarding bacterial growth Iontophoresis is the use of electric current to drive ions of various substances or medications e.g steroids, lidocaine, salicylate, zinc oxide, through the skin into underlying tissues Transcutaneous Electrical Nerve Stimulation (TENS) is the application of low-voltage electrical pulses to the nervous system through the skin TENS may change pain perception as per the Gate-Control Theory whereby high-frequency stimulation of non-nociceptors or axons interferes with relay of pain sensations to higher brain centers It may also act via natural opiates from the pituitary gland (beta-endorphins) and spinal cord (enkephalins), released by low-frequency stimulation of sensory nerves TENS may be useful for acute and chronic, phantom, postoperative, cardiopulmonary, and neurological pain, as well as before painful stretching or debridement Ultraviolet Irradiation (UV) causes vasodilatation that stimulates granular tissue formation leading to tissue repair It has an anti-rachitic effect due to its role in vitamin D formation, and by stimulation of steroid metabolism Bacterial destruction occurs from its stimulation of reticuloendothelial cells, increasing circulatory antibodies, with associated wound healing There are also psychological benefits such as sense of well-being Low-powered Helium-Neon Lasers (Light Amplification by Stimulated Emission Radiation) can help reduce pain reduction and accelerate tissue healing from increase in collagen synthesis, vascularization, and from decrease in microorganisms Lasers may be used for promotion of tissue healing, and management of pain associated with muscle spasm and inflammation Biofeedback gives immediate information-return about physiological functions, and hence allows for active self-control over the function being monitored It includes aural or visual feedback, skin thermal feedback, skin electrical conductance, or electromyographic (EMG) feedback for muscle activity It is useful in general relaxation-training e.g in hypertension, headaches, chronic pain, as well as for training improved motor control of weak muscles 1444 A Clinical Approach to Medicine Traction/Distraction Traction is done by application of forces to the spine or limbs to separate vertebrae, and elongate surrounding tissues such as muscles and ligaments The increase of space between vertebrae, articulating facets, and intervertebral foramen may result in relaxation of paraspinal muscles, and diminution of bulging herniated discs or pressure on nerve roots in the intervertebral foramen It can be helpful in nerve root impingement, subacute joint pain, subacute degenerative joint disease, discogenic pain, chronic spinal compression fracture, joint hypomobility, and paraspinal muscle spasm Intermittent Pneumatic Compression Forcing air with a pump intermittently into inflatable sleeves or boots around an upper or lower extremity results in an increase of interstitial space fluid pressure that encourages fluid return to venous or lymphatic vessels, helping reduce edema Intermittent pneumatic compression can be useful in chronic edema, venous insufficiency, lymphedema, stasis ulcers, amputated limbs, wound healing, and thrombophlebitis prevention Medications Rehabilitation physicians manage certain medical complications more often than other specialties These complications may entail the use of medications such as: • Spasticity Baclofen (GABA analog), diazepam (benzodiazepine), gabapentin (anticonvulsant), clonidine, tizanadine (alpha2-adrenergic agonists), dantrolene sodium (skeletal muscle relaxant), carisprodol, cyclobenzaprine (brainstem neuronal depressants) Others less commonly used or controversial: cyproheptadine (nonselective 5-HT antagonist), opiates (narcotic analgesic), glycine, L-threonine (amino acid inhibitory neurotransmitters), 4-aminopyridine (potassium channel-blocker), orphenadrine citrate (antiparkinsonian agent), 9-tetrahydrocannabinol (narcotic) A Clinical Approach to Rehabilitation Medicine 1445 • • • • • • Autonomic dysreflexia Topical lidocaine (local anesthetic), nifedipine, nitrates (nitroglycerine paste), phenoxybenzamine, propanolol, terazosin, diazoxide, hydralazine, mecamylamine Neuropathic pain Amitriptyline, nortriptyline (tricyclic antidepressants), trazadone (nontricyclic antidepressant), gabapentin, carbamazepine (anticonvulsants), baclofen, tizanidine, clonidine (anti-spasticity agents), mexiletine, lidocaine (anti-arrthymic agents), capsaicin (substance P depletor) Depression Fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram (selective serotonin reuptake inhibitors), amitriptyline, nortriptyline (tricyclic antidepressants) Psycho-modulation Methylphenidate (psychostimulant), bromocriptine (dopamine agonist), propanolol (-blocker), risperidone (antipsychotic), lorazepam, chloral hydrate, zolpidem, nortriptyline, fluvoxamine (anxiolytics, sedatives, and antidepressant) Bladder management Oxybutinin, propantheline, tolterodine, amitiptyline, flavoxate (anticholinergics), ephedrine (sympathomimetic), bethanecol (cholinomimetic), prazosin, terazosin (adrenolytics), baclofen, dantrolene, tizanidine (antispasticity agents) Bowel management Psyllium, isphagula (fiber supplements), docusate, lactulose (stool softeners), senna, bisacodyl (bowel stimulants), gylcerine, paraffin (lubricants), cisapride (peristalsis stimulant) CONCLUSION Rehabilitation medicine is the medical field specializing in care of patients with disabling disease or injury It utilizes a team approach, with optimal functioning and independence of the patient as the ultimate goal Rehabilitation physicians are trained in the assessment and medical management of patients with neurological and musculoskeletal disorders, and their associated complications They are also trained in therapeutic 1446 A Clinical Approach to Medicine exercise, modalities, prosthetics, orthotics, assistive devices for the disabled, and procedures such as electrodiagnosis Rehabilitation is holistic in nature and addresses the restoration, or compensation where necessary, not only of the physical but also psychological, social, educational, vocational, and recreational abilities FURTHER READING 50th Anniversary of the American Academy of Physical Medicine and Rehabilitation, Archives of Physical Medicine and Rehabilitation, 69, Special Issue, 1988 DeLisa JA, Gans BM (eds), Rehabilitation Medicine: Principles and Practice, 3rd ed., Lippincott-Raven, Philadelphia, 1998 Hecox B, Mehreteab TA, Weisberg J (eds), Physical Agents: A Comprehensive Text for Physical Therapists, Appleton & Lange, Norwalk, 1994 Basmajian JV, Wolf SL (eds), Therapeutic Exercise, 5th ed., Williams & Wilkins, Baltimore, 1990 Kirshblum S, Campagnolo DI, DeLisa JA (eds), Spinal Cord Medicine, Lippincott Williams & Wilkins, Philadelphia, 2002 Material in “The Rehabilitation Medicine Team” extracted from DeLisa and Gans,2 “The Tools of Rehabilitation” from Hecox et al.3 and Basmajian and Wolf,4 and “Medications” from Kirshblum et al.,5 and “Levels and Locations for Rehabilitation” from Flick CL, Stroke rehabilitation Outcome and psychosocial consequences, Arch Phys Med Rehabil 80(5 Suppl 1):S21–26, 1999 Rheumatology This page intentionally left blank 82 Diagnosis in Rheumatic Diseases Fong Kok Yong INTRODUCTION Rheumatic diseases encompasses more than 100 different types of conditions associated with the musculoskeletal and/or immune system The symptoms can be straightforward or of a very varied and protean nature Oftentimes the manifestations can even baffle experienced clinicians Any of the organ system in the body can be affected, though it is usually the musculoskeletal symptoms that bring the patient to the doctor A comprehensive history taking process, with special attention to the joint symptoms, supplemented by a thorough physical examination and augmented by focused laboratory investigations, remain the foundations of rational diagnosis in rheumatic conditions There’s no good substitute for the time-tested process of history taking and physical examination In more than 90% of the cases, a diagnosis can be reached after these steps and laboratory investigations serve the function of confirming the diagnosis or in subsetting patients for more targeted therapy Laboratory tests can also help in evaluating the severity and disease course of the rheumatic condition 1449 1450 A Clinical Approach to Medicine HISTORY The history taking process can be focused broadly into categories Firstly, those pertaining to joint symptoms, and secondly, those with predominantly systemic symptoms Joint pain is the most common symptom among rheumatic diseases and hence plays an important part in the diagnosis of rheumatic conditions The pattern of joint involvement, number of joints involved, characteristics of the joint pain and association with joint swellings, are useful diagnostic indicators in the history Table shows the characteristics of joint involvement of some rheumatic conditions seen locally A symmetrical arthritis of the finger joints indicate the possibility of rheumatoid arthritis as compared to asymmetrical involvement in seronegative spondyloarthropathy patients Ankylosing spondylitis patients usually have axial skeleton joint pain presenting with early morning low backache Acute onset of excruciating pain typically point toward the presence of gouty arthritis, with the big toe most commonly involved Pseudogout or calcium pyrophosphate deposition disease (CPPD) can also present in a similar way Differences between them are a higher frequency of knee involvement in CPPD and its usual occurrence in the elderly Primary gouty arthritis usually occurs at a younger age group Table summarizes the broad differences between the conditions Septic arthritis must be excluded in all patients presenting with monoarticular arthritis, even in those with a history of chronic arthritis The consequences for delayed diagnosis in septic arthritis can be catastrophic, i.e severe joint destruction Degenerative joint pains, e.g osteoarthritis, are usually aggravated by movement and weight-bearing stresses, and relieved by rest Inflammatory pain, on the other hand, is aggravated by prolonged rest, hence the common finding of increased pain on waking Movement of a mildly inflamed joint can help relieve stiffness The patient’s age also helps in discriminating between degeneration and inflammation as the former is predominantly a condition of the elderly while inflammatory pain, e.g due to ankylosing spondylitis, is usually in the younger age group Pain occurring at the enthesis (the site where the tendon joins the bone) can be suggestive of soft tissue rheumatism or seronegative spondyloarthropathies The pain is usually localized and aggravated by certain movement of the joints In fibromyalgia (generalized soft tissue rheumatism) the patient complains of characteristic painful areas, which are confirmed as localized Diagnosis in Rheumatic Diseases 1451 Table Characteristics of Joint Symptoms in Some Rheumatic Diseases Joints Pattern of Involvement Number Involved Character of Pain Associated Swelling Osteoarthritis Weight-bearing Variable and DIP joints; cervical and lumbosacral spine Aggravated by movement, relieved by rest Due to fluid in early stages; bony hypertrophy at later stages Gouty arthritis Usually unilateral; big toe, foot or ankle joint Usually Acute onset May be present monoarticular of excruciating during acute pain phase Soft tissue rheumatism Joint is normal; involved para-articular structures Multiple tender points at the sides of joints Localized, constant pain, stiffness on waking None Rheumatoid arthritis Symmetrical involvement of synovial joints, esp MCP and PIP joints Usually multiple Constant, worse in the morning Present during active phase Ankylosing spondylitis Axial joint involvement; usually starting from lower back Variable peripheral joint involvement Constant, May be present worse in the in peripheral early morning joints Systemic Asymmetrical lupus joint erythematosus involvement Variable Constant Psoriatic arthritis Asymmetrical joint involvement, esp DIP joints Variable, Constant usually finger joints May present with “sausagelike” fingers Sjogren’s Syndrome Asymmetrical joint involvement Variable May be present Constant Usually no swelling DIP: Distal Inter-Phalangeal; MCP: Meta-Carpal Phalangeal; PIP: Proximal InterPhalangeal tender spots on palpation.1 Referred pain due to pathology elsewhere , e.g prolapsed intervertebral disk, can usually be picked up during history taking and confirmed by physical examination Joint involvement in systemic lupus erythematosus is usually much milder when compared to 1452 A Clinical Approach to Medicine Table Common Characteristics of Gout and Pseudogout Male : Female ratio Age (years) Commonest joint involved Gout CPPD (Pseudogout) 3–7 : 40 to 50 First MTP 4:1 60 to 70 Knee CPPD: Calcium PyroPhosphate Disease inflammatory arthritides Arthralgia, rather than arthritis, is the usual presentation in lupus patients Patients with Sjogren’s syndrome usually have arthralgia and only a minority has frank arthritis Systemic symptoms as presenting manifestations generally indicate greater severity and a more active disease process Fever, malaise and general debility are symptoms reflective of systemic involvement Other organ specific symptoms like coma in cerebral involvement, generalized edema in renal failure, breathlessness in alveolitis or pulmonary hypertension, Raynaud’s phenomenon in vascular hyperreactivity, may also be prominent presenting symptoms FAMILY HISTORY Most rheumatic diseases are sporadic in occurrence and familial cases are usually the exception rather than the rule However, a strong family history of a rheumatic condition, e.g ankylosing spondylitis will suggest a similar diagnosis in a young individual with persistent low back pain Likewise, a patient with a positive anti-nuclear antibody test and had relatives with autoimmune conditions, e.g thyroiditis, myasthenia gravis, rheumatoid arthritis, autoimmune diabetes mellitus, probably is developing an autoimmune rheumatic condition DRUG HISTORY Drugs can either cause a rheumatic condition or aggravate a subclinical rheumatic condition Drugs, e.g procainamide can cause drug-induced lupus.2 Recognition of this condition and stopping the drug will be beneficial to the overall management of the patient Table shows some of the Diagnosis in Rheumatic Diseases 1453 Table Rheumatic Conditions Associated with Drugs Ingestion Drug-Induced Condition Possible Drugs Lupus Chlorpromazine; griseofulvin; hydralazine; isoniazid; methyldopa; penicillamine; phenytoin; procainamide; quinidine Gouty arthritis Thiazide diuretics; low-dose aspirin Raynaud’s Phenomenon -blockers; ergotamine; bleomycin drugs associated with autoimmune conditions A patient who develops acute arthritis after administration of diuretics or low-dose aspirin, probably has drug-induced gouty arthritis Changing the medication will alleviate the condition and prevent the patient from having unnecessary investigations TRAVEL HISTORY Global travel is a common phenomenon in this modern age and travelers can go to “out-of-the-way” places easily Hence rheumatic conditions uncommon in the traveler’s home country may be acquired during overseas travel A recent episode of bloody diarrhea may not be mentioned by the patient unless specifically asked for in the travel history This may explain joint symptoms due to reactive arthritis following the bout of diarrhea.3 Lyme arthritis4 may not be endemic in the traveler’s home country but may occur if the traveler is infected by the tick-borne spirochete, Borrelia burgdorferi, after a visit to endemic areas in the US or Europe PHYSICAL EXAMINATION A general musculoskeletal examination followed by a more focused examination of the joints involved are very helpful in coming to a diagnosis The general musculoskeletal examination can easily be performed expeditiously and yet yield useful diagnostic signs.5 Examination of the hands, elbows, knees and spine is particularly useful in the diagnosis of rheumatic conditions as shown in Table The site of tenderness can also aid in differentiating the different rheumatic diseases The tenderness can be arising from the joint as a 1454 A Clinical Approach to Medicine Table Some Distinctive Signs Associated with Various Rheumatic Conditions Hands Elbows Knees Spine Osteoarthritis Heberden’s or Bouchard’s nodes; DIP joint deformities Usually normal Crepitus; Genu varus Lower back tenderness; cervical tenderness Rheumatoid arthritis Swan-neck, Boutonneire’s, Mallet finger deformities; Ulnar deviation Rheumatoid nodules Genu valgus Cervical subluxation (Note: Do not forcibly examine the neck if subluxation is suspected) Psoriatic arthritis Dactylitis; DIP joint deformities Psoriatic plaques Usually normal Usually normal Ankylosing spondylitis Usually normal Usually normal Usually normal Lower back and S-I joint tenderness and limitation of spinal movements Gouty arthritis Usually normal Tophi Usually normal Usually normal Progressive systemic sclerosis Sclerodactyl; Raynaud’s phenomenon; digital infarcts Usually normal Usually normal Usually normal DIP: Distal Inter-Phalangeal; S-I: Sacro-Iliac result of fluid distention e.g rheumatoid arthritis or localized to a specific area, e.g lateral epicondyle in tennis elbow In the latter, the joint space is not involved Crepitus on joint movement indicate degenerative changes within the joint, and limited joint movement associated with pain and stiffness can be due to supraspinatus tendinitis (painful arc syndrome) or rotator cuff tendinitis (frozen shoulder) Organ specific examination can be directed by the symptoms elicited during the history taking process, e.g breathlessness in the patient will warrant thorough respiratory (e.g fibrosing alveolitis) and cardiovascular (e.g pulmonary hypertension) examinations Diagnosis in Rheumatic Diseases 1455 LABORATORY INVESTIGATIONS Blood investigations should not be the sole or main diagnostic determinant in rheumatic diseases Their roles are in confirming the clinical diagnosis as well as serving as disease activity markers In general they can be classified into categories: Diagnostic Markers and Disease Activity Markers Table shows the usefulness of some common tests used in rheumatology practice Most tests are used either for diagnostic purposes or in evaluation of disease activity Some quantitative tests, e.g for rheumatoid factor, AntidsDNA autoantibodies, are useful for both purposes Table shows the associations of rheumatic diseases with various autoantibodies Knowing these associations assist us in coming to a more definite diagnosis in difficult cases However one has to bear in mind that the relationship is not exclusive and the same autoantibodies can be present in more than one rheumatic conditions Genetic markers are generally of limited value in the diagnosis of rheumatic condition The known major histocompatibility complex (MHC) Table Common Tests Used in Diagnosis and Evaluation of Rheumatic Diseases Diagnostic Markers ESR CRP Hb, WBC, platelet count Rheumatoid factor Anti-dsDNA ANA Anti- Sm Anti-RNP Anti-Ro Anti-La Anti-Scl-70 Antiphospholipid antibodies* Ϫ Ϫ ϩ/Ϫ ϩ ϩ ϩ ϩ ϩ ϩ ϩ ϩ ϩ Disease Activity Markers ϩ ϩ ϩ ϩ ϩ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ ϩ ϭ Useful; Ϫ ϭ Not useful; ϩ/Ϫ ϭ Sometimes useful *Anti-phospholipid antibodies include: presence of lupus anticoagulants, presence of anticardiolipin antibodies (either IgG or IgM isotype), biological false-positive VDRL test ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein; Hb: Hemoglobin concentration; WBC: Total white cell count; ANA: Anti-nuclear antibodies test; Anti-Sm: Antibodies to the Smith antigen; Anti-RNP: Antibodies to Ribonucleoproteins; Anti-Ro: Antibodies to Ro or SSA antigen; Anti-La: Antibodies to La or SSB antigen; Anti-Scl 70: Antibodies to Topoisomerase I 1456 A Clinical Approach to Medicine Table Autoantibodies and Disease Associations Autoantibodies Associated Rheumatic Condition Anti-Sm Anti-RNP Anti-Ro SLE SLE; MCTD; Raynaud’s Phenomenon Sjogren’s Syndrome; SLE; subacute cutaneous lupus; congenital heart block Sjogren’s Syndrome; SLE Progressive systemic sclerosis PAPS; SLE Wegener’s granulomatosis Anti-La Anti-Scl 70 Anti-phospholipid antibodies Anti-neutrophil cytoplasmic antibodies (c-ANCA) Anti-neutrophil cytoplasmic antibodies (p-ANCA) Anti-Jo Anti-dsDNA Anti-histone Rheumatoid factor (IgM) Vasculitis Dermatomyositis; Polymyositis SLE SLE (drug-induced) Rheumatoid arthritis; SLE SLE: Systemic Lupus Erythematosus; MCTD: Mixed Connective Tissue Disease; PAPS: Primary Anti-Phospholipid Syndrome; IgM: Immunoglobulin M associations are believed to confer susceptibility to development of rheumatic diseases However, there is as yet no firm evidence to suggest associated genotypes can predict development of disease Whether the genetic associations also predict severity is debatable Table shows some rheumatic diseases with their associated HLA antigen types Joint fluid examination is very useful in differentiating between sepsis and joint inflammation The simple Gram-stain test on the fluid had enabled early and definite diagnosis of gonococcal septic arthritis in many instances The presence of Gram-negative diplococci in joint fluid usually enables the clinician to elicit from the patient, albeit after the diagnosis is made, a history of unprotected sexual practices with multiple partners The patient may not volunteer the information initially even if asked specifically Detection of negatively birefringent needle-shaped crystals are diagnostic of gouty arthritis even if the joint involved may be uncommon, e.g wrist Imaging studies in rheumatology help in evaluating the extent and severity of the disease Plain radiographs are usually sufficient in determining whether erosions are present in erosive arthritis or the joint space is narrowed medially in radiographs done on weight-bearing osteoarthritic knees “Fuzziness” or sclerosis of the sacroiliac joints can also be determined on plain radiographs Computed tomography scans Diagnosis in Rheumatic Diseases 1457 Table Genetic Markers and Rheumatic Diseases Rheumatic Disease HLA Type HLA Subtype References Systemic lupus Erythematosus DRB1*15 DRB1*03 N.A 6, Rheumatoid arthritis DRB1*04 8, Ankylosing spondylitis B*27 0401; 0404; 0405; 0101; 0102; 1402; 1001 2704; 2705; 10 Table ARA Revised Criteria for Classification of Rheumatoid Arthritis (1987) Criteria Morning stiffness Arthritis of or more joint areas Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes Classified as Clinical Clinical Clinical Clinical Clinical Laboratory Laboratory RA is diagnosed if at least of the criteria are present For criteria to 4, they must be present for at least weeks and magnetic resonance imaging are usually more sensitive in “picking up” early erosions or finer changes However the perceived advantages have to be balanced against the cost of performing these imaging studies Tissue biopsy may be needed to confirm or clarify a provisional diagnosis, e.g skin — leucocytoclastic vasculitis, kidney — lupus nephritis, synovium — chronic synovitis Renal biopsy helps in the management plan by supplying the histological classification11 or type of the renal involvement in lupus patients A synovial biopsy may differentiate between chronic synovitis and tuberculous infection of the synovium as the cause of recurrent monoarticular effusion CONCLUSION Diagnosis of rheumatic diseases is predominantly clinical in nature This is well-illustrated by the generally accepted guidelines for diagnoses of rheumatoid arthritis12 and systemic lupus erythematosus.13 1458 A Clinical Approach to Medicine Table The Revised ACR Criteria for Classification of Systemic Lupus Erythematosus (1982) Criteria 10 11 Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic Antinuclear antibody Classified as Clinical Clinical Clinical Clinical Clinical Clinical/Laboratory Laboratory Clinical Laboratory Laboratory Laboratory Systemic lupus erythematosus is diagnosed if at least of the criteria are present Tables and illustrate the predominantly clinical nature of the diagnostic criteria The laboratory criteria serve as supplementary factors in helping the clinician come to a more definitive diagnosis Newer laboratory tests not yet replace the clinical process of historytaking and physical examination, but they can help to subset patients into more homogenous groups for potentially more effective targeted therapy REFERENCES Wolfe F, Smythe HA, Yunus MB, et al., The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicentre criteria committee, Arthritis Rheum 33:160–172, 1990 Hess EV, Role of drugs and environmental agents in lupus syndromes, Curr Opin Rheumatol 4:688–692, 1992 Toivanen A, Toivanen P, Reactive arthritis, Curr Opin Rheumatol 9:321–327, 1997 Steere AC, Malawista SE, Snydman DR, et al., Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities, Arthritis Rheum 20:7–17, 1977 Bluestone R, The Five-minute Rheumatologic Exam, in: Bluestone R (ed.), Rheumatology, Houghton Mifflin, Boston, pp 29–37, 1980 Woodrow JC, Immunogenetics of systemic lupus erythematosus, J Rheumatol 15: 197–199, 1988 Diagnosis in Rheumatic Diseases 1459 Scherak O, Smolen JS, Mayr WR, HLA-DRw3 and systemic lupus erythematosus, Arthritis Rheum 23:954–957, 1980 Chan SH, Lin YN, Wee GB, Koh WH, Boey ML, HLA Class genes in Singaporean Chinese rheumatoid arthritis, Br J Rheumatol 33:713–717, 1994 Gao XJ, Gazit E, Livneh A, Stastny P, Rheumatoid arthritis in Israeli Jews: shared sequences in the third hypervariable region of DRB1 alleles are associated with susceptibility, J Rheumatol 18:801–803, 1991 10 Gonzales-Roces S, Alvarez MV, Gonzalez S, et al., HLA B-27 polymorphism and worldwide susceptibility to ankylosing spondylitis, Tissue Antigens 49:116–123, 1997 11 Austin HA, Muenz LR, Joyce KM, et al., Prognostic factors in lupus nephritis Contribution of renal histologic data, Am J Med 75:382–391, 1983 12 Arnett FC, Edworthy SM, Bloch DA, et al., The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis, Arthritis Rheum 31: 315–324, 1988 13 Tan EM, Cohen AS, Fries JF, et al., The 1982 revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 25:1271–1277, 1982 This page intentionally left blank 83 Connective Tissue Disease and Systemic Vasculitis Leong Khai Pang Introduction The term “connective tissue diseases” is a convenient label for the group of diseases characterized by the presence of serum antibodies and other immune cells that recognize a diverse range of self-antigens It encompasses systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), dermatomyositis/polymyositis (DM/PM), systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and antiphospholipid syndrome (APS) There are no pathognomonic laboratory tests for any one of these, so the diagnosis is based on recognizing the pattern of laboratory and clinical features The American College of Rheumatology (ACR) has published classification criteria (not to be equated with “diagnostic” criteria) for almost all the CTDs We can use them for making diagnoses as well, provided we keep their limitations in mind The vasculitides, or inflammation of the blood vessels, are uncommon diseases Vessels of any size or location may be involved, which could lead to occlusion, aneurysm formation or rupture, resulting in 1461 1462 A Clinical Approach to Medicine ischemia or necrosis of the tissues they supply The clinical manifestations are protean and can range from mild to immediately life-threatening Principles of Management There is no cure for the CTDs and primary vasculitides but we have to treat the disease manifestations These illnesses are characterized by disease flares between periods of quiescence Disease flares must be controlled because prolonged periods of active disease lead to organ damage and poorer outcome The term “flare” and “activity” refer to the increased immune-mediated inflammation over the baseline “Severity” indicates the likelihood of sustaining morbidity or mortality from the disease activity Irreversible morbidity is also known as “damage.” Since drugs and other therapeutic modalities have side-effects, we weigh the expected benefits and risks carefully before we use them The decision on whether, when and how to treat depends on the severity and the rate of progression of the disease CONNECTIVE TISSUE DISEASES Systemic Lupus Erythematosus (SLE) SLE is characterized by immune-mediated attack on many organs in the body in the presence of a host of different autoantibodies The range of disease manifestations is broad but generally recognizable Epidemiology Most local rheumatologists agree with the estimate that there are four thousand lupus sufferers in the island, giving us a prevalence rate of about 100 per 100 000 One of the better epidemiology studies showed that prevalence of SLE in Birmingham was 27.7 per 100 000 (49.6/100 00 for females and 3.6/100 000 for males) on January 1992 The prevalence rate was highest among the Afro-Caribbeans, followed by Asians and Caucasians Immunogenetics and pathogenesis Relatives of lupus patients are 20 times more likely to suffer from the same illness than the general population The disease concordance is 24% in monozygotic twins but only 2% in dizygotic ones Connective Tissue Disease and Systemic Vasculitis 1463 HLA DR2 and DR3 are found more often in Caucasian patients than controls In Singapore, the frequency of DR 16(2) was statistically significantly increased in 51 Malay SLE patients However, DR2 does not appear to be associated with SLE based on a study of 26 Chinese patients from National University Hospital Other genes that are linked with the pathogenesis of SLE encode proteins associated with antigen or immune complex clearance (complements and their receptors, mannose-binding protein), apoptosis (fas and fas ligand, poly ADP-ribosyl polymerase), lymphocyte signaling (HLA, TAP, IL-6, IL-10, tumor necrosis factor-␣, T cell receptor chain) and immunoglobulin heavy chain receptors (Fc␥RII, Fc␥RIII) Genome-wide scans for lupus susceptibility implicate multiple genes distributed over numerous chromosomes Indeed, SLE result from the interaction of at least 20 gene products and multiple environmental triggers (which could be drugs, viruses, ultraviolet radiation or sex hormones) The precise way in which these factors interact is unknown, but the result is a loss of self tolerance, with the production of a host of autoantibodies by B cells, helped by activated but dysregulated T cells Manifestations and outcome The most common clinical features of Singapore patients presenting with SLE are hematological (73%), arthritis (57%), malar rash (43%), renal disorder (31%) and photosensitivity (30%) Most SLE patients suffer from constitutional symptoms (fever, malaise, anorexia and weight loss) when their disease is active Their reappearance in a hitherto well-controlled lupus patient may herald a disease flare Mucocutaneous manifestations are common in SLE Four of them, mouth ulcers, photosensitivity, malar or butterfly rash and discoid lupus erythematosus (DLE) are classification