Diagnosing MS

The autoimmune neurologic disorder multiple sclerosis (MS) can be difficult to diagnose. This article describes the tests recommended for diagnosing MS.

Multiple sclerosis (MS) is a complex autoimmune disease that affects the central nervous system. In MS the immune system targets and destroys the protective myelin sheath that covers nerves as well as the affected nerve's underlying axon. The most common neurologic disorder seen in young adults, MS is usually diagnosed in people between the ages of 20 and 40 although, as I explained in a recent blog, the incidence of MS in children has dramatically increased in the last decade. Women represent about two-thirds of all cases.

Similar to most autoimmune disorders, the early stage of MS in most of those affected is characterized by a waxing and waning of symptoms called a relapsing-remitting disease course that usually progresses to a secondary progressive stage. The early stage of MS usually lasts about 11-15 years. Towards the end of this timeframe, relapses begin to occur more frequently and nervous system damage becomes more progressive. In addition, a primary-progressive subset of MS patients representing 10-15 percent of all cases develops a more progressive form of MS in which remissions rarely occur. In the early stages of MS, when treatment intervention is most crucial, diagnosis can be difficult.

For an accurate diagnosis of MS, patients have traditionally needed to be tested during two separate episodes of symptoms related to central nervous system damage separated in time and space that could not be attributed to other causes such as injury or infection. However, the revised criteria of McDonald (2005) allow for MS to be diagnosed after one clinical episode showing diagnostic changes characteristic of MS (using spinal fluid analysis, imaging tests and evoked (auditory, visual and sensory) potentials showing a delayed response with a preserved wave, along with a magnetic resonance imaging (MRI) test showing one or more T2 lesions suggestive of MS performed at least 30 days after the initial onset of symptoms.

For initially evaluating patients suspected of having MS, a lumbar puncture is performed and samples of cerebrospinal fluid are obtained. The spinal fluid is then tested by the laboratory for white blood cells, protein, infectious organisms and intrathecal immunoglobulin G (IG) synthetase by oligoclonal band detection. Patients with MS have an elevated IgG index or oligoclonal bands in spinal fluid but not in serum. In neurologic infection, these changes are seen in both spinal fluid and serum. Along with a careful medical history, imaging tests (used to detect MS lesions, disruptions of the blood brain barrier and changes in both white and gray matter), and tests for evoked potential, a spinal fluid analysis has been regarded as a critical step in diagnosing MS. Unfortunately, older testing methods for IgG oligoclonal bands lacked sensitivity and results were often difficult to interpret.

The Gold Standard

However, researchers in Spain have developed a new oligoclonal band test for diagnosing MS using isoelectric focusing (IEF) and an alkaline phosphatase labeled IgG antibody to detect IgG. This method yields high sensitivity and a sharp pattern of bands that is easily interpreted. Early studies confirm that this procedure is able to detect intrathecal IgG in 96.2 percent of patients with MS and 35.3 percent of patients with central nervous system infection. The specificity of this method in patients with MS is reported to be 92.5 percent. Using the IEF procedure oligoclonal bands can be detected in the spinal fluid of patients with MS and in both serum and spinal fluid in patients with central nervous system infection. Intrathecal IgG synthesis was not found in patients with other inflammatory neurology diseases.

In June 2005, MS researchers and experts from around the world convened to establish specific guidelines for diagnosing MS. Overall, they agreed that a qualitative assessment of spinal fluid for IgG is the single most informative analysis for diagnosing MS. They agreed that methods utilizing IEF along with some form of immunodetection are optimal and that both serum and spinal fluid need to be tested and the results compared. The method developed in Spain described above fits these criteria. Neurologists at the conference recommended that physicians request that laboratories performing the new IEF procedures with sensitive IgG detection be used for the diagnosis of patients suspected of having MS. The guidelines also recommend obtaining a second sample and repeating the test when results are inconclusive or only 1 band is seen.

Recent Developments

A new test procedure is being developed to detect myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with MS. In trials, these antibodies are seen before MS becomes clinically apparent, and they are more likely to be seen in relapsing disease than in primary progressive MS.

Resources:

A new oligoclonal band test for diagnosing MS, College of American Pathologists, CAP Today, April 2006; vol 20 (4): 70-71.

Laurie Barclay and Charles Vega, New guidelines for standards for cerebrospinal fluid analysis in multiple sclerosis, Medscape Medical News, June 16, 2005.