Acute Therapies for MS and other Neuroimmunologic Disorders
Brian Weinshenker, MD, FRCP
Mayo Clinic College of Medicine
This article will address the acute treatments for MS and other neuroimmunologic disorders. First, what is an acute treatment? These are not the treatments that are used to prevent further attacks or to restore function in people with chronic disabilities. Acute treatments are given right at the time that an attack of MS is happening, which is probably our best opportunity to intervene in an effective way and prevent disability. Obviously, the other treatments are very important as well, but probably what we do right at the time that someone is experiencing an acute demyelinating episode, especially transverse myelitis, which often does not lead to full spontaneous recovery, is absolutely critical.
We have not yet been able to define the circumstances in which the treatments are effective for an acute attack. We do not know from the individual patient characteristics who is going to respond to acute treatment. Regardless of how good our treatments currently are, they do not work for everyone. Ideally, we would like to understand which patients respond, because that would tell us a little bit about how they work. When we understand how a treatment works, we are in a better position to target the treatment to those who benefit, and also to optimize the treatment and look for additional treatments that work by a similar mechanism.
We have to define whether these treatments work directly on axons (nerve cells) protecting them from injury or restoring their function, or do they work by an anti-inflammatory mechanism by stopping or suppressing ongoing inflammatory activity.
Graphic: Catastrophic MS: Subtypes
This graphic portrays two different patient circumstances. In the first case, graphic A, the patient experiences an acute worsening. Patients in this scenario had been perfectly stable, and then over a week or so, develop a very severe neurological deficit; this is the case with many patients with transverse myelitis. They could get treated with steroids and many continue to have significant deficits. In graphic B, the patient experiences repeated mini attacks over the course of the year. This is what we commonly see in MS patients. Whether the patient deteriorates in a very short period of time as in transverse myelitis, or there is a step-wise worsening, as in MS, both of these scenarios may lead to a bad result.
Should the treatments in both situations be the same? Intuitively, I would think that in the case of patients who have ongoing inflammatory disease activity (Graphic B – MS); treatments that suppress inflammation would be most effective. In patients that experience rapid deterioration (Graphic A – TM); intuition would lead one to think that a treatment that immediately protects the injured nerve fibers and prevents them from deteriorating would be the most effective approach. The answer is not necessarily a simple one. It seems that in the TM cases with rapid deterioration, and where steroids have failed, plasma exchange is the best strategy, and we think that plasma exchange works by suppressing on-going inflammation by removing pathogenic antibodies.
We have a hard time evaluating the effectiveness of acute treatments, because acute attacks often get better on their own. Even in patients who have very severe attacks with acute demyelination, a significant percentage of them get better even without any therapy. That is good news, of course, but it makes it more difficult for us to be certain that the treatments we are administering have accomplished something when we see the patient get better. In the progressive type of MS, there is a rather predictable progression of disabilities. Ordinarily, the legs are affected first, then the arms, and maybe cognitive function. We are able to use a composite measure called the EDSS which we often use in MS to document the disability and measure the improvement. In the case of acute demyelinating attacks, there are more diverse neurological deficits. It is a harder to quantitate them with a single measure like the EDSS.
Although a patient might say, “I have myelitis,” from the neurologist’s perspective it is important to understand the context in which the “myelitis” occurs. A myelitis (inflammatory attack in the spinal cord) occurring in the context of MS is often much less severe and more likely to get better on its own. When the myelitis occurs in the context of neuromyelitis optica or idiopathic transverse myelitis, the prognosis is more guarded. It is important for us to not only determine that someone has transverse myelitis, but to understand the context of the overall disease. Knowing the disease type tells us something about the prognosis for the future. We are learning that the pathology and also immunology may well be different, and particularly in relationship to treatment with plasma exchanges.
I will be presenting about four acute treatments. These four are representative of the treatments that we apply in the acute setting. The first treatment I will discuss is corticosteroids. We have used corticosteroids for some time; they are very effective and are generally our first line treatment. When corticosteroids fail, we turn to plasma exchange, IVIG or immune suppressive agents, such as cyclophosphamide (historically, the agent most widely applied in demyelinating disease).