criteria of SLE Mouth ulcers are typically painless DLE is a raised, scaly, circumscribed rash that may scar; when the scales are removed, follicular plugging is found Subacute cutaneous lupus erythematosus (SCLE) is a non-scarring rash found in sun-exposed areas, sometimes mistaken for psoriasis SLE causes a nonscarring alopecia, but scars from discoid lesions also result in irreversible hair loss “Lupus hair” breaks easily, giving the patient an unruly and shaggy appearance 1464 A Clinical Approach to Medicine SLE produces a symmetrical and non-erosive arthritis Ligamentous laxity may simulate swan-neck deformities of the fingers, producing Jaccoud’s arthropathy The complaint of weakness or muscle tenderness should prompt us to look for inflammatory muscle disease Fortunately, myalgia (muscle pain) is much commoner problem than polymyositis or dermatomyositis (inflammation of the muscles) Renal manifestations in SLE range from asymptomatic proteinuria to acute renal failure In one study, maleness, higher activity index, proliferative and inflammatory changes on renal biopsy, hypertension and severe infections were associated with progression to chronic renal failure, whereas the institution of treatment and higher education achievement of patient were associated with better renal outcome Cytopenias, in one or more cell lines, is common in lupus patients Anemia and thrombocytopenia are usually due to peripheral immune destruction Before we attribute the cytopenia to SLE, we have to exclude the effects of drugs Abdominal manifestations include serositis, aseptic peritonitis, pancreatitis and acute abdomen Serositis may present as abdominal pain or ascites Pancreatitis can be the presenting feature of lupus Lung involvement in lupus includes pneumonitis, pulmonary fibrosis, pulmonary hemorrhage, shrinking lung syndrome and pulmonary hypertension Chronic pneumonitis may lead to interstitial fibrosis Pulmonary hemorrhage, due to alveolar capillaritis, usually occurs in the context of active lupus and is a life-threatening complication Two local series including more than 50 cases demonstrated that survival ranges from 50–60% Clues to diagnosis are sudden onset or worsening dyspnea, fleeting opacities in the chest X-ray, otherwise unexplained fall in hemoglobin and raised diffusion capacity (DLCO) Shrinking lung syndrome is an unusual but interesting complication where the lung volume actually shrinks in serial chest films due to diaphragmatic dysfunction Pulmonary hypertension can result from micro-embolism to the pulmonary capillary bed or can be idiopathic Severe pulmonary hypertension (systolic pressure Ͼ 70 mmHg) is a grave prognostic factor Pericarditis is common but frequently asymptomatic Libman–Sacks endocarditis is the classic heart lesion of SLE Verrucous vegetations are found on the valve leaflets, most commonly the mitral valve They are frequently not apparent clinically, though they can cause thromboembolism or valve dysfunction Connective Tissue Disease and Systemic Vasculitis 1465 In 1999, the ACR defined 19 syndromes in SLE that involve the central or peripheral nervous systems: aseptic meningitis, cerebro-vascular disease, demyelinating syndrome, headache, movement disorder, myelopathy, seizures, acute confusional state, anxiety disorder, cognitive dysfunction, mood disorders, psychosis, acute demyelinating polyradiculopathy, autonomic disorder, mononeuropathy, myasthenia gravis, cranial neuropathy, plexopathy and polyneuropathy Generally, other causes such as infections or drugs must be excluded before these syndromes are attributed to SLE Mortality from SLE follows a bimodal distribution; patients tend to die early or late in the course of disease Early death is due to disease activity or infection, while that occurring eight to ten years later results from complications of disease or therapy (such as ischemic heart disease) The survival rate of lupus has been improving since the 1950’s when such data first became available In the late 1990’s, patient survival from a prospectively followed-up cohort in Canada was 93% at years, 85% at 10 years, 79% at 15 years and 68% at 20 years In the past 15 years, it was shown that measuring the mortality alone, or even morbidity, is not sufficient for a chronic illness like SLE The patients’ perception of the impact of their disease and its treatment on their lives, also known as health-related quality of life, is regarded as an important outcome measure Instruments for assessing this have been validated for Singapore SLE and reproduction There is a slight risk of developing SLE from oral contraceptive (OC) use In the Nurses’ Health Study involving 121 645 women, past users of OC had a relative risk of 1.9 of developing SLE compared to those who never used them The precise risk of using (OC) to SLE patients is unknown It is safest for patients with nephritis to avoid OC for fear of provoking disease flare, and for those with anticardiolipin antibody (ACA) to so because of the risk of thrombosis Pregnant SLE patients flare more frequently compared to their nonpregnant selves and other non-pregnant patients SLE patients also have a worse obstetric outcome than unaffected women The Lupus Databank Research Program of Toronto reported that of 141 pregnancies in 73 patients, 60% resulted in live births, 23.8% in spontaneous abortions, 2.2% stillbirths and 14% therapeutic abortions About a quarter of the live births were premature Maternal hypertension predicted poor fetal outcome 1466 A Clinical Approach to Medicine The best advice for SLE patients is to avoid OC and to choose barrier methods of contraception They should plan to be pregnant when their disease is inactive The pregnant SLE patient must be monitored closely by her physician and obstetrician for disease recrudescence and abnormal fetal development Investigations Investigations are used to corroborate the clinical diagnosis of SLE, determine the extent of organ involvement and gauge disease activity The antinuclear antibody (ANA) is present in the serum of over 95% of lupus patients However, 34% of 100 normal Singaporeans have ANA positivity at a titer of 1/40, 18% positivity at a titer of 1/80, 8% at 1/160, 3% at 1/320 and 1% at 1/640 This means that the positive predictive value of a positive ANA result for an unselected Singaporean, that is, the chance that the person truly has SLE, is less than 1% The anti-double stranded DNA (anti-ds DNA) antibody is associated with renal involvement and it can be used to track disease activity in many patients The anti-Sm antibody, though found in only 20–30% of SLE patients, is very specific (though not pathognomonic) for the disease Among 94 predominantly Chinese SLE patients from Singapore, 43% have anti-ds DNA antibody, 81% anti-histone antibody, 26% anti-Sm antibody, 32% anti-ribonucleoprotein (anti-RNP) antibody, 63% anti-Ro antibody, 12% anti-La antibody, 9% anti-SL/Ki antibody, 16% anti-ribosomal ribonuclear protein antibody, 5% anti-p70/p80 and 3% anti-proliferatingcell-nuclear-antigen antibody The history and clinical examination help us to determine the extent of organ involvement in SLE and guide further investigations Since cytopenia is found in 70% and renal involvement in 30% of patients at presentation, full blood count, serum chemistries and urinalysis are essential for the evaluation for a newly-diagnosed lupus patient For surveillance of the patient in the outpatient clinic, we regularly order blood count, serum creatinine and urinalysis tests Mild leucopenia and lymphocytopenia usually not warrant further work-up, though significant thrombocytopenia mandates a bone marrow biopsy Anemia is common and possible causes include autoimmune hemolysis, anemia of chronic illness and blood loss via the gastrointestinal tract Connective Tissue Disease and Systemic Vasculitis 1467 Sterile pyuria, microscopic hematuria, cellular casts and persistent proteinuria suggest glomerulonephritis In the presence of these abnormalities, we must determine the creatinine clearance and 24-hour urinary protein excretion Kidney biopsy is often needed for prognostic purposes It tells us the WHO histologic class, the amount of inflammation and of scarring (the activity and chronicity indices) Patients with class IV nephritis (diffuse proliferative) will develop renal failure without treatment However, those with low activity and high chronicity indices are unlikely to respond to cytotoxic drugs and will eventually require renal substitution However, in the presence of active disease and rapidly deteriorating renal function, renal biopsy is not a prerequisite for instituting urgent treatment We have to first rule out other possible causes of azotemia in SLE like urinary tract obstruction, nephrotoxic drugs (including NSAIDs, intravenous contrast media, cyclosporin A and aminoglycosides), infections (systemic and urinary), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIVC), intra-abdominal viscus perforation and renal vein thrombosis Then, pulsed intravenous methylprednisolone followed by intravenous cyclophosphamide often controls the autoimmune assault on the kidneys A brief period of dialysis support may be needed After regaining control of the disease, the subsequent plan usually involves kidney biopsy Elevated anti-ds DNA antibody level, high erythrocyte sedimentation rate (ESR) and hypocomplementemia (usually C3 and C4) are reflective of active disease for most patients However, serologic tests and disease activity are discordant in about 10% of lupus patients (“serologically active and clinically quiescent”) Diagnosis The 1982 American Rheumatism Association (now the ACR) classification criteria of SLE and its 1994 revision have frequently been used to diagnose clinical cases of lupus A patient is classified to have SLE if she satisfies four out of eleven criteria (malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder and antinuclear antibody) simultaneously or serially over any period of time We should be aware that this set of criteria was designed to ensure uniformity in case classification for studies, not for daily practice Of 1468 A Clinical Approach to Medicine necessity, they tend to be relatively insensitive, so, milder SLE patients will be misclassified Nevertheless, the criteria have found their way into clinical use as they are convenient to use and there are no available diagnostic criteria We have to be aware of a few caveats First, patients not have to fulfill these criteria to be diagnosed to have SLE For example, a 20-year old lady who has positive antinuclear antibody (ANA), malar rash and histologically-proven glomerulonephritis obviously has SLE, but does not fulfill the requisite ARA criteria Second, certain features strongly associated with SLE, like alopecia, consistent renal biopsy and hypocomplementemia are not classification criteria because they are not specific or because they are not sought for in all patients Treatment The decision on when and how to treat a patient with SLE depends on our assessment of the extent, severity and rapidity of organ involvement For example, minimal or no treatment is required for a patient with alopecia or mouth ulcers while intravenous corticosteroid and cyclophosphamide are needed to halt and reverse kidney failure due to active glomerulonephritis See Table for a checklist on the management of lupus Categorizing the disease manifestations as minor (mucocutaneous and musculoskeletal) or major and organ threatening (hematologic, renal, cerebral, pulmonary, gastrointestinal or cardiac) helps us to select the correct treatment Prednisolone at a dose of 0.5 mg/kg body weight daily is prescribed for minor manifestations while a dose of mg/kg daily may be needed for major involvement The high dose is maintained for not more than four weeks, after which it is tapered Steroid-sparing drugs should have been started Prednisolone in divided doses is more potent than when it is taken once a day Some patients will flare when the prednisolone dose is reduced below a threshold level; they need a minimal intake of steroid daily Infection and lupus activity share many common manifestations, like fever, headache, meningism, pulmonary infiltrates, pleurisy, pleural effusion, pyuria, colitis, pericarditis and arthritis Do not interpret these merely as disease flare until sepsis has been clearly ruled out Even if the disease is evidently active, it does not mean that a concurrent infection is not present Connective Tissue Disease and Systemic Vasculitis 1469 Table Checklist for Managing SLE Principles Points to Cover Comments Confirm diagnosis Consistent clinical picture Consistent laboratory investigations Consider differential diagnoses Generally, the diagnosis is not difficult Possible differential diagnoses include viral infection, drug-induced lupus and acute HIV infection Determine extent of organ involvement History Clinical examination Investigations directed by clinical suspicion An astute clinician will serve his or her SLE patients better than one who overly relies on investigations Determine disease activity Distinguish reversible (activity) from irreversible (damage) factors Accurately distinguishing activity from infections and irreversible organ damage is crucial, as treatment of each is different Choice of therapy Corticosteroid Antimalarial drugs Cytotoxic drugs Intravenous immunoglobulin Plasmapheresis Experimental therapy The treatment of active lupus is dictated by the extent, severity and rapidity of disease manifestation Collaboration with other health professionals Medical Social Worker Occupational therapist Orthopedic surgeon Physiotherapist Rheumatology Nurse Support group volunteer SLE is a disease that impacts every aspect of a patient’s life No one healthcare provider alone can justice to the complexity of the total management Patient education Diagnosis and relapsing/ remitting nature of disease Drugs: benefits and adverse effects Need for compliance Alternative therapy Fertility and contraception Strategies to prevent flares Hospitalization Support group Coping with family and career Finances Insurance Patients who understands their disease and actively participate in their own management has a better outcome than those who are apathetic Surveillance for disease recrudescence and development of new manifestations and co-morbidities Physician’s vigilance Investigations: activity markers, serum lipids, bone mass density, chest X-ray Patient education There is no cure for lupus and every patient must form a long-term relationship with her or his physician 1470 A Clinical Approach to Medicine Antimalarial drugs, like hydroxychloroquine (5–7 mg/kg body weight per day), are good for constitutional, mucocutaneous and musculoskeletal manifestations of SLE NSAIDs may be needed if arthritis is a prominent feature Photosensitive patients should be instructed to avoid sunlight (even that coming through a windowpane) and use a sunblock with a Sun Protection Factor (SPF) of at least 15 Thrombocytopenia often respond to steroids alone Otherwise, danazol or azathioprine may be used Intravenous gammaglobulin (1 g/kg bodyweight daily for two days) must be used in cases of life-threatening thrombocytopenia to rapidly boost the platelet count Splenectomy may have to be resorted to The value of cyclophosphamide and azathioprine in the treatment of lupus nephritis was established beyond doubt in 1986 Azathioprine can cause immune suppression and transaminitis while cyclophosphamide is associated with immune suppression, hemorrhagic cystitis, ovarian failure and malignancy There is still no consensus on the optimal intensity and duration of therapy In a patient with active proliferative lupus nephritis, it is reasonable to institute steroid therapy (prednisolone mg/kg body weight daily) and monthly pulse cyclophosphamide (0.5 to 1.0 g/m2 body surface area) After six months to a year, depending on the response, cyclophosphamide may be discontinued or replaced with the less toxic drug azathioprine Good control of blood pressure is essential in retarding progressive loss of renal function Mycophenolate mofetil and cyclosporin A are alternative treatment for lupus nephritis Urgent plasmapheresis is the best treatment for pulmonary hemorrhage while corticosteroid and cyclophosphamide are apparently less effective Cyclophosphamide has also been used for neuropsychiatric, as well as aplastic anemia, thrombocytopenia, interstitial lung disease and pulmonary hemorrhage Very aggressive regimes have been used to treat severe lupus, including synchronized plasmapheresis and intravenous cyclophosphamide, stem cell transplant, and immunoablative doses of cyclophosphamide without stem cell rescue Sjogren’s Syndrome (SS) In SS, chronic lymphoctyic inflammation of exocrine glands leads to dry eyes and mouth Fifty percent of patients have salivary gland enlargement Connective Tissue Disease and Systemic Vasculitis 1471 About 60% of all patients will develop extra-glandular features, including arthritis, Raynaud’s phenomenon, lymphadenopathy, lung involvement and vasculitis SS can exist on its own (primary) or is secondary to another connective tissue disease, most commonly RA SS patients have a risk of developing lymphoma, usually of low-grade B cell type There are diagnostic criteria for SS but none are universally accepted Some are strict and insist on minor salivary gland biopsy, while others are lax, only requiring clinical findings of dry eyes and mouth and positive anti-Ro (found in 50–80% of SS patients) or anti-La antibodies (30–60%) There are many causes of dry eyes and mouth (including drugs, aging, chronic hepatitis B or C) and SS should be diagnosed only with evidence of autoimmunity (high ESR and presence of autoantibodies) or lymphocytic infiltration of the salivary gland There is a useful study on the long-term outcome of patients with sicca syndrome One hundred and six patients were referred for dry eyes: primary keratoconjunctivitis sicca was diagnosed in 56, primary SS in 31 and secondary SS in 19 Three of the patients with primary SS died of lymphoma, compared to none in the other two groups Artificial tears and saliva supplements are very useful for symptomatic treatment of dry eyes and mouths Oral pilocarpine mg thrice daily increases tear and saliva production Hydroxychloroquine may modulate some of the immunologic abnormalities and has beneficial effects on the sicca symptoms Dermatomyositis and Polymyositis These are characterized by inflammation of striated muscles Patient presents with muscle ache or weakness, most pronounced at the proximal muscle groups The patient may notice that he has difficulty getting out of his car, combing hair or reaching things on the top shelf The cutaneous features of DM are the heliotrope rash (a purplish rash around the eyelids), a photosensitive rash on the exposed skin, telangiectasia and Gottron’s papules (pathognomonic papules found over the dorsal aspect of the interphalangeal joints) The diagnosis is made on the basis of the proximal weakness, elevated levels of serum muscle enzymes (creatinine kinase, aspartatic transaminase, lactic dehydrogenase and aldolase), consistent electromyography and muscle biopsy 1472 A Clinical Approach to Medicine After a thorough search in Singapore, 35 patients with PM and 40 with DM were found and analyzed The combined incidence of PM/DM worked out to be 0.77 cases per 100 000 population per year At presentation, 86.7% had proximal myopathy, 34.7% arthralgia/arthritis and 18.7% cutaneous vasculitis DM was more likely to be associated with malignancy than PM in this series In Singapore, we must exclude nasopharyngeal carcinoma in patients with DM or PM Other malignancies associated with DM or PM arise from the lung, breast and gastrointestinal tract High-dose corticosteroid (prednisolone 1–2 mg per day) is prescribed as the initial treatment, and it is maintained for at least a month before the dose is tapered Muscle enzymes are useful for determining the disease activity Methotrexate, cyclophosphamide or azathioprine may be added if the response to steroid is unsatisfactory Scleroderma Scleroderma, a rare disease, is characterized by fibrosis of the skin and internal organs It is observed that there is a resemblance between the skin of scleroderma patients and that of those with chronic graft-versushost disease The finding of fetal cells in the skin of parous scleroderma patients suggests a target for immune attack Scleroderma has a diffuse form (systemic sclerosis or SSc) and a limited form (CREST) CREST is an acronym for the clinical features of calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly and telangiectasia PSS is associated with the anti-Scl 70 antibody and CREST with anti-centromere antibody Patients often present with Raynaud’s phenomenon, which is a threecolor change (white, blue and red) of the digits in response to cold, as well as finger puffiness and arthritis Convincing sclerodactyly may take some time to appear Other skin manifestations are finger pulp resorption and telangiectasia Patients may also have dysphagia, reflux esophagitis, malabsorption, pulmonary hypertension or systemic hypertension At present, patients rarely die from renal crisis because of effective antihypertensive drugs (with the credit going to the ACE inhibitors) and availability of dialysis Interstitial lung disease and pulmonary hypertension are now the main causes of mortality Treatment is difficult Patients with Raynaud’s phenomenon should be instructed to keep their extremities warm Oral iloprost has Connective Tissue Disease and Systemic Vasculitis 1473 been shown to help Hypertension, malabsorption and esophagitis are treated in the usual way D-penicillamine, colchicine, methotrexate, cyclosporin A and relaxin (a connective tissue remodeling peptide) have been tried in SSc with minimal or no benefit Mixed Connective Tissue Disease MCTD is a condition characterized by the presence of overlapping features of two or more CTDs (SLE, DM, PM and SSc) together with high titers of the anti-RNP antibody It was reported to have a benign course and to respond well to steroids, but a longer period of follow-up proved the contrary The right of this syndrome to be regarded as an independent entity has been challenged ever since it was described Detractors maintain that patients initially labeled as MCTD eventually evolve to have PSS or SLE They also point out that the definition of MCTD has changed since its original description Proponents argue that some patients remain in the MCTD category since diagnosis and that there is a distinct antibody, the anti-RNP, to justify the distinct status of the condition There is no special treatment for this condition; it depends on the disease manifestation Long-term follow-up is required to determine if the disease evolves to one of the recognized CTD Antiphospholipid Syndrome (APS) APS is diagnosed when a patient has recurrent abortions, thrombosis or thrombocytopenia and antiphospholipid antibodies (demonstrated by the presence of lupus anticoagulant or anti-cardiolipin antibodies) The term “antiphospholipid antibodies” is a misnomer as these antibodies are actually directed against phospholipid-binding plasma proteins, one of which is beta 2-glycoprotein I APS can exist in isolation or together with one of the CTDs, usually SLE Even though the partial thromboplastin time (PTT) is prolonged, the main problem is thrombosis Thrombosis can occur in the arterial or venous system, in vessels of any calibre Some patients may manifest clinical features not associated with coagulation like livedo reticularis, migraine and cardiac valvular vegetations 1474 A Clinical Approach to Medicine The treatment for thrombosis is life-long anticoagulation, aiming for an international normalized ratio (INR) above Patients with repeated abortions may be able to carry a pregnancy to term with aspirin and heparin (either regular or low-molecular weight) SYSTEMIC VASCULITIDES The vasculitides can be primary, or secondary to other diseases like malignancies and drug reactions We can further classify the primary vasculitides according to the size of blood vessels they involve: large (aorta and its main branches), medium-sized (arteries) and small (arterioles, capillaries, venules) Primary systemic vasculitides are uncommon diseases, with a prevalence of 144.5 per million population in UK We summarized useful information on the vasculitides in Table The ACR classification criteria for the main primary vasculitides became available in 1990 In 1994, the participants of Chapel Hill Conference published their definitions of the systemic vasculitides and proposed a uniform set of nomenclature The most significant proposal of the Conference is that microscopic polyangiitis (MPA) (which affects medium-sized vessels and those smaller) should be distinguished from classic polyanteritis nodosa (PAN) (which involve the medium-sized vessels exclusively) Takayasu’s arteritis and temporal arteritis share the same abbreviation and involve the large branches of the aorta Takayasu’s arteritis (TA) presents in people below age 50, while temporal arteritis, also known as giant cell arteritis (GCA) is found in those above that age GCA is found mainly in Caucasians while TA is seen in Japanese and Orientals Classic PAN often presents with constitutional symptoms like malaise, fever and weight loss Testicular pain can sometimes be the presenting sign Arthralgia and skin rash and ulceration are common Classic PAN should spare the kidneys Hepatitis B surface antigen is found in about 5% of patients with PAN, depending on its endemicity in that population The clinical features of MPA are similar to those of PAN but renal disease is found in the majority of patients with MPA and 30% may present with oliguria One of the most recognizable forms of systemic vasculitis is Wegener’s granulomatosis (WG) It is characterized by granulomatous Table The Primary Vasculitides at a Glance Large Vessels Takayasu’s arteritis Age, Sex and Racial Predilections Classification Criteria Large branches of the aorta Ͻ 40 years, Japanese and Orientals out of criteria: Age at disease onset Ͻ 40 years; claudication of extremities; decreased brachial artery pulse; BP difference Ͼ 10 mmHg; bruit over subclavian arteries or aorta; and arteriogram abnormality out of criteria: Age at disease onset Ͼ 50 years; new headache; temporal artery abnormality; elevated erythrocyte sedimentation rate; and abnormal artery biopsy Large branches of the Older patients aorta like the carotids, (Ͼ 50 years), temporal arteries usually Caucasians Medium-Sized Vessels Polyarteritis nodosa Medium-sized Small Vessels Wegener’s granulomatosis Small arteries and veins Middled-age patients, male : female ratio : out of 10 criteria: Weight loss Ͼ kg; livedo reticularis; testicular pain or tenderness; myalgias, weakness or leg tenderness; mono- or polyneuropathy; diastolic BP Ͼ 90 mmHg; elevated BUN or creatinine; hepatitis B virus; arteriographic abnormality; and biopsy of small or medium-sized artery containing PMN Young or middle-aged patients, slight male preponderance Mostly Caucasian patients in out of criteria: Nasal or oral inflammation; abnormal chest radiograph; urinary sediment; and granulomatous inflammation on biopsy Connective Tissue Disease and Systemic Vasculitis 1475 Giant cell arteritis Size of Vessel Involved Size of Vessel Involved Age, Sex and Racial Predilections Hypersensitivity vasculitis Small literature, but found in all races No special predilection Churg–Strauss syndrome Medium-sized to small All size vessels Behcet’s disease All sizes Classification Criteria out of criteria: Age at onset Ͼ 16 years; medication at disease onset; palpable purpura; maculopapular rash; and biopsy including arteriole and venule out of criteria: Middle-aged patients, slight male preponderance Asthma; eosinophilia Ͼ 10%; neuropathy, mono Possible association with or poly; pulmonary infiltrates, non-fixed; paranasal the use of leukotrienesinus abnormality; and extravascular eosinophils receptor antagonists, especially zafirlukast Female preponderance, Middle-eastern and Japanese Recurrence of aphthous ulceration at least times during a 12-month period, plus of the following: Recurrent genital aphthous ulceration; eye lesions; skin lesions; positive pathergy test result 1476 A Clinical Approach to Medicine Table (Continued) Connective Tissue Disease and Systemic Vasculitis 1477 inflammation of the small vessel, including arterioles, capillaries and venules Upper airway (sinusitis), lung (nodules and pulmonary hemorrhage) and kidney involvement (glomerulonephritis) is prominent As many as 90% of the patients systemic WG will test positive for anti-neutrophilic cytoplasmic antibody (ANCA) Limited WG is anatomically restricted to airway involvement and its association with ANCA is weaker, around 70% It may be very difficult to distinguish WG from MPA as they have small vessel vasculitis in the lungs and kidneys and ANCA is found in both; the demonstration of granulomata in WG may allow its differentiation from MPA Characteristic of Churg-Strauss syndrome (CSS) is granulomatous inflammation of the small vessels with eosinophilic infiltration, together with asthma and eosinophilia Other manifestations are fever, weight loss, hypertension, peripheral neuropathy and heart failure Renal involvement is common, and biopsy reveals a focal segmental necrotizing glomerulonephritis, often with crescents Asthma and eosinophilia may precede the development of vasculitis for years Behcet’s disease manifests as recurrent mouth ulcers (in at least 97% of patients), genital ulcers and uveitis Less frequent findings are cutaneous signs (acne-like, follicular or papular), erythema nodosum, epididymitis, CNS lesions or deep vein thrombosis (associated with higher Lp(a) lipoprotein levels) In spite of the fact that vessels of any size can be affected in Behcet’s disease, there is predilection for certain organ involvment: patients may lose their sight but rarely develop renal failure An international study group developed a unified set of diagnostic criteria in 1990 that has become widely accepted Eighteen new patients with primary systemic vasculitis presented to our Department between January 1994 and December 1997 There were male and 10 female, their ages ranging from 17 to 81 years Fifteen were Chinese, two Malay and one Indian According to ACR criteria, there were two cases of CSS, two of PAN, two of Wegener’s granulomatosis (WG) but eleven were unclassifiable (Lau TC, unpublished data) Secondary Vasculitides Vasculitis is a feature of autoimmune diseases like SLE, rheumatoid arthritis and SS Cryoglobulinemia can manifest vasculitic lesions as well 1478 A Clinical Approach to Medicine There are three forms of cryoglobulinemia: Type I is typified by the presence of monoclonal cryoglobulin, often due to a lymphoid malignancy; Type III is a polyclonal cryoglobulinemia; while Type II contains a mixture of the two The vast majority of Types II and III are related to hepatitis C infection The use of horse-derived antithymocyte globulin, interferon-alpha, granulocyte