Acute Therapies for Transverse Myelitis
Benjamin Greenberg, MD, MHS
Assistant Professor, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine
Co-Director of the Johns Hopkins Transverse Myelitis Center

Adapted from a presentation given at the 2006 Rare Neuroimmunologic Symposium

This paper examines the role of various acute therapies for neuroimmunologic disorders that affect the spinal cord.  I would like to begin my discussion by talking about these therapies in the context of the stages of disease common to various neuroimmunologic conditions.  One of the stages is acute inflammation.  Acute inflammation involves the infiltration of immune cells into the nervous system.  These are cells that do not belong in the central nervous system and which act on neurons and glial cells in a deleterious way.  This process is complex in that there are a variety of factors that are secreted by these cells and we are studying the roles these different factors play in the acute injury within the nervous system.   

Another stage in the disease process involves chronic degeneration.  After the inflammation is gone, there can be changes to the nerves that occur over time.  Thus, there is a window of opportunity during the acute phase to limit the extent of damage and then the disease process changes.  Finally, the body does perform some repair (endogenous repair).  This is good news.  In the case of the demyelinating disorders, the body will re-myelinate.  It is never as good as the original, but it helps.  Thinking about these different stages of the disease -- acute inflammation, chronic degeneration, and then repair – also helps us to think about the different areas in which we can intervene with treatments which could result in better outcomes for patients.

Graphic: Immune Mediated Neurologic Disease - Interventions

The different stages of immune mediated disease - acute inflammation, chronic degeneration, endogenous repair - each represent a new opportunity to intervene with different strategies to treat the disease.  The disease process begins with the trigger; what causes the acute inflammatory attack.  What would be most ideal would be for us to identify those triggers and avoid them.  If we could identify the inciting events, we could develop a strategy for avoiding them or altering the way our bodies respond to them.  This is called prevention.  For example, everyone gets a measles vaccine or a tetanus shot, because you can avoid these diseases altogether.  To do so, however, you have to find the trigger.   

The next opportunity for intervention is the stage of acute inflammation.  Acute inflammation presents the first opportunity for these neuroimmunologic disorders, because we have not yet identified the triggers.  When we see a patient who is in the early stages of acute inflammation, we have to rely on various strategies to limit the inflammation.  Another approach we could adopt is neuroprotecton.  This strategy involves putting a shield around the neuron to protect them from the immune cells that have infiltrated the nervous system.  Ideally, the neurons would be protected from damage until the inflammation has been resolved. 

When thinking about intervention strategies during the stage of chronic degeneration, we can employ neuroprotection, as well as the prevention of recurrence.  For patients with Multiple Sclerosis, Devic’s, or recurrent transverse myelitis, after the first attack we focus on the patient’s symptoms and work to improve their functional ability.  We then focus on preventing the disease from coming back.  Finally, during the stage of endogenous repair, we want to focus on treatment strategies that we could use to promote natural healing processes within the body.  We are also interested in strategies to repair the nervous system iatrogenically through the use of stem cells or other cell mediated systems where we can regrow or reconnect the nervous system. 

The remainder of this paper will focus on acute inflammation, specifically, the goals of acute therapy, the strategies for acute therapy and the mechanisms of action of various drugs. There have been no large controlled trials of these various therapies.  Thus, these recommendations will be based on our experience at the Johns Hopkins Transverse Myelitis Center.  The focus is on what we can do to improve outcomes for people who experience these inflammatory attacks.