Corticosteroids are well established and well accepted to be effective. The data from multiple clinical trials is that at the end of three to six months, most patients get better whether you gave corticosteroids or not. Thus, it is difficult to demonstrate that the percentage treated with steroids is any different than those not treated with steroids – when you look at all patients with attacks of demyelinating disease. There is no doubt that they shorten attacks, but it is difficult to be certain as to whether they make a real difference to the ultimate outcome. And this is an important point. When we did the plasma exchange study, we did not look at all patients. We admitted only those patients who had severe attacks and had failed treatment with steroids.
Plasma exchange (PLEX) had been first reported in patients with MS in the early 1980s by Dr. Peter Dau of Chicago. It was used primarily in patients with progressive MS. It was also used in a small number of patients who had severe attacks who did not respond to steroids, and it was rather controversial as to whether it worked. Some results were published that were positive, while others were negative. There was a large, multi-center, controlled clinical trial performed and reported in 1989 (Weiner et al. Neurology 1989). All of the patients in the study had acute MS attacks and were given ACTH (which is a form of steroids) and they were given cyclophosphamide (which is a chemotherapy). We generally do not administer both in this fashion for acute attacks of MS. Additionally, they were randomized to either receive real or sham plasma exchange. The end result was that there was no convincing difference whether or not the patient had received real or sham plasma exchange, although there was maybe a hint in those patients with the most severe attacks who had relapsing remitting MS, that there might be a benefit.
We did not believe that this study answered the question as to the effectiveness of plasma exchange, so Mayo Clinic initiated a randomized, double-masked, crossover, sham controlled study among steroid treatment failures. PLEX was studied as a monotherapy; it was not combined with other therapies. It was a very selective clinical trial involving 22 patients, all of whom had acute, very severe demyelinating disease. A variety of demyelinating syndromes were included in the trial. Some patients had MS, some transverse myelitis, and others had what we call Marburg’s variant of MS; this is a type of MS that presents in the brain with a large tumor-like lesion. All of the patients in the trial had failed steroids. After at least three weeks, they had not recovered. They were randomly assigned to receive real or sham exchange for two weeks. At the end of that two weeks, we made a decision whether they had improved or not, and if they did not, they crossed over and got the opposite treatment. The patients did not find out until the entire clinical trial was over who had what.
When the trial was concluded, we found that 42% of those patients who were receiving courses of active plasma exchange improved, while only 6% improved who did not receive active plasma exchange (they received sham treatment). We required a very robust measure of improvement. We were not interested in minor improvement. We required a moderate to marked improvement in the targeted deficit. We had five patients who were getting sham treatments, and they got no better. These patients then crossed over after two weeks and started getting the active treatment. Of course, because of the way the trial was designed, we did not know which they were getting at the time. Three of these five patients, after two weeks of receiving the active treatment, improved. This was very convincing evidence of the effectiveness of plasma exchange. All of the patients who improved in this study maintained the improvement.
Graphic: Diagnoses of Patients Treated with Plasma Exchange 1984-2000
This graphic represents our experience with plasma exchange at the Mayo Clinic; 59 patients that we reviewed between 1984 and 2000. The graphic identifies the diagnoses of patients that we treated at Mayo with plasma exchange, the most common of which was relapsing-remitting MS. The next most common was acute disseminated encephalomyelitis, followed by acute transverse myelitis and then neuromyelitis optica. The remaining categories of demyelinating disorders represent much smaller numbers of patients.
Graphic: Proportion of Patients with Moderate to Marked Improvement
Of the four most common diagnoses that we treated at Mayo Clinic, our best response to PLEX has been in the patients with neuromyelitis optica; 60% (6 out of 10) have experienced a moderate to marked improvement. Among other categories of patients, and these were primarily patients that were not in our clinical trial, the favorable responses to PLEX were as common (42%) as we had reported in our study. Some people always think that patients in clinical trials usually do better than those treated in regular practice outside of a clinical trial. Our experience outside of our clinical trial mirrored our experience from the study.