colony-stimulating factor and streptokinase, anticonvulsants, sulphonamides and allopurinol have been associated with vasculitis Druginduced vasculitis is generally limited to the skin, but glomerulonephritis, interstitial nephritis, liver granuloma and necrosis and even lung, cardiac and central nervous system involvement have been reported A common histological finding is leucocytoclastic vasculitis (also known as hypersensitivity vasculitis) This appears as a rash on the arms and legs and has a good prognosis It can also be idiopathic or secondary to viral infections Pathogenesis The pathogenesis is unknown but the classic explanation is the deposition of immune complexes below the endothelium, leading to infiltration of leucocytes (chiefly neutrophils), medial necrosis and even inflammation of the surrounding tissues The endothelium itself is also involved When it is activated, it can upregulate the production of cytokines and adhesion molecules and attract and activate leucocytes; this is believed to occur at vascular branches in large vessel vasculitis ANCA and neutrophils are postulated to be involved in the pathogenesis of small-vessel vasculitis Differential Diagnosis Infection, coagulopathy, intravascular lymphomas, atrial myxoma, Buerger’s disease and ergot overuse can also masquerade as vasculitides Cholesterol embolism is a particularly good mimic because the patient can present with acute renal failure and may have a typical skin rash In addition, an elevated ESR and positive ANA and RF may be found It is usually but not necessarily preceded by an arteriographic procedure in the recent or distant past Cholesterol crystals may be demonstrated in the skin or kidneys Sometimes, these may be seen in the retinal arteries on fundoscopic examination Connective Tissue Disease and Systemic Vasculitis 1479 Investigations Biopsy is the definitive way to confirm a diagnosis of vasculitis The skin is a favorite site because of its accessibility, the ease of distinguishing lesional and normal areas and procedural safety If the skin is not affected, muscle, nerve, kidneys or testes could be chosen The biopsy is more likely to be contributory if it is taken from an affected organ than a blind site While biopsy proves that vasculitis is present, it is the accompanying clinical manifestations that determine the type of vasculitis In general, biopsies are preferred over angiograms, unless it is dangerous (e.g involvement of main branches of the aorta) or impractical (e.g suspected mesenteric vasculitis in a stable patient) to obtain them ANCA is present in patients with WG (90% of patients), CSS (48%) MPA (75%) Neutrophils can be activated to release leukotrienes, superoxide and elastase when incubated with ANCA, so the antibody itself is likely to be pathogenic The discovery of ANCA has fundamental significance for the understanding and management of the vasculitides First, it is useful in the diagnosis of WG Second, it may help to predict a disease flare, as 24–50% of WG patients demonstrate a rise in serum ANCA before their disease becomes active Third, the true importance of ANCA lies in its ability to unite conceptually the three small vessel vasculitides (WG, CSS ad MPA), which led the Chapel Hill Consensus to propose that MPA be distinguished from classic PAN (which is not associated with ANCA) ANCA that exhibits a cytoplasmic immunofluorescence pattern in alcohol-fixed neutrophil preparations is called cANCA The main antigen target for cANCA is serine protease (PR3) in 90% of cases The other main pattern, perinuclear immunofluorescence, is produced by pANCA, which is directed mainly against myeloperoxidase (MPO) in 50% of cases but also against elastase and lactoferrin During ethanol fixation, MPO, being cationic, translocates from the cytoplasm to the negatively-charged nuclear membrane Thus, the perinuclear pattern is an artifact of alcohol fixation, and the same antibodies should produce cytoplasmic staining in paraformaldehyde-fixed slides Clinical suspicion is very important for early detection of increasing disease activity Constitutional symptoms such as fever and weight loss suggest disease recrudescence Signs of new organ dysfunction may develop, for example, rising serum creatinine concentration, hemoptysis, 1480 A Clinical Approach to Medicine breathlessness, digital or limb ischemia or a new vascular bruit In active disease, the hemoglobin and albumin levels fall, the ESR and C-reactive protein level rise, and thrombocytosis and leucocytosis become prominent If a decision about disease activity still cannot be made after carefully examining the above clinical information, a repeat a biopsy or angiogram must be resorted to even though these are invasive procedures Treatment The goals of treatment of vasculitis are the induction of disease remission, maintenance of remission and close surveillance for relapse, all the while mindful of the adverse effects of drugs In 1973, Fauci and Wolff reported that oral steroid and cyclophosphamide dramatically altered the outcome of Wegener’s granulomatosis, from an almost uniformly fatal disease to one with a good chance of survival (80% at five years) This provided a paradigm for the treatment of the systemic vasculitides: corticosteroids and cytotoxic drugs used in combination to induce remission, followed by dose tapering once control is obtained There are two problems with this regime: the high frequency of adverse events, and inability to keep the disease in remission indefinitely Nowadays, it is also felt to be too inflexible as patients express a continuum of disease severity and activity The adverse effects of corticosteroid are well known, and may be broadly described as its effects on the immune system (susceptibility to infections), skin, endocrine system, musculoskeletal (avascular necrosis, osteoporosis), ophthalmic (cataract and glaucoma), neuropsychiatric, gastrointestinal and cardiovascular Oral cyclophosphamide at a dose of 12 mg per kg daily results in a higher cumulative dose than monthly intravenous pulses of 0.5 g per square metre body surface area Methotrexate is increasingly used in the treatment of vasculitides like Takayasu’s arteritis, WG and GCA Side effects of methotrexate are bone marrow suppression, pneumonitis, stomatitis, infections, transaminitis, liver fibrosis and cirrhosis, and, rarely, lymphoma Disease flares of WG may be attributable to upper respiratory tract infections, particularly due to Staphylococcus aureus Accordingly, cotrimoxazole has been prescribed to maintain remission and it has shown efficacy, though it is not known if this is due to its antibiotic or Connective Tissue Disease and Systemic Vasculitis 1481 immuno-modulatory (specifically antineutrophilic) effect Other drugs and therapeutic modalities that have been used in small series or isolated reports are azathioprine, intravenous gamma globulin (IVIG), cyclosporin A, pentoxyfylline and plasmapheresis Antivirals, principally interferon alpha, are used to treat hepatitis B and C virus-associated vasculitides FURTHER READING Gaffney PM, Moser KL, Graham RR, Behrens TW, Recent advances in the genetics of systemic lupus erythematosus, Rheum Dis Clin North Am 28:111–126, 2002 Robson MG, Walport MJ, Pathogenesis of systemic lupus erythematosus (SLE), Clin Exp Immunol 31:678–685, 2001 Wallace DJ, Management of lupus erythematosus: recent insights, Curr Opin Rheumatol 14:212–219, 2002 Zimmerman R, Radhakrishnan J, Valeri A, Appel G, Advances in the treatment of lupus nephritis, Annu Rev Med 52:63–78, 2001 Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, Leavitt RY, Lie JT, Lightfoot RW Jr, Masi AT, et al., The American College of Rheumatology 1990 criteria for the classification of vasculitis Introduction, Arthritis Rheum 33:1065–1067, 1990 This page intentionally left blank 84 Rheumatoid Arthritis Humeira Badsha Rheumatoid arthritis (RA) is a systemic, autoimmune disorder of unknown etiology It is characterized by a chronic, inflammatory, symmetrical arthritis, as well as systemic features EPIDEMIOLOGY AND PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA) The estimates of the prevalence of RA are based on the 1987 American College of Rheumatology Revised Criteria for the Classification of Rheumatoid Arthritis (see Table 1).1 Based on these criteria between 1–2% of the world population is affected with RA However the prevalence in Asians is only 0.3%.2 Women are affected two to three times more commonly than men.3 Pregnancy appears to improve RA but the immediate postpartum period and breastfeeding worsen it.4 There is an association between Rheumatoid Arthritis and HLA-DR4.5 Sub-typing of DR in Singaporean Chinese revealed that the association was DRB1*0405.6 In Caucasians the DR association is DRB1*0401 and *0404 1483 1484 A Clinical Approach to Medicine Table 1987 American College of Rheumatology Criteria for the Classification of Rheumatoid Arthritis 1) Morning stiffness in and around the joints lasting at least hour before maximal improvement 2) At least joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints 3) At least area swollen (as defined above) in a wrist, MCP, or PIP joint 4) Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry) 5) Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician 6) Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects 7) Radiographic changes typical of rheumatoid arthritis on posterioanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone not qualify) For the diagnosis of Rheumatoid Arthritis, of the criteria are required MCP ϭ metacarpophalangeal; PIP ϭ proximal interphalangeal; MTP ϭ metatarsophalangeal The etiology of RA7 appears to focus on the relationships between infectious agents, genetics and autoimmunity Heat Shock Proteins (HSP) are major bacterial antigens which could bind to HLA-DR4, triggering the proliferation of antigen-specific T lymphocytes One hypothesis for abnormalities in RA is that an immune response to a HSP is amplified and perpetuated because of molecular mimicry between HSP and HLA-DR4 susceptibility sequences Several viruses have been proposed to predispose to RA (Ebstein–Barr virus, parvovirus, retroviruses), but conclusive evidence is lacking There are reports of increased Proteus antibody titers in RA There is some evidence for genetic predisposition to RA (concordance in monozygotic twins 30% and in dizygotic twins is 3%) but it is felt that this predisposition accounts for only 20–30% of the risk of developing RA There are also hypotheses that X or Y linked factors may account for the female preponderance amongst RA patients Rheumatoid Arthritis 1485 There is a strong role for CD4ϩ T cells, tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL1) in the initiation and maintenance of inflammation in RA In the rheumatoid joint initially, there is synovial endothelial cell damage with exudation of an inflammatory cellular infiltrate This leads to synovial tissue swelling and effusion in the joint As the disease progresses the synovium becomes massively hypertrophic and edematous In the hyperplastic sublining synovial stromal connective tissues there are highly activated and invasive fibroblast-like cells and new blood vessels This highly proliferative and invasive connective tissue stroma called pannus invades and destroys periarticular cartilage and bone leading to bony erosions, and ultimately to deformities and cartilage loss CLINICAL FEATURES There are racial variations in the expression of rheumatoid arthritis K Veerapen et al.8 compared 70 consecutive patients with rheumatoid arthritis in a Malaysian hospital with a similar number of age, sex and duration matched hospital patients in the UK The rheumatoid factor (latex) positivity was 65% in both groups of patients Disease severity was also similar in both groups The Malaysian patients tended to have more wrist involvement and less forefoot deformities than their caucasian counterparts Rheumatoid nodules, vasculitis and other systemic features were also less common in the Malaysian patients There was no difference in the clinical features of the 23 Indian, Malay, and 42 Chinese patients in the Malaysian group Studies of southern Chinese patients have also found extraarticular manifestations to be less common.9,10 The most common mode of onset of rheumatoid arthritis is the insidious development of symptoms over a period of several weeks.11 Patients can also present with explosive, polyarticular, or a monoarticular mode of onset Isolated less severe attacks of monoarticular synovitis lasting few days, resolving spontaneously with periods of spontaneous remission lasting few months can occur These attacks are called palindromic rheumatism and can evolve into classical RA Articular manifestations of RA can be due to inflammatory synovitis (Fig 1) with reversible signs and symptoms, or structural damage with irreversible deformities It is important to differentiate between active 1486 A Clinical Approach to Medicine Fig Early rheumatoid arthritis [characterized by the swelling of the interphalangeal joints (PIP)] synovitis and structural damage as the management of the two entities is different Morning stiffness of greater than one hour or warm, swollen joints are usually indicative of active synovitis Bony deformities and bone on bone crepitus indicate structural damage It is important to exclude other conditions causing synovitis, such as Systemic Lupus Erythematosus (SLE), Seronegative Spondyloarthropathy, and Gout The characteristic clinical features, usual lack of extraarticular manifestations, and laboratory profile are helpful in distinguishing RA from these conditions Septic arthritis should be excluded if there is a single swollen, inflamed joint in a patient with established RA Other causes of pain such as osteoarthritis, fibromyalgia, amyloidosis, and angioimmunoblastic lymphadenopathy should be excluded Factors typical of RA include: pain and stiffness in multiple joints; boggy joint swelling that includes soft tissue and synovial fluid; joints that are tender to touch; symmetrical joint involvement, often of the hands and feet; sparing of the DIP (distal interphalangeal) joints; decreased, painful range of motion of the joints; subcutaneous nodules, low grade fever, small enlarged lymph nodes; raised peripheral white blood cell counts, platelets and ESR (erythrocyte sedimentation rate); anemia and a positive rheumatoid factor The diagnosis of RA is made by estabilished criteria of which the requirement for the presence of objective evidence of synovitis for weeks is important The diagnosis of RA should be confirmed within two weeks of onset of symptoms Involvement of the cervical spine is common,12 manifesting as pain and loss of motion There are several types of cervical spine instability: atlanto-axial subluxation (50–70% of patients), subaxial subluxation (20–25% of patients) and basilar invagination with or without atlantoaxial subluxation (20% of patients) Evaluation of the patient with RA Rheumatoid Arthritis 1487 should always include a careful neurological examination including screening for symptoms such as neck pain, occipital headache, and paraesthesias in the extremities The clinician should also seek symptoms of vertebrobasilar insufficiency (tinnitus, vertigo, visual disturbances, and dysphagia) due to basilar invagination of the cord Care should be taken prior to extension of neck during endotracheal intubation to exclude cord compression or atlanto-axial subluxation by physical examination, as well as flexion-extension X-rays of the c-spine A study of patients with RA12 concluded that operative stabilization of the cervical spine should be done to minimize the risk of irreversible paralysis, regardless of whether neurological signs or symptoms are present, in patients who have atlantoaxial subluxation and a posterior atlanto-odontoid interval of 14 mm or less, patients who have atlanto-axial subluxation and at least mm of basilar invagination, and patients who have subaxial subluxation and a sagittal diameter of the spinal canal of 14 mm or less In virtually all patients with RA, the wrists and hands are involved but the distal interphalangeal (DIP) joints are usually spared Ulnar deviation of the fingers at the metacarpophalangeal (MCP) joints is associated with radial deviation at the wrists Swan neck deformities (Fig 2) due to contracture of the interosseous and flexor muscles and tendons, can develop with a hyperextension at the proximal interphalangeal (PIP) joints and flexion at the DIP joints Boutonniere’s deformity (Fig 3) refers to flexion at the PIP joints and hyperextension at the DIP joints In addition there may be symptoms of carpal tunnel syndrome due to compression of the median nerve at the wrist by inflammatory synovitis Inflammatory tenosynovitis may lead to tendon rupture characteristically affecting the Fig Swan neck deformities [of the 2nd and 3rd fingers characterised by hyperextension at the proximal interphalangeal joints (PIP) and flexion at the distal interphalangeal joints (DIP)] 1488 A Clinical Approach to Medicine Fig Boutonierre deformity (5th finger — flexion at proximal interphalangeal joint and hyperextension at distal interphalangeal joint) extensor tendons of the 3rd, 4th, and 5th fingers Hip joint involvement is less common in Asian populations with RA Knee effusions can be easily detected and aspirated for further evaluation Posterior herniation of the capsule into the popliteal area can create a cystic structure called the Baker’s cyst or Popliteal cyst This cyst can rupture into the calf mimicking a deep vein thrombosis, but can usually be differentiated by ultrasonography Metatarsophalangeal (MTP) arthritis can lead to characteristic cockup deformities and subluxation of the MTP heads on the sole Extraarticular manifestations such as fever and fatigue are common in patients with RA during the active stage of the disease Pleuropulmonary manifestations are common in patients with RA.13 Pleural effusions in RA occur at a prevalence of about 5% Interstitial pulmonary fibrosis occurs in 20–40% of patients with RA, more commonly men and patients with rheumatoid nodules and those seropositive for rheumatoid factor Early interstitial fibrosis may be manifested as ground-glass opacities not visible on plain chest radiographs, but diagnosed on high resolution CT scan of the lungs Open lung biopsies may reveal one of five histological patterns in patients with RA: pulmonary rheumatoid nodules, usual interstitial pneumonitis (UIP), bronchiolitis obliterans with organising pneumonia (BOOP), lymphoid hyperplasia and cellular interstitial infiltrates Cardiac involvement is rare in RA although asymptomatic pericardial effusions may be present in a large proportion of patients Felty’s syndrome14 occurs in about 1% of patients with RA and consists of RA, leucopenia, and splenomegaly It is also associated with rheumatoid nodules, fever, weight loss, sjogren’s syndrome, leg ulcers, vasculits, peripheral neuropathy, hepatomegaly, and pulmonary fibrosis Rheumatoid Arthritis 1489 Pseudo-felty’s syndrome14 occurs in RA patients with neutropenia but a normal total white count due to an increased number of large granular lymphocytes (LGL) These patients have less extraarticular manifestations and may have a chronic lymphoproliferative disease Patients with RA have an increased risk of developing lymphomas.15 An anemia of chronic disease is almost universal in patients with RA An iron deficiency anemia secondary to chronic gastrointestinal blood loss may have to be excluded as many patients with RA are on long-term NSAID (Non Steroidal Anti-inflammatory Drug) treatment Rheumatoid nodules occur in 15–40% of patients and are associated with a positive rheumatoid factor, erosive disease, vasculitis and other systemic features These rheumatoid nodules consist of a central area of necrosis surrounded by palisading histiocytes encircled by granulomatous tissue infiltrated with lymphocytes The nodules usually occur in extensor surfaces and also in viscera such as the lungs and heart Methotrexate treatment can accelerate nodulosis.16 Cutaneous vasculitis as well as systemic vasculitis can develop Splinter hemorrhages and necrotic areas at the finger tips may be caused by vasculitis The presense of such lesions means that the patient should be meticulously examined to exclude systemic vasculitis Keratoconjunctivitis sicca manifested by dryness of the eyes and mouth, may occur as part of a secondary Sjogren’s syndrome Episcleritis can occur but usually runs a self-limited course Scleral inflammation which may resemble a rheumatoid nodule can erode through the sclera into the choroid giving rise to scleromalacia perforans LABORATORY EVALUATION It should be emphasized that the diagnosis of rheumatoid arthritis is based on a good history and physical examination The presence of rheumatoid factors can aid in the diagnosis but their absence does not exclude a diagnosis of rheumatoid arthritis Rheumatoid factors are usually IgM directed against IgG They are detected in 65–85% of patients with RA They are also found in about 3% of healthy people as well as in conditions such as subacute bacterial endocarditis, tuberculosis, leprosy, syphilis, cytomegalovirus, rubella, influenza, parasitic diseases, sarcoid, pulmonary interstitial lung disease, and cryoglobulinemia A raised ESR (Erythrocyte Sedimentation Rate) and CRP (C-reactive protein) may 1490 A Clinical Approach to Medicine indicate active disease Other laboratory abnormalities observed in RA include hypergammaglobulinemia, anemia, occasional hypocomplementemia, thrombocytosis, and eosinophilia All of these tend to occur more often in patients with more severe disease In the initial stages, joint radiographs may demonstrate a peri-articular osteopenia and the characteristic marginal erosions of RA may not be seen till later in the course of the disease Synovial fluid aspirate and biopsy usually demonstrates inflammation, and while not useful to diagnose RA, may help to exclude joint infection Joint fluid from a rheumatoid joint may be straw colored, cloudy and contain flecks of fibrin There are large numbers of white cells with a preponderance of neutrophils in the fluid Synovial glucose level is usually low MANAGEMENT Rationale for Early Aggressive Treatment and Prognostic Factors RA is a potentially serious chronic disease with excessive mortality and disability A 25-year prospective study showed that the median life expectancy was shortened by years in male, and years in female patients with RA.17 In reviewing major studies after 1950, the risk of death in RA patients was found to be twice as high as that of the general population.18 In addition, disability increased from 52% of patients with RA to 84% at the end of 12 years.19 A large portion of the damage appears to be early, as half of RA patients experience some difficulty in the performance of activities of daily living, within two years of disease onset.20 Hence recent consensus favors early aggressive management of RA patients, especially in those with poor prognostic factors (see Table 2).21 Recent years have seen a proliferation of new treatments for RA General Approach to the Treatment of RA Patients It is important to have a well-balanced and coordinated treatment scheme involving education, physiotherapy and occupational therapy The usual approach to drug treatment should be to start with the Non Steroidal Anti-inflammatory Drugs (NSAID’s) and add a Disease Modifying AntiRheumatic Drug (DMARD) early in the course of disease The choice of Rheumatoid Arthritis 1491 Table Indicators of Poor Prognosis in RA 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) More ACR criteria fulfilled Sustained disease activity Rheumatoid factor positive Extra-articular manifestations such as rheumatoid nodules and systemic features Heterozygosity for HLA-DRB1.0401 (DW4) and DRB1.0404 (DW14) Raised ESR and CRP Early erosions and periarticular bone loss Low socio-economic status and low formal education Female sex Insidious onset and severe initial presentation ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; ACR: American College of Rheumatology; HLA: Human leucocyte antigen DMARD would depend on patient and disease characteristic NSAID’s should be avoided in the elderly or in those with contra-indications to its use Low-dose steroids are an alternative in this situation Patients need to be monitored regularly for disease activity parameters as well as drug toxicities Patients should be educated as they need to understand that RA is a lifelong disease, requiring some form of treatment Several patients seek alternative medicine looking for a cure and may fail to continue taking DMARD’s or other prescribed medications Doctors, nurse counsellors and social workers can enforce compliance to treatment as well as help disabled patients gain access to government or other sources of financial assistance Physiotherapists can help patients understand how whole body rest can decrease the systemic inflammatory response The level of physical activity should be increased judiciously as joint inflammation subsides Physiotherapy and occupational therapy help patients maintain joint mobility and overcome existing disabilities Drug Treatment NSAIDs (Non steroidal anti-inflammatory drugs) The anti-inflammatory action of NSAID’s is due to its actions inhibiting cyclooxygenase and decreasing prostaglandins of the E series By shunting arachidonic acid back into the triglyceride pool it also decreases its conversion to leukotrienes 1492 A Clinical Approach to Medicine NSAID associated toxicities 1) Gastrointestinal: Gastric and duodenal ulcers, with hemorrhage and perforation, can occur Other problems encountered are gastritis, gastric erosions, small bowel ulcers, oesophagitis and oesophageal stricture The risks of gastrointestinal complications are higher in older patients, and those with a history of peptic ulcer disease and other comorbid conditions When an NSAID-associated ulcer occurs, the drug should be stopped if possible Omeprazole was found to be more effective than ranitidine23 and as effective but better tolerated than the prostaglandin analogue misoprostol24 in the treatment of NSAID induced ulcers Prophylaxis against NSAID-induced gastric or duodenal ulcers should be considered in patients with risk factors mentioned above Misoprostol in doses of 100–200 g four times a day have been effective in prevention of gastric and duodenal ulcers.25 It is poorly tolerated, causing nausea, diarrhea, and abdominal cramps Omeprazole is effective for the prevention of both gastric and duodenal ulcers whereas ranitidine only prevents duodenal and not gastric ulcers.26 2) Renal toxicitiy: NSAIDs decrease creatinine clearance and increase serum creatinine levels, hence these drugs should not be used in the elderly and in those with impaired renal function or decreased circulating blood volume Acute interstitial nephritis and rarely nephrotic syndrome can also occur with NSAID use 3) Other toxicities: Reversible elevation of liver enzymes and rarely fatal fulminant hepatitis can also occur NSAIDs displace Warfarin from it’s binding sites and can prolong the prothrombin time They also interact with phenytoin and other highly protein-bound drugs NSAIDs can interfere with platelet function and cause prolonged bleeding It is recommended that patients on long term NSAIDs have a full blood count and creatinine level checked every six months Selective cyclooxygenase inhibitor (COX2) There are at least two related isoforms of cyclooxygenase — and (COX1 and COX2) The toxicity of NSAID is due to the inhibition of COX1 and the therapeutic effects are due to COX2 inhibition Selective COX2 inhibitors have been developed including celocoxib (celebrex) in the dosage of 200 mg once daily or 100 mg twice daily and rofecoxib 25 mg Rheumatoid Arthritis 1493 daily In two recent large trials comparing highly selective COX2 agents with traditional NSAIDs, the patients in the selective COX2 agent group had significantly fewer GI events.27,28 There are several caveats, however If antiplatelet therapy is indicated (e.g as risk reduction for cardiovascular disease), an agent such as low-dose aspirin should be used because, unlike non-selective NSAIDs, the selective COX2 inhibitors have no effect on platelet adhesion or aggregation The same precautions that apply to the use of NSAIDs in patients with renal disease should be exercised with the use of COX2 inhibitors DMARDs (Disease modifying anti-rheumatic drugs) The doses and efficacies of DMARDs (Table 3) reported below are based on experiences with caucasian populations.22,29 In a study of Singaporean Chinese, low-dose Methotrexate was found to be effective and safe.30 Based on considerations of safety, convenience, and cost, many rheumatologists select HCQ or SSZ first, but for the patient with very active disease or with indicators of a poorer prognosis, MTX or combination therapy would be preferred If a patient with RA has not achieved remission or a satisfactory response to the initial trial of DMARDs, and if a rheumatologist has not yet been involved in the patient’s care, a rheumatology consultation should be obtained MTX as monotherapy or as a component of combination therapy should be instituted in patients whose treatment has not yet included MTX Methotrexate (MTX) Many rheumatologists select MTX as the initial DMARD, especially for patients whose RA is more active Because of its favorable efficacy and toxicity profile, low cost, and established track record in the treatment of RA, MTX has become the standard by which all new DMARDs are evaluated.31,32 Randomized clinical trials have established the efficacy of MTX in RA, particularly in patients with severe disease MTX retards the progression of radiological erosions.33 Observational studies indicate that more than 50% of patients who take MTX continue the drug beyond years, which is longer than any other DMARD.34 RA patients taking MTX are more likely to discontinue treatment because of adverse reactions than because of lack of efficacy 1494 A Clinical Approach to Medicine Table Baseline Evaluation of Disease Activity and Damage in Patients with Rheumatoid Arthritis Subjective Degree of joint pain Duration of morning stiffness Duration of fatigue Limitation of function Physical examination Actively inflamed joints (tender and swollen joint counts) Mechanical joint problems: loss of motion, crepitus, instability, malalignment, and/or deformity Extraarticular manifestations Laboratory Erythrocyte sedimentation rate/C-reactive protein level Rheumatoid factor* Complete blood cell count† Electrolyte levels† Creatinine level† Hepatic enzyme levels (AST, ALT, and albumin)† Urinalysis† Synovial fluid analysis‡ Stool guaiac† Other Functional status or quality of life assessments using standardized questionnaires Physician’s global assessment of disease activity Patient’s global assessment of disease activity Radiography Radiographs of selected involved joints§ *Performed only at baseline to establish the diagnosis If initially negative, may be repeated 6–12 months