490 Chapter 15 CSF appearances Particles Bloody CSF RBCs of at least 6000 cells/mm 3 Xanthochromia CSF, pink-tinged RBCs of between 500–6000 cells/mm 3 Hazy, opalescent Pleocytosis RBCs > 400 cells/mm 3 WBCs > 200 cells/mm 3 Greenish tinged Purulent fl uid Empyema Oily emulsion After the intrathecal injection of iophendylate (Pantopaque) Sudanophilic globules Fat embolism RBCs – red blood cells, WBCs – white blood cells. Elevated CSF glucose Elevated CSF glucose can be seen in: 1 Premature infants and newborns ◆ The CSF:blood glucose ratio may be as high as 0.8. ◆ The mechanism is still unclear. 2 Hyperglycemia states Low CSF glucose (hypoglycorrhachia) 1 Infections of the CNS ◆ Commonly seen in bacterial, tuberculous, and fungal infections, particularly meningitides. ◆ The level can be as low as 5 mg/dl in purulent bacterial meningitis, but is usu- ally in the range between 20 and 40 mg/dl. • An increase in CSF glucose is of no diagnostic signifi cance apart from refl ecting the presence of hyperglycemia within 4 hours prior to the LP. • With increasing blood glucose, the CSF glucose is secondarily elevated, but to a lesser degree than in the blood. This observation is clinically important as hyperglycemia may mask the occurrence of relatively low CSF glucose, which is indicative of bacterial meningitis. • The CSF glucose is derived solely from the plasma and its concentration is dependent upon the blood level as well as the rate of glucose metabolism by the brain. • The CSF:blood glucose ratio is about 0.6. Therefore, the normal CSF glucose is usually between 45 and 80 mg/dl when a blood glucose is between 70 and 120 mg/dl. Values below 40 mg/dl are considered abnormally low. Diagnostic Tests 491 ◆ Viral infections do not usually cause low CSF glucose except in acute mumps meningoencephalitis, where low CSF glucose can be seen in 25% of cases. ◆ CSF glucose is not low in neurosyphilis, especially in acute syphilitic meningitis. 2 Carcinomatous meningitis ◆ Examples include lymphoma, leukemia, metastasis carcinomas, and melanoma. 3 Infl ammatory disorder of the CNS ◆ Examples include sarcoidosis, vasculitis, and granulomatous infi ltrations of the meninges. 4 Subarachnoid hemorrhage ◆ The maximal fall of CSF glucose is in between the fi rst and sixth day after hemorrhage, and it depends on the extent of rebleeding. Elevated CSF protein 1 Mildly increased CSF protein (45–75 mg/dl) ◆ A slight increase in CSF protein is relatively common in many diseases. Al- though it does not suggest any specifi c disorder, it is characteristic of disor- ders associated with vasogenic brain edema and increased permeability of the blood-brain barrier. ◆ Examples include meningitis, multiple sclerosis, epilepsy, brain tumors, neu- rosyphilis, and brain trauma 2 Moderately increased CSF protein (75–500 mg/dl) ◆ Different pathological processes affecting central and peripheral nervous sys- tem can result in moderately high CSF protein. • Almost all the proteins normally present in CSF are derived from the serum, with the exception of the beta and gamma trace proteins, tau protein, myelin basic protein, and glial fi brillary acidic protein, which appear to originate from the brain itself. • An increase in the CSF protein is the single most useful change in the chemical composition of the fl uid. However, it serves as a nonspecifi c indicator of disease. • Causes of elevated CSF protein vary depending upon the degree of protein elevation in the CSF. While a slight increase in protein content (45–75 mg/dl) is common in many diseases, a very large increase in CSF protein (500–3600 mg/dl) suggests a few certain diagnoses. Therefore, the degree of increased CSF protein is a useful laboratory value to help confi rm or exclude certain neurological disorders. • When a high CSF protein is obtained, which is unexpected and unexplained, physicians should consider the possibility of myxedema, neurofi broma in the subarachnoid space, and radiculoneuropathy. 