KHURRAM BASHIR, MD, MPH: An acute demyelinating relapse is defined as new or worsening neurological symptoms that had been previously stable, associated with objective changes on examination lasting for 24 hours or longer in the absence of infection or fever.

It is important to determine that a relapse is present, because the treatment is going to vary whether there is an underlying condition, such as depression or an infection, or whether patient is experiencing truly inflammatory demyelinating events, in which case we would be using glucocorticoid therapy. And it is important to determine it objectively in my mind and, for that reason, we always try to interview and examine the patients before starting them on high-dose steroids.

The most common clinical presentations of acute MS relapses are in the form of either acute optic neuritis, transverse myelitis or isolated brainstem cerebellar syndrome. These are the most common and most easily recognized presentations in multiple sclerosis.

When we first evaluate patients and educate them about their disease, one of the things we discuss with them is what constitutes a relapse.

SYED RIZVI, MD: Typically, when patients are diagnosed, we go over what a relapse is. They always ask: “Am I going to be in a wheelchair with my next relapse?” And so, they need a lot of reassurance. And you try to explain what are the common relapses. You know, optic neuritis, for example, loss of vision, symptoms of transverse myelitis, motor-sensory symptoms, so that they’re aware that if they do develop any new symptoms they would call and discuss it further.

KHURRAM BASHIR, MD, MPH: When evaluating a patient for an acute relapse, it is important to make sure that there is no underlying disease activity, such as infection or fever that is complicating the clinical picture. Underlying depression can make MS symptoms worse in patients. It can lead to worsened quality of life because of patient's perception of worsening disease as well as worsened self-esteem.

Our current immunomodulator therapies and symptomatic therapies for multiple sclerosis, obviously, have some side effects and these adverse effects can result in worsening of neurological symptoms. For example, interferon therapies associated with flulike symptoms and elevated temperature, and that can result in subjective worsening of symptoms in MS patients.

Our symptomatic therapies can also result in some worsening of depression, worsening of fatigue and worsening of bladder and bowel function, and those have to be evaluated when determining a relapse.

ANDREW GOODMAN, MD: There are certain types of symptoms. Fatigue is one. Dizziness or vertigo may be another. Cognitive changes. People may complain, “I’m a little fuzzy. I’m having a little trouble with word finding or short-term memory.” This sort of thing can be very difficult to measure objectively by the clinician, and yet, from my perspective, I believe that those can be relapses.

KHURRAM BASHIR, MD, MPH: Patients who experience purely sensory relapses with no objective changes on examination, patients who have worsening of bladder or bowel function in the absence of any other spinal cord signs, patients who experience purely fatigue or cognitive impairment without any physical findings: it's always difficult to determine whether these are truly relapses or progressive disease.

When patients present with clinically isolated syndrome, or CIS, we educate them about their risk of developing MS, educate them about the symptoms that they may experience if this was truly a first symptom of MS and, also, the recommendations about MRI surveillance as well as treatment.

Using MRI in Identifying a Relapse

SYED RIZVI, MD: There’s not a strong correlation between MRI lesions and disability. Now, MRI does serve a useful purpose. The T2 lesion burden is useful early on at the time of diagnosis to create or to at least hint towards a prognosis. If you have a lot of T2 lesions, a very high lesion burden, those patients in the trials studied tend to do worse than patients who have a few lesions or absolutely no lesions.

For example, if you have your first episode, which we call a clinically isolated syndrome, those patients are not yet diagnosis with MS, but, you know, are highly suspicious, it’s highly that they will develop MS, these clinically isolated patients have been treated early on, and, you know, and have done better compared to a placebo group or compared to another group.

ANDREW GOODMAN, MD: The issue of MRI relapses is, of course, a controversial one. There are many clinicians who remain unconvinced that MRI is connected to the clinical manifestations of MS. But in fact, serial MRI studies done at the NIH and in other locations really do indicate that there is a subclinical aspect to relapsing MS, and I think it’s reasonable to call new activity on MRI scans, particularly if there’s an area of new or enlarging enhancement on T1 gadolinium-enhanced studies, I think it is reasonable to think of these as MRI relapses.

