Understanding And Treating Multiple Sclerosis

Elizabeth A. Shuster, M.D. and Valerie Armstrong, ARNP
Elizabeth A. Shuster, M.D. is a Neurologist with Mayo Clinic Jacksonville. Valerie
Armstrong, ARNP is with the North Florida Multiple Sclerosis Comprehensive Care Center.

Introduction

Multiple Sclerosis (MS) is a major non-traumatic reason for disability in Americans between the ages of 20 and 50. The cost to our society is huge — over $9 billion dollars a year.¹ In the last decade, significant advances have been made in understanding the pathophysiology of MS. These advances have promoted a sense of urgency to intervene if disability is to be delayed or prevented. For the first time, there are now new partially effective treatments which may alter the natural history of MS.

This article will highlight the clinically significant advances that have occurred in the understanding and treatment of MS patients and discuss some of the issues now facing physicians treating MS patients in clinical practice.

Current Understanding Of Pathophysiology

The early clinical course of 85% of patients with MS is a relapsing one (Relapsing MS). Although complete recovery after relapses may occur, often the patient is left with some neurologic impairment after each relapse. Over time, relapses usually become less frequent, and most patients will experience a slow, insidious progression of neurologic impairment between relapses (Secondary Progressive MS). For 15% of patients, the disease is progressive from onset (Primary Progressive MS). A subset of this group may have superimposed relapses (Progressive Relapsing MS). Pathologically, there is not enough distinction between the clinical types to be certain if they are separate disease entities or different stages of the same disease. The new FDA approved drugs available are, at this time, only approved for the relapsing patients.

The natural history of MS is now better understood than it was in previous decades. It is now impossible to ignore the fact that MS is ultimately a disabling disease for the majority of patients. While 60% of patient with MS will still be walking unassisted 10 years after their first relapse, 5% will be wheelchair or bed confined by year 5, and a full 40% will need assistance with ambulation by year 10. If a patient with MS has a relapse making them nonambulatory, around 50% will not experience enough improvement to become ambulatory again.² Perhaps even more disturbing is that subtle memory and cognitive dysfunction can be demonstrated even when the physical disabilty is considered minor. Given the young age at which MS begins, this means that most patients are significantly neurologically impaired by the fifth and sixth decades of life.

The single most important advance in understanding the pathophysiology underlying the natural history of MS has come from serial MRI scanning. Prior to MRI, MS was believed to be an episodic disorder that started with the first relapse and was in remission between relapses. It was also felt to be a disease relatively confined to myelin loss, with axonal damage or oligodendrocyte cell loss occurring secondarily and only in the later stages of the disease. The secondary progressive phase was felt to be due to the accumulation of damage and scarring from relapses, with axonal loss of demyelinated axons. Studies using serial MRIs, however, have shown that the pathological changes of MS probably precede the first clinical relapse in many patients, and the disease is hardly "silent" between clinical relapses. In fact, the number of new asymptomatic MRI lesions is many times that of clinical relapses in some patients.³ The MRI white matter "lesions" on conventional MRI T-2 weighted sequences do not reveal all of the ongoing damage in the MS patient. MRI spectroscopy has revealed abnormalities of the "normal appearing white matter" as measured by a decrease the the N-acetyl aspartate peak that is in keeping with axonal dysfunction in addition to myelin loss.⁴ MRI studies of brain volume shows that MS patients lose brain volume over time, not necessarily in relationship to the number of countable plaques on T-2 weighted MRI, or clinical exacerbations.⁵ Even though myelin may be the primary focus of the pathology, the combined MRI findings would support that more than myelin is affected early in the disease. Investigations of biopsy specimens and autopsy specimens confirm that axonal damage and oligodendrocyte cell drop out is occurring early in at least some patients with MS.^6,7

The value of MRI in clinical trials of MS was recognized in the late 1980s, and now MRI is utilized as a secondary outcome measure in nearly all major clinical trials.

Etiology Of MS

Their has always been, and remains, much speculation that MS is an infectious disease. In the 1990s, both human herpes viruses, Herpes simplex virus types I and II⁸ and Human herpes virus 6 have been identified in the plaques of individuals with MS. ⁹ A trial of oral acyclovir was, however, disappointing.¹⁰ Chlamydia pneumonia has been isolated from the CSF of some patients,¹¹ and treatment of one patient with an MS like disease with antibiotics resulted in marked improvement.¹² Currently, there is interest in expanding the studies of these agents as etiological agents or perhaps concurrent agents in the pathogenesis of MS. At the present time, there is no indication to treat MS patients with antibiotics.