after disease onset †Performed at baseline, before starting medications, to assess organ dysfunction due to comorbid diseases AST_aspartate aminotrans-ferase; ALT_alanine aminotransferase ‡Performed at baseline, if necessary, to rule out other diseases May be repeated during disease flares to rule out septic arthritis §Helps to establish a baseline for monitoring disease progression and response to treatment Stomatitis, nausea, diarrhea, and perhaps, alopecia caused by MTX may decrease with concomitant folic acid35 or folinic acid36 treatment without significant loss of efficacy Relative contraindications for MTX therapy are Rheumatoid Arthritis 1495 preexisting liver disease, renal impairment, significant lung disease, or alcohol abuse Since the most frequent adverse reaction to MTX is elevation of liver enzyme levels, liver function must be monitored, but the risk of liver toxicity is low.37 Based on the ACR guidelines for monitoring liver toxicity in patients receiving MTX, a liver biopsy should be performed in patients who develop abnormal findings on liver function studies that persist during treatment or after discontinuation of the drug Rare but potentially serious and even life-threatening pulmonary toxicity may occur at any time with any dosage of MTX Lymphoproliferative disorders may rarely occur in patients taking MTX,38 but the relationship to the medication is unclear Since MTX is potentially teratogenic, appropriate contraceptive use is required Hydroxychloroquine (HCQ) and Sulfasalazine (SSZ) In the last decade, a number of studies have documented the symptomatic benefit of HCQ and SSZ, particularly for patients with early, milder forms of the disease.39,40 Although HCQ alone does not slow radiologic damage, early treatment with HCQ has a significant impact on long-term patient outcome Rash, abdominal cramps, and diarrhea are infrequent adverse effects HCQ is generally well tolerated and requires no routine laboratory monitoring, although patients need periodic ophthalmologic examinations for early detection of reversible retinal toxicity.41 The risk of retinal toxicity is increased when the dose exceeds mg/kg The length of time to benefit may vary from month to as long as months SSZ may act more quickly than HCQ, with benefit sometimes as early as month after beginning therapy More importantly, SSZ has been shown to retard radiographic progression of RA SSZ is usually well-tolerated, with most side-effects, which include nausea and abdominal discomfort, occurring in the first few months of therapy The incidence of these side-effects is lessened by starting at a low dosage and then gradually increasing the dosage Leukopenia is an occasional, more serious side effect that may occur at any time, and periodic laboratory monitoring is therefore necessary Clinical response should be apparent within months, and the need for a change in therapy may be determined at that time Drug Dosage Efficacy Toxicity Monitoring Guidelines Methotrexate 7.5–20 mg once weekly oral or IM Start at low dose ϩϩϩ Baseline FBC, Hepatitis B and C serologies and Chest X-Ray FBC, LFT, Creatinine every 1–2 months Sulfasalazine 500–3000 mg/day oral in divided doses Start at low dose ϩϩϩ Liver function abnormalities, liver cirrhosis, interstitial pneumonitis, bone marrow suppression Bone marrow suppression IM Gold 10–50 mg IM weekly ϩϩϩ D-Peniciallamine 250–750 mg/day oral ϩϩϩ Hydroxychloroquine Azathioprine ϩϩ 0.6 mg/kg/day (200–400 mg/day) 2–2.5 mg/kg/day oral ϩϩ Auranofin Etanercept mg twice daily 25 mg subcutaneously twice weekly ϩ ϩϩϩϩ Pancytopenia, nephrotic syndrome, pneumonitis Bone marrow suppression, bronchiolitis, other autoimmune disease Retinal pigmentation (rare) Bone marrow suppression Rare Infections Baseline G6PD FBC every 2–4 weeks for the first months and then every months LFT periodically FBC, UFEME, at every injection FBC, UFEME every weeks initially, then every 1–2 months Ophthalmological evaluation every 6–12 months FBC every month LFT periodically FBC, UFEME every month Monitor for injection site reactions 1496 A Clinical Approach to Medicine Table Disease Modifying Anti-Rheumatic Drugs (DMARDs)22 Table (Continued) Dosage Efficacy Toxicity Monitoring Guidelines Infliximab plus oral and subcutaneous methotrexate Leflunomide 3–10 mg IV every weeks ϩϩϩϩ Infections, same as methotrexate As for methotrexate Diarrhea, alopecia, rash, headache, theoretical risk of immunosuppression infection known teratogen Hepatitis B and C serology in high-risk patients, CBC, creatinine, LFTs monthly for the first months; every 1–2 months thereafter For minor elevations in AST or ALT (Ͻ 2-fold ULN), repeat testing in 2–4 weeks For moderate elevations in AST or ALT (Ͼ 2-fold but Ͻ 3-fold ULN), closely monitor, with LFTs every 2–4 weeks and dosage reduction For persistent elevations of AST or ALT (Ͼ 2- or 3-fold ULN), discontinue leflunomide and eliminate with cholestyramine therapy; perform liver biopsy as necessary Patients also taking MTX should have LFTs at least monthly Creatinine every weeks then monthly FBC, potassium, LFT 1–2 monthly Cyclosporine ϩϩϩ 20 mg/day in a single dose if tolerated; otherwise, 10 mg/day 2–5 mg/kg/day ϩϩϩ Nephrotoxicity, neurotoxicity, hypertension, hirsutism FBC: Full Blood Count; LFT: Liver Function Test; UFEME: urine analysis Rheumatoid Arthritis 1497 Drug 1498 A Clinical Approach to Medicine Newer Drugs Leflunomide Leflunomide is a new pyrimidine synthesis inhibitor now FDA approved in the treatment of RA and shown to be as safe and effective as methotrexate Several randomized, controlled clinical trials (including some conducted in Singapore and other Asian countries) have established leflunomide as an alternative to MTX as monotherapy, especially for patients who cannot tolerate MTX or are experiencing an inadequate response to MTX) The reduction in RA disease activity and in the rate of radiologic progression achieved by leflunomide appears to be equivalent to that of a modest dosage of MTX Leflunomide is also beneficial as combination therapy with MTX, in the absence of a complete clinical response with full doses of MTX The usual dosage of leflunomide is 20 mg per day and liver function tests should be monitored regularly Five percent of patients receiving leflunomide and up to 60% of patients receiving MTX plus leflunomide have elevated liver enzyme levels.42 Since enterohepatic recirculation plays a large role in leflunomide metabolism, leflunomide has a long half-life Without the recommended washout protocol with cholestyramine resin, elimination of the drug would take as long as years Leflunomide is a potent teratogen, and women taking leflunomide who wish to conceive must discontinue leflunomide and undergo cholestyramine washout before attempting conception Obstructive biliary disease, liver disease, viral hepatitis, severe immunodeficiency, inadequate birth control, and rifampin therapy (which raises leflunomide serum levels) are all contraindications to the use of leflunomide Anti-tumor necrosis factor (anti-TNF) therapy The development of genetically engineered biological agents that selectively block cytokines (anticytokine therapy) in the short term represents a major advance in the treatment of RA The most clinically effective anticytokine agents studied to date are antagonists to TNF, an essential mediator of the cytokine inflammatory cascade in RA Two anti-TNF agents are available: etanercept, a recombinant soluble TNF-Fc fusion protein; and infliximab, a chimeric (mouse–human) anti-TNF monoclonal antibody Randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of etanercept and infliximab in improving clinical symptoms and signs in Rheumatoid Arthritis 1499 patients with RA Patients with early RA43 and those with active RA in whom previous DMARD therapy had failed44 showed improvement with etanercept therapy Both etanercept45 and infliximab46 have been shown to be beneficial when used in combination with MTX in patients with ongoing active RA despite adequate doses of MTX alone Infliximab is currently recommended for use only with concomitant MTX therapy Concerns about the short-term and long-term safety of these agents exist TNF-␣ plays an important role in host protection against infection and tumor genesis Postmarketing experience with etanercept and infliximab shows hospitalizations and deaths from serious infections in patients treated with these agents Many of the patients who died while being treated with anti-TNF-␣ had significant chronic infections or risk factors for infection Anti-TNF agents should therefore be used with caution in patients with any susceptibility to infection or a history of tuberculosis, should be avoided in patients with significant chronic infections, and should be discontinued temporarily in all patients with acute infection Postmarketing surveillance has yielded reports of sepsis, tuberculosis, atypical mycobacterial infections, fungal infections, other opportunistic infections, demyelinating disorders, and aplastic anemia Risk of latent tuberculosis should be assessed prior to initiation of a TNF antagonist While the follow-up period with these new agents is still relatively short, thus far there have been no demonstrated increases in the incidence of malignancy in patients treated with etanercept or infliximab compared with the expected rates in the general population At this time, there appears to be no need for routine laboratory monitoring with the antiTNF agents, but patients should be alerted to report any signs or symptoms of infection In addition to the absence of long-term safety data, the disadvantages of anti-TNF agents are the need for parenteral administration and the high cost of these medications Not all patients with RA respond to antiTNF therapy, and disease flares occur after therapy is discontinued Staphylococcal protein A immunoadsorption Extracorporeal immunoadsorption of plasma against a staphylococcal protein A column (Prosorba) was reported to be efficacious in a portion of patients with severe refractory RA.47 1500 A Clinical Approach to Medicine Interleukin receptor antagonists (IL1 receptor antagonists) These have also proven beneficial but are not ready for use Anakinra, a human recombinant form of interleukin-1 receptor antagonist (IL-1Ra) was shown in trials to be efficacious as monotherapy or combination therapy, compared with a placebo, for the treatment of active RA.48 Combination DMARD therapy Conventional treatment with a single DMARD often fails to adequately control clinical symptoms or to prevent disease progression and then combinations of various DMARDs have been used Role of steroids in RA When RA is newly diagnosed rapid, effective suppression of inflammation may be desired with a short course of steroids Parenteral methylprednisolone or hydrocortisone can be used for severe flares of disease or for vasculitis There may be some evidence that long term steroids may slow the progression of joint damage.49 The benefits of low-dose systemic glucocorticoids, however, should always be weighed against their adverse effects The adverse effects of long-term oral glucocorticoids at low doses are protean and include osteoporosis, hypertension, weight gain, fluid retention, hyperglycemia, cataracts, and skin fragility, as well as the potential for premature atherosclerosis These adverse effects should be considered and should be discussed in detail with the patient before glucocorticoid therapy is begun For long-term disease control, the glucocorticoid dosage should be kept to a minimum For the majority of patients with RA, this means Ͻ 10 mg of prednisone per day RA is associated with an increased risk of osteoporosis independently of glucocorticoid therapy Patients taking glucocorticoids at dosages as low as mg/day have an increased risk of osteoporosis, and densitometry to assess bone loss should be performed at regular intervals for the duration of glucocorticoid therapy Measures to prevent glucocorticoid induced osteoporosis should be instituted (1000–1500 mg elemental calcium/ day Ϯ 400–800 IU vitamin D/day Ϯ hormone replacement therapy Ϯ bisphosphonates) Rheumatoid Arthritis 1501 Role of Surgery in RA Surgery is most useful for: • • • • ruptured tendons at the hand and wrist (tendon repair); functional impairment due to end stage joint disease ( joint replacement surgery); joint instability (fusion of thumb, wrist, ankle, C-Spine); and intricate hand surgery to correct deformities has fallen out of favor Management of Complications Vasculitis is treated with high dose steroids and possible addition of drugs such as cyclophosphamide Splenectomy has only a variable effect on the leucopenia of Felty’s syndrome There have been reports of improvement in this syndrome with DMARD therapy, particularly gold, methotrexate and D-penicillamine Popliteal cysts are usually managed by intra-articular injection of steroids but synovectomy may be needed Surgical removal of rheumatoid nodules may help temporarily but the nodules usually recur Surgery is indicated for infected nodules or those that mechanically interfere with usual activities Therapy for rheumatoid lung disease should be instituted during the inflammatory stage and not after fibrosis has occurred High-resolution CT scans of the thorax can demonstrate active alveolitis and these patients should be treated with high-dose steroids and possibly cyclophosphamide CONCLUSION RA is an autoimmune disease affecting mainly the joints, but with significant systemic features Early aggressive management is advocated to prevent joint deformities, disability, morbidity and mortality, especially in those patients with poor prognostic features REFERENCES Arnett FC ES, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al., The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis, Arthritis Rheum 31(3):315–324, 1988 1502 A Clinical Approach to Medicine Edmonds J, Overview of RA in the Asia Pacific region, in: EbFP (ed.), Proceedings of the XIX ILAR Congress of rheumatology: Communication Consultants Singapore, pp 465–468, 1997 Mitchell D, Epidemiology, Rheumatoid Arthritis, Etiology, Diagnosis and Treatment, JB Lippincott, Philadelphia, 1985 Brun JG NS, Kvale G, Breast feeding, other reproductive factors and rheumatoid arthritis A prospective study, Br J Rheumatol 34(6): 542–546, 1995 Stansky P, Association of the B-cell alloantigen DRw4 with rheumatoid arthritis, N Engl J Med 298(16):869–871, 1978 Chan SH LY, Wee GB, Koh WH, Boey ML, HLA class genes in Singaporean Chinese rheumatoid arthritis, Br J Rheumatol 33(8):713–717, 1994 JJ Goronzy CW, Rheumatoid arthritis, epidemiology, pathology and pathogenesis 11 ed: Arthritis Foundation, Atlanta Georgia; 1997 Veerapen K MG, Watt I, Dieppe P, The expression of rheumatoid arthritis in Malaysian and British patients: a comparative study, Br J Rheumatol 32(7):541–545, 1993 Cohen MG LE, Ng PY, Chan KL, Extra-articular manifestations are uncommon in southern Chinese with rheumatoid arthritis, Br J Rheumatol 32(3):209–211, 1993 10 Moran H CS, Muirden KD, Jiang SJ, Gu YY, Hopper J, Jiang PL, Lawler G, Chen RB, A comparison of rheumatoid arthritis in Australia and China, Ann Rheum Dis 45(7):572–578, 1986 11 J Fleming A BR, Corbett M, Wood PH, Early rheumatoid Disease II Patterns of joint involvement, Ann Rheum Dis 35(4):361–364, 1976 12 Boden S, Rheumatoid arthritis of the cervical spine Surgical decision making based on predictors of paralysis and recovery, Spine 19(20):2275–2280, 1994 13 McDonagh J GM, Wright AR, Heycock C, Owen JP, Kelly C, High resolution computed tomography of the lungs in patients with rheumatoid arthritis and interstitial lung disease, Br J Rheumatol 33(20):118–122, 1994 14 Rosenstein ED KN, Felty’s and pseudo-Felty’s syndromes, Semin Arthritis Rheum 21(3):129–142, 1991 15 Gridley G MJ, Ekbom A, Klareskog L, Adami HO, Hacker DG, Hoover R, Fraumeni JF Jr., Incidence of cancer among patients with rheumatoid arthritis, J Natl Cancer Inst 85(4):307–311, 1993 16 Kerstens PJ BA, Jeurissen ME, Fast JH, Assmann KJ, van de Putte LB, Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis An analysis of ten cases, J Rheumatol 19(6):867–871, 1992 17 Vandenbroucke JP HH, Cats A, Survival and cause of death in rheumatoid arthritis: a 25-year prospective followup, J Rheumatol 11(2):158–161, 1984 18 Isomaki H, Mortality in patients with rheumatoid arthritis Rheumatoid Arthritis Pathogenesis, Assessment, Outcome, and Treatment Marcel Dekker, New York, 1994 Rheumatoid Arthritis 1503 19 Sherrer YS BD, Mitchell DM, Young DY, Fries JF, The development of disability in rheumatoid arthritis, Arthritis Rheum 29(4):494–500, 1986 20 Wolfe F CM, The assessment and prediction of functional disability in rheumatoid arthritis, J Rheumatol 18(9):1298–1306, 1991 21 Van Zeben D HJ, Zwinderman AH, Vanderbroucke JP, Breedveld FC, Factors predicting outcome of rheumatoid arthritis: results of a followup study, J Rheumatol 20(8): 1288–1296, 1993 22 Guidelines for management of rheumatoid arthritis American College of Rheumatology Ad Hoc committee on clinical guidelines, Arthritis Rheum 46(2):328–346, 2002 23 Yeomans ND TZ, Juhasz L, Racz I, Howard JM, van Rensburg CJ, Swannell AJ, Hawkey CJ, A comparision of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group, N Engl J Med 338(11):719–726, 1998 24 Hawkey CJ KJ, Szczepanski L, Walker DG, Swannell AJ, Yeomans ND, Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group, N Engl J Med 338(11):727–734, 1998 25 Raskin JB WR, Jaszewski R, Korsten MA, Schubert TT, Fort JG, Misoprostol and ranitidine in the prevention of NSAID-induced ulcers: a prospective, double-blind, multicenter study, Am J Gastroenterol 91(2):223–227, 1996 26 Committee HCONS Progress in prophylaxis against nonsteroidal anti-inflammatory drug-associated ulcers and erosions, Am J Med 104(3A):67s–74s, 1998 27 Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al., Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis VIGOR Study Group, N Engl J Med 343(21):1520–1528, 2000 28 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al., Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial Celecoxib Long-term Arthritis Safety Study, Jama 284(10):1247–1255, 2000 29 Felson DT AJ, Meenan RF, The comparitive efficacy and toxicity of second-line drugs in rheumatoid arthritis Results of two metaanalyses, Arthritis Rheum 33(10):1449–1461, 1990 30 Thumboo J KW, Leong KH, Boey ML, Feng PH, The safety of weekly low dose methotrexate in an Oriental population with rheumatoid arthritis, Ann Acad Med Singapore 26(2):205–209, 1997 31 Andersen PA, West SG, O’Dell JR, Via CS, Claypool RG, Kotzin BL, Weekly pulse methotrexate in rheumatoid arthritis Clinical and immunologic effects in a randomized, double-blind study, Ann Intern Med 103(4):489–496, 1985 32 Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA, Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis, J Rheumatol 17(12):1628–1635, 1990 1504 A Clinical Approach to Medicine 33 Williams HJ, Willkens RF, Samuelson CO Jr., Alarcon GS, Guttadauria M, Yarboro C, et al., Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis A controlled clinical trial, Arthritis Rheum 28(7):721–730, 1985 34 Kremer JM, Phelps CT, Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis Update after a mean of 90 months, Arthritis Rheum 35(2):138–145, 1992 35 Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, et al., The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis, Arthritis Rheum 33(1):9–18, 1990 36 Shiroky JB, Neville C, Esdaile JM, Choquette D, Zummer M, Hazeltine M, et al., Lowdose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis Results of a multicenter randomized, double-blind, placebo-controlled trial, Arthritis Rheum 36(6):795–803, 1993 37 Kremer JM, Alarcon GS, Lightfoot RW Jr., Willkens RF, Furst DE, Williams HJ, et al., Methotrexate for rheumatoid arthritis Suggested guidelines for monitoring liver toxicity American College of Rheumatology, Arthritis Rheum 37(3):316–328, 1994 38 Moder KG, Tefferi A, Cohen MD, Menke DM, Luthra HS, Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study, Am J Med 99(3):276–281, 1995 39 Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M’Seffar A, et al., Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study, J Rheumatol 27(3):623–629, 2000 40 Williams HJ, Comparisons of sulfasalazine to gold and placebo in the treatment of rheumatoid arthritis, J Rheumatol Suppl 16:9–13, 1988 41 Easterbrook M, An ophthalmological view on the efficacy and safety of chloroquine versus hydroxychloroquine, J Rheumatol 26(9): 1866–1868, 1999 42 Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, et al., Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis Results of a randomized, placebo-controlled, phase II study, Arthritis Rheum 38(11):1595–1603, 1995 43 Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al., A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis, N Engl J Med 343(22):1586–1593, 2000 44 Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al., Etanercept therapy in rheumatoid arthritis A randomized, controlled trial, Ann Intern Med 130(6):478–486, 1999 45 Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrell M, et al., Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis, Arthritis Rheum 42(7): 1322–1328, 1999 Rheumatoid Arthritis 1505 46 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al., Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial ATTRACT Study Group, Lancet 354(9194):1932–1939, 1999 47 Felson DT, LaValley MP, Baldassare AR, Block JA, Caldwell JR, Cannon GW, et al., The Prosorba column for treatment of refractory rheumatoid arthritis: a randomized, double-blind, sham-controlled trial, Arthritis Rheum 42(10):2153–2159, 1999 48 Calabrese LH, Anakinra treatment of patients with rheumatoid arthritis, Ann Pharmacother 36(7):1204–1209, 2002 49 Kirwan J, The effect of glucocorticoids on joint destruction in rheumatoid arthritis, N Engl J Med 333:3142–3146, 1995 This page intentionally left blank 85 Seronegative Spondyloarthropathy Koh Wei Howe INTRODUCTION The seronegative spondyloarthropathies are an interrelated group of chronic inflammatory diseases that share common clinical features, including a tendency to affect the axial skeleton, and an association with the histocompatibility antigen HLA-B27.1 Ankylosing spondylitis is the prototype disease of the spondyloarthropathies that include reactive arthritis/Reiter’s syndrome, psoriatic arthritis, chronic inflammatory bowel diseases and juvenile onset spondyloarthropathy The frequency of HLA-B27 occurring in the seronegative spondyloarthropathies varies greatly among the various forms and show differences between ethnic and racial groups.2 Amongst the group of disorders, ankylosing spondylitis has the strongest association with the HLA-B27 (over 95%) and the other disease such as psoriatic arthritis and inflammatory bowel disease, bear weaker associations Typically, patients with seronegative spondyloarthropathies are tested negative for rheumatoid factor 1507 1508 A Clinical Approach to Medicine Table The European Spondyloarthropathy Study Group (ESSG) Criteria for Spondyloarthropathy Inflammatory spinal pain or Synovitis • asymmetrical; or • predominantly in the lower limbs and One or more of the following: • alternate buttock pain; • sacroiliitis; • enthesopathy; • positive family history; • psoriasis; • inflammatory bowel disease; or • urethritis or cervicitis or acute diarrhea occurring within one month before the arthritis Common to all forms of spondyloarthropathies is the greater tendency to afflict males and the development of the disease in the early twenties or late adolescent age.1,3 Characteristic clinical manifestations may involve inflammation at sites of tendon and ligamentous insertions, sacroiliitis and inflammatory spinal disease, peripheral oligoarthritis predominantly of the lower limbs, dactylitis and extra-articular features such as iritis However, a spectrum of clinical syndromes exists in association with the HLA-B27 antigen that may not satisfy established classification criteria These undifferentiated subsets of spondyloarthropathy encompass syndromes such as isolated acute anterior uveitis, seronegative oligoarthritis, dactylitis and enthesitis, and even cardiac valvular lesions with conduction abnormalities Recognition of these distinct entities have led to the development of classification criterias such as the European Spondyloarthropathy Study Group (ESSG) criteria (Table 1)4 that attempts to unify these syndromes under the broader spectrum of spondyloarthropathies ETIOLOGY AND PATHOGENESIS The role of HLA-B27 in conferring disease susceptibility to spondyloarthropathy is widely accepted but the precise mechanism by which it is involved in the pathogenesis of the disease is yet to be confirmed It is suspected that an interplay between genetic and environmental factors, especially infections, is responsible for the development of the disease.5,6 Seronegative Spondyloarthropathy 1509 For example, enteric infections by Gram-negative bacteria such as Yersina, Campylobacter, Salmonella or Shigella, or urogenital infection by Chlamydia are associated with reactive arthritis By definition, reactive arthritis implies that the inflammatory response in the joint is sterile and that the inciting bacteria cannot be cultured from the joint fluid However there is some evidence that bacteria-like product can be detected in synovial tissues of patients with reactive arthritis, suggesting that the persistence of microbial antigens play an important role in perpetuating the inflammatory process in the joints.7 Common features shared by these Gram-negative organisms that cause reactive arthritis are the ability to invade mucosal surfaces and replicate intra-cellularly, and the possession of lipopolysaccharides The evidence for infective trigger in ankylosing spondylitis is less clear but recent research has focussed on Klebsiella pneumoniae as a possible etiological agent especially when peripheral arthritis is present8 and elevated IgA class anti-Klebsiella antibodies in patients with ankylosing spondylitis have been reported.9 The association between gut bacteria and pathogenesis of HLA-B27-related diseases has been a subject of much research The presence of silent inflammatory intestinal lesions in patients with spondyloarthropathy has been observed.10 It is unclear whether these lesions represent a spectrum of the inflammatory bowel disease or if they provide a site for bacterial antigens to enter the circulation and stimulate immunologic inflammatory processes Studies with transgenic animals expressing HLA-B27 has shed more light on the importance of the gene and its interaction with gut bacteria in the pathogenesis of disease Transgenic rats with the human HLA-B27 gene have exhibited inflammatory changes in the joints, skin, intestinal tract, genitals and heart that are similar to B27-associated disease in humans.11 However, the exact mechanism by which the bacteria and the HLA-B27 gene interact to produce the disease is yet to be elucidated The two hypotheses that are often proposed are that the HLA-B27 has a molecular mimicry with enterobacteria or that it presents arthritogenic peptides (derived from bacterial antigens or HLA-B27 itself) to T cells At least 23 different subtypes of HLA-B27 have been identified and they are named B*2701 to B*2723.12 The presence of various subtypes differ in racial distribution and whilst some common subtypes (B*2705, B*2702, B*2704, B*2707) are associated with spondyloarthropathy, others such as B*2706 in Southeast Asians seem to lack the disease association.13 1510 A Clinical Approach to Medicine ANKYLOSING SPONDYLITIS The typical presentation of ankylosing spondylitis is an inflammatory backpain with bilateral sacroiliitis demonstrated on radiographs The disease is more common in men but the sex ratio is much lower than was previously thought (male to female ratio of : in Western population, : in Singapore).3 The prevalence of the disease show different ethnic distribution and is estimated to be between 0.1 to 0.2% of the caucasian population A family history of spondyloarthropathy is present in 10–20% of patients with ankylosing spondylitis.3 The onset of the disease is usually in the early twenties but the disease can also occur in children.1 In juvenile spondyloarthropathy, which starts before the age of 16 years, the initial presentation is commonly a peripheral oligoarthritis and enthesitis without backpain The New York criteria for diagnosis of ankylosing spondylitis has been used for epidemiological studies but lack sensitivity in identifying early and mild disease.14 Clinical Features The sacroiliac joints are often the first sites to be affected and patients may experience unilateral or alternating buttock pain The disease then progresses up the lumbar spine and frequently the neck The characteristics of backache includes an insidious onset, presence of morning stiffness and a pain that is worse with prolong rest and improves with mobilization of the spine On examination, the movement in the lumbar spine is often limited in all directions Patients may have sleep disturbance at night because of the backache and stiffness, and wake up in the morning with great difficulty getting out of bed Fatigue is a common problem for many patients and sleep disorder is probably one contributory cause for the symptom.15 Osteoporosis, vertebral fractures, spondylodiscitis and pseudoarthrosis are complications that may occur in the spine Even in the early and mild stages of the disease, the bone mineral density of patients may be low Peripheral joint involvement occurs in up 25–50% of patients but seems to be more frequent in Oriental patients Hip disease tends to occur in patients with an early onset of disease, less than 20 years of age, and is usually bilateral and insidious in onset (Fig 1) Erosion and ankylosis may result in flexion contractures of the hip joints and some patients may Seronegative Spondyloarthropathy 1511 Fig Bilateral hip involvement in a patient with ankylosing spondylitis require hip replacement surgery later in life The shoulders and knees are other joints that can be affected and ten percent of patients may develop temporomandibular joint disease Another hallmark feature of the spondyloarthropathies is the presence of enthesitis (inflammation at sites of tendon or ligamentous attachment to bones) which commonly occurs at the achilles tendons, heels, ischial tuberosities, tibial tubercles or costosternal junctions Bony ankylosis or fusion of the joints may result from fibrosis and ossification of tissue across the affected joints and hence the name “ankylosing spondylitis” Mild fever, weight loss and malaise are some of the constitutional symptoms that may occur in early disease At some time during the course of their disease, 25–40% of patients develops acute anterior uveitis (iritis) Uveitis is more common in HLA-B27 positive than negative patients It is typically acute, unilateral and results in eye pain, increased lacrimation, blurred vision and photophobia Other extra-articular manifestations occur less frequently and