The results of our clinical trial have received intense scrutiny and there have been concerns raised. One of the issues raised is that the treatment of an acute attack with PLEX does not do anything to address recurrent attacks. My response to this issue is that while we are worried about what the future holds for a person who has experienced a severe attack, our immediate concern is focused on the current acute episode and preventing as much damage as possible from this attack.
No one outside of Mayo Clinic has performed a randomized controlled study to replicate or confirm the benefits of plasma exchange. However, there have been people who have adopted the treatment paradigm of using plasma exchange in the case of acute severe attacks in which steroids have failed to result in improvements. A group at the University of Vermont published a paper on their experience with one patient (Mao-Draayer et al. Neurology 2002; 59: 1074-77).
Graphic: MRI images
They looked at imaging; this patient had an acute cerebral demyelinating event. The patient got steroids, the enhancement or the leakage of dye got better, but the patient had not clinically improved and they still had a huge lesion. The patient then received two weeks of plasma exchange and as is evident from the images, the lesion substantially improved.
Graphic: Plasma Exchange: Further International Experience
This table summarizes a series of papers reporting about experience with PLEX. The first results are published in the Journal of Neurology by a group led by Dr. Neil Scolding (J Neurol 2004 251: 1515) from Bristol, UK. They report on six consecutive patients, which represents all of the patients they have treated with plasma exchange. One patient had transverse myelitis, one with neuromyelitis optica, and four with MS. Six out of six experienced what they consider a major improvement. The degree of improvement from their EDSS varied from 0.5 to 4.5.
The results from Spain, published in the Revisita de Neurologia 2003: 37: 917 by Dr. Meca-Lallana et al involved eleven patients. Nine of the patients had MS, one had transverse myelitis, and one had ADEM. As to their syndromes, they had paraplegia, ataxia or dysphagia. Of the 11 patients, 7 of them experienced major improvement after one month.
A study on treatment of ten patients with severe optic neuritis in Germany (Neurology 2004; 63: 1081) showed a similar high rate of success.
Graphic: Plasmapheresis in severe optic neuritis
These were not just patients with mild optic neuritis; these were patients that were generally blind in one eye. They received steroids and this treatment failed. As the graph demonstrates, after receiving plasma exchange, a large number of patients had improvement in their vision and all of them maintained that improvement after plasma exchange was completed. Some with the very worst visual deficits did not improve. Of course, as I mentioned, in our Mayo Clinic study we have had a number of people that have not improved.
What have these investigators reported about their experiences with plasma exchange? Meca-Lallana indicated that, “Its use should be considered as first line in severe relapses and in swiftly progressing forms [of MS] that do not respond to intravenous methylprednisolone.” (Revista de Neurologia 2003; 37: 917-926).
The Bristol group concludes, “Our study supports the use of plasma exchange in cases of severe steroid-insensitive demyelination of the CNS.” (J. Neurology 2004).
The following was published by Dr. Panitch’s group in Vermont: “This patient’s rapid clinical and MRI response suggests that plasma exchange may be beneficial in this disorder, and could perhaps serve as a diagnostic tool to avoid the need for brain biopsy.” (Neurology 2002; 59: 1074-77). His conclusions go further than I would have in regard to avoiding the need for brain biopsy. He suggests that if the patient responds to plasma exchange that proves it is demyelinating (inflammatory).
Regarding their study of optic neuritis, Ruprecht et al state, “We therefore favor the hypothesis that plasma exchange had a therapeutic effect in our series and propose a larger prospective controlled trial to address this.” (Neurology 2004; 63: 1081).
Graph: Catastrophic MS: Subtypes
Based on the available data, I would use plasma exchange on the patient with an acute severe attack (A) as opposed to a patient who has ongoing repeated smaller attacks of inflammatory disease activity (B) for whom the goal would be suppression of ongoing inflammation.
