Neurologic Disease in Women - part 7 potx

NEUROLOGIC DISEASE IN WOMEN 282 87. Frith JA, McLeod JG. Pregnancy and multiple sclerosis. J Neurol Neurosurg Psych 1988;51:495–498. 88. Thompson DS, Nelson LM, Burns A, Burks JS, Franklin GM. The effects of pregnancy in multiple sclerosis: a retrospective study. Neurology 1986;36:1097–1099. 89. Nelson LM, Franklin GM, Jones MC, Multiple Sclero- sis Study Group. Risk of multiple sclerosis exacerbation during pregnancy and breastfeeding. JAMA 1988;259: 3441–3443. 90. Weinshenker BG, Hader W, Carriere W, Baskerville J, Ebers GC. The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middle- sex County, Ontario. Neurology 1989;39:1438–4440. 91. Bernardi S, Grasso MG, Bertollini R, Orzi F, Fieschi C. The influence of pregnancy on relapses in multiple sclerosis: a cohort study. Acta Neurol Scand 1991;84: 403–406. 92. Roullet E, Verdier-Taillefer MH, Amarenco P, Gharbi G, Alperovitch A. 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Sexual disturbances arising from multiple sclerosis. Acta Neurol Scand 1984;70:299–306. 120. LaRocca NG. Employment and multiple sclerosis. Health Services Research Reports Monograph , National MS Society, 1995. 121. Harvey C. Economic costs of multiple sclerosis: how much and who pays? Health Services Research Reports Monograph, National MS Society, 1995. ptic neuritis is the most common optic nerve-related cause of visual loss in young women of childbear- ing age. It is important not only with respect to visual function in affected patients but also to their neurologic prognosis. The term optic neuritis means inflammation of the optic nerve. When optic neuritis occurs with a swollen optic disc, it is called papillitis or anterior optic neuritis. When the optic disc appears normal, the terms retrobulbar optic neuritis or retrobulbar neuritis are used. The pathogenesis of most cases of isolated optic neuritis is presumed to be demyelination, similar to that seen in multiple sclerosis (MS). In the absence of signs of MS or other systemic disease, however, optic neuritis is referred to as isolated, monosymptomatic, or idiopathic. Optic neuritis does not always present as an acute loss of vision. It may develop as insidious progressive or nonprogressive visual dysfunction, and it may even be asymptomatic. Patients with asymptomatic optic neuritis have laboratory evidence of optic nerve dysfunction and may also have subtle clinical evidence of optic nerve dam- age if appropriate studies are performed. Because this book is about those neurologic diseases that occur mainly in women, this chapter deals exclusively with acute, chronic, and subclinical demyelinating or idiopathic optic neuritis. For a discussion of optic neuritis caused by processes other than MS, the reader is referred to the chapter entitled “Optic Neuritis” by Smith (1). IDIOPATHIC AND PRIMARY DEMYELINATING OPTIC NEURITIS Optic neuritis almost always occurs as an isolated phenomenon without any neurologic or systemic accompa- niments or sequelae or as a demyelinating process that pre- cedes the development of MS. There are three forms of optic neuritis: (i) acute, (ii) chronic, and (iii) subclinical. Acute Idiopathic or Demyelinating Optic Neuritis Acute idiopathic or demyelinating optic neuritis is by far the most common type of optic neuritis that occurs throughout the world and is the most frequent cause of optic nerve dysfunction in the young adult population (2). Much of our knowledge regarding this form of optic neuritis was obtained from a study, begun in 1988, called the Optic Neuritis Treatment Trial (ONTT) and continued throughout the 1990s as the Longitudinal Optic Neu- ritis Study (LONS) (3–18). The ONTT was a multicen- ter controlled clinical trial that was funded by the National Eye Institute of the National Institutes of Health 283 Optic Neuritis Neil R. Miller, MD 19 O NEUROLOGIC DISEASE IN WOMEN 284 (NIH) in the United States. The investigators in this trial enrolled 455 patients with acute unilateral optic neuritis. A similar study was performed in Japan (18). Although the primary objective of these studies was the assessment of the efficacy of corticosteroids in the treatment of optic neuritis, the ONTT and LONS, as well as the Japanese Optic Neuritis Study have also provided invaluable information about the clinical profile of optic neuritis, its natural history, and its relationship to MS. The entry criteria for patients who were entered into the ONTT were a clinical syndrome consistent with unilateral optic neuritis, including a relative afferent pupillary defect and a visual field defect in the affected eye. Visual symptoms had to have begun within 8 days of randomization. The patient could have no history of a previous episode of optic neuritis in the affected eye, no previous corticosteroid treatment for optic neuritis or MS, and no evidence of a systemic disease other than MS as a cause for the optic neuritis. The Japanese trial had similar criteria for entry. Demographics The annual incidence of acute optic neuritis is estimated in population-based studies to be between 1 and 5 per 100,000 (19–25). The majority of patients are between the ages of 20 and 50 years, with a mean age of 30–35 years. Nevertheless, optic neuritis can occur at any age, including children in the first and second decades of life and adults in their sixth to eighth decades. Women are much more commonly affected than men, at a ratio of approx- imately 4:1. Caucasians are affected much more often than are African-Americans, Africans, or Hispanics (26,27). Symptoms The two major symptoms in patients with acute optic neuritis are loss of central