SYED RIZVI, MD: There’s not such a thing as MRI relapse, but, you know, for every new lesion in MRI, the reason you can have a silent MRI lesion is typically because it did not involve a strategically focal area. So you can see an MRI relapse if you have a new lesion on MRI. If that lesion in MRI was in the motor cortex, that same lesion could have produced motor weakness of the other side and would be relapse. Just because the lesion is in a different part of the brain or the silent part of the brain, you know, we don’t call it relapse, because clinically nothing happened.

So, MS is a disease which is relapsing-remitting mostly clinically. But on MRI, if you do see on MRIs you will see the lesions come and go all the time.

KHURRAM BASHIR, MD, MPH: Some people define MRI relapses as presence of gadolinium-enhancing lesions in the absence of changes on examination. Out of every eight new lesions that appear on cranial MRI on serial followups, only one lesion would be clinically symptomatic.

In the spinal cord, the ratio of development of lesions to clinical relapses is 1 to 3, with one relapse for every three new lesions. And so a lot of disease activity actually occurs on MRI, which is not represented clinically.

When MS patients experience a relapse, it usually is associated with either development of a new T2 lesion associated with gadolinium enhancement or enlargement of a previously present lesion.

Gadolinium enhancement signifies breakdown of the blood-brain barrier and is believed to be the first event in development of a relapse.

An MRI done at the time of a clinical relapse may or may not show gadolinium enhancement, because the duration of gadolinium enhancement varies anywhere from four hours to four weeks, and it may have already resolved by the time the MRI was done.

The use of glucocorticoids for acute MS relapses has traditionally been, for clinical relapses that can be objectively determined on examination or are impacting day-to-day activities of a patient. The treatment of gadolinium-enhancing lesions on MRI, or what some people call MRI relapses, is currently controversial.

Some MS specialists would recommend and favor treating all inflammatory-enhancing activity, and others would not. In our practice, we would reserve steroids use for patients with clinical relapses.

SYED RIZVI, MD: It’s very important to treat the patient and not the MRI, because the MRI may not strongly correlate with physical disability. So, it does serve a useful purpose when you see them early on at the time of diagnosis, because if you have a high lesion load, patients may not do as well as patients who have a low lesion load or just a few lesions.

For example, if you have no lesions on an MRI on an initial episode, the chances of developing MS in about 10 to 14 years is only about 10 or 11%. So, it gives you an idea how active the disease is. But once you’ve made that diagnosis, MRI lesions, or the typical T2 lesions we look at, may not correlate well with disability, so it’s very important that you look at the patient and you treat the patient rather than just treat the MRI, although MRI obviously has some role in overall management.

Treatments for an Acute MS Relapse

KHURRAM BASHIR, MD, MPH: The treatment of acute MS relapses can vary from expectant observation to use of IV glucocorticoid therapy, oral prednisone therapy and, in some centers, even IVIG therapy.

The decision to choose the appropriate regimen rests on the clinician's comfort level with that particular therapy as well as the severity of relapses.

SYED RIZVI, MD: For most purposes, relapses can present in all sorts of ways, and a lot of people may just have minor sensory relapses without any significant disability. Most people will not probably treat that, unless you think the sensory disturbance is part of a spinal cord abnormality.

So, sensory disturbances or sensory relapses tend to be minor. Patients recover sooner, and most physicians probably don’t feel that treating with steroids will make a whole lot of difference. So we therefore try not to opt to treat simple sensory relapses.

On the other hand, if somebody had a brain stem relapse or a spinal cord relapse resulting in motor weakness, or a cerebellar relapse resulting in significant balance problems, then, you know, treatment with steroids may speed up the recovery and may affect the ultimate outcome, although, as far as we know, there’s no real evidence suggesting that treatment with steroids would alter the ultimate outcome for a patient down the line.

KHURRAM BASHIR, MD, MPH: Our current understanding of what constitutes a suboptimal response based purely on relapses is somewhat limited. We have two comparisons when deciding that a patient is suboptimally responding, based on relapses. One comparison is patient's baseline relapse activity and relapse rate. And the second comparison that we can use is based on natural history studies of MS patients, whether based on large cohorts of patients followed carefully or placebo-controlled of -- placebo-treated patients in clinical trials.

