Often in medicine, terms become associated with a condition and the meaning is lost. The first case to be presented in this series is a prime example: "oligoclonal banding" might be synonymous with multiple sclerosis, but what does it mean?
The case: A 36-year-old male experienced what he described as "tingling" in the left lower extremity, which lasted about a month and resolved. He later experienced a separate episode of tingling in an area of his abdominal wall, which also resolved after some time. He further relayed a recent history of "clumsiness" and several falls. Diagnostic tests included neuro imaging, a lumbar puncture and a host of chemistry tests to rule out possible mimics of multiple sclerosis.
What was done with the fluid from the LP?
The obvious tests included Gram stain and culture, cell counts, cytology, protein and glucose to rule out an infectious or neoplastic process. Additionally, CSF protein electrophoresis was done.
What are the hallmarks of multiple sclerosis in CSF?
Multiple sclerosis is an autoimmune demyelinating disorder. The key finding is intrathecal synthesis of immunoglobulin, proteins produced by plasma cells of the immune system directed against myelin and other antigens. This can be evaluated qualitatively with electrophoresis or quantitatively by calculating the IgG index.
What does electrophoresis show?
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Gel electrophoresis separates protein in the fluid of interest based on size and molecular charge; it has a sensitivity of about 50 percent for the detection of oligoclonal bands in MS. Electrophoresis with isoelectric focusing is a special type of electrophoresis in which a pH gradient is created in the gel and proteins are separated according to their pI values (the pH at which a protein has no net electric charge). Electrophoresis with isoelectric focusing is much more sensitive and is the gold standard for detection of oligoclonal bands.
Normally, immunoglobulin present in the body is polyclonal, and it should form a smear on electrophoresis. The formation of a discrete band usually means that a monoclonal protein is present; this occurs in monoclonal gammopathies or some lymphomas, for example. If multiple discrete bands are present, there are a few proteins that are clonal, and each migrates differently because its size or charge is slightly different. This is called oligoclonal banding.
What is needed to evaluate a person for MS?
A peripheral blood (serum) sample and a CSF sample are both required. This is because one must evaluate the proteins both inside and outside the central nervous system in order to tell where the proteins are being produced.
What does the serum versus CSF electrophoresis tell you?
- Two bands distinguish CSF from serum: prealbumin and beta-2 transferrin, both of which are enriched in CSF.
- Normal would be a perfect smear with a lack of discrete immunoglobulin bands in both the serum and CSF.
- There are a number of patterns of oligoclonal banding, based on whether the clonal bands are in the serum, CSF or both.
- It is possible to have systemic (outside the CNS) production of clonal proteins that cross the blood brain barrier, which would result in identical bands in both places.
- If bands are seen in both serum and CSF, but there are additional bands unique to the CSF, there is both systemic and intrathecal immunoglobulin synthesis. The differential diagnosis would include multiple sclerosis as well as infectious and autoimmune disease.
- The pattern most specific for MS would be oligoclonal bands present only in the CSF, and none in the serum.
How can CSF analysis be quantified?
The IgG index is a quantifiable way of analyzing intrathecal versus systemic production of protein. It represents the ratio of CSF IgG to CSF albumin compared to the ratio of serum IgG to serum albumin. The immunoglobulin can also be expressed as a percentage of total protein or of albumin. Elevation of CSF immunoglobulin relative to other protein, namely albumin, indicates intrathecal synthesis.
Is oligoclonal banding specific for MS?
Elevated IgG index can be seen in more than 90 percent of patients with clinically definite MS, and oligoclonal banding is seen in more than 95 percent of patients with clinically definite MS.
However, similar abnormalities can also be seen in paraneoplastic disorders, neurosarcoidosis, autoimmune disorders, and some infections, including neurosyphilis, neuroborreliosis, HSV, and measles.
Is the CSF analysis sufficient for a diagnosis of MS?
No, the presence of oligoclonal bands or an elevated IgG index is not equivalent to a diagnosis of MS. While full discussion of the MacDonald criteria is beyond the scope of this article, the main point is this: diagnosis requires demonstration of lesions separated by space and time. In the classic form of MS, diagnosis is made on clinical findings and/or neuroimaging; CSF analysis may support decision making but is not part of the diagnostic criteria. In the primary progressive form of MS, which is more difficult to diagnose clinically, the criteria require one year of disease progression as well as neuroimaging and/or CSF analysis.
Back to the patient: Our 36-year-old male patient was found to have 15 immunoglobulin bands in the CSF, 13 of which were unique; his IgG index was also elevated. This represents intrathecal as well as systemic production of immunoglobulin. The differential diagnosis based only on the CSF findings includes MS as well as infectious and autoimmune causes. In conjunction with the laboratory data and based on MRI findings of 13 lesions in the brain and 3 lesions in the spinal cord, the patient was diagnosed with multiple sclerosis. Appropriate therapy was begun.
Janice Tyler is a resident at Harvard Medical School, Boston.
For Additional Reading:
- Andersson, M., et al. "Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report." Journal of Neurology, Neurosurgery & Psychiatry 57.8 (1994): 897-902.
- Avasarala, Jagannadha R., Anne H. Cross, and John L. Trotter. "Oligoclonal band number as a marker for prognosis in multiple sclerosis." Archives of neurology 58.12 (2001): 2044.
- Filippi, Massimo, and Maria A. Rocca. "MR imaging of multiple sclerosis."Radiology 259.3 (2011): 659-681.
- Freedman, Mark S., et al. "Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement."Archives of neurology 62.6 (2005): 865.
- Lee, K. H., et al. "Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: A prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT." Neurology 41.5 (1991): 657-660.
- Mattson, David H., Raymond P. Roos, and Barry GW Arnason. "Isoelectric focusing of IgG eluted from multiple sclerosis and subacute sclerosing panencephalitis brains." Nature (1980): 335-337.
- McLean, B. N., R. W. Luxton, and E. J. Thompson. " 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 113.5 (1990): 1269-1289.
- Olek, Michael J. "Diagnosis of multiple sclerosis in adults." (2008).
- Paty, D. W., et al. "MRI in the diagnosis of MS A prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT." Neurology 38.2 (1988): 180-180.
- Polman, Chris H., et al. "Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria." Annals of neurology 69.2 (2011): 292-302.
- Schäffler, N., et al. "Accuracy of diagnostic tests in multiple sclerosis-a systematic review." Acta Neurologica Scandinavica 124.3 (2011): 151-164.