EDITORIAL: PREVENTING PROGRESSION

J. Theodore Phillips, MD, PhD, The Multiple Sclerosis Center at Texas, Neurology & Baylor University Medical Center, Dallas

It seems the total worldwide number of persons with MS is increasing, with some requiring more specialized care. Important advances have been made in the psychosocial issues, cognitive concerns, fatigue, and bladder control problems that affect these patients. As well, MS specialty centers are becoming more common. However, the challenge of halting, or at least slowing, secondary progressive MS (SPMS) continues, as does the need to find more effective treatments for advanced and aggressive disease. The presentations selected for this Multiple Sclerosis Forum Report™ reflect some of the latest, most significant advances in understanding and treating MS.

The challenge of predicting the progressive stages of MS is a particularly daunting one. Yet most of these cases arise from lesser degrees of MS, many of which might have been considered in their earliest stages to be "benign MS." Although this designation may in fact be appropriate for a distinct minority group of individuals with truly mild and non-progressive MS, all natural history studies to date indicate that most persons with MS demonstrate notable, progressive worsening over time. Furthermore, the accurate categorization of benign MS can at this time only be a retrospective one.

Because development of sustained disability progression occurs over years in most persons, rather than over a shorter time frame, it has been easy, for physicians and persons with MS alike, to be sometimes lulled into a false sense of disease mildness and relative stability.

Several published studies have recently shown that a majority of untreated persons with relapsing-remitting MS (RRMS) will achieve the clinical designation of SPMS within ten to 15 years of disease onset. Other long-term follow-up studies show that many instances of untreated MS designated "benign" at ten years may nonetheless convert to permanently disabling SPMS within 20-30 years. One conclusion is that most untreated MS worsens significantly and irreversibly over time, and that early treatment can help slow and, in some cases, prevent progression.

Currently, partially effective disease-modifying agents (beta-interferon and glatiramer acetate) are available, which are capable of altering the natural course of RRMS. Unfortunately, a comparably effective and safe treatment has yet to be found for SPMS once established. It is possible that at this time the best "therapy" for SPMS is prevention.

If we are to prevent MS progression, how early should treatment with a disease-modifying agent begin, especially in the mildly affected, treatment-reluctant patient? To wait until clear clinical evidence of sustained worsening appears is clearly waiting too long. Newer imaging techniques have demonstrated definite subclinical, widespread evolution of the MS disease process(es) from even the first clinical demyelinating event. The clinically apparent manifestations of MS appear to represent only a small portion of what is yet to be uncovered about MS. Especially in the current absence of any medical treatment capable of restoring neurological function once sustained worsening has occurred, and given our inability to predict who will belong ultimately to the small group (probably no more than ten percent of the total) of relatively benign MS, it would seem that the most reasonable approach is early and aggressive treatment of all persons with RRMS. This position is in accordance with a recent recommendation of the National Multiple Sclerosis Society.

Despite the fact that many neurologists have adopted this newer, more aggressive attitude, patient surveys continue to show that many feel they are not yet sufficiently affected by MS to warrant early and continuous treatment with a disease-modifying agent. This is a situation that can only be improved by the continued, thoughtful, and aggressive education of our patients. Until a time when better treatments are uncovered, we as neurologists can best combat disease progression by trying to prevent-or at least slow-the damaging effects of MS with agents most effective in countering progression and relapses.

MULTIPLE SCLEROSIS AT THE MILLENNIUM

History and Future of MS Care

T. Jock Murray, OC, MD, Dalhousie University & QE II Health, Halifax, Nova Scotia, Canada; Professor Ian McDonald, MD, Harverian Librarian at the Royal College of Physicians, London, United Kingdom

The condition known as multiple sclerosis (MS) was given its name by the French physician, Jean Martin Charcot in 1868. By that time, there had been numerous reports throughout Europe of patients who apparently were afflicted with MS, but Charcot pulled all the threads together and thus is credited with "discovering" MS. He described the illness in remarkable detail, both clinically and pathologically, including evidence of inflammation post-mortem. His report triggered a flurry of other accounts, and the challenge then became understanding the cause of this disease, a quest that has occupied physicians for over a century, said T. Jock Murray, OC, MD.

The first suspected case of MS, however, probably predates Charcot by many centuries. In 1390, a young Dutch woman, Saint Lidwina, fell while ice skating and subsequently developed a progressive disease that kept her confined to bed until her death 34 years later. Prominent physicians of the day prescribed a variety of "medicines" and herbs, however, the Duke of Holland's physician recognized Saint Lidwina's condition as one that could not be cured. "The disease," he said, "comes from the hand of God." He advised offering no treatment, as it would only "impoverish her father."

The next "published" case of what appears to be MS occurred in the illegitimate grandson of King George III, Augustus Frederick d'Este. As a young man in the 1790s, d'Este developed what was probably optic neuritis. He charted his personal struggle with the progressive disease in a diary that now resides at the Royal College of Physicians in London. D'Este was encouraged to drink plenty of "steel water" and sherry, to douche his eyes, and to feast on beefsteak. He was also prescribed the medicinals of the day: silver, mercury, iron, arsenic, and opium-these served as the backbone of neurologic treatment into the 20th century, along with such things as "nervine tonics," spa therapy, massage, and even electricity applied over the skull.