these include aortitis, mitral valve incompetence, conduction abnormalities, myocardial dysfunction, apical pulmonary fibrosis, cauda equina syndrome, amyloidosis and IgA nephropathy Investigations and Assessment of Disease Status Hematological investigations may show non-specific abnormalities such as raised ESR and serum IgA; and a normochromic, normocytic anemia The rheumatoid factor and anti-nuclear antibodies are usually negative 1512 A Clinical Approach to Medicine Fig Antero-posterior view of the lumbosacral spine showing bilateral sacroiliitis Radiographic evidence of bilateral sacroiliitis supports the diagnosis of ankylosing spondylitis and an antero-posterior view is sufficient to detect the changes (Fig 2) Other imaging modalities such as bone scan, computerized tomography (CT) scan and magnetic resonance imaging (MRI) are more sensitive in detecting changes of sacroiliitis but are not routinely required “Squaring” of the vertebral body seen on lateral spine radiographs is one of the earliest features present Subsequently, ossification of the superficial layers of the annulus fibrosus results in the formation of syndesmophytes The bridging of vertebral bodies by the syndesmophytes, fusion of apophyseal joints and ossification of interspinous ligaments can result in ankylosis of the spine and give the appearance of a “bamboo spine” on the radiograph (Fig 3) However, the radiographic changes may take years to be apparent and the initial X-rays may appear normal A radiological scoring system, Bath Ankylosis Spondylitis Radiology Index (BASRI) has been devised to grade radiological changes in patients with ankylosing spondylitis It uses a scale of 0–4 to grade the severity of change in the sacroiliac joint, lumbar and cervical spine.16 The HLA-B27 test is not necessary for diagnosis in the majority of cases when the clinical and radiological features are characteristic of the disease It should not be used as a “confirmatory” test to diagnose or exclude the Seronegative Spondyloarthropathy 1513 Fig Ankylosis of the vertebral spine giving the appearance of a “bamboo spine” disease because it is present in about 7% of the normal local population, and is absent in about 5% of patients with ankylosing spondylitis The axial skeleton is predominantly involved in the disease and assessing the degree of inflammation in the spine clinically is more difficult compared to a largely peripheral arthritis such as rheumatoid arthritis Various instruments in the form of self assessment questionnaires (e.g Bath Ankylosis Spondylitis Disease Activity Index, BASDAI; Functional Index, BASFI) and metrological measurements (Bath Ankylosing Spondylitis Metrological Index, BASMI) have been devised in an attempt to assess the state of the disease.17 Management At present, there is no known cure for ankylosing spondylitis but drug treatments can control the patient’s symptoms whilst physiotherapy helps to reduce joint stiffness, increase mobility and strengthen the muscles The non-steroidal anti-inflammatory drugs (NSAIDs) are often effective in treating the active inflammation Indomethacin is probably the most common NSAID used but others such as diclofenac and naproxen are also effacious when used in the full therapeutic dose Patients should 1514 A Clinical Approach to Medicine be advised that these drugs have anti-inflammatory properties and are not merely “pain-killers” They should be taken regularly for a period of time rather than when necessary The use of phenylbutazone has been discouraged due to the potential risk of bone marrow suppression, although the drug is very effective in treating ankylosing spondylitis The common side-effect of all NSAIDs is gastrointestinal toxicity and concommitant prescription of gastroprotective agents should be considered in those at higher risk of developing the side effect, such as a past history of peptic ulcer disease Cyclo-oxygenase-2 (COX2) inhibitors (e.g Celecoxib and Rofecoxib) are a group of anti-inflammatory drugs that are associated with less serious gastrointestinal side-effects as compared to conventional NSAIDs, and they can also be used in the treatment of ankylosing spondylitis especially in patients who are at risk of developing peptic ulcer disease Sulphasalazine is effective as a second-line agent in treating patients with active peripheral arthritis but there is little evidence for its use in purely axial skeleton disease.18 However, like most second-line agents, there is a delay in onset of therapeutic efficacy with sulphasalazine of up to three months Low-dose weekly methotrexate has also been used with some success in patients who not respond well to NSAIDs and sulphasalazine The inhibition of pro-inflammatory cytokine tumor necrosis factor (TNF) alpha has a beneficial effect on the disease activity of patients with spondyloarthropathy Drugs such as thalidomide and pamidronate, which has some inhibitory effect on TNF-␣, has been reported to be effective in the treatment of ankylosing spondylitis Patients with ankylosing spondylitis that have been treated with biological therapies (e.g infliximab) that specifically block the action of TNF have shown significant improvement in disease activity However, these agents have to be given parenterally and are presently reserved for those patients who have severe disease A few studies have reported that pulse methylprednisolone may be beneficial but it should probably be used only in patients with severe, acute peripheral arthritis as a “bridging therapy” at the initiation of sulphasalazine treatment because of the delayed response of the latter drug Oral systemic steroids have no role in the long-term treatment of the disease because it does not modify the disease process and may have deleterious side effects Local corticosteroid injections are useful for treating severe refractory enthesitis or peripheral arthritis (especially after an aspiration of the joint is performed for large joint effusion) as well as for Seronegative Spondyloarthropathy 1515 persistent sacroiliitis Treatment of acute iritis requires steroid eye drops and rarely systemic steroids or immunosuppressive agents when it is severe Fatigue, sleep disturbance and joint pains may improve with the use of low dose amitriptyline as adjuvant therapy.19 The importance of regular physical exercises to maintain spinal mobility and limit deformity cannot be over-emphasized Smoking is to be discouraged and daily breathing exercise serves to enhance chest expansion Intensive group physiotherapy and hydrotherapy programs provide substantial improvement in patient’s disease, at least in the short-term.20 Patient should be advised to adopt a proper posture, keep their spine straight and use firm mattresses when sleeping Patients with severe hip disease may require total hip arthroplasty that can significantly improve their functional ability Cervical spine surgery is sometimes performed for severe kyphosis and neurological complications, and the long-term outcome is often good.21 REACTIVE ARTHRITIS (REITER’S SYNDROME) Reactive arthritis (ReA) is a form of seronegative spondyloarthropathy that encompasses the more familiar term called Reiter’s Syndrome By definition, the inflammatory arthritis that occurs in ReA is sterile and develops sometime after an infection, often in urogenital or intestinal tract, or throat The typical triad of oligoarthritis, conjunctivitis and urethritis is described in Reiter’s syndrome but incomplete “forme fruste” disease have been observed The common initiating infectious agents include Chlamydia trachomatis in genitourinary tract infection and Salmonella, Shigella, Campylobacter or Yersinia in enteric infections The spectrum of clinical syndromes range from mild arthralgia to severe peripheral arthritis and axial skeleton involvement Enthesitis, frequently at the heel resulting in achilles tendinitis or plantar fascitis, is a typical feature of ReA and some patients develop diffuse sausage-like swelling or dactylitis of the fingers and toes Mucocutaneous lesions such as circinate balanitis, painless oral mucosal ulcers and keratoderma blenorrhagica (papular, pustular and crusting skin lesion on the palms and soles of the feet) are characteristic extra-articular features that may be present NSAIDs are the mainstay of drug treatment in ReA and should be given at full therapeutic dose regularly for an adequate course Patients 1516 A Clinical Approach to Medicine with large joint effusion or persistent synovitis may benefit from joint aspiration and intra-articular corticosteroid injection provided septic arthritis has been excluded Systemic oral steroid is to be used only if the arthritis is severe and not adequately controlled by NSAIDs The dose should be tailed down when the arthritis improves and its long-term use should be avoided Sulphasalazine, starting at a low dosage and gradually increasing to about 2–3 g daily, is a useful second-line agent for chronic ReA Other agents that has been tried are low dose methotrexate, gold and azathioprine Antibiotic treatment has little role in the management of enteric ReA and it possibly has only some benefit in the treatment of chronic chlamydia-induced ReA REFERENCES Khan MA, Ankylosing spondylitis: Clinical features, in: Klippel JH, Dieppe PA (eds.) Rheumatology, 2nd ed., Mosby, London, pp 6.16.1–6.16.10, 1998 Khan MA, HLA-B27 and its subtypes in world populations, Curr Opin Rheumatol 7:263–269, 1995 Koh WH, Boey ML, Ankylosing spondylitis in Singapore: a study of 150 patients and a local update, Ann Acad Med Singapore 27:3–6, 1998 Dougados M, van der Linden S, Juhlin R, et al., The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathies, Arthritis Rheum 34:1218–1227, 1991 Feltkamp TEW, Khan MA, de Castro JAL, The pathogenetic role of HLA-B27, Immunol Today 7:5–7, 1996 Lopez de Castro JA, Structure, function and disease association of HLA-B27, Curr Opinion Rheum 6:371–377, 1994 Granfors K, Jalkanen S, von Essen R, et al., Yersinia antigens in synovial fluid cells from patients with reactive arthritis, N Engl J Med 320:216–221, 1989 Maki-Ikola O, Nissila M, Lehtinen K, et al., Antibodies to Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis in the sera of patients with axial and peripheral form of ankylosing spondylitis, Br J Rheumatol 34:413, 1995 Cooper R, Fraser SM, Sturrock RD, Gemmell CG, Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease, Br Med J 296:1432–1434, 1988 10 Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppala K, High frequency of silent inflammatory bowel disease in spondyloarthropathy, Arthritis Rheum 37:23–31, 1994 Seronegative Spondyloarthropathy 1517 11 Hammer RE, Maika SD, Richardson JA, et al., Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human B2-m: an animal model of HLA-B27associated human disorders, Cell 63:1099–1112, 1990 12 Feltamp TEW, Mardjuadi A, Feng Huang, Chou CT, Spondyloarthropathies in eastern Asia, Curr Opinion Rheum 13:285–290, 2001 13 Ren EC, Koh WH, Sim D, Boey ML, Wee GB, Chan SH, Possible protective role of HLA B2706 for ankylosing spondylitis, Tissue Antigen 49:67–69, 1997 14 Bennett PH, Burch TA, Population studies of the rheumatic diseases, Amsterdam: Exercpta Medica 456–457, 1968 15 Jones S, Koh WH, Steiner A, Garrett S, Calin A, Fatigue in ankylosing spondylitis: its prevalence and relationship to disease activity, sleep and other factors, J Rheumatol 23:487–490, 1996 16 Mackay K, Mack C, Brophy S, Calin A, The Bath Ankylosing Spondylitis Radiology Index (BASRI): a new, validated approach to disease assessment, Arthritis Rheum 41:2263–2270, 1998 17 Calin A, Ankylosing spondylitis: defining disease status and the relationship between radiology, metrology, disease activity, function, and outcome (Dunlop-Dottridge lecture), J Rheumatol 22:740–744, 1995 18 Clegg DO, Reda DJ, Weisman MH, Blackburn WD, et al., Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis: a Department of Veterans Affairs Cooperative study, Arthritis Rheum 39:2004–2012, 1996 19 Koh WH, Pande I, Jones S, Samuels A, Calin A, Low dose amitriptyline in ankylosing spondylitis: a short term, double-blind, placebo controlled study, J Rheumatol 24: 2158–2161, 1997 20 Seah R, Fernandez G, Phua HS, et al., Ten-day outpatient spondyloarthropathy intensive management programme: The outcome of sessions [abstract], in Proceedings of the 19th ILAR Congress of Rheumatology, Satellite Meeting for Allied Health Professionals Singapore, June 9–11, Communication Consultants, Singapore, 1997 21 Koh WH, Garrett SL, Calin A, Cervical spine surgery in ankylosing spondylitis: is the outcome good? Clin Rheumatol 16:466–470, 1997 This page intentionally left blank 86 Gout Julian Thumboo INTRODUCTION Gout is a common condition in which hyperuricemia leads to urate crystal deposition in joints, skin, kidneys and other extra-articular structures Urate crystal deposition results in a characteristic clinical syndrome of episodic arthritis affecting one or more joints, associated with urate deposits in the skin (tophi), bursae and kidneys.1 EPIDEMIOLOGY Gout is a common condition which usually affects middle-aged men and post-menopausal women The yearly incidence of gout ranges from 0.20 to 0.35 per thousand, with an overall prevalence of 2.0 to 2.6 per thousand.1 In South East Asia, the prevalence of gout (per thousand) has variously been reported as 1.6 in rural Thailand and 17 in rural Java In Taiwan, the prevalence of gout was higher in urban than rural areas, being 6.7 versus 1.6 per thousand respectively The incidence of gout increases with age and increasing serum urate levels Gout is rare 1519 1520 A Clinical Approach to Medicine before puberty and before the menopause A diagnosis of gout in such individuals should trigger a search for secondary causes Gout is negatively associated with rheumatoid arthritis, though the reasons for this are unclear Serum urate levels generally range from 180 to 240 mol/L before puberty At puberty, serum urate levels in males increase by 60 to 120 mol/L, while those in females remain relatively constant After menopause, serum urate levels in females rise steadily and approach urate levels found in males.1 Both genetic and environmental risk factors may contribute to the development of hyperuricemia and gout A genetic contribution is suggested by the markedly differing prevalence of gout in different populations.2 Known risk factors for hyperuricemia and gout include obesity, renal impairment, use of drugs (diuretics, alcohol, etc.) and hypertension (detailed below) PATHOGENESIS OF GOUT Uric acid is a breakdown product of purine nucleotides and deoxynucleotides (which form part of DNA and RNA, are precursors of several cofactors and co-enzymes, and are involved in cellular metabolism) Enzymatic nucleotide cleavage of both dietary and endogenous purines gives rise to purine bases These bases are metabolized to hypoxanthine or xanthine, which are in turn converted to uric acid by the enzyme xanthine oxidase (which is inhibited by allopurinol) In humans, the liver, which expresses xanthine oxidase, is the main site of purine metabolism Two-thirds of the daily human purine load is generated from endogenous purine metabolism, with the remaining one-third coming from dietary purines.3 At a pH of 7.4, 98% of uric acid is ionized as monosodium urate (MSU) Uric acid therefore exists predominantly as urate in serum In parts of the urinary tract where the pH is less than 5.7, uric acid predominates and may crystallize in this setting because of its poorer solubility, resulting in the formation of urate calculi Saturation of MSU in human plasma occurs at 420 mol/L.4 Above this level, MSU crystallizes in synovium and tissues, causing the clinical syndrome of gout The solubility of MSU is temperature dependent, and drops two-fold from 37ЊC to 25ЊC This favors the crystallization of MSU in the cooler peripheries, and accounts for the predilection of gout for peripheral joints Gout 1521 CLINICAL FEATURES The natural history of gout passes through phases: asymptomatic hyperuricemia, acute gout, inter-critical gout, and chronic tophaceous gout Extra-articular manifestations (mainly cutaneous and renal) typically manifest in the later stages of articular disease A family history of gout is present in 6–80% of cases Gout is more common in males and usually presents in middle age, with a peak incidence in the 50–59 year age group Ninety percent of females with gout present after the menopause In a hospital-based series of patients with gout in Singapore, 19% of patients had a family history of gout, with a male: female ratio of 3.4:1 and a mean age of 43.7 years at onset (range 16–78 years) ASYMPTOMATIC HYPERURICEMIA Asymptomatic hyperuricemia (AH) is defined as the presence of raised serum uric acid levels without the presence of gout, tophi or renal involvement AH is a relatively common phenomenon which often does not lead to gout It develops in predisposed males at puberty and in females after menopause, and is typically persistent Gout usually develops after 20–30 years of hyperuricemia, and the risk of developing gout increases with the degree of hyperuricemia (Table 1).5 The risk of developing urate renal calculi increases with the degree of hyperuricemia and the daily urinary uric acid excretion rate AH itself does not cause a decline in renal function, and correction of AH does not protect against development of renal insufficiency.4 For these reasons, AH generally does not require pharmacological treatment Table Risk of Gout in Subjects with Hyperuricemia Serum Uric Acid Level (mol/L) Yearly Risk of Gout (%) Ͻ 420 420–534 Ͼ 534 0.1–0.5 0.5–1.2 4.9–5.7 Uric acid: mg ϭ 59.48 mol ϭ 0.05948 mmol 1522 A Clinical Approach to Medicine Acute Gout Acute gout is characterized by episodic attacks of pain, swelling and erythema, usually of lower extremity joints, initially lasting less than a week These attacks gradually increase in duration, frequency and severity and may be associated with constitutional features (fever, leucocytosis and elevation of the erythrocyte sedimentation rate) Men are more commonly affected, with attacks usually starting after the age of 30 years Attacks before this age should suggest a secondary cause for gout (Table 2) Affected joints are exquisitely tender, with a markedly limited range of movement Severe attacks are associated with desquamation of the overlying skin Once the acute attack has resolved, the patient is typically free of symptoms Gout of the big toe metatarsophalangeal joint (also referred to as podagara) occurs at presentation in 50% and eventually in 90% of subjects Other lower extremity joints are typically affected, although any joint in the body may be involved Attacks are triggered by factors that raise or lower serum urate levels (alcohol, drugs (especially diuretics, low dose aspirin, heparin or cyclosporin), dietary excess or fasting (e.g before Table Causes of Hyperuricemia Increased Urate Production Reduced Urate Excretion Primary (i.e Genetic) Overproducers (10% of primary gout) Defined enzyme mutations Undefined enzyme mutations Underexcretors (90% of primary gout) Reduced urate renal clearance or fractional excretion Secondary (i.e Acquired) High Purine intake Obesity Alcohol consumption Fructose consumption Myeloproliferative disorders Psoriasis, haemolytic anemias, and other disorders with increased catabolism Sustained exercise Renal disorders (renal failure, lead nephropathy) Medications (low dose aspirin, cyclosporin, thiazide diuretics, pyrazinamide, ethambutol, laxative abuse) Dehydration and other causes of decreased renal perfusion Hypertension Hypothyroidism, hyperparathyroidism Ketones, lactate (starvation, ketoacidosis) Gout 1523 surgical procedures), infections, gastrointestinal hemorrhage or iodinated contrast media) or mechanical trauma Gout may present atypically, resulting in delays in diagnosis and treatment In postmenopausal women and the elderly, gout may be polyarticular at onset,6 and if left untreated, may become chronic, mimicking rheumatoid arthritis Gout also tends to occur in already pathological joints (e.g Heberden’s nodes) and may also co-exist with septic arthritis Inter-critical Gout Seven percent of subjects have only attack of gout: these subjects tend to have a mildly elevated serum uric acid levels (Ͻ 420 mol/L (8 mg/dL)) and normal urinary uric acid excretion The majority of subjects have recurrent attacks of gout, usually recurring within years of the first attack With increasing urate deposition in affected joints, attacks increase in duration, frequency and severity, become polyarticular and resolve more gradually Patients remain well between attacks Chronic Gout If untreated, gout eventually becomes chronic rather than episodic because of increasing urate deposition in joints Chronic gout is characterized by a low-grade inflammatory arthritis punctuated by acute attacks Tophi are often present Extra-articular Involvement If untreated, after 20 years, 55–72% of patients with gout will develop tophi and 30% will develop nephrolithiasis Tophi are due to deposition of urate in the skin, and appear as yellow or chalky white, firm nodular or fusiform swellings, developing after an average of 11.6 years (range 3–42 years) of gout They are related to the degree and persistence of hyperuricemia, and are therefore a marker for more severe disease Tophi are classically found over the helix of the ear, but are found more commonly over the toes and fingers They contribute to the destructive arthritis of chronic gout, may ulcerate, become secondarily infected, and may occur in unusual sites (e.g spinal cord, myocardium, eye) Tophi can be differentiated from rheumatoid nodules by their distinctive yellow or chalky white discolouration, or 1524 A Clinical Approach to Medicine by demonstrating the typical negatively birefringent needle-shaped crystals of monosodium urate in material aspirated from a tophus Urate deposition in the kidney may occur in the interstitial medullary tissue, resulting in urate nephropathy, or in the tubules, pelvis or ureter, resulting in uric acid calculi or acute uric acid nephropathy Urate nephropathy is characterized by deposition of urate crystals in the medulla with a distinctive giant cell reaction on renal biopsy, and may be associated with mild albuminuria Although a distinct entity, urate nephropathy is not thought to have a significant effect on renal function Uric acid calculi are present in 10–20% of subjects with primary gout, related to the degree of hyperuricemia and urinary uric acid excretion In patients with secondary gout, particularly related to rapid tumor lysis from cytotoxic drug use, uric acid calculi may develop in up to 40% of subjects Acute uric acid nephropathy also occurs in this setting, with precipitation of uric acid in the distal tubules and collecting ducts (the site of maximal urinary acidification and concentration) Calcium containing stones, particularly calcium oxalate, are 20–30 times more common in patients with gout Associated Conditions Hyperuricemia and gout are associated with several conditions Insulin resistance has been associated with hyperuricemia, and may contribute to the association of gout with cardiovascular disease Hyperinsulinemia and insulin resistance occur in 95% and 76% of patients with gout respectively.3 Obesity is associated with dietary excesses, which in turn predispose to hyperuricemia and gout in both Caucasian and Chinese populations Hyperlipidemia, most commonly hypertriglyceridemia, is also associated with gout, and may be related to insulin resistance3 or reduced activity of lipases Hypertension is present in up to a third of patients with gout, and may be associated with gout in several ways Diuretic therapy for hypertension causes hyperuricemia and so predisposes to gout; hypertension per se reduces renal urate excretion, possibly through a reduction in renal blood flow; renal deposition of microtophi may cause renal damage leading to renal hypertension; and excessive alcohol intake predisposes to both hypertension and gout Ethanol increases uric acid production by increasing adenosine triphosphate turnover and decreasing renal uric acid excretion In a hospital-based Gout 1525 series of patients with gout in Singapore, hypertension was found in 36%, hyperlipidemia in 25%, ethanol consumption in 44% and ischemic heart disease in 13% of patients Hyperuricemia has been associated with cardiovascular disease and increased cardiovascular and all-cause mortality For example, in a prospective study of 49 413 Japanese male railroad workers, subjects with serum uric acid exceeding 505 mol/L (8.5 mg/dL) was associated with an increased relative risk (RR) of death from all causes (RR 1.62), coronary heart disease (RR 1.52), stroke (RR 2.33), hepatic disease (RR 3.58) or renal failure (RR 8.52), when compared with subjects with serum uric acid levels of 300 to 380 mol/L (5.0 to 6.4 mg/dL) This observation is not surprising, given the associations of hyperuricemia with known risk factors for cardiovascular disease It is however unclear if hyperuricemia is merely a marker for these risk factors or itself is an additional, independent risk factor, as several large epidemiological studies have yielded conflicting results In practice, patients with hyperuricemia should be assessed for presence of cardiovascular risk factors and managed accordingly DIFFERENTIAL DIAGNOSIS The diagnosis of gout should be considered in the setting of an acute monoarthritis or episodic mono- or oligo-arthritis Acute Monoarthritis Gout often first presents as an acute inflammatory monoarthritis In this setting, the differential diagnosis7 encompasses other crystal arthropathies (e.g pseudogout), and most importantly, septic arthritis Diagnostic joint aspiration is the investigation of choice Synovial fluid should be sent for cell and differential counts, polarized light microscopy, gram stain and pyogenic culture As acute gout is uncommon in premenopausal women and patients with rheumatoid arthritis, an acute monoarthritis in these settings is more likely to be due to septic arthritis Acute monoarthritis of the metatarsophalangeal joint of the big toe is rarely due to septic arthritis and may be treated with NSAIDs, with joint aspiration reserved for cases that not respond to treatment In acute gout, examination of synovial fluid from an inflamed joint yields intracellular, negatively birefringent needle-shaped crystals in synovial fluid 1526 A Clinical Approach to Medicine (typical of MSU) in virtually all patients.4 The presence of extracellular MSU crystals is not specific for gout, as they are seen in 5% of subjects with AH and up to 20% of subjects with renal failure with no history of arthritis Cell counts in acute gout may exceed 50 000/mm3 and show a neutrophil predominance, a pattern commonly seen in septic arthritis As gout and septic arthritis can co-exist, a patient with gout who fails to respond to therapy should be re-evaluated for septic arthritis History of Episodic Mono- or Oligoarthritis Patients are usually well between attacks of gout If evaluated between attacks, the diagnosis of gout is suggested by the typical history of episodic mono- or oligoarthritis affecting lower extremity joints, and confirmed by the presence of negatively birefringent crystals typical of MSU on aspiration of a joint or tophus In patients who have not received urate lowering therapy, examination of synovial fluid from an asymptomatic but previously inflamed knee joint yields typical MSU crystals in up to 97% of cases, while synovial fluid from a previously unaffected knee joint yields MSU crystals in up to 22% A lower yield of MSU crystals is found in patients previously treated with urate lowering medications Recurrent self-limiting attacks of first MTP arthritis are typical of gout, and generally not require joint aspiration INVESTIGATIONS Investigations are useful to confirm the diagnosis of gout, and to determine the cause of hyperuricemia The diagnosis of gout is established by demonstrating (using polarized light microscopy) the negatively birefringent needle-shaped crystals typical of MSU in synovial fluid Elevated serum urate levels are suggestive but not diagnostic of gout, as uric acid levels may be normal in up to 25% of proven cases of acute gout, and are often raised in patients with arthritis from causes other than gout Serum urate levels do, however, reflect the severity of tissue urate deposition, and are therefore useful in titrating the dose of urate lowering therapies Investigations to determine the cause of hyperuricemia should include a full blood count (raised cell counts suggest myeloproliferative disorders and a raised mean corpuscular volume suggests alcohol use) and a serum creatinine level (raised in renal failure) Other investigations Gout 1527 to determine the cause of hyperuricemia should be guided by clinical evaluation (Table 2) and might include thyroid function tests, serum calcium levels and urine lead levels etc It is often helpful to determine if the hyperuricemia is due to uric acid over-production or under-excretion by performing a 24-hour urinary uric acid collection while the subject is on a low purine diet.8 Overproducers of urate have a 24-hour urinary urate excretion of Ͼ 4.5 mmol while on a low purine diet, and a normal or increased urinary urate clearance (normal value to 14 mL/min).8 A specific enzyme defect can however be identified only in a minority of these patients.9 Underexcretors of urate have a 24-hour urinary urate excretion of Ͻ mmol on a low purine diet,8 a low urate clearance or a urate/ creatinine ratio of Ͻ 0.07 Other than soft tissue swelling during acute gout, radiographic features of gout usually develop after to years of disease Eccentric soft tissue prominences due to deposition of urate in soft tissue may be seen Erosions are due to tophus or pannus formation, and are typically punched out, with sclerotic margins, an overhanging margin of bone, and may be intra-, peri- or non-articular Other radiographic features include the relative preservation of joint space and lack of periarticular osteopenia An intravenous urogram or sonographic evaluation is needed to identify urate calculi, which are radiolucent TREATMENT The aims of treating gout are to abort acute attacks rapidly, prevent recurrent attacks of gout and prevent or reverse complications of urate deposition in the joints and kidneys Effective treatments are available for gout Modification of dietary habits and reversible causes of hyperuricemia apply in the treatment of all patients Pharmacological therapies are tailored to treat the acute attack, to prevent attacks and to lower serum urate concentrations Modification of Diet and Reversible Causes of Hyperuricemia Dietary modification alone may lower serum urate levels by 60–120 mol/L3,5 and may reduce the frequency of gouty arthritis.10 General measures to reduce hyperuricemia include reduction in dietary purines, treatment of obesity, cessation of alcohol and drugs associated 1528 A Clinical Approach to Medicine with hyperuricemia and control of co-existing hypertension Traditionally, dietary advice