Miller-Fisher variant of GBS Opic neuritis
Bell's palsy Trigeminal neuralgia
Wilson's disease Neurosyphilis (paretic)
H'lLV-l Poliomyelitis Spinal cord tumor
Stiffman's syndrome ALS
Chronic inflammatory demyelinating polyradiculopathy (CIDP)
Myopathy or myositis Cerebellitis
Paraneoplastic cerebellar disease
Inherited neuropathies Neurosyphilis (tabes dorsalis)
See CBS pr, cell cts, OCB
cell cts pr, gl, cell cts pr pr
See above VDRL, pr, cell cts, pr, gl, IgG, OCB pr, gl, cell cts pr, gl, cell cts, cytology pr, gl, cell cts pr, cell cts, IgG, OCB pr, cell cts pr, cell cts pr, cell cts pr, gl, cell cts pr, gl, cell cts pr, gl, cell cts pr, cell cts, abs pr, gl, cell cts
See above See above VDRL, pr, gl, cell cts
See GBS/comments Mild pr (45 to 60 mg/dl), 50 percent with mild
WBC (mononuc) nl CSF
+ + VDRL, pr: 50 to 100 mg/dl, cell cts: 25 to 75 leukocytes/mm2
mild pr (50 to 200 mg/dl), nl gl, mild CSF WBC (mononuc)
WBC (mononuc), + cyt pr (90 to 150 mg/dl), nl gl, nl cell cts nl pr, nl cell cts, IgG, ? + OCB
mild pr & cell cts pr, nl cell cts mild pr (50 to 60 mg/dl), nl cell cts pr (100 to 200 mg/dl), nl gl, mild WBC (5 to 50 cell/mm3 )
mod pr (50 to 200 mg/dl), nl gl, nl cell cts mildly pr, nl gl, cell cts usually <100/mm2 (mononuc)
mild pr, mild
WBC (8 to 20 cells/mm3 ) + anti-Yo or anti-Hu ab pr (50 to 400 mg/dl), nl cell cts, gl (secondary diabetes)
Pr more common nl than in CBS + OCB increase risk of MS
Abnormal CSF helps r/o Bell's palsy
Not routinely performed; may have substance P and monoamines
Not routinely performed. Abnormal CSF helps r/o Parkinson's disease
Abnormal CSF helps r/o Huntington's disease
Abnormal CSF helps r/o Wilson's disease
CSF abnormalities increase with duration of disease
Serum + HTLV-1 ag
CSF WBC with time
Froin's syndrome (spinal cord block) may sig
Care must be taken not to induce tetany. Normal cell cts differentiate from meningitis
Pr peaks between 1 and 3 wks. Cell cts > 5 should prompt search for another cause
Similar to GBS; Pr elevation correlates with severity; + WBC in 10 percent
Not routinely performed
Usually secondary to varicella-zoster
Anti-Yo in ovarian, uterine, or breast CA. Anti-Hu seen in lung CA
CSF may resemble paretic form, but parameters improve w/progression
Key: abs = antibodies, ACE = angiotensin converting enzyme, AD = Alzheimer's dementia, ag = antigen, AST = aspartate aminotransferase, bact = bacteria, CA = cancer, cell cts = cell Counts, cerebrovasc = cerebrovascular, CK-BB = creatinine kinase BB isoenzyme, CSF = cerebrospinal fluid, CVA = cerehrovascular accident (stroke), cyt = cytology, degen = degenerative, gl = glucose, gs = gram stain, LA = lactic acid, LDH = lactate dehydrogenase, MBP = myelin basic protein, mononuc = mononuclear cells, NPH = normal pressure hydrocephalus, NSE = neuron specific enolase, OCB = oligoclonal bands, OP = opening, o/w = otherwise, pr = protein, r/o = rule out, rx'd = treated, nl = normal, sig = significantly, VDRL = venereal disease research laboratory test, wks = weeks, WNL = within normal limits, xanth = xanthochromia.