The first comparison is becoming less and less available, because patients are being started on treatment fairly early in their disease, and they don't really have much of a baseline relapse frequency that is determined.

And so our understanding of MS relapses at this time is that, on average, MS patients have a relapse about every twelve to fifteen months and this is variable among patients. On average, every twelve to fifteen months, in a large cohort of MS patients. And, if a patient on therapy is experiencing one or greater than one relapses a year, that relapse frequency is unacceptable.

SYED RIZVI, MD: As far as steroid use is concerned, you want to treat your relapses, if you can confirm them as being relapses. You certainly don’t want to treat pseudo-relapses, because, say, if you have an infection, you’ll just make it worse. So, if you’re not sure there’s a relapse, I would not consider treatment. Steroids have side effects and all that. But they should be reserved for significant relapses, relapses which are confirmed, rather than pseudo--relapses.

Glucocorticoids: Mechanism of Action

ANDREW GOODMAN, MD: The mechanism of action of glucocorticoids in acute MS relapses is not completely understood. We do understand that corticosteroids have a great number of physiologic effects, including, in broad brush strokes, reducing edema associated with inflammation. Glucocorticoids can also lower the lymphocyte count by direct lysis of lymphocytes and may be immunosuppressive by that mechanism.

In addition, they reduce proinflammatory cytokines and may even have a role on the physiology itself of axons when they are inflamed to improve function. In the longer term, and this is not entirely clear, how well glucocorticoids may work when given on a schedule over the longer term, there may also be an immunosuppressive effect beyond the immediate antiinflammatory effect.

I should make another point, that glucocorticoids, even within a period of hours, tend to stabilize the blood-brain barrier, so that there have been studies looking at gadolinium-enhanced MRI scans showing a stabilization of the blood-brain barrier and, therefore, less or no gadolinium enhancement within hours of their infusion.

Glucocorticoids: Benefits

KHURRAM BASHIR, MD, MPH: The use of glucocorticoids in MS relapses has been a standard therapy for a long time, primarily because of the improvement that is seen following their use. Patients tend to recover from acute relapses very quickly. A person who is unable to see or unable to walk, if they can recover within a few weeks as opposed to a few months, that is a significant amount of clinical recovery.

ANDREW GOODMAN, MD: The best evidence that we have, in my estimation, of the value of glucocorticoids for an acute flare-up or relapse of MS, comes from the studies of optic neuritis, the so-called Optic Neuritis Treatment Trial. And in this study (which, again, focused on optic neuritis, and not everybody had MS at the time, but just focusing on the MS patients) it was clear that high doses of intravenous methylprednisolone, as a form of glucocorticoid, followed by a short, tapering course of prednisone, did result in resolution of symptoms, in this case, visual symptoms, sooner than placebo.

What was not clear is that after a number of months—the longer term follow up—six months in particular was what was looked at in this study, it was not clear that there was a different outcome as far as the residual effects of the relapse. So, the conclusion was that we can get to a better outcome more quickly, but that the ultimate outcome from, at least, an optic neuritis flare appears to be about the same.

KHURRAM BASHIR, MD, MPH: A person presenting with optic neuritis, based on optic neuritis treatment trials, should be treated with three days of IV methylprednisolone therapy followed by twelve-day taper of oral prednisone. Some people argue that, because the optic neuritis treatment trial did not show a difference at six months or a year, it may be worth observing these patients rather than treating them with steroids.

Patients who present with brainstem or cerebellar relapses, which are more likely to produce significant disability, probably should be treated more aggressively and the earlier, the better.

ANDREW GOODMAN, MD: Transverse myelitis as a manifestation of MS, in my experience, can be somewhat more difficult to treat with corticosteroids. And again, based on my experience, we will often need to treat longer, and sometimes with repeated courses of corticosteroid, until the symptoms begin to improve and stabilize.

KHURRAM BASHIR, MD, MPH: The treatment of transverse myelitis, because it is more likely to result in physical disability for patients, needs to be more aggressive and earlier in treatment. Transverse myelitis in multiple sclerosis can present as purely sensory relapses, in which case patients can be observed, but when there is involvement of bowel or bladder function or involvement of gait, those patients need to be treated with high-dose glucocorticoids early.