492 Chapter 15 ◆ Common causes include: 2.1 Infectious causes ■ Bacterial meningitis ■ Tuberculous meningitis (usually >100 mg/dl) ■ Brain abscess ■ Neurosyphilis 2.2 Infl ammatory disorders ■ Aseptic meningitis ■ Polyneuritis 2.3 Metabolic disorders ■ Myxedema ■ Uremia ■ Alcoholism 3 Greatly increased CSF protein (>500 mg/dl) ◆ The elevated CSF protein of >500 mg/dl is infrequent. ◆ When this level is obtained, a few possible diagnoses should be considered: ■ Spinal block due to cord tumors ■ Arachnoiditis ■ Subarachnoid hemorrhage ■ Some cases of purulent meningitis and tuberculous meningitis Low CSF protein 1 CSF leaks ◆ CSF extradural leaks occurring following LP can result in mildly low CSF pro- tein in some cases. ◆ Usually associated with post-LP headache. 2 Removal of a large CSF volume ◆ For example, for cytologic study. 3 Pseudotumor cerebri or benign intracranial hypertension ◆ About one-third of patients with pseudotumor cerebri have low CSF protein. 4 Acute water intoxication ◆ Patients with acute water intoxication may have increased intracranial pres- sure resulting in low CSF protein. • Protein level in lumbar CSF between 3 and 20 mg/dl is considered below the normal range. • The possible mechanism resulting in low CSF protein involves an increased rate of protein removal to the venous system. • Patients with severe hypoporteinemia or malnutrition do not have low CSF protein. Diagnostic Tests 493 5 Others ◆ Normal young children aged between 6 months and 2 years. ◆ Hyperthyroidism, with a return to normal average level after therapy. ◆ Leukemias (no clear explanation). CSF eosinophilia 1 Parasitic diseases ◆ Cysticercosis ◆ Trichinosis ◆ Toxocara cati ◆ Angylostrongylus cantonensis ◆ Gnathostoma spinigerum ◆ Larva migrans 2 Infl ammatory disorders ◆ Tuberculous meningitis ◆ Neurosyphilis ◆ Subacute sclerosing panencephalitis ◆ Chemical meningitis, for example, following myelography, pneumoencepha- lography, subarachnoid hemorrhage, intrathecal administration of radioiodi- nated serum albumin and penicillin 3 Others ◆ Tumors, e.g. Hodgkin disease ◆ Obstructive hydrocephalus with shunt ◆ Allergic reaction to medications, e.g. penicillin Specialized CSF tests CSF oligoclonal bands • Eosinophils are not generally seen in normal fl uids, although a single cell can be seen occasionally with a normal total cell count using the cytocentrifuge. • The most common cause of a prominent CSF eosinophilia (usually 5–10%) is parasitic disease. Infl ammatory diseases account for the second most common cause of CSF eosinophilia, although the eosinophilia is usually of a lesser degree (2–4%). • The use of a variety of supporting media, including agarose gels and polyacrylamide gels, for the electrophoretic separation provides a visual separation of homogeneous immunoglobulins as bands when stained appropriately. 494 Chapter 15 Oligoclonal bands are commonly seen in the following neurological conditions: 1 Multiple sclerosis (MS) ◆ Oligoclonal bands are seen in 83–94% of patients with defi nite MS. 2 Subacute sclerosing panencephalitis (SSPE) ◆ Oligoclonal bands are present in 100% of patients with SSPE. 3 CNS infections ◆ 50% of patients with bacterial, viral, fungal, or spirochetal CNS infections have oligoclonal bands in the CSF. 4 CNS infl ammatory disorders (the percentage of positive CSF oligoclonal bands in these conditions vary). ◆ CNS vasculitis ◆ Neurosarcoidosis ◆ CNS lupus ◆ Guillain-Barré syndrome (GBS) ◆ Behçet disease Elevated CSF myelin basic protein • Three patterns of bands can be observed in the gamma region: monoclonal, polyclonal, and oligoclonal (a few, 2–5 bands). • The oligoclonal bands imply that each band represents a homogeneous protein secreted by a single clone of plasma cells. A single oligoclonal band is commonly seen in otherwise normal CSF of normal subjects. However, two or more bands are considered abnormal and their presence usually suggests an immune-mediated process in the CNS. • Myelin basic protein (MBP) is a product of oligodendroglia. It is an antigen in the induction of experimental allergic encephalomyelitis (EAE). When there is damage of the CNS, MBP or its peptides, which represent an important part of the myelin, can appear in the cerebrospinal fl uid (CSF), blood, and urine. • Its concentration in normal CSF is very low, <0.4 mg/dl. • While it is suggested that elevated CSF MBP may be an indicator for multiple sclerosis, elevated CSF MBP has been found in many other conditions that cause nonspecifi c myelin