Longitudinally Extensive Transverse Myelitis: An Interview with Brian G. Weinshenker, M.D.
Professor of Neurology, Mayo Clinic College of Medicine
Rochester MN USA

The Mayo Clinic has been at the forefront of research in the neuroimmunologic disorders.  Studies by the Mayo researchers are providing us with tremendous insights into the diagnoses of these rare disorders, their complex definitions and relationships, their causes, and their acute treatments and long-term management strategies.  Mayo has recently published the results of three critical studies which report the discovery of an antibody blood test for neuromyelitis optica, and proof  that this antibody binds to aquaporin 4, a protein involved in the movement of water through the “blood brain barrier.” Most importantly to the transverse myelitis community, a positive result from this blood test indicates a significant risk of recurrence of long length transverse myelitis after a first attack of transverse myelitis. These three original articles will be reprinted in the next publication of the TMA Journal (January, 2007).  Dr. Weinshenker will also provide us with an introductory article to these studies to help us more clearly understand the significance of these findings for the neuroimmunologic community. 

The Transverse Myelitis Association recognizes the critical findings and recommendations emanating from the longitudinally extensive transverse myelitis study.  Dr. Weinshenker graciously accepted our invitation for the following interview so that we could communicate these results and recommendations to our membership as quickly as possible.  It is important that you carefully review this information and discuss the recommendations with your neurologist.

Dr. Weinshenker, what is the background behind your recent discovery about the risk of recurrence in transverse myelitis?

Dr. Weinshenker: We have known for a number of years that transverse myelitis is a syndrome and not a specific disease with a single cause.  Broadly, once rare causes of transverse myelitis, such as blood vessel disorders and direct viral infections are excluded, most cases likely represent autoimmune conditions wherein the immune system attacks the spinal cord.  However, even within this autoimmune group, the condition seems to be heterogeneous.  Two major groups can be defined largely based on the size of the spinal cord lesion.  Small lesions affecting the outer parts of the spinal cord tend to occur in patients with, or at risk to develop, multiple sclerosis; partial transverse myelitis may be the first indication of future multiple sclerosis.  In contrast, patients who have the more severe forms of transverse myelitis have lesions in the spinal cord extending over the length of three or more vertebrae (longitudinally extensive transverse myelitis, LETM).  Such patients seem to be at low risk for developing multiple sclerosis; many, probably the majority, will never experience another attack.  However, approximately 20% are at risk for having recurrent attacks.  Until the present time, we have known little about the specific cause of transverse myelitis in this group of patients and the nature of the autoimmune reaction.  Furthermore, we have not been able to identify those patients who are at risk for a recurrent attack. 

Neuromyelitis optica (NMO) is a condition defined by attacks of LETM, as well as attacks of optic neuritis which cause loss of vision.  We know that some patients who experience LETM will later develop optic neuritis and be diagnosed with neuromyelitis optica.  Recently, by studying the serum of patients with neuromyelitis optica, our group has identified a specific antibody marker that can be detected by a technique called immunofluorescence; we have called it NMO-IgG (NMO antibody).  Mayo Medical Laboratories offers this test as a clinical test for NMO and related disorders.  We have known for roughly the last three years that this test is positive in patients with NMO and also patients with recurrent LETM, but is negative in patients with MS or who have transverse myelitis attacks similar to those seen in multiple sclerosis. 

What has your recent research in patients with LETM shown?
           
Dr. Weinshenker:  After we discovered this marker in patients with recurrent LETM, we asked how often it would be positive in patients with a first attack of LETM and how well it would predict the risk of recurrence of optic neuritis.  We studied 29 patients with a first attack of LETM whose serum was referred to the Mayo Clinic for testing NMO-IgG, the new antibody marker for NMO.  Thirty-eight percent had a positive test.  In follow-up over a period of one year, there was a major difference in the risk of developing recurrent LETM or optic neuritis between the group that had a positive test for NMO-IgG versus the group that had a negative test.  None of 14 patients who had a negative test developed a relapse of myelitis or optic neuritis at one-year of follow-up, whereas 5 out of 9 patients with a positive test (44%) developed recurrent transverse myelitis and 1 out of 9 (11%) developed optic neuritis. 

What are your recommendations based on your study?
           
Dr. Weinshenker:  Based on our results, we recommend that all patients with LETM should be tested for NMO-IgG and that patients with a positive test receive treatments that are effective in reducing the risk of relapse of NMO.  These agents would include immunosuppressive drugs, such as azathioprine (Imuran), prednisone, or mycophenolate mofetil (CellCept).  Specific recommendations should be made by the treating neurologist.  The optimum length of treatment is unclear.  However, the risk of relapse likely persists for several years and we have arbitrarily recommended a period of five years of treatment after an episode of LETM in a patient who tests positive for the NMO-IgG antibody marker.

We understand that our study is the first to show this result, and confirmatory studies will be necessary.  It is a relatively small study in terms of the number of patients studied.  However, the differences in risk appear to be large and convincing despite these small numbers.  We could not identify any bias in the length of follow-up that would negate the validity of our results.  Accordingly, we suspect these results will be supported by further research. 

Who should be tested?
           
Dr. Weinshenker:  We recommend that any patient who has LETM within the past five years should be tested.  The risk probably declines with time when clinical follow-up does not reveal any subsequent episodes.  At this time, it is hard to justify testing patients who have been symptom-free for five years beyond the first event of LETM.  However, the data on which this recommendation is based are scant and should be left up to the discretion of the treating neurologist given the information that I have outlined.

Are there other markers that predict the risk of attack?
           
Dr. Weinshenker:  Investigators at Johns Hopkins University have also reported that an antibody marker, SSA, that is present in patients with Sjögren’s syndrome is associated with risk of relapse in patients with LETM.  In fact, patients with NMO and patients who are positive for NMO-IgG are frequently positive for other autoantibody markers including SSA.  In our study, the NMO-IgG marker that we discovered was more sensitive than the SSA antibody.  All patients who relapsed were positive for NMO-IgG, which was not the case for SSA.  NMO-IgG is also a more specific test for NMO than SSA.  Accordingly, we feel that NMO-IgG is the preferred test at the present time to predict a risk of recurrent attacks of LETM.

What other implications does your study have in regards to our understanding of transverse myelitis?
           
Dr. Weinshenker:  This study suggests that patients with the most severe form of transverse myelitis, LETM, often have a first episode or limited form of NMO.  It suggests that approximately 40% of patients with LETM may have a condition that is immunologically related to NMO and that research into the cause and treatment of NMO will also have a strong impact on the treatment of LETM.
           
For example, plasma exchange is known to be very effective in attacks of LETM and also in patients with LETM and optic neuritis attacks who have NMO.  Recent research has shown that the antibody marker referred to above reacts with a protein in the brain called aquaporin 4.  Although it remains to be proven that this antibody actually causes the damage in NMO, and is not just a blood test marker, there is reason to be optimistic that we have discovered the antibody that is actually the perpetrator of the immune-mediated damage in this condition.  Discovery of a target for the immune system in this disorder is the first step in identifying a specific way to inhibit the immune system attack in this condition.  Far more research is necessary, however, before we can be certain that NMO IgG is the actual perpetrator of the damage that occurs in NMO and not just a marker.  Either way, it appears that NMO-IgG will be a very useful clinical test for predicting risk of relapse for patients with LETM.