The current consensus is that MS is an autoimmune disease, perpetuated by a defect in immune mechanisms that allow for myelin-reactive T-cells to activate, undergo clonal expansion, and enter the nervous system where they promote inflammation against their target, myelin. This activation favors a helper T-lymphocyte type 1 profile (sometimes called a proinflammatory profile) and include the production of cytokines including tumor necrosis factor alpha, interferon gamma, interleukin-1, interleukin-12, and the matrix metalloproteinases. The new treatments for MS, beta interferons and glatiramer (formerly copolymer 1), would support that the immune mechanisms are important in the disease. Preliminary trials of many different agents have been performed and are underway. It is clear that the whole immune picture remains only partially understood. For example, inhibition of tumor necrosis factor alpha did not reduce MS attacks as anticipated.¹³ The practicing physician can easily become overwhelmed and confused trying to read the experimental literature; a recent review article by Noseworthy¹⁴ gives a concise summary for those interested in reading more.

Relapse Reducing Treatments

In the last decade, 3 new treatments have been FDA approved for the treatment of relapsing multiple sclerosis (Table 1). These are: interferon beta 1b (Betaseron®), interferon beta 1a (Avonex®), and glatiramir acetate (Copaxone®). All of these reduced the frequency of clinical attacks of MS and the number of new or enhancing MRI lesions in randomized, double-blinded, placebo-controlled clinical trials involving patients with relapsing MS.^15-19

The two beta interferons are slightly different chemically: interferon beta 1a is human interferon produced by genetic engineering in mammalian cells (Chinese hamster ovary). Interferon 1b is human interferon produced by genetic engineering in bacterial cells (E. coli) and has a substitution of a cysteine for a serine; it is not glycosylated as is interferon beta 1a or natural human interferon beta.

The interferons act by a number of immune modulatory actions. In the clinical trials, interferon beta 1b (Betaseron®) (at a dose of 8 MIU QOD, SC) reduced the frequency of MS attacks by about one third, and reduced the development of new, gadolinium enhancing T-1 weighted MRI lesions by about sixty percent. Interferon 1a (Avonex®) (at a dose of 6 MIU weekly, IM) reduced attacks by about 20%, and showed slowing or disease progression over 2 years.

In a European study, interferon beta 1b was shown to slow the progression of MS in patients in the secondarily progressive stages of the disease as well.²⁰ Recently, two studies of interferon beta (both 1a and 1b) in the U.S. involving secondarily progressive patients were completed and should be published shortly (presented at AAN meeting, San Diego, April 29-May 6, 2000).

Another interferon beta 1a preparation, (Rebif®), is available in Europe and Canada. The interferon is chemically identical to the 1a product currently available in the U.S. but differs in the diluent which is more acidic. The clinical trials in Europe and Canada have raised the question of the need for higher doses of interferon beta 1a than are currently available in the U.S. for at least a subgroup of patients with more impairment;²¹ a comparison study is currently underway in the U.S.

There is some concern about long term efficacy of interferon beta. Neutralizing antibodies form in up to 40% of patients using the 1b form over 3 years, in up to 20% of patients using the 1a form subcutaneously, and in 5% of patients using the 1a form intramuscularly. Even more confusing, in some patients who develop antibodies, they disappear over time. It is not clear that efficacy is adversely affected by initial antibody formation. The test for antibodies, although now available commercially, is not considered as important as clinical parameters in determining efficacy.

The third new agent available in the U.S., glatiramer acetate, is a preparation of synthetic peptides made up of L-alanine, L-gluatmine, L-lysine, and L-tyrosine, that are presumed to mimic the antigenic sites on myelin. Glatiramer was originally designed to be an agent that would establish demyelinating disease in animal models; instead, it gave immunized animals protection. It is believed to act by stimulating clones of T-cells that suppress the activation of inflammatory myelin-reactive T-cell clones. In a randomized, double-blinded, placebo controlled clinical trial, at a dose of 20 mg per day SC, it reduced attack frequency by about 30%.¹⁸ It also reduced the appearance of new gadolinium enhancing lesions by MRI.¹⁹