breakdown, as listed below, suggesting that it has limited diagnostic usefulness. Therefore, elevated CSF MBP should not be used as a sole criterion in the diagnosis of multiple sclerosis. • According to McDonald diagnostic criteria for multiple sclerosis, positive CSF defi nes the presence of oligoclonal bands or a raised IgG index, not by the presence of MBP. CSF MBP cannot serve as a reliable marker of activity in multiple sclerosis. Diagnostic Tests 495 The list below only includes the common causes of elevated CSF MBP. 1 Demyelination/multiple sclerosis ◆ Approximately only 20% of MS patients have elevated CSF MBP. ◆ Specifi c correlations have not been established between the CSF IgG level, the presence of oligoclonal bands, the MBP concentration, and the antibody re- sponse to MBP. 2 Stroke: resulting in very high CSF MBP 3 Trauma: resulting in very high CSF MBP 4 Tumors 5 CNS infections 6 Polyneuropathies 7 Dementias 8 Leukodystrophies CSF 14-3-3 protein Conditions that may result in positive CSF 14-3-3 protein 1 Sporadic Creutzfeldt-Jakob disease ◆ Sensitivity varies from 53% to 96%, depending on studies. ◆ The test is less sensitive in patients with variant CJD, but high specifi city means that the detection of CSF 14-3-3 in a patient with suspected vCJD has a high positive predictive value. • The 14-3-3 protein is a normal neuronal protein that is released into CSF in association with acute neuronal injury. The 14-3-3 proteins are part of a family of regulatory molecules, located predominantly in the cytoplasm. These proteins are found in large quantities in the cerebral tissue and are involved in several key regulatory processes, including cellular death and apoptosis. Therefore, it is a nonspecifi c marker for extensive neuronal injury. • Although it has been suggested that the presence of 14-3-3 protein in CSF is a reliable marker for sporadic Creutzfeldt-Jakob disease (sCJD) and the World Heath Organization and American Academy of Neurology have recommended the use of this test to either confi rm or exclude an sCJD diagnosis under appropriate clinical circumstances, more recent studies have found only modestly positive sensitivity in sCJD and reported more false- positive conditions. False-negative results can also occur. • It is recommended that the CSF 14-3-3 protein test be ordered in patients who have a high degree of clinical suspicion of sCJD. The negative test result does not always rule out the diagnosis of sCJD. The presence of the CSF 14- 3-3 protein in an appropriate clinical context reinforces the sCJD clinical diagnosis but may not be able to differentiate sCJD from other causes of rapidly progressive dementia. 496 Chapter 15 ◆ The value of CSF 14-3-3 in GH-related iatrogenic CJD depends on the clinical stage of the disease, being highly sensitive in a later stage. 2 Meningoencephalitis 3 Dementias ◆ Multi-infarct dementia ◆ Dementia of Alzheimer disease ◆ Diffuse Lewy body disease dementia 4 Cerebral neoplasms 5 Various causes of encephalopathy 6 Anoxic brain damage 7 Down syndrome 8 Paraneoplastic syndromes 9 Transverse myelitis CSF angiotensin-converting enzyme (CSF ACE) Various neurological conditions are associated with altered levels of CSF ACE. • Elevated CSF ACE ◆ Neurosarcoidosis (55%) ◆ Systemic sarcoidosis (5%) ◆ Guillain-Barré syndrome ◆ Bacterial and viral meningitis ◆ Brain tumors ◆ Behçet disease • Decreased CSF ACE ◆ Alzheimer disease ◆ Parkinson disease ◆ Progressive supranuclear palsy • Angiotensin-converting enzyme (ACE) catalyzes the formation of angiotensin II by cleaving the C-terminal histidylleucine dipeptide from angiotensin I. • The indications are that ACE is involved in an autonomous renin- angiotensin system of the brain that participates in physiologic processes inside the brain. Since ACE is produced by the epitheloid cells of the sarcoid granulomas, it is implicated as a test for both systemic sarcoidosis and neurosarcoidosis. However, ACE concentration in the CSF can be high and low in various other conditions. • Elevated levels of serum or CSF ACE are not specifi c for neurosarcoidosis. Diagnostic Tests 497 Blood/serum tests Autoantibodies in neurological disorders Autoantibodies Suggested clinical diagnosis Rheumatoid factor This