vision and pain in and around the affected eye. LOSS OF CENTRAL VISION. Loss of central visual acuity is reported by over 90% of patients (4,19). Vision loss is typically abrupt, occurring over several hours to several days. Progression over a longer period can occur but should make the clinician suspicious of an alternative disorder. The degree of visual loss varies widely from a minimal reduction to complete blindness with no perception of light. The majority of patients describe diffuse blurred vision, although some recognize that the blurring is predominantly central. Occasionally, patients complain of a loss of a portion of peripheral field, such as the inferior or superior region or even the temporal or nasal region. The visual loss is monocular in most cases in adults, but in children and in a small percentage of adults, both eyes are simultaneously affected. OCULAR OR ORBITAL PAIN. Pain in or around the eye is present in more than 90% of patients with acute optic neuritis. It is usually mild, but it may be extremely severe and may be more debilitating to the patient than the loss of vision. It may precede or occur concurrently with visual loss, usually is exacerbated by eye movement, and generally lasts no more than a few days (4,19). The presence of pain is a helpful differentiating feature from anterior ischemic optic neuropathy, particularly when the pain is severe and when it occurs or worsens during movement of the eyes, features uncommon in the 10 to 12% of ischemic optic neuropathy patients who experience pain (28,29). POSITIVE VISUAL PHENOMENA. Up to 30% of patients with optic neuritis experience positive visual phenomena, called photopsias, both at the onset of their visual symptoms and during the course of the disorder. These phenomena consist of spontaneous flashing black squares, flashes of light, or showers of sparks, sometimes precipitated by eye movement or certain sounds (30–33). Signs An examination of a patient with acute optic neuritis reveals evidence of optic nerve dysfunction (Table 19.1). Visual acuity is almost always decreased, but varies from a mild reduction (e.g., 20/15 to 20/20) to no light perception. Contrast sensitivity and color vision also are impaired in almost all cases. The reduction in contrast sensitivity often parallels the reduction in visual acuity (34), although in some cases, it is much worse (3). The reduction in color vision is often much worse than would be expected from the level of visual acuity (35,36). Stan- dard color vision testing with the Ishihara or Hardy- Rand-Rittler pseudoisochromatic plates commonly reveals abnormalities in the affected eye, whereas the TABLE 19.1 Features of Typical Optic Neuritis in Adults • Acute unilateral loss of visual acuity and color vision • Periocular pain, often exacerbated with eye movement • Visual field defect, usually central • Ipsilateral relative afferent pupillary defect • Absence of anterior or posterior segment inflammation • Normal or swollen optic disc • Spontaneous visual improvement beginning in 2 to 4 weeks • Strong relationship with multiple sclerosis OPTIC NEURITIS 285 more sensitive Farnsworth-Munsell 100-Hue test can reveal more subtle defects. Even when the patient can detect all the pseudoisochromatic figures correctly, a care- ful comparison of the appearance of a single plate by each eye may reveal a striking difference in color and brightness between the two eyes. Like visual acuity, visual field loss can vary from mild to severe, may be diffuse or focal, and can involve the central or peripheral field (37–39). Indeed, although the classic visual field defect in acute optic neuritis is the central scotoma, almost any type of field defect can occur in the affected eye (39). A relative afferent pupillary defect (RAPD) is demonstrable with the swinging flashlight test in all unilateral cases of optic neuritis and in cases with bilateral but asymmetric neuritis (40–43). When such a defect is not present, either there is a coexisting optic neuropathy in the fellow eye (e.g., from previous or concurrent asymptomatic optic neuritis) or the visual loss in the affected eye is not caused by optic neuritis or by any other form of optic neuropathy. The use of a neutral density filter may help uncover a subtle relative afferent pupillary defect in patients with suspected optic neuritis (44). In this test, a 0.3 log-unit neutral density filter is placed in front of one eye and a swinging flashlight test is performed. The filter is then placed in front of the other eye and the swinging flashlight test is again performed. If there is no RAPD, the result of the swinging flashlight test should be the same regardless of which eye is behind the neutral density filter; that is, there should be a mild observable RAPD. On the other hand, if a minimal RAPD is already present, then placing the filter in front of the eye with the RAPD should make it more obvious, whereas placing the filter in front of the oppo- site eye should result in normal pupillary responses (44). Patients with optic neuritis also can be shown to have a reduced sensation of brightness in the affected eye by asking them to compare the brightness of a light shone in one eye and then the other (1). This test is simple to perform and extremely helpful in the patient with a ques- tionable RAPD. About one-third of patients with acute optic neuritis have some degree of disc swelling (4,19) (Figure 19.1). In most cases, the degree of swelling is quite mild; however, in some cases, the swelling is so severe that it mim- ics the “choked disc” seen in patients with papilledema (Figure 19.2). The degree of disc swelling usually