Regimens for Glucocorticoids

ANDREW GOODMAN, MD: There’s really no consensus, in my view, as to what is the best or the correct dose or, for that matter, the correct formulation of corticosteroid to use in MS relapse. That being said, I think many practitioners tend to use three to five days of infusions of methylprednisolone, generally at about 1 g/day. And this is often followed by a tapering course of either prednisone or methylprednisolone in an oral form, formulation, given for anywhere from two to four weeks, depending on how high the dose is, before the taper is begun. In my experience, we will generally taper with prednisone in the range of 60 to 100 mg following the three to five days of 1,000 mg of methylprednisolone.

KHURRAM BASHIR, MD, MPH: Glucocorticoids for acute MS relapses can be used in several different formulations. They can be used as IV methylprednisolone therapy, high-dose oral prednisolone therapy or even as ACTH, or adrenocorticotropic hormone therapy, that can be given either subcutaneously or intramuscularly. All these approaches have been shown, in various clinical trials, to be an effective therapy for acute relapses.

SYED RIZVI, MD: There’s no standard way of giving steroids. Most people use 3 to 5 grams given over three to five days. But, I know people who use 500 mg a day for several days, and there have been a couple of studies looking at 2 g/day.

KHURRAM BASHIR, MD, MPH: The duration of therapy for acute MS relapses varies depending on the formulation used. With IV methylprednisolone, the therapy varies from 500 to 1000 mg a day for three to five days. The oral prednisone therapy usually starts at a dose of 1 mg/kg and is tapered over two to four weeks.

And the ACTH regimen is a therapy for acute relapses for eight days to sixteen days of therapy, either given subcutaneously or intramuscularly.

SYED RIZVI, MD: There are a couple of trials which are actually looking at comparing IV versus oral high-dose steroids, and it may happen that a couple of years down the line, if there is enough data, we might start using high-dose oral rather than IV.

ANDREW GOODMAN, MD: There are high-dose oral regimens that some clinicians have used, and I’ve used them in my practice, as well, from time to time. For example, there was a period in the past couple of years where there was in fact a shortage, and sometimes and absolute inability to find intravenous methylprednisolone, so we were forced to use oral preparations.

KHURRAM BASHIR, MD, MPH: A small number of patients seen in any large clinical practice of MS would be very steroid-responsive. These patients, any time you try to take them off of glucocorticoid therapy, would experience disease activity, either as relapses or progression and, for these patients, chronic low-dose steroids can be instituted to try to suppress disease activity.

Another approach that has been tried with glucocorticoids is pulsed steroid therapy, either given monthly or quarterly to try to modify disease course. And, based on the European study, there is data that it is helpful in preventing relapses, MRI disease activity and progression.

SYED RIZVI, MD: Pulsed steroids are used commonly for the treatment of MS. Typically, when you have somebody who’s worsening, they can be used as a bridge towards possibly an ultimate use of a drug like Novantrone, just because they’re safer to use and the side effects are pretty tolerable.

So, so, when you use pulse steroids, basically you can use it every month, you can use it every two months or every three months. There’s a little bit of evidence supporting that, you know, maybe pulse steroids do help. Apart from patients who may, all the time, come and say that, you know, the steroids do work for a couple of weeks, and then the effect starts wearing off. That could be just a steroid effect and not really an effect on the disease. But the Zivadinov study looked at patients who were given steroids when they had their attacks versus patients who received steroids every four months routinely for about five years, and that study did show that patients who received steroids regularly had less brain atrophy and less number of T1 lesions, suggesting possibly an effect on neurodegeneration and overall disease process.

Similarly, if you look at patients who are treated in the postpartum period, where there’s a higher frequency of relapses, there have been a couple of small studies suggesting that if you use monthly steroids preventively in order to prevent a relapse, patients who receive steroids tend to do better than patients who did not.

For our purposes, in our offices, we all use monthly or every two month, every three month steroids, trying to catch up or trying to suppress disease activity in combination with a platform therapy, which could be any of the drugs.