in patients with gout has emphasized a low purine/protein diet Table lists foods with high and low purine content Patients are generally advised to avoid organ meats, excessive amounts of meat and seafood, and should be informed that consuming large amounts of food with low purine content may result in a higher purine load than consuming small amounts of food with high purine content The value of this traditional low purine diet in gout has been called into question recently.3 Low purine diets tend to be rich in carbohydrates and saturated fat,3 which worsen insulin resistance in subjects with concomitant gout and insulin resistance Increasing insulin resistance leads to higher serum insulin levels, which in turn result in increased serum urate levels by increasing renal resorption of urate Interestingly, in a pilot study in 13 male patients with gout, a diet designed to lower insulin resistance and reduce weight (1600 kcal/day, 40% from carbohydrates, 30% each from protein and fat) but with no restriction in purine-rich foods reduced both serum uric acid levels and the frequency of gouty arthritis.10 Asymptomatic Hyperuricemia AH itself does not cause a decline in renal function, and treatment of AH with urate lowering drugs does not protect against development of renal insufficiency.4 The aim of treating AH is to reduce the risk of developing gout by correcting reversible causes of hyperuricemia (Table 2) using non-pharmacological interventions Urate lowering drugs (usually Table Purine Content of Common Foods Moderate/High Purine Content Meats in excess, especially organ meats and seafood Yeast and meat extracts Alcoholic beverages Legumes: beans, peas, lentils, oats Spinach, mushrooms, asparagus, cauliflower Low Purine Content Fruits Lettuce, green vegetables (other than those listed above) Cereals and cereal products (e.g bread) Dairy products Eggs Gout 1529 allopurinol) should only be considered if there is a high risk of urate nephrolithiasis (i.e when 24-hour urinary uric acid excretion exceeds 6.5 mmol/day and serum uric acid persistently exceeds 600–720 mol/L), especially in the context of decreased renal function.4 In other situations, the adverse effects of urate lowering drugs outweigh the benefits Treating the Acute Attack Non-pharmacological treatments include resting and cooling the affected joint/s In an unblinded, randomized trial of 19 patients with acute gout, application of ice packs for 30 minutes, times a day to affected joints lead to greater reduction in pain and joint swelling than was seen in a control group who received identical medications but did not use ice packs Pharmacological treatments (Table 4) include the options of nonsteroidal anti-inflammatory drugs (NSAIDs), oral colchicine or corticosteroids (oral or intra-articular) The choice of which drug to use depends on the risk to benefit ratio in a particular patient NSAIDs improve symptoms within day and are the treatment of choice if not contraindicated (Table 4), or if the patient is not at high risk of developing a peptic ulcer (i.e age Ͻ 75 years; no past history of peptic ulcer disease, gastrointestinal bleeding or cardiac disease; no concomitant steroid or anti-coagulant use; and no functional disability) Oral colchicine or corticosteroids may be used if NSAIDs are contraindicated Colchicine is effective in 90% of patients if used within 24 hours of the onset of an attack, and in 75% of patients if used after more than 24 hours.11 It relieves pain in most patients within 18 hours of ingestion, but the majority of these patients develop diarrhea within 24 hours of taking colchicine Because of this narrow therapeutic index compared with NSAIDs, colchicine should only be used when NSAIDs are contraindicated Intravenous colchicine is highly effective in the treatment of gout but has potentially fatal sideeffects, and should only be given by those experienced in its use It is important to remember that both colchicine and NSAIDs are contraindicated in patients with renal or hepatic insufficiency and in the very elderly In such patients, corticosteroids may be used When or joints are affected, intra-articular corticosteroids provide rapid relief of symptoms and avoid the need for oral corticosteroid administration When more than joints are affected, a short course of oral corticosteroids (0.25 to 0.5 mg/kg/day depending on the severity of the attack and the health of Medication/Dosage Adverse Effects Contraindications Pharmacokinetics Comments Non-steroidal antiinflammatory drugs (NSAIDs) Peptic ulcer disease, renal insufficiency Peptic ulcer disease, renal, liver, cardiac failure Varies among NSAIDs Treatment of choice for acute gout Colchicine Acute attack: mg initially, then 0.5 mg every to hours till pain is relieved, a total of mg has been administered or GI symptoms develop Maximum of 10 mg/ week of colchicine Prophylaxis: 0.5 to 1.0 mg/day Vomiting, diarrhea, hemorrhagic gastroenteritis, bone marrow suppression, confusional state, seizures, myopathy, alopecia Renal or hepatic dysfunction (decreased clearance of colchicine leads to accumulation and toxicity) Inhibits phagocytosis of urate crystals by neutrophils Hepatic and renal excretion; Long half life (because of enterohepatic circulation) Increased toxicity if drugs inhibiting cytochrome p-450 are taken concomitantly Myopathy may be more common with concomitant use of statins or cyclosporin Allopurinol 100 to 800 mg/day as a single dose (as half-life of oxypurinol is 30 hrs) Rash in 3%, at times heralding Allopurinol Hypersensitivity syndrome (see text) Marrow suppression may result if used with Azathioprine and 6-mercaptopurine Inhibits xanthine oxidase Metabolized to oxypurinol, which also inhibits xanthine oxidase Allopurinol allergy is increased 10-fold in penicillin allergic patients Maximum effect on urate levels seen after 4–14 days Oxypurinol excretion increased by uricosuric agents Renal and hepatic toxicity (rare) 1530 A Clinical Approach to Medicine Table Medications Used in the Treatment of Gout Probenicid (half-life 6–12 hrs) Start with 250 mg bd, increasing to 0.5 to 1.0 gm tds Urate renal calculi, gastrointestinal symptoms, rarely peptic ulceration, hemolytic anemia (if G6PD deficient) Overexcretors (urate calculi formation) History of renal calculi Uricosuric Drug interactions (see text) Salicylates decrease effectiveness Reduce dose if 24-hr urate excretion Ͼ 4.5 mmol/day to prevent urate calculi Ineffective if creatinine clearance Ͻ 50 mL/min Sulfinpyrazone (half-life 3–6 hrs) Start at 50 mg bd, increasing to 100 mg tds- qds Maximum dose 800 mg/day Nausea, vomitting, leucopenia, interstitial nephritis Overexcretors (urate calculi formation) History of renal calculi Potent uricosuric Also inhibits platelet function, preferred uriscouric in patients with coronary artery disease Ineffective if creatinine clearance Ͻ 50 mL/min Benzbromarone 40–200 mg/day (half-life hrs) Diarrhea Potent uricosuric Effective if creatinine clearance Ͼ 20 mL/min, used in transplant gout Limited availability Gout 1531 1532 A Clinical Approach to Medicine the patient, given in divided doses) with a rapid taper over to weeks once the acute attack is subsiding is generally effective Practice Points in Treating an Acute Attack Medications are most effective in reducing inflammation when given early in the course of an attack, and should be given as soon as acute gout is suspected If a patient is on urate-lowering drugs when an acute attack occurs, these drugs should not be ceased, as the resultant rise in urate levels may worsen or prolong the acute attack If a patient is not on urate-lowering drugs when the acute attack occurs, these drugs should only be started two weeks after an acute attack has subsided, as the fall in urate levels which occurs when urate-lowering therapy is initiated may worsen or prolong an acute attack Attacks of gout, which are refractory to one of these medications, often improve with the addition of a second medication.12 The combination of NSAIDs and oral corticosteroids should be used with caution, especially in the elderly, because this combination carries a 15-fold increased risk of peptic ulceration in the elderly If the acute attack does not show signs of subsiding after 48 hours of treatment, the patient should be re-evaluated for other possible conditions mimicking an acute gouty flare, especially septic arthritis and other crystal arthropathies Acute attacks of gout may be prevented by reducing urate deposition in joints through the use of urate-lowering drugs Urate-lowering drugs are indicated for the prevention of acute attacks if these occur frequently (some authorities suggest Ͼ times per year) or severely affect a patient’s lifestyle Preventing Attacks (Prophylaxis) Both colchicine and low dose NSAIDs are effective in preventing recurrent attacks of gout Colchicine is thought by some authors to have less adverse effects than NSAIDs with long-term use, and is less costly, but no comparative studies have been performed to date Attacks of gout are prevented by colchicine 0.5 mg once a day in 27% of patients, by colchicine 0.5 mg twice a day in an additional 63% of patients and by colchicine 0.5 mg three times a day in the remaining 10% of patients.13 A combination of colchicine and NSAIDs may be useful if attacks persist while on either drug The initiation of urate-lowering therapy increases the frequency of gouty attacks in 10–24% of subjects Prophylactic colchicine or NSAID therapy is often given to prevent these attacks The optimal Gout 1533 duration of such therapy is unclear, but most authors recommend a period of 6–12 months, as acute attacks generally cease 6–12 months after the serum urate level has normalized Lowering Serum Urate Concentrations Urate-lowering drugs act by reducing uric acid production (allopurinol) or increasing urate excretion (uricosuric agents, e.g probenecid, sulfinpyrazone, benzbromarone) The resultant fall in serum urate favors dissolution of monosodium urate crystals in joints and other tissues, reducing the tissue load of urate and thus the frequency and severity of attacks of gout Urate-lowering drugs are indicated in the presence of tophi, recurrent urate renal calculi, urate nephropathy or frequent attacks of gout (Ͼ per year) Clinical experience suggests that attacks of gout cease after 6–12 months when the serum uric acid level is kept below a target level of 360 mol/L A target serum uric acid level of less than 300 mol/L is generally necessary for resorption of tophi In general, uricosuric agents should be used in subjects who under-excrete uric acid, and allopurinol in subjects who over-produce uric acid, who have renal impairment or uric acid renal calculi or in whom urate levels are elevated despite treatment with uricosurics Uricosurics are generally started in low doses to minimize the risk of urate calculi associated with increased urate excretion This risk can be further reduced by alkalinizing the urine (e.g with mist sodium bicarbonate or Shohl’s solution) and maintaining adequate urine flow by ingesting у L of fluids a day By reducing the transport of other organic acids across cell membranes, probenicid increases serum levels of penicillins, indomethacin, sulphonylureas, heparin, dapsone, rifampicin and reduces serum levels of allopurinol.14 Aspirin was previously thought to negate the uriscouric effect of probenecid, but more recent data has shown that the addition of aspirin 325 mg per day in subjects taking stable doses of probenecid did not significantly influence serum or urinary urate levels Allopurinol is associated with a rare but often fatal allergic reaction termed the allopurinol hypersensitivity syndrome (AHS) This syndrome is characterized by fever, a rash (toxic epidermal necrolysis, erythema multiformae or generalized exfoliative dermatitis), eosinophilia, leucocytosis, hepatitis, worsening renal function, other visceral involvement and vasculitis, and typically develops after weeks 1534 A Clinical Approach to Medicine (range 1–728 days) of allopurinol use It is fatal in up to 27% of patients, and is more common in patients with renal insufficiency, possibly due to the accumulation of oxypurinol It has therefore been suggested (but not universally accepted) that allopurinol doses should be adjusted for renal function (100 mg/day if creatinine clearance is 30 mL/min, 200 mg/day if creatinine clearance is 60 mL/min and 300 mg/day if creatinine clearance is 100 mL/min) Allopurinol should be ceased in patients who develop a drug rash Desensitization of patients with allopurinol allergy has been successfully performed, but should only be attempted if other options to lower urate levels have failed In Singapore, AHS-related mortality occurred in 13% of patients in one series, and the indication for allopurinol use was unclear in over 50% of subjects with AHS In practice, hyperuricemia in many patients is due to the combination of over-production and under-excretion of urate In this situation, allopurinol is effective in lowering serum urate levels Urate-lowering therapy should be continued in patients whose symptoms have been controlled by such therapy Cessation of urate-lowering therapy in 21 patients with tophaceous gout whose tophi had resolved with such therapy, resulted in the recurrence of gout and tophi in 17 and patients respectively after a mean of 19 months (range 4–52 months) and 38 months (range 4–107 months) respectively Extra-articular Manifestations Tophi, depending on their size, generally resolve over or more months with maintenance of serum urate levels below 300 mol/L Surgical removal of tophi is generally inadvisable, and in a series of 45 patients, was associated with delayed wound healing (Ͼ week) in 50% of patients, especially those with infected tophi at the time of surgery Urate nephropathy at times improves with urate-lowering therapy Acute uric acid nephropathy can be prevented by prophylactic administration of allopurinol before chemotherapy is given; in the event that acute uric acid nephropathy still develops, hemodialysis is preferred to peritoneal dialysis as the former is 10–20 times more effective in removing uric acid from the circulation Urate calculi are treated with allopurinol (which decreases urinary uric acid excretion), hydration and alkalinization of urine to a pH of 6.0 to 6.5 Gout 1535 Indications for Specialist Evaluation Gout is common, and the vast majority of patients can be managed by primary care physicians Referral for specialist evaluation may be required if attacks of gout persist despite standard therapy, if renal impairment or renal calculi are present, or if a secondary cause for hyperuricemia (e.g a myeloproliferative disorder) is identified SPECIFIC CLINICAL SITUATIONS Gout in the Elderly Gout in the elderly may present atypically,15 with a higher prevalence of polyarticular gout, a propensity to affect the small joints of the hands, and a higher rate of occurrence in females These features, if associated with the ongoing low-grade inflammation seen with long-standing gout, may mimic late-onset rheumatoid arthritis Other atypical features are the early development of tophi in unusual locations (especially the finger pads), a strong association with diuretic use and the development of gout in preexisting osteoarthritis of the hands In elderly patients with gout, colchicine is favored over NSAIDs because the latter have increased side effects in this age group, especially GI bleeding.9 Allopurinol should be used with caution in the elderly if renal impairment is present, because of the increased risk of developing the allopurinol hypersensitivity syndrome Gout in the Young (Onset Ͻ 30 Years of Age) and in Premenopausal Women The development of proven gout in these groups of patients suggests the presence of a genetic defect leading to increased purine production or decreased renal excretion of uric acid.9 A family history of gout is found in 50% with onset under 25 years of age and in 80% with onset between 12 and 19 years of age Early identification of these subjects is useful, as treatment may prevent joint and renal damage Transplant Gout Post-transplant hyperuricemia and gout are related to diuretic use and cyclosporin-mediated inhibition of uric acid excretion They are common 1536 A Clinical Approach to Medicine after renal and cardiac transplants but are uncommon after liver transplants.12 Transplant gout may be severe and rapidly progressive, with polyarticular involvement and early development of tophi, which classically appear like drops of chalky material under the skin (“liquid tophi”) NSAIDs and colchicine (if not contraindicated because of renal impairment) may be used to treat acute attacks Urate-lowering therapy is often required, and is complicated by resistance to uricosuric agents (due to cyclosporin or renal disease) and marrow suppression related to allopurinol inhibition of azathioprine metabolism Benzbromarone may be the drug of choice in such situations, as leucopenia is common with allopurinol therapy even if the azathioprine dose in such patients is reduced by two-thirds (as is generally recommended) ACKNOWLEDGMENTS The author would like to thank SRN Thio Szu-tien and Ms Wee Hwee Lin for thoughtful comments on the manuscript REFERENCES Kelly WN, Schumacher HR, Gout, in: Textbook of Rheumatology, Kelly WN, Harris ED, Ruddy S, Sledge CB (eds.), Philadelphia, pp 1291–1336, 1993 Wortmann RL, Gout and hyperuricemia, Curr Opin Rheumatol 14:281–286, 2002 Fam AG, Gout, diet and the insulin resistance syndrome, J Rheumatol 29:1350–1355, 2002 Kelly WN, Wortmann RL, Hyperuricemia, in: Textbook of Rheumatology, Kelly WN, Harris ED, Ruddy S, Sledge CB (eds.), Philadelphia, pp 498–506, 1993 Emmerson BT, The management of gout, New Eng J Med 334:445–451, 1996 Annonymous, Lancet: 703–704, 1993 Hudson NP, Acute monoarticular arthritis, in: Diagnostic Strategies for Common Medical Problems, Robert J Panzer, Edgar R Black, Paul F Griner (eds.), American College of Physicians, Philadelphia, PA, PP 318–324, 1991 Emmerson B, Identification of the causes of persistent hyperuricemia, Lancet 337:1461–1464, 1991 Dieppe PA, Investigation and management of gout in the young and elderly, Ann Rheum Dis 50:263–266, 1991 10 Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J, Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased Gout 1537 proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study, Ann Rheum Dis 59:539–543, 2000 11 Aherns MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M, Does colchicine work? The results of the first controlled study in acute gout, Aust N Z J Med 17:301–304, 1987 12 Rosenthal AK, Ryan LM, Treatment of refractory crystal-associated arthritis, Rheum Dis Clin North Am 21:151–161, 1995 13 Wallace SL, Singer JZ, Therapy in gout, Rheum Dis Clin North Am 14:441–457, 1988 14 Fox IH, Antihyperuricemic drugs, in: Textbook of Rheumatology, Kelly WN, Harris ED, Ruddy S, Sledge CB (eds.), Philadelphia, pp 822–831, 1993 15 Agudelo CA, Wise CM, Crystal-associated arthritis, Clin Geriatr Med 14:495–513, 1998 This page intentionally left blank 87 Osteoarthritis Colleen Kim Thomas DEFINITION AND INTRODUCTION Osteoarthritis (OA) refers to the joint condition of degenerative articular cartilage damage Some favor the term osteoarthrosis to reflect the generally non-inflammatory nature of the condition Others prefer the phrase degenerative arthritis, since the prefix osteo- has little meaning with regard to descriptive value of the pathological process In terms of disease burden, it is by far the most common joint disorder and is a major cause of pain and poor mobility in the geriatric population At least one-third of those above 65 are affected radiologically The weight bearing joints, mainly knees and hips, as well as finger joints, have a propensity to be affected Lumbar or cervical spondylosis refer to OA affecting the facet or apophyseal joints of the low back and neck respectively Spinal degenerative disease, however, is a large topic by itself that is outside the scope of this chapter and will not be discussed 1539 1540 A Clinical Approach to Medicine Table Secondary Causes of Osteoarthritis Post injury Chronic overuse Joint dysplasias Hypermobility Hemarthrosis, e.g hemophilia Post-inflammatory damage: 1) Inflammatory arthropathies, e.g rheumatoid arthritis 2) Septic arthritis 3) Crystal arthropathies, e.g gout, pseudogout Osteonecrosis (avascular necrosis) Osteochondritis Endocrine disorders affecting bone growth, e.g acromegaly Metabolic disorders leading to abnormal joint deposition, e.g hemachromatosis, ochronosis, mucopolysacharidoses CAUSES OA may be “primary”, that is, degenerative change that is consistent with age, and predisposed to by genetic differences in collagen quality, obesity and usage, or “secondary”, that is accelerated by a superimposed pathological process or traumatic event that leads to premature cartilage loss (Table 1) RISK FACTORS FOR PRIMARY OSTEOARTHRITIS The most simplistic consideration of primary osteoarthritis would be age-related cartilage degeneration worsened by abnormal loading such as increased use and body mass However, striking epidemiological/ gender specific differences in incidence, age of onset and joints affected indicate genetic/hormonal factors affecting cartilage resistance to degradation Age OA prevalence increases markedly with age; from 1% in those under 30 to over 30% of those above 65 years.1 Osteoarthritis 1541 Obesity Correlation of obesity with osteoarthritis is well demonstrated especially for knee OA Occupation Jobs entailing overuse of a particular joint will predispose to OA Sportsmen fall in this group and may have secondary OA from injury as well Another well-quoted example is that of jackhammer operators suffering OA in the elbow, a joint uncommonly affected to a significant degree Gender/estrogen status The pre-menopausal privileged status of estrogen adequacy, besides preserving the heart and bone density, is also protective to joints OA occurs more frequently in women in the post menopausal age group compared to men of similar age, and more so in those not on estrogen replacement therapy.2 Women tend to have more joints affected, and generalized OA is also more common in women Overall prevalence is equal for males and females because of an excess of males in the younger age group contributed by post-traumatic causes, whereas females in the postmenopausal age group outnumber males of a similar age OA of the knees is more common in women, while hip OA is more common in men Joint dysplasia Genu varum or valgum, slipped capital femoral epiphysis, Perthes disease, acetabular dysplasia are all causes of secondary OA However undetected minor subclinical degrees of these conditions may be responsible for some cases designated idiopathic or primary hip OA Race Hip osteoarthritis is rare in Southern Chinese3 and Africans, thought to be related to the rarity of congenital hip disorders, slipped upper femoral epiphysis and Perthes’disease in these populations 1542 A Clinical Approach to Medicine Hypermobility Patients with various degrees of hypermobile joints are predisposed to OA later in life, due to cartilage damage caused by minor degrees of frequent subluxation Family history Generalized osteoarthritis is noted to run in families OA of the hands has a heritability of up to 65%4 and is considered a familial disease with a polygenic inheritence Bone density Patients with osteoarthritis have higher bone density than those without One reason could be that obesity predisposes to OA but has a positive effect of bone mass PATHOGENESIS OF OSTEOARTHRITIS From a simplistic understanding of OA being caused by chronic mechanical stress leading to cartilage disintegration, there has been a surge of research in recent years towards the elucidation of the complex degenerative cascades at molecular level Normal cartilage tissue consists of chondrocytes which are embedded within the extracellular matrix they secrete Matrix components comprise collagen and proteoglycans chief of which is aggrecan Proteoglycans have the property of retaining water due to their content of chondroitin sulphate and keratan sulphate and are responsible for resistance to loading and shock-absorbing properties Proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-(TNF-␣), prostaglandins, free radicals and damaged matrix components are released from chondrocytes and synovial cells as a result of cartilage damage.5 These trigger the synthesis of the cartilage degrading proteinases upon binding to specific chondrocyte receptors These enzymes belong mainly to the zinc containing matrix metalloproteinase (MMP) family A major player in this family is the MMP aggrecanase The other group of important proteinases are the cathepsins Osteoarthritis 1543 Natural inhibitors of these proteinases (tissue inhibitor of metalloproteinases TIMP) keep this process in check In OA, there is a shift towards increased cartilage degradation, due to factors such as chronic joint pressure increase, hormonal changes after menopause, as well as age-related changes in chondrocyte metabolic activities There is some evidence that limited cartilage repair activities take place in OA affected joints, mediated by growth factors produced by chondrocytes, synovial cells and subchondral bone These are all being intensely studied in the hope of identifying the pathways to switching off cartilage degradation and promoting cartilage synthesis, thus moving towards a true cure for OA at the molecular level PATHOLOGY OF THE OA JOINT With micro-injury caused by inordinate stresses and age related chondrocyte changes, cartilage quality declines The damaged cartilage retains water and swells Microfissures appear, which deepen and are manifested as surface fibrillation, the first obvious arthroscopic feature in early OA Loose bodies may result from fragments that become totally detached The defect left by the loss of these fragements may give rise to periarticular microcysts Closer apposition of bony surfaces causes subchondral sclerosis The final outcome of this process is ulceration to the underlying bone Besides cartilage changes, there is also ligamentous strain and bursitis from deranged joint biomechanics Mild synovial inflammation with lymphoplasmocytic and histiocytic infiltration is also found Degenerative ligamentous and meniscal tears can occur Osteophytosis occurs in areas of increased biomechanical strain in the weakened joint THE CASE FOR AN INFLAMMATORY COMPONENT IN OA Joint fluid analysis, while generally non-inflammatory, with cell counts less than 200/mm3, may be mildly inflammatory with counts up to 2000/mm.3 This, together with the fact that some cases respond to intraarticular steroid injection and/or NSAID use, is indicative of a minor 1544 A Clinical Approach to Medicine inflammatory component in at least some cases Synovial hypertrophy is found in nearly 3/4 of patients, and is also presumed to be an inflammatory response In cases where there seems to be an increased inflammatory component, hydroxyapatite crystal-induced inflammation may play a role Calcium hydroxyapatite, being visible only by electron microscopy, does not figure in the routine detection of crystal arthropathy using conventional polarizing light microscopic techniques; however this type of crystal arthropathy may account for mildly inflammatory cases diagnosed as osteoarthritis The role of inflammatory cytokines in perpetuating osteoarthritic joint destruction is recent thinking that is different from traditional concepts of a purely passive mechanical joint degradation However, still the basic pathological starting point of cartilage degeneration caused by mechanical injury beyond the tensile strength of cartilage still holds The local nature of the disease is evidenced by the lack of constitutional symptoms and markers of systemic inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) PATTERN OF JOINT INVOLVEMENT IN OA Primary OA affects the following joints in a bilateral fashion: 1) Knees 2) Hips 3) Hands: distal interphalangeal, proximal interphalangeal joints, carpometacarpal joints of the thumb 4) Feet: metatarsaophalangeal joint of the big toe 5) Spine: facet joints of the cervical and lumbar spine Involvement of other joints is to be regarded as atypical and secondary sources should be sought; e.g post traumatic ankle OA, rheumatoid shoulders, calcium phosphate dihydrate deposition in wrists HAND OA Middle-aged women are usually affected, who present with pain and bony hard swelling of the distal interphalangeal joints called Heberden’s Osteoarthritis 1545 nodes, and/or proximal interphalangeal joints called Bouchard’s nodes Involvement of the carpometacarpal joint of the thumb produces a characteristic squaring of the hands Cystic outpouchings along the joint line may be seen which when aspirated yield a clear viscous joint fluid This type of OA has a familial tendency Occasionally, there may be a fairly rapid progression of these joint changes within months, beyond what can be explained by chronic wear and tear alone This has been termed “inflammatory OA” by some, although there is no evidence of acute phase reactant elevation Deformities that develop not uncommonly get misconstrued as rheumatoid arthritis This little understood process may well constitute a separate subset of OA SYMPTOMS Pain The main and eventually most disabling symptom in OA is the pain that develops gradually often over years The joint pain is worsened by using the involved joints and relieved by rest For hip and knee osteoarthritis, pain might be exacerbated on prolonged standing and walking, and especially using stairs Pain at rest and night symptoms are not typical, but suggest an inflammatory, septic or neoplastic lesion There has been much research and postulation as to the genesis of pain in OA Subchondral microfractures have been demonstrated, as well as venous congestion and increased intraosseus pressure Osteophyte irritation of nerve endings and direct periosteal loading due to cartilage denudation are other possibilities The pain from hip arthritis is generally located in the groin and may radiate to the anterior thigh or knee Pain over the lateral aspect of the hips, however, comes from local causes like trochanteric bursitis and not the hip joint itself Radicular distribution of pain, weakness and numbness caused by foraminal stenosis from osteophytes at facet joints in lumbar spondylosis can mimic hip OA Furthermore radiographs in the elderly may reveal degeneration in both regions It is important to distinguish the two especially where surgical intervention is planned, since imaging abnormalities 1546 A Clinical Approach to Medicine alone may not correlate with symptoms Hip pain generally does not radiate below the knee and is reproduced during range of movement testing Pain on spinal movements and neurogenic claudication point to a spinal pathology A sudden increase in pain in an osteoarthritic joint may be due to an acute event such as osteonecrosis An area of localized pain could be from bursitis caused by abnormal joint mechanics, such as anserine bursitis of