Why do some patients respond to plasma exchange, while others do not? We seem to see an all or nothing response. Either there is an excellent response or no response. That result tends to suggest that there should be some simple explanation. We have not seen partial responses or a whole gradient of responses; that would suggest a more complex or multi-factorial explanation. Thus far, clinical predictors of response are weak. We looked at a number of clinical predictors and we did find that those patients who had lost all of their reflexes had a poor response. We also found that women did not do as well as men. Whether that will hold up or not, I do not know. Time to treatment was not strongly predictive of response. The time between the attack and when the patient was treated with plasma exchange did not seem to have an impact on their response to the treatment. It was thought that maybe if they were treated really quickly, they might do better than if the treatment were delayed by days or weeks. There may be some truth to that, but we saw people even three months out who were doing well. So, that was not the whole explanation.
Graph: Response versus Pathology
One clear-cut answer seemed to come from one of my colleagues, Dr. Lucchinetti. Working with Dr. Keegan, also at Mayo Clinic, she looked at patients with MS who underwent plasma exchange and had brain biopsies. Dr. Lucchinetti classified these patients into one of three different pathological types. Pattern II is a pattern associated with antibody deposition in the brain. Every patient who had pattern II, the antibody mediated form of MS, responded to plasma exchange, and none of the patients with the other patterns of MS seemed to respond. Fortunately, these other forms of MS are less common. Type II pathology seems very predictive of outcome to plasma exchange treatment. It points again to the importance of trying to identify those patients who have antibody-mediated disease. It seems to be a common situation in patients who have these acute severe forms of disease.
The next treatment I will discuss is IVIG or intravenous immunoglobulin. IVIG works in a number of ways, including binding to other antibodies that may be deleterious, binding to macrophages and interfering with their function. Macrophages are among the most common cells in inflammatory infiltrates. It is known to bind complement components. It also binds to B-cells and maybe by cross-linking them leads to cell death of these B-cells. We know from a control study, that as is the case with interferon use, IVIG reduces attacks and the numbers of MRI lesions in relapsing remitting MS. A recent European study demonstrated that it is not effective in secondary progressive MS. There have been no clinical trials of IVIG treatment in MS. There are a lot of anecdotal reports of patients who have ADEM who have failed treatment with steroids and seem to respond to IVIG. Some of this series of patients who have been diagnosed with a limited form of ADEM, I would have called transverse myelitis. It would be interesting to consider IVIG as an alternative to plasma exchange, but it needs to be tested before it is accepted. Until a proper comparative study is done, I do not recommend IVIG as a first line treatment; we do have the data to demonstrate the effectiveness of plasma exchange.
Cyclophosphamide, as I mentioned earlier, was used as a standard treatment for attacks in all of the patients who were in the controlled trial of plasma exchange by Weiner et al in 1999. There is less evidence to support the use of cyclophosphamide for acute attacks of MS and this is a much less commonly employed acute treatment.
Graph: Cyclophosphamide Studies in Rapidly Progressive “Transitional” MS
Cyclophosphamide has a controversial history for use in progressive MS. Some of this controversy may be due to the fact that progressive MS is heterogeneous. Some patients deteriorate because of gradual nerve fiber dropout in primary progressive or secondary progressive MS and others seem to experience a rapidly worsening inflammatory form of the disease that is sometimes called transitional MS. A number of relatively small studies in that select group of patients with rapidly progressive, transitional MS, who have a large number of gadolinium-enhancing lesions on MRI have demonstrated impressive results with cyclophosphamide; a high percentage of patients are apparently stabilized or improved. However, these are uncontrolled studies (no control group); nonetheless, they are believable and do fit with my experience.
I have reviewed four different treatments for acute inflammatory attacks in MS and other neuroimmunologic disorders, concentrating on plasma exchange. In conclusion, we need better ways to define what we mean by acute MS and a better understanding of the mechanisms involved in acute MS. This understanding would help us to better comprehend how the treatments we are applying really work. Do they work by suppressing active disease and inflammation, enhancing nerve function, or by preventing nerve cell death (i.e., neuro-protective)? Corticosteroids are the standard first line treatment for inflammatory attacks. If there is a steroid refractory attack (steroids fail to result in improvement), we suggest the use of plasma exchange. In those cases of rapidly worsening, fulminant MS (the step wise worsening that was displayed in the previous graphs as patient B), immuno-suppression with agents, such as cyclophosphamide or mitoxantrone, is probably the best strategy at the present time.