At the present time, there are no biological markers that are clinically useful in choosing a particular treatment for an individual patient or determining if the treatment is effective. Most physicians use clinical parameters predominantly in deciding on therapy changes. About 25% of patients will stop therapy, most often because they do not perceive a clinical benefit, or because the medications make their MS symptoms worse.²² However, these medications are not likely to improve patients, only reduce the frequency of attacks and possibly delay progression of permanent impairment. Patients must understand this and be supported through the side effects, which diminish with time in most. In general, the interferons have more side effects, particularly fever, chills, and flu like myalgias; these can be reduced by starting at a partial dose and working up to a full dose over weeks and by using acetominophen or non-steroidal anti-inflammatory drugs. Depression is occasionally precipitated or exacerbated by the interferons. Site reactions with subcutaneous injections can be minimized by getting the solution to room temperature before injecting, using a steroid cream, and chilling the skin before injection. Both the interferons and glatiramer can make spasticity worse. Glatiramer has been associated with a peculiar idiosyncratic reaction resembling a panic attack that may occur shortly after injection. Repeated reactions of this type are uncommon; reassurance is all that is necessary in most cases. None of the new treatments are approved for use during pregnancy or nursing. The interferons are considered Class C drugs, and glatiramer Class B.

Plasma Exchange Trial For Severe Demyelinating Attacks

Since the 1980s, there has been interest in plasma exchange for MS patients. The immune activation products that are responsible for perpetuating the inflammatory process of MS are produced in the periphery, as well as in situ, in the CNS plaques. Early studies of plasma exchange did not universally show efficacy and the treatment never became standard. There were many reasons that the early studies may not have shown efficiacy; the most significant being that they did not target patients most likely to benefit from plasma exchange — the patient who was in the throws of a recent, severe attack of MS.

Indications for plasma exchange include:

1. Disabling attack within the last 3 months that has not responded to 5 or more days of IV corticosteroids of at least 500 mg daily; and
2. Absence of contraindication to plasma exchange.

A recent, randomized,double-blinded, sham-controlled, plasma exchange trial showed that 40% of this select group of patients (with MS or other demyelinating conditions) who did not improve with the conventional high dose steroid treatment improved significantly (i.e., walked again) after plamsa exchange. All patients were treated within 3 months of the onset of their attack. Plasma exchange did not prevent the patients from further attacks.²³

Other Therapies — Old And New

Not all patients respond or tolerate the new injectable drugs described above. Methotrexate, azathioprine, and IVIG have all shown efficacy in clinical trials of relapsing MS patients.^24-27 None are currently FDA approved for MS at this time. Cytoxan, although sometimes used for aggressive MS, has never shown efficacy in a randomized, placebo-controlled trial.

Mitoxantrone was recommended for approval by the FDA advisory panel, and final word from the FDA should be forthcoming within the year.

It has been evaluated in phase III trials in Europe and was shown to reduce attack frequency and MRI lesion development.²⁸ The cardiac toxicity of this drug will likely limit its usefulness to those patients who have more aggressive disease.

Treating Patients With Relapsing MS

Having treatments for MS forces the practicing physician to make decision on whom to treat. The decision should be simple, but is not always so. MS can be a benign disease. The treatments we currently have are only partially effective, costly, and can have significant side effects. They may not be entirely safe with respect to fertility and fetal development. We have very limited information on long term results; there is only preliminary evidence that the treatments will prevent progressive disability over the long course of the disease. "Stretching" of the clinical trial results is inviting, but we must still proceed with some caution and humility.

There is consensus among neurologists who frequently treat MS patients that all patients with clinically active, relapsing disease should be treated. We cannot yet predict who will fall into the benign MS category, but we know it is not the majority. The medical advisory committee for the National MS Society came out strongly supporting treatment for most patients.²⁹ Patients not started on treatment should be followed closely to insure their disease has not become more active or insidiously progressive.

There remains uncertainty regarding treatment in the following groups of patients:

1. Patients who have experienced a single clinical episode consistent with demyelination, who have an MRI scan that suggests MS, but who do not yet fulfill the diagnostic criteria of definite MS.
2. Those patients who have had a remote, benign attack, and have their second, mild attack many years later.
3. Patients who are already totally disabled by their disease and have been in the secondarily progressive phase for many years.

Although we want to believe all of these patients groups have more to gain than lose by treatment, we do not yet have the evidence to support that this is so.

