Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (101 page)

The qualitative test of IgG on unconcentrated CSF is the single most informative test. It has a greater sensitivity and specificity than the quantitative IgG test. A diagnosis of MS can be made when oligoclonal bands are found in the CSF, which are not seen in the serum, consistent with intrathecal synthesis. The test is best performed using isoelectric focusing (IEF) with immunodetection by blotting or fixation run with a simultaneous serum sample on an adjacent track with positive and negative controls. A diagnostic study will show one of five recognized staining patterns of oligoclonal banding
^4,5
:

   Type 1: No OCBs in CSF and serum samples

   Type 2: OCBs in CSF but not serum, indicating intrathecal IgG synthesis

   Type 3: OCBs in CSF with additional identical OCBs in CSF and serum but still indicating intrathecal IgG synthesis

   Type 4: Identical OCBs in CSF and serum, indicating a systemic immune reaction with a normal or abnormal blood–CSF barrier and passive transfer of OCBs to the CSF

   Type 5: Monoclonal bands in CSF and serum, indicating the presence of a monoclonal gammopathy

If results are equivocal, negative, or show only a single band on IEF and the clinical suspicion for MS is high, the lumbar puncture and CSF analysis should be repeated. Ninety percent of patients with MS have OCBs in their CSF, at least two of which are
not
present in simultaneously examined serum. Rarely, patients with MS may have normal CSF immunoglobulins and lack OCBs. Positive results also occur in ≤10% of patients with noninflammatory neurologic disease (e.g., meningeal carcinomatosis, cerebral infarction) and ≤40% of patients with inflammatory CNS disorders (e.g., neurosyphilis, viral encephalitis, progressive rubella encephalitis, subacute sclerosing panencephalitis, bacterial meningitis, toxoplasmosis, cryptococcal meningitis, inflammatory neuropathies, and trypanosomiasis).

OCBs are not known to correlate with severity, duration, or course of MS, and they persist during remission. With steroid treatment, the prevalence of OCBs may be reduced by 30–50%. The evaluation of light chains may help in cases of equivocal oligoclonal IgG patterns.
^4,5

IgG Index

The immunoglobulin level, predominantly IgG, is elevated in the CSF relative to other proteins in MS. This finding is expressed as the IgG index (the normal value is less <0.66). It is an indication of IgG synthesis in the CNS. An increase in
production
of IgG is expressed as the ratio of CSF to serum albumin to rule out increased IgG due to disruption of the blood–brain barrier. Ninety percent of MS patients have an index of >0.7. CSF IgM and IgA may also be increased but are not useful for diagnosis.
^1,3

The CSF IgG does not correlate with duration, activity, or course of MS. It may also be increased in other inflammatory demyelinating diseases (e.g., neurosyphilis, acute GBS), 5–15% of patients with miscellaneous neurologic diseases, and a few normal persons. Recent myelography is said to invalidate the test. The CSF IgG synthesis rate (3.3 mg/day) is increased in 90% of MS patients and 4% of non-MS patients.
³
PCR demonstrates an expansion of B-cell clones.

Other Useful Tests

The presence of
myelin basic protein
indicates recent myelin destruction. It is increased in 70–90% of patients with MS during an acute exacerbation and usually returns to normal within 2 weeks. A weakly reactive result (4–8 ng/ mL) indicates an active lesion >1 week old. Normal is <1 ng/mL. Myelin basic protein is useful for following the course of MS but not for screening; it may be helpful very early in the course of MS before OCBs have appeared or in approximately 10% of patients who do not develop these bands. It does not predict progression.
¹
It is frequently increased in other causes of demyelination and tissue destruction (e.g., meningoencephalitis, leukodystrophies, metabolic encephalopathy, SLE of the CNS, brain tumor, head trauma, amyotrophic lateral sclerosis, cranial irradiation and intrathecal chemotherapy, and 45% of patients with recent stroke) and other disorders (e.g., diabetes mellitus, chronic renal failure, vasculitis, carcinoma of vasculitis, immune complex diseases, and pancreas). It is falsely increased by CSF contamination with blood. It is associated with certain histocompatibility antigens (e.g., Caucasian patients with B7 and Dw2 antigen).
²

The
albumin index
(ratio of albumin serum to CSF) is a measure of integrity of the blood-to-CSF barrier. Use of this index can prevent false misinterpretation of increased CSF IgG concentrations. An increase indicates CSF contaminated with blood (e.g., traumatic tap) or increased permeability of the blood–brain barrier (e.g., aged persons, obstruction of CSF circulation, diabetes mellitus, SLE of CNS, GBS, polyneuropathy, cervical spondylosis).
¹

CSF total protein
is usually normal or may be mildly increased in approximately 25% of patients and is not a very useful test by itself. Decreased values or values >100 mg/dL should cast doubt on the diagnosis of MS.

CSF gamma globulin
is increased in 60–75% of patients regardless of whether the total CSF protein is increased. Gamma globulin ≥12% of CSF total protein is abnormal if there is not a corresponding increase in serum gamma globulin but may also be increased in other CNS disorders (e.g., syphilis, subacute panencephalitis, meningeal carcinomatosis) and may also be increased when serum electrophoresis is abnormal due to non-CNS diseases (e.g., RA, sarcoidosis, cirrhosis, myxedema, multiple myeloma).

Peripheral blood studies and routine CSF tests yield no changes of diagnostic value. Antimyelin antibodies initially were thought to be a marker of MS and progression of disease. However, subsequent evidence suggests that these antibodies are not associated with an increased risk of progression or with MS disease activity.
^6,7

Natalizumab (Tysabri)
a recombinant humanized IgG4kappa monoclonal antibody that is used in the treatment of recurring MS and Crohn disease. Tysabri antibodies that block the efficacy of the drug may develop. Testing for Tysabri antibodies is commercially available.

References

1.  McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.
Ann Neurol.
2001;50:121–127.

2.  Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria.
Ann Neurol.
2011;69(2):292–302.

3.  McLean BN, Luxton RW, Thompson EJ. A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications.
Brain.
1990;113(Pt 5):1269.

4.  Barclay L. New guidelines for standards for CSF analysis in MS.
Arch Neurol.
2005;62: 865–870.

5.  Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.
Arch Neurol.
2005;62:865.

6.  Lampasona V, Franciotta D, Furlan R, et al. Similar low frequency of anti-MOG IgG and IgM in MS patients and healthy subjects.
Neurology.
2004;62:2092.

7.  Kuhle J, Pohl C, Mehling M, et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis.
N Engl J Med.
2007;356:371.

NEOPLASTIC DISORDERS OF THE CNS