proportionately in response to a rising or falling plasma glucose event with a 4-hour lag time. This linear ratio of CSF to plasma glucose concentration decreases as the plasma glucose exceeds 500 mg/dl. The reason for this decrease is unclear, but it may reflect the saturation of the carrier-mediated transport of glucose at high plasma concentrations.^ As a result, it is important to obtain a concomitant serum glucose level at the time of the CSF sample. Although an elevated CSF glucose level (hyperglycorrachia) results from an elevated plasma glucose level, a decreased CSF glucose concentration (hypoglycorrachia) may be due to a variety of causes including hypoglycemia. The other etiologies include bacterial meningitis y (including typical bacteria, tuberculosis, and neurosyphilis), fungal meningitis, certain viral meningitides (mumps),y subarachnoid hemorrhage,^] carcinomatosis meningitis, chemical meningitis, and meningitis resulting from parasitic organisms (cysticercosis, trichinosis, amebiasis). If 0.4 is used as the lower limit of the normal CSF to serum glucose ratio, values below 0.4 have a sensitivity of 80 to 91 percent and a specificity of 96 to 98 percent for bacterial meningitis versus aseptic meningitis (inflammatory cells without evidence of a common bacterial pathogen). y , y The CSF glucose value often returns to normal before other CSF determinations (such as protein or lactate), and some investigators have suggested serial determinations to guide treatment decisions. y The CSF glucose level may take several weeks to return to normal despite the normalization of the protein concentration and cell count.y
The majority of CSF protein is derived from the serum, and the CSF to serum albumin ratio is approximately 1:200. This ratio implies that the entry rate of protein from the serum to the CSF is approximately 200 times less than its exit rate. M The CSF protein concentration varies at different levels of the neuroaxis and generally increases from the cephalad to caudal levels. Elevation in lumbar CSF protein is a nonspecific but sensitive indicator of CNS disease. M TabJe 26:2 illustrates the various disorders that can cause an elevation in the CSF protein level. y A very high CSF protein concentration (greater than 500 mg/dl) is an infrequent finding but can occur with bacterial meningitis, subarachnoid hemorrhage, or spinal-subarachnoid block. When a significant amount of blood is present in the CSF (e.g., subarachnoid hemorrhage), a correction for the total protein concentration should be calculated. The presence of 1000 RBCs in the CSF results in the increase of protein by 1 mg/dl. A spinal-subarachnoid block can cause Froin's syndrome and is usually the result of a spinal cord tumor and can cause very significant elevations in CSF protein (greater than 1000 mg/dl).y Protein concentrations of 100 mg/dl or greater have sensitivity and specificity for bacterial meningitis of 82 and 98 percent, respectively, as compared with aseptic meningitis, y and if the concentration is 200 mg/dl, the sensitivity is 86 percent and the specificity is 100 percent. y A lower than normal CSF protein level may occur in young children (6 months to 2 years of age), in patients with pseudotumor cerebri, and in patients with unintended loss of CSF from frequent LPs, a lumbar drain, or a lumbar dural CSF leak.
Figure 26-6 Formula for the determination of cerebrospinal fluid immunoglobulinum Fishman RA: Cerebrospinal fluid in diseases of the nervous system. In Fishman RA [ed]: Cerebrospinal Fluid in Diseases of the Nervous System, 2nd ed. Philadelphia, W.B. Saunders, 1992, p 431.)
Certain proteins arise within the intrathecal compartment. Among these are immunoglobulins produced by CNS lymphocytes, transthyretin (produced by choroid plexus), and various structural proteins found in brain tissue (including glial fibrillary acidic, tau, and myelin basic proteins). The last group of proteins and transthyretin are found only in trace amounts, whereas immunoglobulins comprise a substantial fraction of normal CSF (5 to 12 percent). Electrophoretic techniques can be used to define the gammaglobulins as a heterogeneous group of proteins. Because serum IgG comprises nearly 20 percent of the total serum protein, a variety of formulas have been used to correct the CSF IgG level for the contribution derived from the blood in order to determine the CNS IgG synthesis rate ( Fig
26-6 ). Contamination of the CSF with blood may significantly elevate the IgG index and the IgG synthesis rate.
The electrophoretic separation of CSF proteins can be accomplished through the use of agarose gel and by the staining of the bands that are produced. Within the gamma region, three patterns of bands may be observed including one clone (monoclonal), many clones (polyclonal), and a few bands (three to five bands, or oligoclonal bands).[yi Each band represents a homogeneous protein that is secreted by a single clone of plasma cells.
Oligoclonal bands (OCB) are present in the CSF when three to five bands are seen on gel electrophoresis. This finding implies that a single clonal population of plasma cells is responsible for each band. More than one oligoclonal band rarely occurs in normal CSF. A serum sample should also be obtained simultaneously with the acquisition of the CSF to determine whether the OCB are unique to the CSF. Oligoclonal bands are present in 83 to 94 percent of patients with multiple sclerosis, 100 percent of patients with subacute sclerosing panencephalitis, 25 to 50 percent of patients with other inflammatory CNS disorders (CNS lupus, neurosarcoidosis, cysticercosis, Behcet's and viral, fungal, and bacterial infections), as well as most with some brain tumors, and Guillain-Barre syndrome. Because OCBs are present in such varied conditions, their presence offers little to a specific diagnosis.
Examining the CSF with Gram's stain is useful to diagnose bacterial meningitis. y A Ziehl-Neelsen acid-fast stain should also be performed if tuberculous meningitis is a diagnostic possibility. CSF cultures should be done in the setting in which an infectious process is suspected. Bacteria that commonly cause meningitis are routinely cultured on standard preparations. Mycobacterium can also be cultured, yet several weeks (or more) may be required to grow these organisms. Viral cultures may be ordered; however,
the yield is generally low. Fungal cultures should be performed in clinical settings of suspected chronic meningitis. SPECIALIZED TESTS
In addition to these routine studies, various specialized tests may also be useful in specific clinical settings.