The first group is particularly troublesome. There is strong evidence that the majority of patients with an isolated demyelinating episode, and a positive MRI scan, will go on to develop clinically definite MS over the next five to ten years.³⁰ There is some evidence that a course of IV methylprednisolone, one gram daily for 3 days, followed by a short taper, can delay the onset of clinically definite MS.³¹ Although it is tempting to extrapolate the data we currently have and to diagnose MS based on "a high risk MRI", we do not yet have evidence that patients should be started on long term immunomodulating therapy. A study designed to determine whether or not interferon beta 1a will delay the conversion to MS in this group of patients (CHAMPS trial) was recently completed and the preliminary report was that interferon beta 1a delayed the onset of clinically definite MS by approximately 10 months, but did not prevent it (reported at AAN meeting, San Diego, April 29-May 6, 2000). Some neurologists in the field are recommending a repeat of the MRI in 6 months to a year, and if the scan shows significant changes, making the diagnosis of MS at that time, and treating accordingly. This may be a reasonable approach. New diagnostic criteria for MS will likely be forthcoming if the findings of monosymptomatic treatment trial is considered to be impressive enough after full review of the data.

Primary Progressive MS — Is It A Different Disease?

Clinically, this group of patients makes up about 10 to 15% of multiple sclerosis. Men make up 43% of this group. Disability accumulates faster — with the mean time for needing a walking aid eight years, as opposed to fifteen years for patients with RR MS.² Pathologically, it is not clear that this group can be distinguished from the relapsing patients, although they tend to have more oligodendrocyte drop out and a less inflammatory pathology. At the present time, there is not treatment proven or FDA approved for patients who have the primarily progressive course of the disease. There is currently an ongoing, multicenter trial of glatiramer in this group of patients; Mayo Clinic Jacksonville is a site for this trial.

Managing The Problems Of MS

The treatment of MS patients goes far beyond the use of the disease modifying drugs. The symptoms of MS include fatigue, pain, weakness, incoordination, tremors, incontinence of bowel and bladder, and cognitive dysfunction. Complications can include treatment side effects, (e.g., steroid induced osteopenia), pressure sores, contractures, urinary tract infections, and dependent edema. In addition, the psychosocial problems are often overwhelming for the patient and their family. Transportation to and from medical appointments can prevent the patient from getting adequate help with problems promptly and efficiently, often leading to greater severity and need for higher intensity of service. It is not within the scope of this article to cover all of the aspects of treating the symptoms and complications of MS. The reader who is interested in reading more is referred to two texts listed in the references.^{32, 33}

In the 1970s, MS Treatment Centers began in Minneapolis, Minnesota, and New York City, New York. Since then, over 100 MS Treatment Centers have evolved. In Canada, each province has a designated MS Treatment Center where patients can get comprehensive care and/or participate in research trials. In August of this year, the North Florida Multiple Sclerosis Comprehensive Care Center opened at St. Luke's Hospital. This is a joint venture between St. Luke's Hospital and the North Florida Chapter of the National Multiple Sclerosis Society. Patients can be referred to the center by their primary care physician or their neurologist, or self-refer. The center's nurse practitioner will do a comprehensive needs assessment and make recommendations to the patient and the patient's physician. Specific needs such as medication education and injection training, and drug follow-up can be arranged for patients. Physical therapy, occupational therapy, dietary support, social service support, MRI scanning, medication administration, and subspecialty consultations can all be arranged as appropriate. Second opinions on diagnosis or treatment decisions can be arranged at the Mayo Clinic Jacksonville.

Conclusion

Multiple sclerosis remains one of the most enigmatic diseases of neurology. It is increasingly clear that the disease is a continuous, or at least semicontinuous process, and will lead to some disability for most patients. In spite of the fact that intensive study has been devoted to finding the cause, it remains elusive. It is only in the last decade that any impact has been made in altering the natural history of the disease. Intervention early with effective therapy will assuredly be better than waiting until significant impairment has become established. Unfortunately, only partially effective therapies are currently available. They are a step in the right direction. They have also focused attention on the importance of addressing the needs of the young adult with neurological disability. Many interventions are available that can improve the functioning of persons with MS. Optimal care for the MS patient involves a diverse group of health care providers.

REFERENCES

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August, 2000/ Jacksonville Medicine

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