does not correlate with the severity of either visual acuity or visual field loss (4,19,45). Disc or peripapillary hemorrhages and segmental disc swelling are less common in eyes with acute optic neuritis than in eyes with anterior ischemic optic neuropathy (4,46). The majority of patients with acute idiopathic or demyelinating optic neuritis have a normal optic disc in the affected eye, unless they have had a previous attack of acute or asymptomatic optic neuritis or have ongoing chronic optic neuritis (4,19). With time, however, the optic disc usually becomes pale, even as visual acuity, color vision, visual field, and other aspects of visual sen- sory function improve. The pallor may be diffuse or local- ized to a particular portion of the optic disc, most often the temporal portion (Figure 19.3). Slit lamp biomicroscopy in eyes with demyelinating optic neuritis is almost always normal. In some patients FIGURE 19.1 Mild optic disc swelling in a patient with acute anterior optic neuritis (papillitis). FIGURE 19.2 Severe optic disc swelling in a patient with acute anterior optic neuritis (papillitis). Note resemblance to papilledema. NEUROLOGIC DISEASE IN WOMEN 286 with anterior optic neuritis, a few vitreous cells may be observed, particularly in the vitreous overlying the optic disc. In such cases, sheathing of retinal veins also may be present, especially in patients with MS. Indeed, patients with acute optic neuritis and mild uveitis or retinal phlebitis have an increased risk of developing MS compared with patients with isolated optic neuritis (47,48). When the cellular reaction is extensive, however, etiolo- gies other than demyelination should be considered, including sarcoidosis, syphilis, cat scratch disease, and Lyme disease. Visual Function in the Fellow Eye Although bilateral, simultaneous acute optic neuritis is uncommon in adults, a relatively high percentage of patients with acute unilateral optic neuritis have abnormal visual function in their asymptomatic fellow eye, including decreased visual acuity, disturbances of color vision, and visual field defects (4,8). The majority of these deficits resolve over several months, suggesting that such abnormalities are caused by subclinical but concurrent acute inflammation. Diagnostic, Etiologic, and Prognostic Studies Studies in patients with presumed acute optic neuritis are usually performed for one of three reasons: (i) to determine if the cause of the optic neuropathy is something other than inflammation, particularly a compressive lesion; (ii) to determine if a cause other than demyelination is responsible for inflammation of the optic nerve; or (iii) to determine the visual and neurologic prognosis of optic neuritis. DIAGNOSTIC STUDIES. The major concern of a physician evaluating a patient with sudden visual loss associated with evidence of an optic neuropathy is whether the optic neuropathy is truly optic neuritis or is an acute manifestation of compression from an orbital, canalicular, or intracranial mass. Magnetic resonance imaging (MRI) is the neuroimaging technique of choice in the setting of presumed optic neuritis. It can identify with a high degree of sensitivity mass lesions such as aneurysms that can cause an acute optic neuropathy, and it also can detect evidence of demyelination in the optic nerve, including foci of T2-bright signal, areas of enhancement, and/or enlargement of all or a portion of the nerve (49–54) (Figure 19.4). These abnormalities are much less likely to be seen in patients with other forms of acute optic neuropathy, such as anterior ischemic optic neuropathy (54). ETIOLOGIC STUDIES. Although systemic and local infectious and inflammatory disorders can cause acute optic neuritis, the majority of such rare cases can be identified by a thorough history and confirmed by appropriate laboratory studies. Thus, in patients without a history of (or suggestive of) sexually transmitted disease, sarcoidosis, cat scratch disease, Lyme disease, systemic lupus erythematosus, or similar disorders, the likelihood of such a condition being responsible for acute optic neuritis is exceptionally low (4,5,55). Serologic tests, chest radiographs, and cerebrospinal fluid (CSF) analysis are unwarranted in such cases unless the patient’s course does not follow that of typical optic neuritis. The most important application of MRI in acute optic neuritis is the identification of signal abnormalities consistent with demyelination in the white matter of the brain, usually in the periventricular region (Figure 19.5) (9,19,56,57). The presence of such lesions suggests not only that the diagnosis of optic neuritis is correct but that the cause of the optic neuritis is demyelination. Another application of MR in patients with acute optic neuritis is MR spectroscopy. This technique can be used to determine changes in the concentration of N- acetyl-aspartate, a neuronal marker, which may reflect axon dysfunction or loss in normal-appearing white matter and may predict those patients who are at increased risk to develop MS (58). PROGNOSTIC STUDIES. A substantial percentage of patients with isolated optic neuritis develop MS within months to years after the onset of optic neuritis. It would be helpful if there were certain studies that FIGURE 19.3 Diffuse optic disc pallor after an attack of acute retrobulbar optic neuritis. Despite appearance of disc, the patient had 20/20 vision in this eye. OPTIC NEURITIS 287 could be performed in a patient with isolated optic neuritis that would allow the accurate prediction of the odds of subsequent development of MS. In fact, multiple studies indicate that the results of MRI