The measurement of the CSF acid-base status is not normally part of the routine evaluation of this body fluid. In experimental studies, normal subjects have a CSF pH that is slightly lower than the pH of arterial blood and a pCO 2 that is higher. In contrast, bicarbonate levels are generally equal. Comparisons between CSF obtained through cisternal and lumbar punctures reveal that the pH is typically lower and pCO 2 higher in lumbar CSF. Again, bicarbonate levels are not significantly different. The variations between the cisternal and lumbar CSF samples may reflect differences in rates of local metabolism relative to clearance rates, y and the clinical measurement of the lumbar CSF pH may be an unreliable indicator of the metabolic state of the CNS.
Because the concentration of CSF lactate is dependent on CNS glycolysis, y the measurement of this agent may be helpful in the diagnosis of bacterial meningitis. This concentration of lactate increases proportionally to the number of inflammatory cells in the CSF. y A lactate concentration of 4.2 mmol/L accurately predicted 24 out of 25 cases of bacterial meningitis, whereas no patients with presumed viral meningitis had a lactate level that exceeded this value. Unlike the glucose concentration, CSF lactate levels typically remain elevated for a significant time after appropriate therapy is initiated. y This finding may be helpful in the diagnosis of bacterial meningitis when antibiotics had been given before the acquisition of CSF. Increased lactate may also result from a cerebral hemorrhage, malignant hypertension, hepatic encephalopathy, diabetes mellitus, and hypoglycemic coma. y
The measurement of CSF glutamine can be a helpful test in diagnosing patients with confusion in the setting of hepatic encephalopathy. Glutamine is formed by the combination of ammonia, which is toxic to the CNS, and alpha-ketoglutarate in the brain. This process helps protect the CNS from the effects of ammonia. Normally, the CSF concentration of ammonia is less than one half of arterial levels, but may increase dramatically in patients with hepatic failure. M Although a correlation exists between increased levels of ammonia and glutamine and the severity of encephalopathy, technical difficulties exist that hamper the ability to use these indices in acute settings.^
Various biogenic amines (and their metabolites) may be measured within the CSF, including dopamine (homovanillic acid [HVA]), serotonin (5-hydroxyindoleacetic acid [5- HIAA]), and norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]). Significant ventricular to lumbar gradients exist for HVA and 5-HIAA, although MHPG levels are nearly equivalent. Decreased lumbar CSF levels of HVA and 5-HIAA have been reported in patients with parkinsonism and Alzheimer's disease. Whereas decreased HVA levels have also been documented in the ventricular CSF of patients with dystonia, cerebral palsy, MS, and posthypoxic states, no significant differences in 5-HIAA levels are apparent. Biogenic amine levels have also been studied in psychiatric patients, and whereas normal HVA levels are present in the lumbar CSF of patients with schizophrenia, decreased 5-HIAA concentrations are present in depressed subjects. Increased lumbar CSF MHPG levels have been identified in patients with cerebral infarction and hemorrhage. Animal studies further reveal that changes in biogenic amine levels in the CSF parallel CNS changes; however, delays in the clearance of these metabolites from the CSF complicate the interpretation of the values obtained. Because of these physiological constraints and the nonspecific nature of changes in biogenic amine levels, their measurement remains a research tool and has little clinical applicability.
Tumor cells can also be found in the CSF and occur in association with neoplasms of the brain or meninges. The cytopathological identification of these cells requires the acquisition of large volumes of CSF (more than 20 ml) and the sample should be brought immediately to the laboratory to minimize cell lysis and morphological changes. Serial LPs may be necessary to obtain positive cytological results. In a study of the usefulness of CSF cytology and autopsy, Glass and co-workers reported that 26 percent of patients with metastatic brain tumors had positive CSF cytology. y In another study, the cytological examination of the CSF identified metastatic involvement of the meninges in 70 percent of cases. y The detection of other CSF markers may be useful for the diagnosis of primary or metastatic malignancies including astroprotein (glioblastoma), carcinoembryonic antigen (carcinomas), beta-2-microglobin (lymphoblastic leukemia and lymphoma), alpha-fetoprotein (germ cell tumors), chorionic gonadotropin (choriocarcinoma and testicular tumors), and ferritin (carcinomas). y
Finally, it is possible to measure a wide variety of enzymes in the CSF, although few are clinically important and most are not routinely obtained. An elevated lactate dehydrogenase (LDH) may occur in bacterial meningitis'38! and cortical versus lacunar strokes. y Elevated levels of CSF creatinine kinase-BB are also present in a wide variety of conditions that cause parenchymal damage. Lysozyme levels are increased in processes similar to those previously mentioned, whereas adenosine deaminase elevations can occur in tuberculous meningitis. y
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