In thinking about the goals of acute therapy, I am going to draw an analogy to how we have approached the treatment of patients with acute strokes.  There has been a major public health campaign for the last decade to raise awareness in the population about the symptoms and signs of a stroke.  We learned that people knew the signs and symptoms of a heart attack.  If a person experienced sudden chest pain radiating down their left arm and shortness of breath, they would come to the emergency room.  They would get evaluated for the heart attack within a reasonable amount of time.  What we found is that a lot of patients who were having symptoms of stroke: numbness, weakness, slurred speech, sat at home for hours or days waiting for it to get better.  By the time they made it to a doctor, there was little we could do to help them.  When the neurology and neurovascular community developed the drug TPA that could be used to reverse the symptoms of stroke if given within a certain window of opportunity (three hours from the onset of symptoms), it sparked a massive public health campaign to teach doctors and patients about the signs and symptoms of stroke.  Now, most people are savvy enough to know that if they suddenly, become weak on one side of the body, they should probably contact their doctor or go immediately to an emergency room, because they have three hours of opportunity to minimize the effects of stroke.  It was the acute therapy that was driving the public health campaign, and the acute therapy that was driving the professional education campaign.  We need to begin to apply this same idea of a critical window of opportunity for treating neuroimmunologic disorders.

So what are the goals of acute therapy?  We want to limit inflammation in order to prevent cells from infiltrating the blood-brain barrier.  We also want to eliminate components of the immune system that are in inappropriate places.  Another goal we have in acute therapy is to limit the effects of substances that lead to nervous system damage.  We want to directly inhibit substances that are neurotoxic.  We are learning from the work of Dr. Adam Kaplin, that we want to inhibit IL-6 in the case of Transverse Myelitis.  In the case of Devic’s, we are learning from the Mayo researchers that we might want to inhibit NMO-IgG; the circulating antibody that may be causing damage.  Finally, we want to protect the nervous system.  Neuroprotective strategies aim to shield neurons from damage even in the presence of inflammation. 

Turning now to the mechanisms of action for the acute therapies, I will begin with a discussion of steroids.  There are several mechanisms of action for these drugs.  First, steroids dampen the inflammatory profiles from the cells (the cytokine cascade).  Cytokines are proteins that can damage the nervous system.  The steroids are used to shut down their production.  Secondly, steroids stop T-cells and B-cells from activating in the first place.  Third, steroids decrease the extravasation of immune cells into the central nervous system.  They diminish the number of cytokines floating around and decrease the number of cells getting across the blood-brain barrier.  Finally, steroids actually kill off some of the activated immune cells by facilitating the apoptosis of activated immune cells.  Apoptosis is the self-destruction of cells.  We do not want these immune cells attacking the nervous system.  Thus, steroids have a variety of mechanisms for achieving these therapeutic goals. Steroids, over the short term, are considered quite safe, but can cause mood changes, sleep disturbance, elevated blood sugars and slight risks of infections.

Next, I will describe intravenous immunoglobulin (IVIG).   Immunoglobulins are antibodies.  IVIG is pooled antibodies from thousands of donors. When a patient gets an IVIG infusion, they are getting exposed to a massive amount of antibodies.  The idea is that these antibodies will do several things.  They neutralize pathogenic antibodies.  There may be antibody-antibody interactions; and the ‘bad’ ones may be obstructed by the antibodies we are infusing.  They may suppress pathogenic autoantibody production.  This may work like a feedback response.  By flooding the body with antibodies, the cells in the body that make antibodies may get a signal to shut down and stop producing, because there are now more than enough antibodies present from the infusion.  There are a variety of other possible ways that IVIG gets rid of pathologic antibodies, including the acceleration of native IgG degradation, the inhibition of complement binding, the blockage of Fc binding mediated phagocytosis, the interruption of antigen recognition and the suppression and neutralization of T-helper cell cytokines, metalloproteinase and chemokine production.  In general, IVIG is very safe, but it has the potential to cause allergic reactions, headaches, and kidney and lung problems.

Another strategy for treating acute inflammation is plasma exchange (PLEX) or plasmapheresis.  PLEX involves inserting a ‘central line’ – a special IV placed into a large vein and then being hooked up to a machine that cleanses or filters the blood.  The process takes about two hours.  Blood flows out of the body, is filtered and then is returned to the body.  If there is an antibody moving around in the system that is causing problems, this is a mechanism to try and get rid of it.  This procedure is not universally available and requires that a patient be near a facility that has the ability to offer it.  The risks of PLEX include the risks associated with placement of the central line; infections, bleeding (because clotting factors are removed along with the antibodies) and electrolyte changes.