So the evidence is not a lot, but there are a couple of small studies. But from a clinical point of view, a lot of use pulse steroids in our practice as combination treatment, and we do see a benefit. You know, sometimes when patients are worsening and having breakthrough disease and we put them on pulse steroids, they may stabilize. Similarly, you know, these patients a lot of times may get other benefits.

ANDREW GOODMAN, MD: This is not standard practice, but there are patients who either don’t respond or don’t tolerate other treatments or need a combination of treatments to try and get a better effect. And so one of the approaches that practitioners are using is repeated schedule doses of corticosteroid. There is absolutely no consensus, in my view, as to what that schedule should be.

Frequently, doctors will use monthly single-day pulses, or doses, of 1,000 mg of methylprednisolone, and others will use a three-day course of methylprednisolone, 1,000 mg, given every other month. The idea of not giving it too frequently is to avoid long-term side effects of corticosteroids that are well-known to all doctors.

KHURRAM BASHIR, MD, MPH: The long-term benefit of glucocorticoid therapy is less well-established and is controversial. A number of studies done in the 1970s and 1980s demonstrated that, although steroids were effective in the short term, they did not reduce the frequency of relapses and did not prevent progression of disability in the long run. There has been some recent data from Europe that has demonstrated that pulsed IV methylprednisolone therapy used quarterly in MS patients is effective in reducing frequency of relapses, MRI disease activity and progression of disability over the course of five years.

In terms of long-term effects of glucocorticoids, the data is mixed. A number of clinical trials done in the '70s and '80s demonstrated that, although steroids helped with recovery from relapses, they had no impact on long-term prevention of relapses or long-term prevention of disability.

SYED RIZVI, MD: From a clinical point of view, these patients may recover faster, and the ultimate disability may be limited on the short term. But if you look at all these patients in the long term, corticosteroids do not really affect the long-term disability. So, if you were to have an X amount of disability at year 1 after treatment of relapse with steroids, you would probably have that. But you may recover better on the short term.

KHURRAM BASHIR, MD, MPH: Optic neuritis treatment trial demonstrated that patients who were treated with IV glucocorticoids followed by oral prednisone were less likely to have recurrent optic neuritis in the same or the opposite eye, compared to patients who were treated with either placebo or oral prednisone without preceding IV solumedrol therapy. So, there is some beneficial effect of using high-dose IV glucocorticoids followed by prednisone in preventing future relapses, at least up to a year out.

Glucocorticoids: Side Effects

KHURRAM BASHIR, MD, MPH: The commonly-seen adverse effects of high-dose glucocorticoid therapy include changes in emotions, either depression or euphoria, changes in sleep patterns, increased appetite with subsequent weight gain, metallic taste in mouth, a flushing sensation while the IV infusions are going on and also effects on blood sugar. The use of glucocorticoids in patients who have comorbid conditions such as hypertension or diabetes or congestive heart failure needs to be considered carefully.

Glucocorticoids can induce glucocorticoid-induced hyperglycemia. They can increase hypertension and, because of the fluid retention associated with use of steroids, they can also exacerbate conditions such as congestive heart failure.

ANDREW GOODMAN, MD: Rarely, we will see a cardiac arrhythmia or even myocardial infarction occur in the setting of high-dose corticosteroid, presumably from increased cardiac output and, therefore, increased workload on the heart, or by inducing a dangerous arrhythmia. Fortunately, this is a rare occurrence. It is known that corticosteroids sometimes are associated with GI bleeding, again, a relatively rare occurrence, from my experience.

KHURRAM BASHIR, MD, MPH: Avascular necrosis of the hip is a rare complication of glucocorticoid use, but it's a serious complication. In this condition, there is lack of blood supply and necrosis of the head of the femur as it enters the hip joint. And it can be a very painful condition, and if well-established, it necessitates a total hip arthroplasty.

SYED RIZVI, MD: Aseptic necrosis can even happen after a single dose. So it can happen in patients who will use it for three to five days. So it’s important to let them know, because if they’re having hip pain, for example, they may be more likely to call you if they’re aware of possible side effects.

KHURRAM BASHIR, MD, MPH: Hepatic steatosis, or fatty liver, is a medical condition that can occur in patients who gain weight, but it's also a complication of chronic steroid use, because of increased weight gain and appetite.