in the patient with isolated acute optic neuritis correlate with the eventual development of MS (59–61). The more white- matter lesions that are present in the brain of a patient with acute optic neuritis, the greater the risk of MS over the subsequent 10 years (Figure 19.6) (61). Among patients with isolated optic neuritis in the ONTT, the cumulative percentage developing MS within 10 years of the onset of the optic neuritis was 39%; however, among patients with normal MRI, 24% developed MS compared with 64% of patients with more than three lesions (61). As noted above, MR spectroscopy may one day be useful in predicting which patients with optic neuritis are at increased risk to develop MS; however, there is at present insufficient information to determine if this is the case or if the technique could ever be cost-effective. Just as patients with acute optic neuritis and multiple white-matter lesions in the brain have a high risk of developing MS, certain patients with acute optic neuritis have a very low risk of developing MS. Patients with acute, painless anterior optic neuritis associated with a normal MRI scan have a probability similar to that of a normal age- and sex-matched population of developing optic neuritis over the succeeding 10 years (61). SEROLOGIC AND CEREBROSPINAL FLUID STUDIES. Immunologic abnormalities in the CSF are common in patients with optic neuritis, occurring in up to 79% of cases (55,57,62,63). As in patients with MS, CSF pleocytosis, elevated protein concentration, elevated levels of myelin basic protein, increased IgG ratio and IgG synthesis, oligoclonal bands, kappa-light chains, and increased concentrations of cytokines may be detected. Although the predictive value of these CSF findings for the development of MS is somewhat controversial, there appear to be certain CSF and even serologic risk factors that increase the likelihood that a patient with isolated optic neuritis will eventually develop MS. These include oligoclonal banding and elevated levels of myelin basic protein, CSF and serum elevations of cytokines, and positivity for certain HLA types (55,57,64–66). However, the robust predictive value of baseline MRI diminishes the relative usefulness of these other studies in the individual patient with acute optic neuritis who wishes to have some idea of prognosis for the development of MS. FIGURE 19.4 Magnetic resonance imaging (MRI) of the optic nerve in a young woman with acute optic neuritis affecting the right eye. A. Enhanced T1-weighted axial image shows extensive enhancement and diffuse enlargement of the right optic nerve from the back of the eye to the optic canal. B. Enhanced T1-weighted coronal image shows enhancing right optic nerve in cross section. AB NEUROLOGIC DISEASE IN WOMEN 288 Natural History The natural history of acute demyelinating optic neuritis is to worsen over several days to 2 weeks, and then to improve. The improvement initially is fairly rapid. It then levels off, but further improvement can continue to occur 1 year after the onset of visual symptoms (11,15,67). Among patients in the ONTT who received placebo, visual acuity began to improve within 3 weeks of onset in 79% and within 5 weeks in 93%. For most patients in this study, the recovery of visual acuity was nearly complete by 5 weeks after onset. The mean visual acuity 1 year after an attack of otherwise uncomplicated optic neuritis, is 20/15, and this level of vision remains for up to 10 years following the attack, unless the patient develops another process (61). Indeed, even patients who have recurrences of optic neuritis tend to experience a return of visual acuity to near normal levels, and fewer than 10% of patients have permanent visual acuity less than 20/40 10 years after an attack (61). Other parameters of visual function, including contrast sensitivity, color perception, and visual field, improve in conjunction with the improvement in visual acuity and also tend to remain stable over the subsequent decade (61). The visual improvement that occurs with acute optic neuritis tends to do so regardless of the degree of visual loss, although some correlation exists between the severity of visual loss and the degree of eventual recovery (5,12,68). In the ONTT, of the 167 eyes in which the baseline visual acuity was 20/200 or worse, only 10 (6%) had this level of vision 6 months later. Of 28 patients whose initial visual acuity in the affected eye was light perception or no light perception, 18 (64%) recovered to 20/40 or better (5,12). Factors such as age, gender, optic disc appearance, and pattern of the initial visual field defect do not appear to have any apprecia- ble effect on the visual outcome (15). Race does seem to be a factor, however, with Africans and African-Amer- icans tending to have a poorer outcome than Caucasians (26,27). Even though the overall prognosis for visual acuity after an attack of acute optic neuritis is extremely good, some patients have persistent severe visual loss after a single episode (4,5,19,69). Furthermore, patients with recovered optic neuritis frequently complain that their vision in the affected eye is “not right,” “remains fuzzy,” or that colors are “washed out” (70). One cause of these symptoms is probably a subtle abnormality in the visual field, in which patients experience an abnormally rapid disap- pearance of focal visual stimuli and abnormally rapid fatigue in sensitivity. These patients typically complain that when they look at something, it appears as if they have “holes” in their vision, some of which fill in while other new ones appear: the so-called “Swiss cheese” visual field Years after