test is rather nonspecifi c but sensitive (90%) in rheumatoid arthritis ANA Nonspecifi c (high titer may suggest the presence of autoimmune disorders, >90% of SLE patients have a high ANA titer) Double-stranded DNA (peripheral pattern) SLE Active renal diseases Single-stranded DNA (peripheral pattern) Sensitive for SLE but nonspecifi c Antihistone (homogeneous pattern) Drug-induced lupus SLE Anti-Sm (speckled pattern) Specifi c for SLE, renal and CNS disorders Anti-RNP (speckled pattern) Polymyositis with MCTD SLE Scleroderma Sjögren syndrome Anti-Jo-1 Polymyositis with interstitial lung disease Anti-PM-Scl Polymyositis with scleroderma Anti-Ro (SSA) SLE Sjögren syndrome Anti-La (SSB) Primary Sjögren syndrome cANCA Wegener granulomatosis Microscopic periarteritis • Many autoantibodies are useful in clinical diagnosis of many neurological disorders that may be autoimmune in origin. These include many infl ammatory disorders, vasculitides, neuropathies, myopathies, myasthenia gravis, and paraneoplastic syndromes. • However, the diagnosis of autoimmune disorders should not be made solely on the positivity of the test. False-positive results do occur with many autoantibodies. In addition, the signifi cance of each antibody also depends on the titer level as well as clinical presentations. Most of the time, additional tests are required in conjunction with relevant autoantibodies before a fi nal diagnosis can be made. Continued 498 Chapter 15 Autoantibodies Suggested clinical diagnosis pANCA Polyarteritis nodosa Glomerulonephritis Anti-Scl-70 ANA (nucleolar pattern) Progressive systemic sclerosis (anti-Scl-70 is specifi c but insensitive) Antiphospholipid SLE Systemic autoimmune disorders Ach receptor Anti-striated Myasthenia gravis VGCC Lambert-Eaton syndrome Anti-GM 1 ganglioside Lower motor neuron syndrome that resembles amyotrophic lateral sclerosis Anti GAD Stiff man syndrome IDDM Cerebellar ataxias Rarely – epilepsy ANA – antinuclear antibody, SLE – systemic lupus erythematosus, MCTD – mixed connective tissue disease, cANCA – anti-neutrophilic cytoplasmic antibody, cytoplasmic pattern, pANCA – anti-neutrophilic cytoplasmic antibody, perinuclear pattern, RNP – ribonuclear protein, VGCC – voltage-gated calcium channel, GAD – glutamic acid decarboxylase. Clinical indications for chromosomal analysis in pediatrics 1 Head and neck abnormalities ◆ Hypertelorism or hypotelorism ◆ High nasal bridge ◆ Microphthalmia ◆ Mongoloid slant (especially in non-Asians) ◆ Occipital scalp defect ◆ Small mandible ◆ Small or fi sh mouth (hard to open) • Abnormalities in chromosome structure or number are the single most common cause of severe mental retardation, but they still comprise only one-third of total causes. • Abnormalities of autosomal chromosomes are frequently associated with infantile hypotonia. • Clinical features that suggest chromosomal aberrations are listed below. These features, when present in combination with global developmental delay, should lead the clinician to consider genetic analysis in these patients and/or their families. Diagnostic Tests 499 ◆ Small or low-set ear ◆ Upward slant of eyes ◆ Webbed neck 2 Limb abnormalities ◆ Abnormal dermatoglyphics ◆ Low-set thumb ◆ Overlapping fi ngers ◆ Polydactyly ◆ Radial hypoplasia ◆ Rocker-bottom feet 3 Genitourinary abnormalities ◆ Ambiguous genitalia ◆ Polycystic kidney (Ref: Fenichel GM. Clinical Pediatric Neurology, 4th edition, 2001. Philadelphia, WB. Saunders.) Ceruloplasmin The following conditions can cause false-positive low ceruloplasmin: 1 Hypoproteinemic states ◆ Nephrotic syndrome ◆ Protein-losing enteropathy • Ceruloplasmin is an acute phase protein. It is a ferroxidase that has an essential role in iron metabolism and contains greater than 95% of the plasma copper. • Because ceruloplasmin accounts for 95% of the serum copper, measurement of this value will also be abnormally low in patients with Wilson disease (usually <20 mg/dl, and a level >35 mg/dl almost excludes the diagnosis). On the contrary, the low level of ceruloplasmin can also be seen in the conditions listed below. • Therefore, the diagnosis of Wilson disease cannot be based solely on the low level of ceruplasmin. • A separate condition, aceruloplasminemia, is an inherited disorder of iron metabolism caused by the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of adult-onset neurologic disease, retinal degeneration, and diabetes mellitus. The neurological symptoms, which include involuntary movements, ataxia, and dementia, refl ect the sites of iron deposition. [...]