The use of glucocorticoid therapy, either intravenously or orally, can accelerate the development of cataracts in patients, leading to earlier cataract extraction and intraocular lens placements.

SYED RIZVI, MD: Typically, if I have somebody who’s on chronic steroid use or even long-term pulse steroids, I would have them see an ophthalmologist to make sure they’re not developing early cataracts.

KHURRAM BASHIR, MD, MPH: Long-term use of glucocorticoid therapy has been associated with increased risk of osteoporosis. In patients that we treat with glucocorticoid therapy, we usually monitor them with DEXA scans to try to monitor their bone densities. We also encourage them to use calcium and vitamin D on a regular basis, and this is encouraged in all our MS patients. And, if they develop osteopenia or osteoporosis, we're fairly aggressive in treating them with medications to prevent further worsening.

SYED RIZVI, MD: So, steroids have side effects, but if you use it for a shorter period of time, then you’re talking about three to five days, the side effects are very limited. Most of these patients can tolerate these side effects, and they may include weight gain for a couple of days, some fluid retention, a little bit of anxiety, although sometimes you have to worry about frank psychosis, although it’s rare. If you have a patient who has a psychiatric condition, you want to be really careful when using steroids Similarly, if you have somebody who’s depressed, sometimes depression can worsen significantly, so you need to be really careful when using steroids in people who are depressed. Other common side effects which can happen on the short term may include headaches, rashes.

The side effect profile can be worse if you’re using corticosteroids for longer periods. And so I’m talking about using oral prednisone, for example, for weeks and months, and it has been used in other conditions. Then, you worry about hypertension, you worry about your blood sugars going up. I mean, those two can also happen in short-term, but are much less common than when you’re using it for long periods. You have to worry about problems with skin, bruising and all that, which usually is not a big deal, but cosmetically can be a problem. And then the big one which comes in is osteoporosis, which typically is not seen when a steroid is used for short-term periods, but may become a significant problem if you use it for long-terms. Now, when you use it in a pulse fashion, when you use it like we use pulse steroids, we haven’t seen a lot of osteoporosis. But we do recommend monitoring: doing a bone density study and using calcium and vitamin D up front.

Other Therapies

ANDREW GOODMAN, MD: The role of immunoglobulins or intravenous immunoglobulins, known as IVIg, is controversial. There have been studies around the world that have demonstrated an effect on preventing relapses and an effect on MRI in certain studies. The effect on preventing disability has been less robust and difficult to confirm.

KHURRAM BASHIR, MD, MPH: Intravenous immunoglobulins have been used for treatment of acute relapses, as well as prolonged treatment of multiple sclerosis, as preventative therapies in a number of clinical trials. The data is more limited than for interferons or glatiramer acetate. It can shorten the duration of an acute MS relapse. It has also been shown to reduce the frequency of relapses by about 26%. One of the clinical trials with IVIG in secondary progressive MS did not demonstrate any benefit in preventing progression of disease.

ANDREW GOODMAN, MD: But, if the question is the use of intravenous immunoglobulin to try and help a person recover from an individual relapse, the studies have not, in my estimation, shown a value there. In particular, I’m thinking of two studies that were done at the Mayo Clinic that really failed to show an improvement or recovery from severe relapses.

SYED RIZVI, MD: I’m not aware of any evidence in which IVIG given in an acute setting makes a difference, although there was a recent optic neuritis trial which may have suggested that if you give it within three months or so, there may be a better recovery.

ANDREW GOODMAN, MD: I don’t believe there’s a standard or consensus regimen for IVIG. Certainly for individual relapses, but even for prevention of relapses. The dosing that has been used in the various clinical trials has varied quite widely, and I don’t think any consensus has been reached in the MS community about what the best approach is to using it.

KHURRAM BASHIR, MD, MPH: IVIG is currently used in multiple sclerosis based on our understanding of how it works in other immunological conditions, such as myasthenia and others. Currently, the dose that is used is 0.4 mg/kg single dose. IVIg can be used either in a dose of 0.4 mg/kg intravenously per day over four to six hours for three to five days for an acute relapse. It can also be used as pulsed IVIg therapy once a month for prevention of relapses and long-term management of MS. The downside of IVIg used is, obviously, its cost.