Randomization Life Table of Development of CDMS According to Baseline MRI Grade Log-Rank P-value < 0.0001 CDMS % 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 Grade 4 (N = 81) Grade 2–3 (N = 56) Grade 0–1 (N = 184) FIGURE 19.6 Graph showing relationship of risk of developing multiple sclerosis (MS) after an attack of acute optic neuritis and initial appearance of brain magnetic resonance imaging (MRI) in patients enrolled in Optic Neuritis Treatment Trial and followed for at least 10 years since the attack. Grade 0–1 indi- cates normal MR scan, whereas grades 2–4 indicate increas- ing numbers of white-matter lesions in the periventricular region. Note that the more lesions present at the time of an attack of acute optic neuritis, the higher the likelihood of developing MS over the subsequent 10 years. FIGURE 19.5 Magnetic resonance image (MRI) of the brain in a young woman at the time of an attack of acute retrobulbar optic neuritis. The patient had no history of previous neurologic symptoms and had no neurologic signs on examination. T1- weighted axial image shows multiple ovoid lesions in the periventricular white matter of both cerebral hemispheres. OPTIC NEURITIS 289 (71). This phenomenon is not limited to optic neuritis, however; it can occur in other optic neuropathies. Following an episode of acute optic neuritis, some patients describe transient visual blurring during exercise, during a hot bath or shower, or during emotional stress (72,73). This phenomenon, called Uhthoff’s symptom, also may occur with chronic or subclinical optic neuritis, with Leber hereditary optic neuropathy, and with optic neuropathies from other causes (74,75). Neverthe- less, it occurs in about 10% of patients after an attack of demyelinating optic neuritis and, when present, may be a marker for abnormal brain MRI and for the subsequent development of MS (76). Some patients with Uhthoff’s symptom note that their visual symptoms improve in colder temperatures or when drinking cold beverages. Two major hypotheses regarding Uhthoff’s symptom are that (i) the elevation of body temperature interferes directly with axon conduction and (ii) exercise or a rise in body temperature changes the metabolic environment of the axon which, in turn, interferes with conduction (77–79). Patients who experience an attack of acute optic neuritis have an increased risk of developing a recurrent attack in the same eye or an acute optic neuritis in the fellow eye (5,80). The risk of a recurrent or new attack of optic neuritis in patients enrolled in the ONTT over 10 years was 35%, with most of the patients experiencing recurrent or new events in the first 5 years after the initial attack (5,61,80). Patients who experience one or two recurrent attacks of acute optic neuritis usually experience substantial improvement in vision, often to normal; however, after multiple attacks of optic neuritis, visual function may improve little or not at all (81,82). Neurologic Prognosis Optic neuritis is the initial manifestation of MS in about 20% of patients (83). Several prospective studies have been performed to determine the potential for the development of MS in patients who experience an attack of acute optic neuritis. Although retrospective studies pro- vide figures ranging from 11.5% to 85% (20,24,81,82,84), a study from Germany reported that the risk of developing MS after an attack of acute optic neuritis was 54% over the subsequent 8 years (85). The LONS found that the overall risk of developing MS was almost 40% in patients followed 10 years after an attack of acute optic neuritis (61), and an Australian group of investigators reported a 52% risk of MS after acute optic neuritis in a 13-year prospective study (86). Other prospective studies indicate that the risk of MS eventually increases to about 75% in women and 34% in men with 15 to 20 years of follow-up (87–89). Among 95 incident cases of acute optic neuritis in Olmstead County, Minnesota, the estimated risk of MS was 39% by 10 years, 49% by 20 years, 54% by 30 years, and 60% by 40 years (25). The average time interval from an initial attack of optic neuritis until other symptoms and signs of MS develop varies considerably; however, most studies indicate that the majority of persons who develop MS after optic neuritis do so within 7 years of the onset of visual symptoms (83,61). It therefore seems appropriate to consider most cases of acute optic neuritis a limited form of MS and to counsel patients appropriately (90). We believe that most patients should be told about the relationship between optic neuritis and MS and that this conversation should include a frank discussion of MS and its prognosis. Most patients appreciate this approach and handle this information much better than most physicians anticipate. Indeed, if the physician does not discuss the association of optic neuritis and MS with his or her patient, the patient will almost certainly find out about it from a friend, acquaintance, another physician, or the Internet. Certain risk factors increase the likelihood that a patient with acute optic neuritis will eventually develop MS. As noted above, the most highly predictive baseline factor is multiple lesions in the periventricular white matter on MRI (60). Gender also appears to be a risk factor, but only in patients with a normal MRI. Among patients in the ONTT who had a normal MRI at the time of their attack of acute optic neuritis, 8% of men and 28% of women have developed evidence of MS (61). Other risk factors for the development of MS in both men and women are Caucasian race, a family history of MS, a history of previous ill-defined neurologic