The AAN has issued a new evidence-based guideline for the clinical evaluation and treatment of transverse myelitis (TM).
The AAN guideline, the first ever for TM, is based on a systematic review of research findings published from 1996 to March 2009. The findings of 65 studies were used to draw up the recommendations.
TM occurs in one to eight in a million people per year (a range that includes mild to severe cases) and is usually characterized by MRI signal abnormality in the spinal cord, CSF pleocytosis, or both. The guideline noted that “the lesion typically spans multiple vertebral segments and is not radiologically or pathologically transverse; the term transverse has been retained because of the importance of a spinal sensory level in making the diagnosis.”
To gain insight into the recommendations, Neurology Today talked with Thomas Scott, MD, professor of neurology at Drexel University School of Medicine, who led the author panel of the AAN Therapeutics and Technology Assessment Subcommittee that drew up the guideline. Dr. Scott is involved in multiple sclerosis research at Allegheny General Hospital in Pittsburgh, where he practices.
WHAT ARE SOME KEY POINTS IN THE GUIDELINES?
A lot of the big new news revolves around the NMO (neuromyelitis optica) antibody and its therapeutic usefulness. We also see a trend of a gradual move away from treating relapsing forms of myelitis with interferons unless multiple sclerosis [MS] is proven, and more of a movement toward using plasma exchange for acute treatment and toward treating with immunosuppressive agents for the relapsing form of myelitis that is associated with NMO antibodies.
WHY DID THE AAN DECIDE TO ISSUE GUIDELINES ON TRANSVERSE MYELITIS?
It was a good time to focus on it. There is a lot of interest in the NMO-IgG antibody — the discovery of the antibody and research into its therapeutic usefulness. It was challenging to take all the various research information about TM and apply it to the evidence-based medicine guideline format, but we knew that if we could, we would have a useful document. By looking at the best available studies in the context of a structured review format, we were able to really focus on the specifics of what we know about TM, as well as what we still need to know. There will not be a lot of surprises here for neurologists who specialize in MS, but it should help clarify some issues for general neurologists.
IS THERE A BETTER WAY TO IDENTIFY PATIENTS WITH TM EARLIER?
TM is usually not subtle and is easily recognized. But to further characterize the syndromes of TM as specific disease states is more of a challenge for clinicians. A lot of TM turns out to be multiple sclerosis, and in the vast majority of those cases the diagnosis is straightforward because these patients present with cerebral MRIs classic for MS. When TM presents without these classic MS lesions, the diagnosis and treatment of other more specific disease states are challenging.
ARE THERE DEMOGRAPHIC, CLINICAL, AND LABORATORY FEATURES THAT HELP DISTINGUISH TM FROM OTHER CAUSES OF ACUTE AND SUBACUTE NON-COMPRESSIVE MYELOPATHY?
In general, patients with spinal cord infarcts tend to be older than patients with TM. The guideline also noted that there are no studies to indicate what specific clinical features of myelopathy — such as the time of onset to maximal neurological deficit —might be useful for sorting out myelitis versus other myelopathies.
As for laboratory findings, “an elevated CSF leukocyte count (greater than 10 cells/mm3) is possibly useful in identifying patients with inflammatory myelopathies (including TM) as opposed to those with spinal cord infarcts.”
IF A DIAGNOSIS OF TM IS ESTABLISHED, HOW DOES A CLINICIAL DETERMINE THE CAUSE?
The guidelines note that the “main etiologies of TM-like syndromes are MS, parainfectious myelitis, NMO, and myelitis due to systemic disease (such as systemic lupus erythematosus).” However, even after several years of -follow-up, 15 percent to 36 percent of patients cannot be given a more specific diagnosis than ‘idiopathic' TM.
A review of the evidence found that demographic features (ethnicity, sex, age) are not yet shown to be useful in distinguishing causes of myelitis. However, clinical presentation is possibly important. Specifically, patients with myelopathy who present as having APTM (acute partial transverse myelitis) have a higher risk of transition to MS compared with patients with ACTM (acute complete TM).
In patients with APTM, “MS-like brain MRI abnormalities” are often seen, and “indicate a high risk of ‘conversion' to clinically defined MS,” typically three to five years after onset, according to the guideline. Even without such MRI lesions, APTM patients seem to have a higher chance of developing MS compared to ACTM patients.
Furthermore, the longitudinal extent of MRI lesions may be “useful in determining the cause of TM,” especially “distinguishing between TM due to NMO spectrum disorders, which tend to have lesions extending across three or more vertebral segments, and TM in MS patients or patients with idiopathic APTM (lesions usually smaller).”
HOW CAN CLINICIANS BEST IDENTIFY PATIENTS WHO ARE AT INCREASED RISK FOR RECURRENCE?
Patients with NMO antibodies are at much higher risk for recurrent TM than patients without NMO antibodies. The guidelines found that “there is insufficient evidence concerning whether the presence of SSA antibodies predicts recurrence after a first episode of TM. When a specific cause for TM is not apparent, it is recommended to consider testing for NMO.”
WHAT THERAPIES WORK BEST FOR TM PATIENTS WITH ACUTE ATTACKS?
During the acute phase clinicians often use steroids; however, the guideline found insufficient evidence to support a recommendation for steroids. This is an example of ‘we do it anyway' in the ‘clinical context section' of the TTA (Therapeutic and Technology Assessment Subcommittee), even though there isn't sufficient evidence in the literature. We recommend plasma exchange when patients do not recover well after steroids. For patients who are NMO positive, we recommend that clinicians may consider immunosuppression with rituximab. According to the guideline, “There is insufficient evidence to support or refute” whether other therapies — such as azathioprine, cyclophosphamide, and IGIV — are helpful in alleviating TM attacks. We note there are many anecdotal reports of success with a wide variety of immunosuppressives.
WHAT TYPE OF RESEARCH IS NEEDED FOR TM THERAPY?
We need prospectively designed research trials because almost everything we have now has been done retrospectively. Trials would likely have to be multicentered to have enough patients to get meaningful results.
The guideline specifically notes that randomized trials of therapeutic interventions for TM, such as plasma exchange or immunosuppression, should be done using active comparators.
We also need to understand more about who is at most risk for recurrent transverse myelitis not associated with NMO. We still don't know how long to treat patients who are NMO positive with immune suppression.