... Neurological Differential Diagnosis: A Prioritized Approach Roongroj Bhidayasiri, Michael F Waters, Christopher C Giza, Copyright © 2005 Roongroj Bhidayasiri, Michael F Waters and Christopher C Giza Appendix A Clinical Pearls Medications 510 Emergency neurological medications Status epilepticus Cerebral edema Acute stroke Spinal cord pathology Drug overdose Malignant hyperthermia Anticoagulation 510. .. non-compressible vessel, surgery, or organ biopsy in past 10 days, serious GI bleed in last 3 months, serious trauma or CPR in past 10 days, diabetic proliferative retinopathy, anticoagulation, platelets 185 or DBP > 110) despite conservative control measures (topical NTG or labetolol up to 20 mg IV), bacterial endocarditis, 10. .. absence of toxic side-effects • Liver transaminases should be periodically monitored, especially after initial dosing • Women of child-bearing age should always be co-treated with folate • Long-term side-effects may include coarsening of facial features, hirsutism, and gingival hyperplasia • Phenytoin is metabolized via the cytochrome P450 oxidase system (CYP2C9 and CYP2C19 isoforms in particular) The metabolism... 2.5–3.5 3–4 2–3 2–3 2–3 Dosing Weight Day 1 Day 2 Day 3 Day 4+ 5 mg 7.5 mg 10 mg 12.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 5 mg 5 mg 7.5 mg 7.5 mg 2.5 mg (adjust PRN) 2.5 mg (adjust PRN) 2.5 mg (adjust PRN) 2.5 mg (adjust PRN) Loading method 85 years 50–75 kg 75 100 kg >100 kg Nonloading method 85 years 50 100 kg >100 kg 2 mg/day 2.5 mg/day 4 mg/day Check INR in 5 days and adjust PRN... activity of daily living AED antiepileptic drug ALS amyotrophic lateral sclerosis ALT alanine aminotransferase Anti-MAG anti-myelin-associated glycoprotein ASD atrial septal defect AST aspartate aminotransferase CABG coronary artery bypass graft CBC complete blood count CMT charcot-Marie-Tooth disease CMV cytomegalovirus CO carbon monoxide CPK creatinine phosphokinase CPR cardiopulmonary resuscitation... evoked potential VF visual field Vim ventral intermediate nucleus VP ventriculo-peritoneal VSD ventricular septal defect Neurological Differential Diagnosis: A Prioritized Approach Roongroj Bhidayasiri, Michael F Waters, Christopher C Giza, Copyright © 2005 Roongroj Bhidayasiri, Michael F Waters and Christopher C Giza Index 1 4-3 -3 protein, lumbar puncture 495–6 abducens nerve 9, 18–19 absence seizures... remains elevated >10 No bleeding Administer 3 mg vitamin K sq Reassess in 6 hours Repeat PRN >20 Serious bleeding Administer 10 mg vitamin K sq with fresh frozen plasma as needed Reassess in 6 hours Repeat PRN >20 Life-threatening bleeding Administer 10 mg vitamin K sq along with sq prothrombin complex concentrate Reassess in 6 hours Repeat PRN Prognostication Predicting outcome in hypoxic-ischemic coma... endocarditis, 10 days postpartum period, or active menstruation Tissue plasminogen activator (tPA): ◆ Action: converts plasminogen to plasmin which degrades fibrin clots ◆ Half-life: 5–8 minutes, prolonged in liver failure ◆ Dosing: 0.9 mg/kg to a maximum of 90 mg 10% total dose IV bolus over 1 minute, remaining 90% over 1 hour ◆ Follow-up: ICU monitoring, maintain blood pressure 5 Increase total weekly dose 10 20% Increase total weekly dose 5 10% No change Decrease total weekly dose 5 10% Decrease total weekly dose 10 20% Stop warfarin until INR . sclerosis (anti-Scl-70 is specifi c but insensitive) Antiphospholipid SLE Systemic autoimmune disorders Ach receptor Anti-striated Myasthenia gravis VGCC Lambert-Eaton syndrome Anti-GM 1 ganglioside. without the pressure rising to more than 10 cm of water. 509 Appendix A Clinical Pearls Medications 510 Emergency neurological medications 510 Status epilepticus 510 Cerebral edema 511 Acute stroke. Drug-induced lupus SLE Anti-Sm (speckled pattern) Specifi c for SLE, renal and CNS disorders Anti-RNP (speckled pattern) Polymyositis with MCTD SLE Scleroderma Sjögren syndrome Anti-Jo-1 Polymyositis with