the knee and trochanteric bursitis of the hip These should be identified and separately managed, with much relief obtained from intrabursal steroid injections as discussed in the treatment section Stiffness Stiffness in the early morning, or after a period of rest and relieved by activity, is a hallmark of an inflammatory arthropathy OA patients can also have a similar experience of a transient nature, lasting a few minutes or seconds This is called the gel phenomenon More than 30 minutes of stiffness, however, suggests an inflammatory pathology Joint stiffness and pain of any pathology is often worse in cold and damp weather Instability Buckling of the knee, especially with steps, may occur due to ligament degeneration, pain or muscular deconditioning Locking This happens occasionally due to loose cartilage fragments or torn mensicus fragment jamming motion Limitation of Function Loss in the range of motion is apparent in hip and knee OA when squatting and sitting cross legged, postures frequently assumed in the daily lives of Asian patients, becomes difficult Dexterity in fine movements becomes affected in hand OA, especially when the first carpometacarpal or scaphotrapezoid joint are affected, making thumb opposition less efficient Osteoarthritis 1547 Fig An elderly lady with severe OA knees, joint remodeling and varus deformity Photograph courtesy of A/Prof Lo Ngai Nung, Dept of Orthopedic Surgery, Singapore General Hospital Motion restriction is thought to be due to osteophyte formation and joint surface remodeling Signs Deformity, typically, a varus deformity, occurs in the knee joint due to cartilage loss in the medial compartment (see Fig 1) Bony hard swelling, e.g nodal enlargement of finger joints and bony enlargement of the knee joint, is characteristic, and is caused by bone remodelling Tenderness occurs at joint margins and tendon attachments Limitation of movement is confirmed on passive range of motion testing Crepitus is palpated on passive motion Periarticular muscle wasting, typically the quadriceps for knee OA, is due to disuse Effusion and synovial thickening reflect a mild inflammatory reaction to the degenerative damage However, a markedly swollen and tender joint 1548 A Clinical Approach to Medicine may be due to crystal arthropathy or infection, both of which can occur on top of the degenerative process IMAGING Plain Radiography Medial joint narrowing Genu varus Fig Radiograph of OA knees showing osteophyte formation, subchondral sclerosis and medial joint space narrowing Radiograph courtesy of Mr John Chen, Dept of Orthopedic Surgery, Singapore General Hospital Features seen in OA are: • • Osteophyte formation or bony proliferation at joint margins This osteophytic lipping is a diagnostic feature of osteoarthritis Assymmetric joint space narrowing affecting the compartment exposed to greatest stress e.g lateral aspect of the hip joint, medial compartment Osteoarthritis 1549 • • • of the knee joint This feature is an indirect reflection or cartilage volume loss In contrast, the inflammatory arthropathies tend to affect joint spaces symmetrically Subchondral sclerosis caused by abnormal bone loading at areas of cartilage thinning Subchondral cyst formation with bony walls in the stressed area Alteration in the shape of bony ends caused by bony remodeling Views to request: • • • Weight bearing films especially of the knee joint reveal more information and should be requested rather than supine anteroposterior views Joint space narrowing and varus/valgus deformities may not be otherwise demonstrated Tunnel views through the knee joint are the alternative to best demonstrate abnormalities where the patient has difficulty standing Skyline views are used to demonstrate patellofemoral osteoarthritis There may not be correlation between the degree of bony abnormalities and symptoms Marked degenerative changes on radiographs may be associated with little pain and minimal changes and the reverse is also true There are many theories as to the cause of osteoarthritic pain, as discussed in the clinical features section Indications for joint replacement surgery must be based on symptoms and function rather than severity of bony changes Magnetic Resonance Imaging (MRI) Plain radiographs delineate pathology after significant bony changes have occurred in moderately advanced disease However, for soft tissue abnormalities, MRI is an excellent imaging modality that has revolutionized musculoskeletal imaging It is superior to CT in its image quality and capacity to select any plane.6 In selected cases of OA, MRI is indicated and can replace diagnostic arthroscopy in delineating pathology, especially in cases of increased pain or locking in knee OA This may be due to degenerative meniscal tears, which tend to occur in the posterior horn of the medial meniscus 1550 A Clinical Approach to Medicine INVESTIGATIONS Blood tests are unneccessary for the diagnosis of OA, which is can generally be made on clinical grounds supported by radiography Nevertheless, panel tests for joint pain that comprise rheumatoid factor, ESR and CRP are often ordered These should not be elevated in OA If ESR and CRP are raised and the clinical diagnosis of OA is clear, other causes should be sought A common mistake is to diagnose RA when the acute phase elevation is found in a patient with OA of the hands Similarly, low titre RA factor may be seen in the elderly and RA should not be diagnosed when there are no clinical features for this Synovial fluid analysis in OA should usually return a cell count of below 2000 cells/mm3, and is usually in the region of 200–300 cells/mm3 If higher cell counts are obtained, septic, crystal or inflammatory arthritis need to be excluded TREATMENT Weight Reduction This is often difficult as the severe OA patients have a limitation to the amount of exercise tolerated Major dietary changes may need to be made to address the low caloric demands of the sedentary lifestyle Physiotherapy and Occupational Therapy With increased pain on movement and excessive loading contributing to OA, it may seem surprising that exercise is recommended therapy for joint maintenance.7 A healthy neuromucular system provides 30% greater shock attenuation OA joints result in deconditioning and atrophy of associated muscles leading to greater loading on the joint An exercise programme can improve muscle bulk, mobility and stability Passive excercises such as quadriceps strengthening are combined with active low impact excercises, of which swimming is an excellent from, as the joint is supported in a weightless environment Stair climbing and jumping are considered to be activities of maximal joint stress and should be minimized Walking aids and knee guards for joint instability, wedged insoles to reduce medial compartment knee pressure, patella taping, splints for OA of the thumb can be provided by a trained occupational therapist Osteoarthritis 1551 The aim of all these efforts is to maximize function while the patient learns to tailor living activities to the capacity of the OA joint PHARMACOTHERAPY Treating OA pain can be a most difficult task for the clinician, who is faced with an indefinite chronic pain issue in a non-terminal patient who needs to be functional Often these individuals are compelled to take daily analgesics on a long term basis, not without complications, especially with NSAIDs Topical Agents Preparations such as topical NSAID gels and capsicum creams are useful in mild cases and can reduce the dosage of oral drugs needed Paracetamol This safe drug should be maximized as a first-line oral agent NSAIDs and Coxibs Non-steroidal anti-inflammatory agents (NSAIDs) prove superior in analgesic properties compared with paracetamol in some; as such, the clinician is often compelled to prescribe these on a long-term basis Peptic ulcers, gastrointestinal hemorrhage and nephropathy are known complications Before commencing these drugs, the patient should be clearly counselled as to the potential toxicities and to be alert for symptoms of melaena, hematemesis or epigastric pain A baseline creatinine and hemoglobin level is advisable NSAID’s should be avoided in significant renal impairment Appropriate measures to reduce the adverse effects of NSAIDs include: emphasizing to the patient to use them only when absolutely necessary; minimizing the amount prescribed to the patient each visit, cycling the drugs with parecetamol, narcotics and drug-free days, and prescribing them with a H2 blocker, proton pump inhibitor or misoprostol The use of antacids has no protective value against peptic ulcers It is important to obtain a detailed drug history, as often patients have visited several practitioners and are unknowingly consuming multiple NSAIDs 1552 A Clinical Approach to Medicine The new generation of selective COX-2 inhibitors (COXibs) are less toxic to the gastrointestinal tract but are much more costly Narcotic Analgesics Drugs such as codeine phosphate provide a stronger analgesic effect than paracetamol Constipation, sedation and tolerance are effects that must be monitored, especially in the elderly Tramadol is useful agent in pain management with the advantage of less likelihood of tolerance Glucosamine and Chondroitin Sulphate Manufacturers claim that these molecules8,9 build up cartilage by providing the building blocks of matrix conponents It has not been proven by radiolabelled studies that they are actually absorbed as an intact molecule or localize to the diseased joint However, glucosamine has been shown to decrease the joint space narrowing These are classified as nutritional supplements and thus can be bought over the counter As these are not controlled drugs, the quality and drug content of different brands vary widely They are well-tolerated and both topical and oral preparations have been shown to reduce pain The bovine source of chondroitin should be communicated to those who avoid beef for religious reasons These preparations also incur additional cost; and if no analgesic effect occurs after months, it would be prudent to discontinue them MISCELLANEOUS SUPPLEMENTS In recent years there has been interest in the search for drugs that could possibly retard the process of cartilage degeneration, as opposed to pain relief only Candidate agents have been classified as disease modifying osteoarthritic drugs DMOAD’s or chondroprotective agents Drugs reported to have these effects include tetracyclines, chloroquine, tamoxifen, tranexemic acid, vitamin C and D While these have not been proven to have sufficient therapeutic benefit for routine clinical use, research into potential DMOAD’s may bring hope to future generations of OA sufferers Osteoarthritis 1553 ROLE OF INTRA-ARTICULAR INJECTIONS FOR OA On occasion, intra-articular steroid injections give significant and prolonged benefit This is especially true if inflammation is present and if there is little cartilage loss If one or two injections not give benefit, there is no reason to continue injections Hyaluronan is a glycosaniminoglycan that is found in normal synovial fluid but reduced in OA joints “Viscosupplementation”10 refers to the injection of similar molecules in an attempt to improve lubrication and shock absorbing properties of synovial fluid There are products available commercially: Synvisc® (Hylan G-F 20) given as injections weekly, or Hyalgan® (sodium hyaluronate) given as injections weekly Studies give conflicting results in terms of efficacy It is not certain that these compounds confer lubricative properties as their intra-articular half-life is short; therefore their mechanism of action is not clear These injections are costly, retailing at approximately SGD$110 for Hylan and SGD$180 for Synvisc If response is equivocal, there is no valid reason to continue The main side-effect is that of injection site reactions, especially if there is extravasation of the injected fluid TREATING BURSITIS AS A CAUSE OF PAIN IN OA Due to abonormal mechanical forces and gait disturbances in OA, secondary bursitis may develop, causing pain over and above that attributable to the osteoarthritic joint These localized causes of chronic pain and sometimes acute tenderness often go unrecognized Pain can be dramatically alleviated with a localized steroid injection into the inflamed bursa by a trained practitioner, such as a rheumatolgist or orthopedic surgeon Anserine bursitis The anserine bursa is located below the medial joint line of the knee and is related to the conjoint tendons of the semimenbranosus, gracilis and sartorius muscle (anseri or goose feet tendon) Inflammation of this structure can cause severe pain, sometimes acute in onset and difficulty walking Localizing and palpating the structure reproduces the pain and confirms the diagnosis 1554 A Clinical Approach to Medicine Trochanteric bursitis True hip joint pain will be localized in the groin or radiating down the thigh to the knee Pain located on the lateral aspect of the hip, not arising from the joint itself but often from an inflamed trochanteric bursa Sometimes patients will complain of pain at night upon lying on the affected side SURGERY There are several operative strategies used in the surgical management of OA: 1) Arthroscopic measures Lavage, debridement, partial meniscetomies are procedures that can improve symptoms 2) High tibial osteotomy and femoral osteotomy are techniques to realign joints thereby reducing asymmetric pressures on articular surfaces They are employed in younger people with salvageable joints in order to delay or avoid the need for joint replacement 3) Joint replacement, or the resurfacing of joint surfaces with metal, plastic or ceramic prostheses, has revolutionized the management of OA in the last 30 years, giving new hope to those who would otherwise be crippled by a severely degenerate joint Venous thrombosis is a post-operative complication that can be reduced by prophylactic heparin Prosthesis infection is the most feared complication and occurs in less than 1% Long-term joint cement loosening is a major technical issue Prostheses nowadays can last for 15 years or more Nonetheless, therefore the operation should be delayed for as long as possible in the younger active age group to avoid the need for revisions in later life Post joint replacement, intensive physiotherapy is important in the restoration of mobility and muscle strength to avoid rapid muscle deconditioning that can arise from the immobility due to post-operative pain Operative techniques and hardware have improved over the years such that post-operative recovery is faster and protheses last longer Patients nowadays demand better range of motion The latest versions of Osteoarthritis 1555 knee replacement inplants even allow for squatting and sitting crosslegged, postures valued in Asian lifestyles In the case of knee replacements, a new advance has been the less invasive technique of unicompartment replacement, or resurfacing of one joint compartment only Either the medial or lateral compartment is replaced, preserving the greater part of the joint that is relatively less damaged This allows a more natural propioception and full knee flexion CONCLUSION The view that OA is a benign condition compared to the potentially crippling inflammatory arthropathies is not a fair reflection of the morbidity caused by the severe pain, loss of mobility and decreased ability to perform aerobic exercise posed by weight-bearing joint involvement The disease burden in communities of the ubiquitous OA will be even greater as life expectancy increases, pushing up health care costs with increased demand for joint replacements It is ironic that excellent disease control can now be achieved in most cases of inflammatory arthritis but no disease modifying agent can reliably reverse osteoarthritis In recent years, a surge of research interest in the pathogenesis of osteoarthritis will hopefully lead to new therapeutic modalities Meanwhile, there is little else to offer besides physiotherapy and analgesia, before joint replacement becomes necessary for severe cases ACKNOWLEDGMENTS The author is grateful to: A/Prof Lo Ngai Nung, senior consultant orthopedic surgeon, Singapore General Hospital, for contributing the photograph on OA knees and his helpful comments on the section dealing with surgical aspects of OA; and Mr John Chen, consultant orthopaedic surgeon, Singapore General Hospital, for contributing the radiograph of OA knees REFERENCES Felson DT, Epidemiology of hip and knee osteoarthritis, Epidemiol Rev 10:1, 1988 Spector TD, Perry LA, Jubb RW, Endogenous sex steroid levels in women with generalised osteoarthritis, Clin Rheumatol 10:316, 1991 1556 A Clinical Approach to Medicine Hoagland FT, Yau ACMC, Wong WL, Osteoarthritis of the hip and other joints in southern Chinese in Hong Kong, J Bone Joint Surg Am 55:545, 1973 TD, Cicuttini F, Baker J, Loughlin J, Hart D, Genetic influences on osteoarthritis in women: a twin study, BMJ 312:940–943, 1996 Martel–Pelletier J, Alaaeddine N, Pelletier JP, Cytokines and their role in the pathophysiology of osteoarthritis, Front Biosci D694–D703, 1999 Waldschmidt JG, Braunstein EM, Buckwalter KA, Magnetic resonance imaging of osteoarthritis, Rheum Dis Clin North Am 25:451–465, 1999 Minor M, Exercise in the management of osteoarthritis of the knee and hip, Arthritis Care Res 7:198, 1994 McAlindon TE, LaValley MP, Gulin JP, Felson DT, Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis, JAMA 283:1469–1475, 2000 Brief AA, Maurer SG, Di Cesare PE, Use of glucosamine and chondroitin sulfate in the management of osteoarthritis, J Am Acad Orthop Surg 9(2):71–78, 2001 10 Simon LS, Viscosupplementation therapy with intra-articular hyaluronic acid: fact or fancy? Rheum Dis Clin North Am 25:345, 1999 88 Soft Tissue Rheumatism Feng Pao Hsii INTRODUCTION Musculo-skeletal problems account for approximately 18% of primary care consultations Half of such consultations were related to soft tissue rheumatism Hence soft tissue rheumatism is an important cause of morbidity in the community Primary care and general medical practitioners should be familiar with the more common form of this Soft tissue rheumatism may be due to localized or regional pathology, or present with generalized symptoms (Table 1) The Upper Limb Shoulder pain Soft tissue disorders of the shoulder as a group comprise the most common causes of shoulder pain in the general population Of these, conditions that affect the rotator cuff are the commonest especially rotation cuff tendinitis followed by bicipited tendinitis, adhesive capsulitis or frozen shoulder occurring in decreasing order of frequency The clinician should 1557 1558 A Clinical Approach to Medicine Table Soft Tissue Rheumatism The Upper Limb Shoulder Pain Rotator Cuff Tendinitis Bicipital Tendinitis Adhesive Capsulitis (Frozen Shoulder) Elbow Pain Lateral Epicondylitis (Tennis Elbow) Medial Epicondylitis (Golfer’s Elbow) Olecranon Bursitis Hand Pain Carpal Tunnel Syndrome De Quervain’s Tenosynovitis Digital Stenosing Tenosynovitis (Trigger Finger) Ganglia Dupuytren’s Contracture The Lower Limb Hip Pain Trochanteric Bursitis Ischiogluteal Bursitis Iliopsoas Bursitis Piriformis Syndrome Knee Pain Osgood–Schatter Disease Prepatellar Bursitis Infrapatellar Bursitis Anserine Bursitis Popliteal Cyst (Baker’s cyst) Internal Derangement Patellofemoral Pain Syndrome Ankle and Foot Heel Pain Achilles Tendinitis Retrocalcaneal Bursitis Plantar Fasciitis Metatarsalgia Generalized Aches and Pains Polymyalgia Rheumatica Fibromyalgia Low Back Pain Biomechanical Causes Medical Causes Management Soft Tissue Rheumatism 1559 also be mindful of referred pain to the shoulder from pathology in the neck, the chest or abdomen 1) Rotator Cuff Tendinitis This is the most common cause of shoulder pain It can either be acute, subacute or chronic, and the pain is localized to the anterolateral aspect of the shoulder often with radiation to the lateral upper arm The pain is increased with abduction — the painful arc — but in severe cases pain occur with abduction past 80 or 90 degrees Possible causes of rotator cuff tendinitis include trauma, repetitive use, age-related decreased vascularity, degeneration in tendons, osteophytes on the inferior part of the acromio-clavicular joint or inflammatory processes such as rheumatoid arthritis Acute tears of the rotator cuff tendon either following trauma or spontaneously especially in an older person also present with similar symptoms Very often, there is marked loss of shoulder abduction Treatment should include non-steroidal anti-inflammatory drugs (NSAIDs), local heat and gentle range of movement exercise Local corticosteroid injection into the sabacromial space is the single most effective therapy in most cases Repeat injections may be necessary if improvement is transient or suboptimal 2) Bicipital Tendinitis Bicipital tendinitis results from inflammation of the sheath of the long head of the biceps along the course proximal near the insertion in the bicipital groove Most often, the condition results from impingement of the long head by the acromion and is frequently associated with rotator cuff tendinitis, glenohumeral instability or overuse of the affected limb The clinical picture consists of anterior shoulder pain and is increased with overhead activities Passive range of motion is normal Bicipital pain can be reproduced by supination of the forearm against resistance with the elbow flexed to 90 degrees or by flexion of the elbow against resistance Treatment of bicipital tendinitis is similar to that of rotator cuff tendinitis 3) Adhesive Capsulitis (Frozen Shoulder) Adhesive capsulitis or frozen shoulder is often idiopathic but be associated with other shoulder problems It also occurs more commonly in 1560 A Clinical Approach to Medicine diabetics, after cerebrovascular accidents, immobility or hypothyroidism In this condition the capsule becomes thickened and contracted The pain is felt in the shoulder and over the lateral upper arm The onset of frozen shoulder is often insidious and is associated with initial loss of external rotation Eventually motion of the shoulder is restricted in all three planes Both active and passive motion are impaired in contrast to other shoulder disorders such as rotation cuff tendinitis Treatment consists of symptomatic measures with analgesics and local heat, an active exercise program stopping short of aggravating pain and local steroid injection into the subacromial bursa and glenobumeral joint Elbow pain Soft tissue disorders in the elbow may be the result of lateral epicondylitis, medial epicondylitis or olecranon bursitis 1) Lateral Epicondylitis This is the most common soft tissue disorder of the elbow and is also known as tennis elbow It presents as pain over the lateral aspect of the elbow and is exacerbated by wrist and finger extension It occurs primarily in the middle-aged and is common among those who not play tennis Risk factors include repetitive movements of the forearm especially repetitive wrist turning, hand gripping, tool use or hand-shaking Tennis elbow therefore is an occupational hazard among carpenters, gardeners, dentists and even politicians It is of course a common injury among tennis players especially beginners Another common cause nowadays is typing on the computer keyboard — especially if the keyboard is elevated above the level of the elbows Treatment of lateral epicondylitis consists of rest from the precipitating activity, application of heat or ice and nonsteroidal antiinflammatory drugs A local steroid injection adjacent to the tendon attachment to the epicondyle may help 2) Medial Epicondylitis Medial epicondylitis also known as golfer’s elbow is less common and less disabling than lateral epicondylitis It commonly occurs in Soft Tissue Rheumatism 1561 those who engage in cumulative repetitive strain of the common flexors of the fore-arm such as occurs in golfing, baseball pitching or work-related activities Pain onset is typically insidious and localized to the region of the medial epicondyle Tenderness is present around the region and increases with resistive flexion of the wrist Treatment consists of rest, local ice or heat, NSAIDs or local corticosteroid injection Surgical release of the common forearm flexor tendon is rarely necessary 3) Olecranon Bursitis A variety of conditions may affect the olecranon burea These include traumatic olecranon bursitis, septic olecranon bursitis and nonseptic inflammatory olecranon bursitis The latter may be associated with conditions such as rheumatoid arthritis, gout or psoriatic arthritis Aspiration may be needed if there is doubt about the presence of infection or crystal In nonseptic olecranon bursitis treatment may not be needed or may occasionally be with a local steroid injection Septic olecranon bursitis is treated with the appropriate antibiotics and repeated closed aspiration Systemic inflammatory disorders such as gout and rheumatoid arthritis may involve the olecranon bursa Treatment is directed at the underlying cause Occasionally local corticosteroid infections may be helpful Hand pain The most common soft tissue disorders of the hand and the wrist include carpal tunnel syndrome, de Quervain’s tenosynovitis, trigger finger or digital stenosing tenosynovitis, ganglia and Dupuytren’s contracture 1) Carpal Tunnel Syndrome Carpal tunnel syndrome is most frequent in the middle-aged or the elderly The condition can result from a variety of possible anatomic (e.g narrowing of the carpel tunnel), physiologic (diabetes, pregnancy or hypothyroidism) as well as patterns of use including repetitive wrist flexion and extension This condition is increasingly seen in users of computer keyboards Compression of the median nerve produces numbness, tingling or pain in the thumb, forefinger and middle finger although frequently dysaesthesias are felt in all the fingers Patients frequently complain 1562 A Clinical Approach to Medicine of nocturnal exacerbation of symptoms (frequently relieved by shaking the hand) and of dropping objects Reproduction of the patient’s symptoms occur with percussion over the volar wrist distal to the skin crease, (Tinel’s sign) or by asking the patient to flex both wrists against each other for minute (Phalen’s sign) Reduced pin-prick or more commonly two-point discrimination in the median nerve distribution is found A late sign is atrophy of the thenar eminence or weakness of thumb abduction Treatment of the condition includes nocturnal wrist splinting, anti-inflammatory drugs, corticosteroid injection and correction of any underlying cause, e.g hypothyroidism Persistent symptoms despite these measures may require surgical decompression 2) De Quervain’s Tenosynovitis This condition is frequently confused with acute arthritis of the wrist Synovitis of the tendon sheath of the abductor pollicis longus and extensor pollicis brevis presents with pain and swelling over the radial side of the wrist distal to the radial styloid process This condition most frequently results from repetitive wrist motion in the radial or ulnar direction The pain is reproduced with the Finkelstein’s test — flexing the thumb and passively ulnar deviating the wrist Treatment includes splinting of the wrist and thumb, application of local heat and anti-inflammatory drugs Local steroid injection into the tendon sheath is effective in most persistent cases 3) Digital Stenosing Tenosynovitis (Trigger Finger) The most common repetitive soft tissue injury of the hand is the socalled trigger finger The thumb and middle finger are most commonly affected although the condition can affect any finger It results from fibrosis of the flexor tendon sheath and is associated with repetitive fine motor tasks Increased friction of the tendon passing through the stenotic sheath leads to pain and/or fibrotic thickening of the sheath This leads to formation of a nodule, thus locking the finger with flexion Frequently, the finger must be forcibly extended by the patient Diabetes, hypothyroidism and other systemic conditions should be considered when multiple digits are involved Treatment with rest, splint or NSAIDs may be effective but corticosteroid infiltration of the tendon sheath is the most effective treatment Soft Tissue Rheumatism 1563 4) Ganglia Ganglia are benign cystic lesions of the hands and wrists that appear to result most commonly from synovial out-pouching Most (70%) occur on the dorsum of the wrist They may present as painless, slowly growing masses or they may be painful and rapidly growing lesions Treatment with aspiration and steroid injection is indicated for symptomatic ganglia Surgical resection is occasionally necessary 5) Dupuytren’s Contracture This condition is the result of nodular thickening of the palmar fascia producing flexion deformities of the involved digits most commonly the fourth digit Identified risk factors include alcoholism and diabetes The contractures are asymptomatic and progression is quite variable Progressive deformity and impaired hand function should prompt surgical referral for fasciectomy Lower Limb Hip pain 1) Trochanteric Bursitis Patients with trochanteric bursitis present with a deep, aching pain over the lateral upper thigh The pain is often intensified by waking and may be worse at night especially when the patient is lying on the affected side The diagnosis is confirmed with palpation of the posterior aspect of the greater trochanter, which elicits local tenderness in this area The actiology of trochanteric bursitis is unknown However, potential risk factors include local trauma, overuse activities such as jogging and leg length discrepancies Treatment consist of avoiding aggravating activity, anti-inflammatory drugs, physiotherapy and local injection of steroids 2) Ischiogluteal Bursitis The ischiogluteal bursa lies over the ischial tuberosity and facilities gliding of the gluteus maximus muscle cover the tuberosity Prolonged sitting on hard surface or repeated leg flexion and extension in the sitting position may lead to ischiogluteal bursitis The diagnosis is made by the characteristic history and by eliciting tenderness on palpation of the ischial tuberosity with the patient lying supine and with the hip and knee flexed 1564 A Clinical Approach to Medicine Treatment consists of using a cushioning “doughnut” seat and performing knee-to-chest stretching exercises while lying on the cushion A local injection of corticosteroids is useful in refractory cases, although care should be taken to avoid the sciatic nerve 3) Iliopsoas Bursitis The iliopsoas bursa lies over the anterior surface of the hip joint under the iliopsoas muscle Typically patients present with an inguinal mass that may be painful The condition has been described in association with a number of hip disorders including osteoarthritis, rheumatoid arthritis, osteonecrosis and septic arthritis CT and MRI are considered the optimal imaging methods to diagnose iliopsoas bursitis Treatment of the underlying hip disease generally is sufficient although surgical excision sometimes is required 4) Piriformis Syndrome The piriformis muscle is an abductor and external rotator of the hip that