complaints, a previous episode of acute optic neuritis, and winter onset of optic neuritis (10,17). None of these factors predicts the development of MS as much as the results of MRI, however (60). Although the evidence of immunologic dysfunction (especially oligoclonal banding) in the CSF is common in patients with acute optic neuritis, whether or not their presence in patients with clinically isolated optic neuritis increases the risk for the subsequent development of MS remains controversial. Studies indicate that 25 to 50% of patients with isolated acute optic neuritis and abnormal CSF remain free of neurologic manifestations of MS for many years (if not for life), whereas 10 to 50% of patients with acute optic neuritis and normal CSF develop other manifestations of MS during the same period (55,91). In view of these findings, it seems that CSF abnormalities alone are not a primary risk factor in determining whether a patient with acute optic neuritis eventually develops clinical evidence of disseminated demyelination. Considerable evidence suggests that genetic factors play a role in the development of MS (92–95). This is based on the familial incidence of the disease, twin studies, and HLA typing patterns. The major predisposing genes in MS are the HLA class II molecules, in particular the haplo- NEUROLOGIC DISEASE IN WOMEN 290 type HLA-DR2, which is especially common among MS patients of Northern and Western European ancestry. This haplotype represents a susceptibility locus in specific populations, but a direct contribution to the pathogenesis of the disease is likely small, and presence of the haplotype is not necessary for disease expression in all patients. Indeed, patient groups with MS in different ethnic populations are immunogenetically distinct and thus have HLA polymorphisms that are common within each population but that are different from other populations. HLA type does not seem to strongly influence the subsequent risk for MS in patients with isolated optic neuritis, however. Although the combination of HLA typing and MRI may slightly increase predictive ability, MRI is a much stronger and reliable indicator of risk. Most studies suggest that patients in whom acute optic neuritis is the initial manifestation of MS tend to have a more benign course than patients in whom MS presents with nonvisual symptoms and signs. Other studies, however, report no difference in the eventual outcome of the disease. Treatment Several theoretical reasons exist to consider treating patients with acute optic neuritis: i) to improve visual outcome, ii) to speed visual recovery, and iii) to protect the patient against the development of MS (96,97). No drugs have been shown to improve the ultimate visual prognosis after an attack of acute optic neuritis compared with the natural history of the disorder. Specif- ically, the ONTT, the LONS, and similar studies performed in Japan and Europe indicate that the treatment of acute optic neuritis with a 2-week course of low-dose prednisone (1 mg/kg/day) does not improve short- or long-term visual outcome and does not speed visual recovery (5,19,61,98). In addition, this treatment is associated with a higher incidence of recurrent and new attacks of optic neuritis (5,61). Thus, it is inappropriate to treat any patient with acute, presumed demyelinating optic neuritis with this regimen. Treatment with 1 gram of methylprednisolone sodium succinate for 3 days, in either divided doses or a single daily dose, followed by a 2-week course of lower- dose prednisone (1 mg/kg/day) speeds recovery of visual function by 3 to 6 weeks, although it does not affect visual outcome (5). As noted earlier, a substantial percentage of patients who experience an attack of acute optic neuritis subsequently develop MS. In addition, MS may present as a soli- tary nonvisual manifestation, such as an episode of weak- ness or numbness of an extremity or double vision from an oculomotor nerve paresis or internuclear ophthalmo- plegia. The Controlled High-Risk Subjects Avonex ® Mul- tiple Sclerosis (CHAMPS) study was designed to determine if interferon beta-1a has any effect on the development of MS in patients who experience an initial acute demyelinating episode (99). The CHAMPS study followed a randomized, double-blind, placebo-controlled design with a total of 383 patients enrolled between 1996 and 2000. All subjects had experienced an initial, acute demyelinating event, 50% of whom had acute optic neuritis and had at least two white-matter lesions consistent with prior subclinical demyelination in the brain by MRI. All patients were first treated according to the ONTT protocol within 14 days of symptom onset with IV methylprednisolone (1 gm/day) for 3 days, followed by oral prednisone (1 mg/kg/day) for 11 days, followed by a rapid taper. Dur- ing the second week of steroid therapy, about 50% of the patients began receiving weekly intramuscular injections of Avonex ® (30 mcg), whereas the remaining 50% began receiving weekly IM placebo injections. The primary outcome measure chosen for the CHAMPS study was the rate of development of clinically definite MS defined as a new neurologic lesion in a different central nervous system (CNS) location lasting more than 48 hours, progressive neurologic disease following 1 month of stable or improved symptoms, or an increase in Kurtzke Expanded Disability Status Scale (EDSS) of 1.5 points without relapse. The secondary outcome measure of the study was the effect of Avonex ® on objective MRI findings. The CHAMPS study was terminated early when an interim preplanned review of the data showed that Avonex ® had a beneficial effect