Finally, another option is the use of cyclophosphamide (Cytoxan®).  This is a chemo-therapeutic agent (alkylating agent) that destroys the proliferating cells of the immune system (lymphocytes).  While its effects on the immune system are profound, caution must be used due to the potential for complications, such as low blood counts, infections and bleeding within the bladder.

It would be great if we had a well designed and proven strategy for treating people who have attacks of transverse myelitis, Devic’s or NMO with defined approaches based on a clear set of criteria.  We have been trying to achieve that goal for years, but we encounter significant difficulties when designing acute strategies.  There are a number of problems we face when trying to put together trials to prove the safety and efficacy of acute therapies.  First, there have only been a very limited number of clinical trials.  We have very little information from trials, and thus have limited guidance in developing future trials.  Designing prospective, blind trials for these therapies is difficult.  The neuroimmunologic disorders are rare.  It is hard to power a study with very few patients in a study.  Recruiting enough people into a study to prove that something is statistically significant is difficult to accomplish. 

Further, it is difficult to successfully blind patients and physicians.  For instance, it is hard to blind a patient as to whether or not plasmaphoresis is occurring, because of the procedure involved.  It has been done, but it is difficult to do in a controlled fashion.  Another problem with designing studies involves the heterogeneity within these disorders, which obscures the data.  There are a number of types of MS and there are a number of types of TM.  There is great variability within the classification of each of these disorders and there are differences between patients or subsets of patients.  How are we going to define the group to be studied?  Finally, outcome measures are limited.  How do we decide whether an acute therapy has succeeded or not?

I am going to share our experience at the Johns Hopkins Transverse Myelitis Center with our acute treatments of TM.  While we have found significant trends among our patients, caution must be used because these observations are not based on controlled studies.  For each situation, individual strategies must be devised.

We have noted that some features about patients that present with acute transverse myelitis might be useful for predicting which treatment strategy they will likely be responsive.  There are clinical features about the patient that must be taken into account.  The level of disability at the time of presentation is most critical.  The American Spinal Injury Association (ASIA) scale is a clinical tool used to define the level of dysfunction in the setting of spinal cord diseases.  Patients are ‘scored’ in terms of their motor, sensory and bowel/bladder function.  They are given a composite letter score of A, B, C, D or E.  On this scale, an ‘E’ is normal and an ASIA ‘A’ patient has complete loss of function below the level of the spinal cord injury.

In our experience, patients who are ASIA ‘A’ at nadir (at their worst) respond significantly better to regimens that include cyclophosphamide, regardless of other factors.  Patients who are non-ASIA ‘A’ (not complete) do not necessarily have improved outcomes from the addition of cyclophosphamide  to their regimen, and may not need the risk of cyclophosomide.  They may get a benefit by just providing steroids and plasma exchange, and not going on to a regimen that includes cyclophosphamide. 

We have also identified another group of patients who seem to have a selective response to regimens that include cyclophosphamide; patients with spinal cord inflammation in the setting of an autoimmune disorder.  Some patients with diseases, such as Lupus and Sjogren’s syndrome have transverse myelitis as a manifestation of their disease.  Still other patients with transverse myelitis have evidence of immune system dysfunction without meeting criteria for specific diseases.  Thus, when a patient presents with transverse myelitis we will routinely screen for a group of auto-antibodies.  If these tests are positive, they are indicators that a patient will have a preferential response to regimens that include cyclophosphamide.

In the absence of these criteria, we routinely use intravenous steroids, PLEX or a combination of the two.  While these recommendations are not based on controlled trials, they can be used to help guide therapy.  Most important, however, is the institution of some therapeutic intervention as soon as transverse myelitis is recognized - time is cord.  A spinal syndrome has to be recognized; the diagnosis that it is inflammatory has to occur rapidly.  We have to risk-stratify the patient and pick the treatment in a reasonable amount of time in order to protect as much of the spinal cord as possible.