occupies the greater sciatic foramen Inflammation of the piriformis muscle insertion produces pain in the region of the sacro-iliac joint often extending into the buttock causing pain with ambulation Examination disclose pain and often weakness on resisted abduction and external rotation of the thigh Straight leg raising frequently is positive but other neurological signs are negative Treatment include stretching exercises, anti-inflammatory drugs and in resistant cases local injection of steroids Knee pain Many soft tissue disorders affect the knee joint including various forms of bursitis (involving the prepatellar and infrapatellar bursa, anserine bursa, the popliteal bursa) and a variety of internal derangements within the joint itself such as tears of the meniscal cartilage or the collateral or cruciate ligaments Other common causes of knee pain include the patellofemoral syndrome (formerly called chondromalacia patella), tendinitis and medial and lateral ligament strain A variety of knee pain syndromes occur in the adolescent and are unique to this age group 1) Osgood–Schlatter Disease Osgood–Schlatter disease is one such condition that generally presents with activity-related pain around the tibial tubercle The Soft Tissue Rheumatism 1565 2) 3) 4) 5) 6) condition is believed to result from submaximal repeated stress on the junction of the patellar ligament, tibial tubercle and tibia The tibial tubercle is swollen and tender Prepatellar Bursitis The condition presents as a painful, red swelling anterior to the knee cap and is seen most often in people who kneel a lot — e.g roofers and carpet fitters Active knee extension is often quite painful Infection of the joint should be excluded by aspirating any bursal fluid Infrapatellar Bursitis The deep infrapatellar bursa lies between the upper position of the tibial tuberosity and patellar ligament Infrapatellar bursitis presents in a similar fashion as prepatellar bursitis although the location of swelling and tenderness is on either side of the patellar ligament Anserine Bursitis The anserine bursa lies under the insertion of the thigh adductor muscle on the medial side of the knee Anserine bursitis is a term loosely applied to pain and associated tenderness in this region Nocturnal pain often leading to use of a pillow between the knees is characteristic Obesity and osteoarthritis of the knees appear to be predisposing factors Optimal treatment is injection of local steroid with local anesthesia Popliteal Cyst (Baker’s Cyst) Any cause of synovitis in the knee can lead to a popliteal cyst Symptoms consist of fullness and tightness in the popliteal space that increases with walking It can be detected clinically by palpation of fullness in the popliteal fossa Rupture of a Baker ’s cyst leads to swelling of the calf and should be confirmed by Doppler ultrasound Treatment of the condition require treating any underlying condition Direct aspiration of the cyst should rarely be attempted because of the proximity of neurovascular structures Internal Derangement Internal derangement of the knee refer to disruption of the unusual functioning of the ligaments and menisci In the young adult, it is often the result of athletic or sports trauma and in the elderly degenerative tears are more frequent Symptoms include knee pain, knee locking and giving way 1566 A Clinical Approach to Medicine MRI is widely used to diagnose suspected meniscal tear and to help plan the therapeutic approach These include meniscal repair, partial menisectomy or total menisectomy Non-operative treatment can be considered in the older patient with degenerative meniscal tear 7) Patellofemoral Pain Syndrome Chondromalacia patella has been used synonmously with patellofemoral pain but this term should be abandoned because it refers to a pathological rather than a clinical entity Patellofemoral pain syndrome is used most commonly to describe poorly localized anterior knee pain The condition is believed to result either from anatomic abnormalities or from repetitive microtrauma to the patella surface Non-operative treatment modalities include avoidance of overuse, exercise, orthoses and antiinflammatory medication Surgery may occasionally be necessary to correct any anatomical defects Ankle and foot pain Soft tissue disorders of the ankle and foot are extremely common and often result from ill-fitting foot wear (e.g high heels, extremely narrow toe box), overuse injuries (e.g running) or abnormal diomechanical factors (e.g excessive pronation, flat feet) 1) Heel Pain The most common causes of heel pain are Achiller tendinitis, retrocalcaneal bursitis and plantar fasciitis Calcaneal spur can also present with heel pain 2) Achilles Tendinitis This is generally caused by repetitive trauma and microtears of the tendon at its insertion on the calcaneus Occasionally the condition can be seen in patients with seronegative spondyloarthropathies The usual presentation is gradual onset of pain with foot pushoff and examination reveals tenderness and occasional thickening of the tendon Rest, anti-inflammatory drugs, a heel lift, gentle stretching exercises and local heat application are effective treatment measures The Achilles tendon is vulnerable to rupture in the elderly In resistent cases, carefully applied local injections along the sides of the tendon can be attempted Soft Tissue Rheumatism 1567 3) Retrocalcaneal Bursitis The retrocalcaneal bursa resides between the Achilles tendon and a pad of fat posterior to the talus Retrocalcaneal bursitis is associated with posterior heel pain made worse with passive dorsiflexion of the ankles The condition may be associated with tender swelling on both sides of the insertion of the tendon Cause include repetitive trauma due to athletic activity, rheumatoid arthritis and all of the seronegative spondyloarthropathies Treatment is the same as for Achilles tendinitis 4) Plantar Fasciitis Plantar fasciitis is attributed to repetitive microtrauma to the attachment of the plantar fascia at the calcaneus Local pain with weight bearing on the undersurface of the heel is the typical presentation Examination shows local tenderness over the anteromedial position of the plantar surface of the calcaneus made worse on dorsiflexion of the toes Associated conditions include enthesopathy due to any of the seronegative spondyloarthropathies Subcalcaneal bursitis may be difficult to distinguish from plantar fasciitis although passive dorsiflexion of the toes does not increase symptom Treatment consists of a heel pad or cushion, rest, application of local heat, stretching exercises and anti-inflammatory drugs Local injection of corticosteroids may be useful Rarely, surgical approaches such as fasciotomy may be required in resistant cases 5) Metatarsalgia Metatarsalgia is the symptom of pain across the plantar surface of one or more MTP joints It may be due to diverse causes including muscle imbalance, fat pad atrophy, Morton’s neuroma, hallux vulgus, callosities, flat or cavus foot, arthritis of the MTP joints, intermetatarsophalangeal bursitis, tarsal tunnel syndrome and arterial insufficiency Treatment consists of treating the underlying cause, use of metatarsal pads and flexion exercises Arch support are recommended for patients with flat or pronated feet Generalized Aches and Pains Polymyalgia Rheumatica This condition is rare in patients under 60 years of age The onset is often acute with severe proximal girdle aching and stiffness Patients have 1568 A Clinical Approach to Medicine great difficulty turning over in bed at night and dressing in the morning There may be pain on shoulder movement, but often there is little to find on examination The ESR is usually higher than 50 mm/hr The differential diagnoses include degenerative joint disease, early rheumatoid arthritis, polymyositis and hypothyroidism Myositis due to drugs like statins is another common cause Sometime the condition may affect the pelvic girdle and patients complain of stiffness and pain in getting into or out of a car The condition often responds dramatically to a course of steroid therapy Fibromyalgia This is the most common rheumatic cause of chronic diffuse pain characterized by the clinical features of chronic, widespread musculoskeletal pain and diffuse soft tissue tenderness Formerly known as fibrositis, the term fibromyalgia has become popular more recently in the absence of inflammatory signs Although the pathophysiology of the condition remains unknown the weight of evidence suggests that psychological factors play a prominent and probably crucial role in particular depression The diagnosis of fibromyalgia has been fascilitated by classification criteria developed by the American College of Rheumatology (ACR) They are: 1) History of chronic widespread pain-chronic — longer than months and widespread — present above and below the waist and on both sides of the body 2) Pain in 11 of 18 tender points on digital palpation — occiput, low cervical, trapezius, supraspinatus, second rib, lateral epicondyle, gluteal, greater trochanter, knee For classification purposes patients are said to have fibromyalgia if both criteria are satisfied The condition is typically insidious in onset with the patient complaining of “pains all over” There often is a prior history of depression, anxiety disorder, and work problems, and females are more commonly affected than males Physical examination is essentially normal Moderate pressure over muscles and tendon insertions (tender points) typically elicits marked tenderness with grimacing and/or withdrawal The condition may be Soft Tissue Rheumatism 1569 associated with irritable bowel syndrome, tension headaches, migraine Occasionally fibromyalgia can co-exist with systemic rheumatic diseases like SLE The treatment of fibromyalgia includes reassurance that the condition is not a progressive, crippling or life-threatening entity Depending on the severity of the condition, a combination of low-aerobic exercise program and antidepressants (like amitriptyline, fluoxetine, paroxetine, sentraline) is effective in alleviating symptoms in most patients Patients should also be encouraged to take an active role in the management of their condition Low Back Pain Low back pain is among the most common symptoms to affect human beings Up to two-thirds of all individual will experienced low back pain during their life time 1) Biomechanical Causes Those account for over 90% of low back pain These include structural spine abnormalities like kyphosis and scoliosis, muscle spasm and degenerative disorders like intervertebral disc disease, osteoarthritis, spinal stenosis ad spondylolithesis 2) Medical Causes These include inflammatory conditions like infection and spondyloarthropathy, and metabolic conditions like osteoporosis and osteomalacia Occasionally, low back pain may also be caused by psychogenic conditions like depression and fibromyalgia and one must remember referred pain due to abdominal aneurysm, retropertoneal lesion, pyelonephritis, pancreatic disease and occasionally prostatitis The management of low back pain include a careful history and physical examination, relevant laboratory work-up and imaging techniques like plain radiography, bone scanning or MRI Optimal constructive therapy include a brief period of rest, symptomatic medication therapy tailored to the individual and physical modalities such as stretching and flexiblility exercises Occasionally, referral to an anesthesiologist, orthopedic surgeon or neurosurgeon may be necessary This page intentionally left blank Index 13-cis retinoic acid 945 ␣-glucosidase inhibitors 281, 287 ab dependent cellular cytotoxicity (ADCC) 680 abciximab 682 (ReoPro) 680 ACE inhibitors 1259 acetylcholine 524 acetylcysteine 531 acromegaly 17 ACTH 382 acute bronchitis 1379 acute cholecystitis 530 acute coronary syndrome 3, acute cystitis 1228 acute glomerulonephritis 17 acute hyperglycemic crises 282 acute lymphoblastic leukemia (ALL) 582 acute monoarthritis 1525 acute myeloid leukemia (AML) 582 acute pulmonary edema 20 acute pyelonephritis 1230 acute respiratory distress syndrome 1388 adrenal 381 adrenal crisis 398 adrenal dysfunction 365 adrenal insufficiency 377 adrenal venous sampling 19 adrenocortical adenoma 19 aggrecan 1542 agnogenic myeloid metaplasia 612 airflow limitation 1315 airway 213 albuminuria 268, 288 aldosterone 382, 390, 398, 402 alemtuzumab 682 all-trans retinoic acid (ATRA) 585 allogenic transplant 632 allopurinol 1533 1571 1572 Index allorestricted CD45-specific CTL 691 alpha fetoprotein (AFP) 909 alpha interferon 581, 631 alpha-blockers 24 Alzheimer’s disease 1083, 1085 familial 1086 amylin 288 amyloid polypeptide 267 amyotrophic lateral sclerosis (ALS) 1021 anagrelide 606 androgens 382, 403 anemia 571 chronic disease 577 due to hematologic diseases 579 endocrine disorders 579 hemolytic 575 malignancy 578 renal disease 579 angioedema 148 angiotensin 382, 392 angiotensin receptor blockers 1259 angiotensin-converting enzyme (ACE) inhibitor 19 ankylosing spondylitis 1450 Ann Arbor staging classification 621 anserine bursitis 1553 anthracycline 584, 587, 588 anthrax 1397 anti-cancer vaccines 676 anti-cardiolipin antibodies 1473 anti-CD 33 monoclonal antibody 581 anti-histamines 144 anti-hypertensive agents 273 anti-idiotype Abs 679 anti-platelet therapy 288 antibody-dependent enhancement 828 antinuclear antibody (ANA) 1466 antiphospholipid antibodies 664 antiphospholipid syndrome 1461, 1473 antithrombin 658, 663 antithrombin III deficiency 662 aortic aneurysm 530 aortic dissection 3, 4, 5, 10, 20 aortic regurgitation 116 aortic stenosis 116 APACHE-II 533 apathetic thyrotoxicosis 373 apolipoprotein E 1087 Aprotinin 531 Ara-C 593 arsenic trioxide 587 arthritis gouty 1450 lyme 1453 osteo 1450 reactive 1453 rheumatoid 1450 septic 1450 aspergillosis 1380, 1404 aspirin 288 asplenia 791 asymptomatic bacteriuria 1232 atherogenic lipoprotein phenotype (ALP) 265 atherosclerosis 265 atopic dermatitis 151 ATRA syndrome 586 atrophic glossitis 559 atypical diabetes 264 autoimmune 295 autoimmune adrenal failure 377 autoimmune cytopenias 599 autoimmune diseases 596 autoimmune hemolytic anemia 596 autologous stem cell transplantation 594 autonomic dysreflexia 1445 autosomal dominant 608 Avandamet 282 B cell differentiation antigens 597 B lineage 588 -cell failure 266 basiliximab 682 bentiromide (NBT-PABA) test 535 benzbromarone 1531, 1533, 1536 Index 1573 beta human chorionic gonadotropin (b-hCG) 909 beta-blockers 24 bilateral adrenocortical hyperplasia 19 blast 582, 590 crisis 591–593 bombesin 524 Bone marrow aspiration 588 bone marrow transplant (BMT) 584–598 brachial neuritis (neuralgic amyotrophy) 1028 bradykinin 527 bronchiectasis 1379 bronchoalveolar lavage 1386, 1393, 1395 bronchoscopy 1382, 1386, 1397 bullectomy 1332 Burkitt’s lymphoma 626 busulphan 591 C-peptide levels 543 CA 19-9 539 calcium hydroxyapatite 1544 calcium pyrophosphate deposition disease (CPPD) 1450 calcium-channel blockers 24 campath-1H 681 cancer rehabilitation 1436 candidiasis 1404, 1406 captopril renal scintiscan 19 carbohydrate antigen 15-3 (CA15-3) 909 carbohydrate antigen 19-9 (CA19-9) 909 carbohydrate antigen 125 (CA125) 909 carcinoembryonic antigen (CEA) 909 carcinoids 383 carcinoma, hepatocellular 450 cardiovascular complications 271 cardiovascular mortality 278 cardiovascular risk 268 Carney’s Complex 384, 389 carpal tunnel syndrome 1032 cationic trypsinogen gene 534 celecoxib (a COX-2 inhibitor) 942 cell-based anti-cancer vaccines 684 central alpha-blockers 24 central obesity 265, 268 cerebral thrombosis 268 cervical and lumbar radiculopathy 1027 cessation of smoking 286 Charcot–Marie–Tooth (CMT) 1031 chemical carcinogens 872 chimeric anti-CD 20 monoclonal antibody (Rituximab) 581 chimeric antibodies 680 chlorambucil 598 chlorpropamide 276 cholecystokinin (CCK) 524 cholesterol embolism 1478 chondroitin sulphate 1542, 1552 chromium 288 chromium picolinate 288 chromosomal translocations 869 chromosome abnormalities 596 chronic glomerulonephritis 17 chronic lymphocytic leukemia 619 chronic myeloid leukemia (CML) 601 chronic obstructive pulmonary disease (COPD) 1315 chronic pyelonephritis 17 Churg–Strauss syndrome 1477 chymotrypsin 527 CLL 595 clonal cytogenetic 583 clonality 597 coeliac plexus block 538 colchicine 1529 color-flow imaging 111 combination oral hypoglycemic agents 282 combination therapy 271, 279, 284, 285 complicated UTI 1233 complications, diabetic 263, 265 connective tissue diseases 1461 1574 Index constrictive pericarditis 119 contact dermatitis 156 continuous subcutaneous insulin infusion (CSII) 331 copper 562–569 Cor pulmonale 1319 coronary artery disease 267, 286 corticotrophin 399 cortisol 382, 386, 388, 390, 397, 402 cotazym 536 Courvoisier’s sign 539 CREST 1472 cricothyrotomy 233 Crohn’s disease (CD) 457 cryptococcosis 1404 cubital tunnel syndrome 1032 Cullen’s sign 528 Cushing’s Syndrome 17, 273, 383, 385, 386 cutaneous drug eruption 161 cyclophosphamide 589, 1470 cystduodenostomy 532 cystgastrostomy 532 cytarabine 587 cytogenesis 609, 613 cytogenetics 582–595 cytokines 676 cytopenias 598 cytoreduction 606, 610 cytosine arabinoside 584 D cells 524 daclizumab 681, 682 decontamination 194 deficiency protein C 662 protein S 662 degenerative arthritis 1539 dementia 849, 863, 1083–1091 dendritic cells 688 dengue 825 depression 290, 1092 dermatomyositis/polymyositis 1461 dermographism (factitious urticaria) 147 dexamethasone 386, 400, 402, 587 dexamethasone suppression test 20 DHEA 403 Diabetes Control and Complications Trial (DCCT) 331 diabetes education 269 diabetic ketoacidosis 268, 365 diabetic nephropathy 17, 263 diazoxide 543 dilated cardiomyopathy 117 disseminated intravascular coagulation (DIC) 527, 586 diuretics 24 diverticultitis 530 DMOAD’s 1552 DNA damage 871 double-bypass surgery 542 drug hypersensitivity syndrome 165 drug resistance 805, 812 duplex renal sonography 19 duplex ultrasound 660 dyslipidemia 263, 268, 285, 286 dyspepsia 421 dyspnea 1294, 1319 Early Treatment Diabetic Retinopathy Study (ETDRS) 333 ectopic pregnancy 530 eczema 150 EEG 959 elastase 527, 528 electrophysiology 960 empyema 1316, 1388, 1396–1399, 1401 endoscopic retrograde cholangiopancreatography (ERCP) 536 endoscopic retrograde pancreatography 524 endoscopic ultrasound (EUS) 536 endothelial vasoactive factors 17 Index 1575 enthesis 1450 eosinophils 590 epiglottitis 1378 ERCP, emergency 529 erythema-multiforme 164 erythropoietin 603 esophageal-tracheal combitube 227, 235 essential thrombocythemia (ET) 601 criteria 609 estrogens 403 etanercept 683 European Nicotinamide Diabetes Intervention Trail 334 EUS-guided FNA biopsy 541 extracorporeal shock wave lithotripsy (ESWL) 537 ezetimibe 287 factal growth retardation 266 Factor V Leidon 662 febrile neutropenia 796, 797 fecal fat excretion test 535 ferritin 560 fetal malformation 611 fibrates 287, 318 fibromuscular dysplasia 17 fibromyalgia 1450, 1568 fine needle aspiration cytology (FNAC) 536 fish oils 287 fluid overload 281 free fatty acids (FFAs) 266 full blood count 553–555 GAD antibodies 329 gastrinomas 543 geriatric syndromes 849, 865 glibenclamide 276, 277 gliclazide 277 glimepiride 277 glipizide 277 Glivec (see tyrosine kinase) 595 glomerulonephritis 1207–1210, 1212, 1213, 1216–1218, 1220 glucagonomas 543 glucocorticoid 390, 393, 400 gluconeogenesis 266 glucophage retard 279 glucosamine 1552 glucose toxicity 265–267, 273, 283 glucovance 282 glutamic acid decarboxylase (GAD) antibody 264 glycemic control 270, 271, 1257 glycogenolysis 266 gout 1519 graft-versus-host disease (GVHD) 584, 679 graft-versus-leukemia 593 granulocytes 590 Graves’ disease 372 Grey Turner’s sign 528 Guillain–Barre Syndrome 1029 HAMA response 680 hazardous chemicals 192 HbA1c 270, 271 HDL-cholesterol 265, 270, 285–288 Heimlich maneuver 216 Helicobacter pylori 873 hematopoiesis 601 extramedullary 612 hematopoietic stem cell transplantation (HSCT) 679 hemochromatosis 263 hemodialysis 1281 hemoptysis 1296, 1381, 1385, 1399 hemorrhagic stroke 20 heparin 670 hepatic glycogenolysis and gluconeogenesis 282 high tibial osteotomy 1554 Hippel–Lindau disease 543 HLA-B27 antigen 1507 1576 Index HMG-CoA reductase inhibitors (statins) 287 homocysteinemia 662 human anti-chimeric Ab (HACA) 681 human-anti-humanized Ab responses (HAHA) 684 human-anti-mouse-Abs (HAMA) 679 humanized antibodies 681 humulin 283 Hunter and Hurdler Syndromes 112, 114 hyaluronan 1553 hydroxycobalamin 567 hydroxyurea 589, 606 hyperaldosteronism 390, 403 hypercalcemia 347, 399, 525 hypercoagulability state 288 hypercoagulate states 662 hypergastrinemia 544 hyperglycemia 263, 268, 284, 400 postprandial 278, 282 hyperglycemic hyperosmolar states (HHS) 365 hyperinsulinemia 265, 284, 543 hyperkalemia 394 hyperlipidemia 525, 1265 hypernatremia 391 hyperosmolar hyperglycemic nonketotic states 268 hypersomnia 1340, 1350 hypertension 265, 268, 288, 384, 390, 403, 1262 pregnancy-related 17 hypertensive crisis 397 hypertensive encephalopathy 20 hyperthyroidism 17, 273 hypertriglyceridemia 525 hypertrophic cardiomyopathy 117 hyperuricemia 1521 hyperviscosity 603 hypoadrenalism 273, 399 hypocalcemia 527 hypogammaglobulinemia 596 hypoglycemia 275, 276, 278, 279, 282, 284, 399 nocturnal 284 postprandial 271 hypokalemia 19, 384, 391–393 hyponatremia 399 hypopituitarism 273 hypothyroidism 17, 273, 304–307 ICA antibodies 329 idiopathic myelofibrosis 601 Ilozyme 536 imaging 959 immune reconstitution syndrome 796 immunophenotyping 583, 588 immunosuppressive therapy 788 immunotherapy 675 impaired glucose tolerance (IGT) 264, 265, 266 incidentaloma 390, 401, 402 infliximab 683 influenza 830 influenza vaccination 1329 insomnia 1340, 1346, 1352 Insulatard 283 insulin 282 intravenous 284 pump 331 insulinomas 543 interferon 610, 676 interferon-alpha (IFN-␣) 592, 606 interleukin-2 678 interleukins 677 International Prognostic Index 622 International Workshop on CLL 597 interstitial fibrosis 591 interstitial nephritis 17 intestinal obstruction 530 intradermal corticosteroid 158 intraductal papillary mucinous tumors (IPMT) 542 intrauterine malnutrition 266, 267 intubating laryngeal mask 232 intubation 232 Index 1577 iontophoresis 1443 iron deficiency 573 iron dextran 564 irritable bowel syndrome 421 islet cell antibody 264 joint replacement 1554 kallikrein 527 keratan sulphate 1542 ketonuria 284 koilonychia 559 lactic acidosis 279 lanreotide 543 LAP 590 laryngotracheitis 1378 latent autoimmune diabetes in the adult (LADA) 329 latent autoimmune diabetes of adults (LADA) 264 LDL composition 286 LDL-cholesterol 270, 285–287 legionella 1383, 1386, 1387, 1388 lentiviral or bacterial vector expression systems 692 leucopheresis 589 leukemia 621 leukemogenicity 606 leukemogens 611 leukoerythroblastic 609, 612 anemia 612 leukopenia 612 leukotrienes 527 lexipafant 531 lichen simplex chronicus 154 lipase 528 lipid-lowering drugs 287 lipotoxicity 265, 267 low molecular weight heparin (LMWH) 670 lumbar puncture 958 lung infiltrates 790 lung transplantation 1333 lung volume reduction surgery 1333 lupus anticoagulant 664, 1473 lymphocytosis 596 lymphoma 596, 598, 624 macroangiopathy 267 macrocytosis 592 macrovascular complications 282 magnetic resonance angiography 19 magnetic resonance imaging 529 malaria 830 mammography 878–884 matrix metalloproteinase (MMP) 1542 mechanical ventilation 1326, 1332 megakaryocytes 609 megaloblastic 592 melioidosis 1383, 1387 MEN I 543 mercaptopurine 588 mesenteric ischemia 530 mesenteric vessel occlusion 530 metformin side-effects 279 methimazole 373 methotrexate 588 microalbuminuria 271, 274, 1255 microangiopathy 267 microlithiasis 530 microscopic polyangiitis 1474 microvascular complications 268, 270, 271 miglitol 281, 282 migratory thrombophlebitis 539 mineralocorticoid 17, 392, 393, 401 minimal residual disease 583 minor histocompatibility antigen 690 mitral regurgitation (MR) 114 mitral stenosis (MS) 112 mixed connective tissue disease 1461, 1473 modified Glasgow criteria 533 monoclonal antibodies 581, 590, 598, 676, 678 monoclonal gammopathy 596 1578 Index monounsaturated fats 273 motor neuron diseases 1021 MRCP (magnetic resonance cholangiocreatography) 536 mucinous adenocarcinomas 538 mucinous cystic neoplasms (MCN) 542 murine monoclonal antibodies 679 muscular dystrophy 1033 Myasthenia Gravis 1024 mycophenlate mofetil 159 mycoplasma 1379, 1383, 1384, 1394 myeloid metaplasia 612 myeloma 627 myeloproliferative disorders 601 myelosuppression 591, 593, 607 mylotarg (see gemtuzumab ozagomicin) 681 myopathy inflammatory 1035 metabolic 1034 myotonia 1035 narcolepsy 1338, 1342, 1349 nasopharyngeal airways 220 nateglinide 278 nephropathy 330 diabetic 263, 267, 274 neurofibromatosis 394, 395 neuropathy 330 neutropenia 589, 593, 612 neutrophilia 604 Niacin 569 niaspan 287 nicotinic acid 287 non-invasive ventilatory support 236 non-steroidal anti-inflammatory agents (NSAIDs) 1551 non-steroidal anti-inflammatory drugs (NSAIDs) 1529 nystagmus 966 obesity 266, 288 obstructive sleep apnea 1342 occupational asthma 1311, 1313 octreotide 531, 543 OKT3 679 omega-3 fish oils 287 oral immune suppressant 159 oralin 289 orlistat 268, 275 osteoarthrosis 1539 ovarian tumor 530 palivizumab 683 pancreas cystic tumors 542 divisum 524 endocrine 523 exocrine 523 pancreaticojejunostomy 538 pancreatitis 524–533 pancreolauryl tests 535 pancytopenia 584, 612 PAP smear 876, 877 papillomavirus 873 paralysis 964 parasitic infestation 562 parasomnia 1339, 1351 Parkinson’s Disease 1071, 1072, 1074, 1075, 1077–1080 PEG-interferons 594 pegylated interferons 593 peptic ulcer 530 percutaneous route (PTC) 541 pericardial tamponade 119 periodic leg movements 1341 peripheral adrenergic inhibitors 24 peripheral arterial disease 268 peripheral neuropathy 267 peritoneal dialysis 1281, 1287 peroxisome proliferator activation receptors-gamma (PPARg) 280 pharyngitis 1377 pheochromocytoma 17, 383, 388, 394 phototherapy 159 physical urticarias 147 piglitazone 281 Index 1579 pigmentation change 157 pimecrolimus 159 pioglitazone 280, 281 pituitary microadenoma 20 plasma aldosterone 19 plasma free metanephrine level 20 plasma renin activity 19 pneumocystis carinii 1384, 1386, 1394, 1404 pneumonia 1293, 1297, 1382, 1389, 1391, 1392 pneumothorax 4, 5, poikilocytes 612 polyarteritis nodosa 1474 polycystic kidney disease 17 polycythemia 602 secondary 605 polycythemia rubra vera (PRV) 601 diagnostic criteria 605 polymyalgia rheumatica 1567 polysomnography 19, 1342, 1348 polyunsaturated fats 273 pompholyx 156 pramlintide 288 premixed insulins 283 preprandial glucose 270 pressure urticaria 148 primary aldosteronism 17 probenicid 1531, 1533 propylthiouracil 373 prostatic specific antigen (PSA) 909 prostatitis 1231 proteinuria 1260 proteoglycans 1542 prurigo nodularis 155 pseudocyst 529 pseudogout 1450 pseudomonas aeruginosa 1379, 1384 pulmonary embolism 660 pulmonary rehabilitation 1331 purine nucleoside analogs 598 pyridoxine 569 quinolone 1389, 1396 radioactive phosphorus 606, 610 Rai Staging System 597 random plasma glucose 272 Ranson criteria 533 Raynaud’s phenomenon 1472 reactive arthritis 1507, 1509, 1515 renal artery stenosis 17 renal transplantation 1281 renin 382, 391, 398, 401 renin-producing tumors 17 renoprotection 1276 repaglinide 278, 287 restrictive cardiomyopathy 117 retinoic acid receptor 586 retinopathy 263, 267, 271, 275, 330 retrovirally transduced CD40-stimulated B cells 691 riboflavin 569 rituximab 680, 683 rosiglitazone 280, 281 rotator cuff tendinitis 1454 salphingitis 530 Scleroderma 1472 seborrheic dermatitis 153 secondary osteoarthritis 1540 secretin 524 secretin magnetic resonance pancreatography (S-MRP) 535 secretin stimulation test 535 selective COX-2 inhibitors (COXibs) 1552 sensory loss 962 seronegative spondyloarthropathy 1450 serous cystadenoma 542 SIADH 277 sibutramine 275 sinusitis 1376 Sjogren’s syndrome 1452, 1461, 1470 sleep apnea 17 sleep oximetry 19 sleep/wake cycle 1340, 1352 small dense LDL-cholesterol 265, 285 1580 Index smoking cessation 1328 solar urticaria 148 solitary plasmacytoma 632 somatostatin 524, 531 somatostatinomas 543 sphincter of Oddi dysfunction 525 spinal muscular atrophy 1024 spirometry 1320, 1323 splenectomy 614 spondyloarthropathy 1507, 1514 statins 309 stent, self-expanding metallic 542 Steven–Johnson syndrome 164 Stockholm Diabetes Intervention Study (SDIS) 331 stone theory 534 streptococcus pneumoniae 1376, 1383, 1394 stridor 1294, 1299 substance P 524 sulfinpyrazone 1531, 1533 sulphonylurea 276, 287 sulphonylurea failure 276 supraspinatus tendinitis 1454 synacthen test 377 syndrome X 265 systemic lupus erythematosus 1451, 1461 systemic sclerosis 1461 T cell receptor (TCR) gene transfer 691 T-cell antigen 597 T-lineage 588 tacrolimus 159 Takayasu’s arteritis 1474 tamoxifen 943 temporal arteritis 1474 teratogenicity 607 tetany, hypocalcemic 528 tetrahydrolipostatin 275 thalassemia intermedia 574 major 574 minor 560, 575 thalidomide 632 theophylline 1325, 1328 therapeutic endoscopy 472–474 thiazolidinedione 287 precautions 281 side-effects 281 thrombocytopenia 582, 593, 596, 612 thrombocytosis 605–607 thrombophilia 661, 662 thrombopoietin 608 thrombosis venous 659 thymomas 383 thyroid storm 365, 372 thyrotoxicosis 295–304, 372 tinea amiantace 153 TNF-␣ 678 TNF- 678 tophaceous gout 1521 topical corticosteroid 158 topical immune suppressant 159 total pancreatectomy 542 toxic epidermal necrolysis 164 tracheostomy 227, 233 transferrin saturation 560 transplant liver 790, 793 trastuzumab 684 triglyceride 265, 270, 285–288 trisomy 12 596 trochanteric bursitis 1554 troglitazone 280 troponin 8, 9, 10 tuberculosis 1398, 1401, 1402 tuberous sclerosis 543 tularemia 1398 tumor antigen RNA-transduced DCs 692 tumor lysates 686 tumor markers 909 tumor necrosis factor 678 tumor suppressor genes 870 tumor-associated Ags 686 tumor-protein/keyhole limpet hemocyanin (KLH)-pulsed DCs 692 Index 1581 tumor-specific Ags 686 Type DM 327 tyrosine kinase activity 591 BCR-ABL 594 inhibitor (Glivec) 581 UK Prospective Diabetes Study (UKPDS) 270 ulcerative colitis (UC) 457 ultralente insulin 283 unfractionated heparin 670 urethritis 1228 uricosurics 1533 urinary incontinence 860 urinary iron loss 561 urinary metanephrine 20 urinary tract infection 1223 urticaria 143 uvulopalatoplasty 19 vasoactive intestinal peptide (VIP) 524 vector surveillance 843 venography 660 vincristine 588 VIPomas 543 viscosupplementation 1553 vitamin A, C, E 531 von Recklinghausen’s disease 543 Waldenstrom’s macroglobulinemia 623 warfarin 671 Wegener’s granulomatosis (WG) 1474 wheezing 1294 Whipple resection 542 Wirsung 523 young Type DM 264 yttrium-90 682 Zollinger–Ellison syndrome 544 ... proximal to a known nodal site Clinical stage Pathological stage Mandatory staging investigations: 1) Careful history for “B” symptoms and examination as described above 2) Bone marrow aspirate and... not adequate for diagnosis of lymphoma Careful examination for peripheral lymph node enlargement may save a patient an unnecessary mediastinal biopsy or exploratomy laparatomy If a high-grade... with 2- view mammography and clinical examination Another 25 21 6 women were randomized to a control group who had a clinical examination at the initiation of the trial followed by the usual health