in slowing the rate of development to clinically definite MS (CDMS). Most patients had been enrolled in the study for 24 months, and the positive effect of interferon beta-1a had been noted at each 6-month follow-up visit. Kaplan-Meier analysis revealed that Avonex ® reduced the development to CDMS in these patients by 43% compared with placebo (p=0.002). The cumulative probability of developing CDMS after 3 years demonstrated a rate ratio of .56 (p=0.002) and an adjusted rate of .49 (pϽ0.001), with a 35% chance of developing MS on the drug versus a 50% chance on placebo. Flu-like symptoms were seen in the Avonex ® -treated group, but the safety and tolerabil- ity of Avonex ® was comparable to placebo (99). With regard to the second outcome measure, Avonex ® was associated with a 1% increase in the volume of lesions seen on MRI versus a 16% increased volume seen with placebo after 18 months. There were also fewer new and enlarging lesions and 67% fewer enhancing lesions in the treated group compared with the placebo group. The results of the CHAMPS study indicate that treatment with Avonex ® shortly after an initial demyelinating event in patients with white-matter brain lesions on MRI substantially reduces the risk of the development of CDMS in such patients (99,100). Another clinical trial in Europe, PRISMS (Preven- tion of Relapses and Disability by Interferon beta-1a Sub- OPTIC NEURITIS 291 cutaneously in Multiple Sclerosis), was a double-blind, placebo-controlled study of 560 patients with EDSS scores of 0 to 50, from 22 centers in nine countries (101). These patients were randomly assigned to receive subcu- taneous recombinant interferon beta-1a (Rebif ® ) in a dose of 22 mcg (n=189), the same drug but in a dose of 44 mcg (n=184), or placebo (n=187) 3 times a week for 2 years. Neurologic examinations were performed on all patients every 3 months. All patients had MRI twice yearly, and 205 patients had monthly scans during the first 9 months of treatment. It was found that the relapse rate was significantly lower at 1 and 2 years with both doses of Rebif ® compared with placebo. In addition, time to first relapse was prolonged to 3 and 5 months in the 22 mcg and 44 mcg groups, respectively, and the proportion of relapse-free patients was significantly increased (pϽ0.05). Rebif ® also delayed the progression in disability and decreased accumulated disability compared with placebo; the accumu- lation of burden of disease and number of active lesions on MRI was lower in both treated groups than in the placebo group (101). PRISMS 4 reported the 3- and 4-year follow-up of patients in the original study (102). This report also included 172 randomized patients who initially received placebo but who were subsequently placed on Rebif ® in a dose of 22 or 44 mcg 3 times a week. The investigators concluded that clinical and MRI benefit continued for both doses up to 4 years, with evidence of a dose response; however, outcomes were consistently better for patients treated all 4 years with Rebif ® than for patients in the crossover groups (102). Trials with a third form of interferon beta— Betaseron ® —have shown results similar to those of the PRISMS and CHAMPS studies (103). Several therapies other than interferon beta have been or are currently being evaluated in patients with optic neuritis. For example, Noseworthy et al. (104) found that the administration of intravenous immunoglobulin (IVIg) to patients with persistent visual loss after an attack of acute optic neuritis did not improve vision to a degree that merited general use. Management Recommendations In a patient with the typical features of optic neuritis, a clinical diagnosis can be made with a high degree of cer- tainty without the need for ancillary testing. (See Table 19.2). Brain MRI is a powerful predictor of the short-term probability of MS (for at least the first 10 years) and should be considered for all patients with acute optic neuritis. We would avoid the use of low-dose oral prednisone alone to reduce the risk of recurrent or new attacks of optic neuritis, but we would consider treating patients with abnormal MRIs and patients with normal MRIs who wish to experience a greater speed of recovery with 1 g of methylprednisolone per day for 3 days, followed by a 2-week course of oral prednisone in a dose of 1 mg/kg/day (105,106). We and others also recommend referral of all patients with white-matter lesions on MRI to a neurologist for the consideration of treatment with interferon beta-1a to reduce the risk of subsequent MS (105-108). CHRONIC DEMYELINATING OPTIC NEURITIS It was once stated that, for all intents and purposes, chronic optic neuritis does not occur. The reason for this dogmatic statement was that many patients with mass lesions compressing the intracranial portion of the optic nerve were being diagnosed as having chronic optic neuritis, thus leading to the delayed treatment of the underlying lesion, with resultant permanent visual loss and even death in some cases. Thus, the statement that chronic optic neuritis was never a tenable diagnosis was made in an effort to raise the consciousness of the majority of physicians to look for another potentially treatable cause of unilateral progressive optic neuropathy. In fact, chronic optic neuritis not only occurs but is not uncommon, occurring in about 10% of patients with MS. There are two types of chronic optic neuritis, both of which occur insidiously. One does not progress, whereas progressive visual loss occurs in the other. Some patients with chronic MS are aware of their visual disturbance, whereas others are unaware of the problem but can be shown