ANDREW GOODMAN, MD: Very little is known about the mechanism of action of IVIg in MS. Presumably, it acts as in immunosuppressant, perhaps by blocking FC receptors of antibodies, perhaps by reducing proinflammatory cytokines, and even possibly improving remyelination in axons that have had inflamed or damaged myelin.

There is recent evidence, particularly a study from the Mayo Clinic, that does seem to indicate that there are certain patients with rather severe relapses who have not responded to steroid who may in fact respond favorably to plasma exchange. The Mayo Clinic group has estimated that that ranges to perhaps 40% of such patients. In my own practice, I’m convinced that this can be worthwhile.

In particular, we’ve seen patients with rather severe optic neuritis, at times bilateral optic neuritis, not responding favorably to corticosteroids who have had a rather dramatic improvement once plasma exchange was begun. So, I am convinced that the Mayo Clinic data are showing us something of value.

KHURRAM BASHIR, MD, MPH: Given as a treatment on alternate days for a total of ten days. It has been shown to improve recovery in acute steroid-unresponsive demyelinating relapses.

ANDREW GOODMAN, MD: There are occasional patients who have such severe relapses that they’re not responding to any of the usual approaches, such as high-dose corticosteroids and, at times, plasma exchange when it’s used. In such cases, I’ve rarely recommended cyclophosphamide to try to suppress the immune system in the hope of allowing some recovery from that severe relapse.

Conclusion

KHURRAM BASHIR, MD, MPH: The goal of MS care is comprehensive treatment of patients, not just with immunomodulators, but also providing symptomatic therapy, psychosocial support and education to patients and their families so as to improve their quality of life and improve productivity.

ANDREW GOODMAN, MD: The goals of treatment is, as we have available to us now, are to reduce symptoms from acute relapses, hopefully minimize those. But also to prevent relapses from occurring as much as possible in the hope that, by preventing relapses and preventing residual neurologic deficits after a relapse, we may be able to minimize the longer-term pattern of progressive disability that seems to be an inevitable part of the natural history of MS in the majority of cases.

SYED RIZVI, MD: When you have a relapse, it’s important to know the severity of the relapse, because there are patients who may go on for many, many years and do extremely well. And if you talk to these patients, a lot of times they just have minor sensory relapses, or they’ve had relapses which are short-lasting with almost complete recovery.

Then there are patients who have developed a lot of disability, and these patients sometimes will tell you that they get relapses and they don’t get better to where they were, and they’re left with a little bit of damage or a little bit of disability which, you know, in time, if you get more of these relapses with incomplete recovery, they lead to a worse prognosis with more accumulation of disability. So, it’s important when you’re talking about treating relapses, when you’re talking about long-term treatment, it may be important to see what kind of relapses these patients are getting, whether they are just minor, short-lasting relapses or relapses with lasting disability.

Typically, relapses are treated with steroids, corticosteroids. Rarely you may treat them with IVIg. There are a series of cases from Mayo Clinic in which patients with very severe relapses not responding to steroids were treated with plasmapheresis and tend to get better. But, you know, it’s been used in clinical practice, and especially in severe relapses or severe brain stem relapses, found to be useful in some circumstances.

Other drugs, none of the immunomodulating agents, none of the immunosuppressive agents such as Cytoxan or mitoxantrone or Novantrone have been found to be useful and are not expected to be useful to treat acute relapses. Other oral treatments such as methotrexate, Imuran, CellCept and various other treatments we use have not really and we don’t really feel will be useful for treatment of acute relapses.

In relapsing-remitting disease, by definition, you have to have relapses, and when a patient is initially diagnosed, in the first several years there may be an increased frequency of relapses which can range from anywhere from once a year to once every few years. And as time goes, even without treatment, the rate of relapses decreased, and that may overlap with gradually progressive worsening disability, in which case, if a person has stopped having relapses and they’re still getting worse, they’re going to call it secondary progressive disease. So, relapses are important early on, and may actually, if the rate is higher, may point towards worsening disability down the line.