to have an optic neuropathy by clinical testing (e.g., visual acuity, color vision, visual fields, ophthalmoscopy) (109–111). Most patients with chronic unilateral optic neuritis develop visual symptoms after other signs and symptoms of MS have developed, and it is for this reason that the percentage of patients with MS and evidence of chronic progressive optic neuritis increases the longer patients are followed. Nevertheless, slowly progressive visual loss or TABLE 19.2 Management of Acute Optic Neuritis in an Adult • Avoid low-dose oral steroids • Obtain a brain MRI before and immediately after IV injection of a paramagnetic contrast agent • Use high-dose IV/low-dose oral steroid regimen in patients with an abnormal MRI or those in need of rapid visual recovery, such as monocular patients or those with occupational requirements • Consider treatment with interferon beta-1a for patients with abnormal MRI scan to reduce the risk of developing clinically definite MS [...]... inflammatory demyelinating polyneuropathy N Engl J Med 1986;314:461–465 43 Hahn AF, Bolton CF, Zochodne D, Feasby TE Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy A double-blind, placebo-controlled, cross-over study Brain 1996;119: 10 67 1 077 310 NEUROLOGIC DISEASE IN WOMEN 44 Chaudry V, Escolar DM, Cornblath DR Worsening of multifocal motor neuropathy during pregnancy... DISEASE IN WOMEN 65 Söderström M, Link H, Xu Z, et al Optic neuritis and multiple sclerosis: anti-MBP and anti-MBP peptide antibody-secreting cells are accumulated in CSF Neurology 1993;43:1215–1222 66 Link J, Söderström M, Kostulas V, et al Optic neuritis is associated with myelin basic protein and proteolipid protein reactive cells producing interferon-gamma, interleukin-4, and transforming growth... 1992;86:3 17 322 63 Söderström M, Lindqvist M, Hiller J, et al Optic neuritis: findings on MRI, CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up J Neurol 1994;241:391–3 97 64 Deckert-Schlüter M, Schlüter D, Schwendemann G Evaluation of IL-2, sIL2R, IL-6, TNF-a, and IL-1b in serum and CSF of patients with optic neuritis J Neurol Sci 1992;113:50–54 294 NEUROLOGIC DISEASE. .. porphyrias in young to middle-aged women In acute intermittent porphyria, variegate porphyria, and hereditary coporphyria, enzymatic defects affecting the heme biosynthesis pathway result in excessive production of porphyrins and their precursors Precipitating factors, such as sex hormones, induce delta-aminolevulinic acid (ALA) synthase, the rate-limiting enzyme in heme biosynthesis, leading to the... Uhthoff’s symptom in optic neuritis: relationship to magnetic resonance imaging and development of multiple sclerosis Ann Neurol 1991;30:180–184 77 Rasminsky M The effects of temperature on conduction in demyelinated single nerve fibers Arch Neurol 1 973 ; 28:2 87 292 78 Bode DD The Uhthoff phenomenon Am J Ophthalmol 1 978 ;85 :72 1 72 2 79 Selhorst JB, Saul RF, Waybright EA Optic nerve conduction: opposing effects... contributing factor Symptoms persist for months and subside with the discontinuation of lactation Reassurance, proper positioning, and nocturnal splinting are often the only therapy needed Guillain-Barré Syndrome GBS has an increased incidence in the 2 weeks following delivery ( 27) Possible explanations include exposure to certain risk factors at the end of pregnancy and an increased cell-mediated... followed by intravenous gammaglobulin in the treatment of Guillain-Barre syndrome Lancet 19 97; 349: 225–230 35 Rockel A, Wissel J, Rolfs A GBS in pregnancy—an indication for Caesarian section? J Perinat Med 1994;22: 393–398 36 Brooks H, Christian AS, May AE Pregnancy anaesthesia and Guillain-Barre syndrome Anaesthesia 2000;55: 894–898 37 Feldman JM Cardiac arrest after succinylcholine administration in a pregnant... of the thigh, meralgia paresthetica 300 NEUROLOGIC DISEASE IN WOMEN meralgia paresthetica Pregnancy is commonly an inciting factor Symptoms usually begin in the last trimester of pregnancy (24) Increased abdominal protuberance and weight gain may cause a stretch injury to the nerve, alter the angle of the nerve through the inguinal ligament causing mechanical injury, or entrap the nerve as it penetrates... H Pathologic findings in nerve and muscle biopsies from 47 women with silicone breast implants Neurology 1999;53:293–2 97 The Commonwealth Fund 1998 Survey of Women s Health Women s Health Issues 2000;10:35–38 Massey JM Domestic violence in neurologic practice Arch Neurol 1999;56:659–660 21 Muscle Disease in Women James M Gilchrist, MD ny discussion of muscle disease in women is dominated by the effects... (SSCP); (DOVAMS-S)] can detect mutations in 78 .5% of patients with previously unidentified mutations (21) This bloodbased method improves the overall success rate in finding the genetic defect in DMD and BMD to 93% In the remaining 7% of families, DNA linkage analysis is indicated (18) This necessitates obtaining blood from members of the family, especially affected males, if alive Prenatal testing can be . developing clinically definite MS NEUROLOGIC DISEASE IN WOMEN 292 complaints of blurred or distorted vision in one or both eyes are the first symptoms of underlying neurologic disease in some. of the disease, twin studies, and HLA typing patterns. The major predisposing genes in MS are the HLA class II molecules, in particular the haplo- NEUROLOGIC DISEASE IN WOMEN 290 type HLA-DR2,. myelin basic protein and proteolipid protein reactive cells producing interferon-gamma, interleukin-4, and transforming growth factor-b. J Neuroim- munol 1994;49:9–18. 67. Keltner JL, Johnson

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