But around the turn of the nineteenth century, physicians were attempting to pinpoint a cause for MS and therefore treat it more specifically. Oppenheim, in 1908, thought MS was due to toxins, such as copper, lead, and mercury, and devised methods of ridding the body of these. Marie, a student of Charcot, felt MS was an infection and directed treatment accordingly. Buzzard thought MS was due to a spirochete, much like neurosyphilis; other physicians claimed to have isolated the organism and to have developed an effective vaccine. The spirochete theory, in fact, persisted until the 1950s.

By the 1930s, the treatment arsenal was broad but ineffective: malarial treatments, typhoid vaccines, milk injections, arsenic, intramuscular mercury, and X-rays. In this decade, however, another theory took hold. As blood became a central focus in medicine, the idea emerged that MS could have a vascular, thrombotic focus and could be amenable to anticoagulants and special diets.

"The point from all these various treatments is that the popular theories of the causes of MS are what directed the treatments at the time," Dr. Murray said. Today, the same applies, as the concept of inflammation is the focus and drugs that modulate the immune system constitute first-line management.

"But the problems continue," he said. "Current treatments won't do enough for patients long-term," he added. Recent attention has turned to axonal damage as the true endpoint, rather than demyelination, and future therapies that address this area may hold the greatest hope.

Professor Ian McDonald, MD, of the Royal College of Physicians, London, summarized some of the latest discoveries regarding the pathologic characteristics of MS, which may lead to future treatments:

• There is local breakdown of the blood-brain barrier in association with inflammation.

• MR spectroscopy reveals myelin breakdown products, such as lipid. "Lipid peaks" that appear and resolve show the sequence of demyelinating events.

• Evidence of demyelination can be detected within 24 hours of the first onset of symptoms. Demyelination may occur even earlier than the inflammatory phase of lesion development.

• In optic neuritis, demyelination is present at onset and one month later. The nerve fibers may, in some instances, learn how to conduct without the presence of the myelin sheath.

• Functional MRI studies of patients after recovery from optic neuritis show an altered pattern of activation. Multiple regions of the brain "light up," rather than a single targeted region.

Such "recovery" and compensation involving remyelination and the development of new sodium channels are likely responsible for the complete remission of disease seen in most patients in the early stages of MS. But disability later becomes progressive, perhaps because recovery processes fail. While axonal loss becomes more extensive, its association with clinical severity remains unclear.

What has been demonstrated, however, is that the magnitude of "black holes" on T1-weighted MRI is correlated with axonal loss, and progression of disability is related to progression in the number and area of black holes. The underlying mechanism of axonal loss is thought to be the inflammatory process, however, whether this is a cumulative effect due to specific mediators, or precipitated by various triggers remain unresolved questions, Dr. McDonald concluded.

Managing an MS Center

Rick Munschauer, MD, Baird MS Research Center, Buffalo, New York

In managing an MS center, the foremost management principle is to "manage to a shared operational vision," Rick Munschauer, MD, said at a Consortium workshop on the topic.

He advised attendees to understand the daily frustrations within your center and your center's strengths and weaknesses, set goals for improvement and growth, identify obstacles to such growth, and uncover inefficient operations and determine how to improve upon them.

After developing an operational shared vision within your center, start thinking of your services in terms of "professional lines of business," he said. Each neurologist and service, such as IV therapy or speech therapy, is a separate line of business that someone "owns," or manages. Each of these lines of business must be defined and their potential determined.

For each line of business, quality indicators must be identified, quality control measures developed, and quality and financial goals established. Goals should be based on the needs of your patient population and linked to tangible objectives, such as referrals from more physicians. Finally, you must determine your resources for achieving these goals, he said.

The efficiency of operations becomes the next challenge. Most management consultants now recommend a nontraditional team approach to management. One neurologist works with one nurse, and has one dedicated secretary responsible for the neurologist's schedule. Patients are directed to one staff person for specific questions, that staff person works with one designated nurse, and that nurse works with one designated neurologist. This method eliminates scheduling conflicts and errors, leads to greater patient satisfaction, and fits well with the "line of business" approach, Dr. Munschauer said.

Making the office better organized-having the receptionist pull charts ahead of time and keep the examining rooms stocked-can also save time and improve profitability. Such changes can be initiated through good communication. "Everyone should make a list of annoyances, and as a group you can figure out simple changes that will make a big difference," he told attendees. "For example, now I have a nurse explaining methotrexate to patients, doing timed 25-foot walks, [and] taking vital signs. If you are still doing these things, you are not using your particular skills as a neurologist."

SECONDARY PROGRESSIVE MS

Pathophysiology and Current Treatment Options

John R. Richert, MD, Professor of Neurology, Georgetown University Medical Center, Washington, DC; Hillel Panitch, MD, Professor of Neurology, University of Maryland School of Medicine, Baltimore; and Patricia K. Coyle, MD, Professor of Neurology and Director of the Stony Brook MS Comprehensive Care Center, State University of New York School of Medicine, Stony Brook

Considerable evidence exists that MS is an immune-mediated inflammatory disease that is triggered by an unidentified environmental factor in genetically susceptible individuals. Myelin is destroyed and central nervous system lesions are formed through an autoimmune reaction that seems to be orchestrated by a combination of T cells, B cells, and macrophages.

One theory of the pathogenesis of MS may involve the concept of "molecular mimicry." In this scenario, a foreign protein resembling an endogenous myelin antigen triggers an autoimmune response; the foreign antigen is presented by major histocompatibility complex molecules to the T cell; in certain individuals, a self-antigen is mistaken for the foreign antigen, leading the T cell to attack the body tissues that contain the self-antigen, such as myelin basic protein, explained John R. Richert, MD, at a symposium on secondary progressive MS (SPMS).

Once MS has commenced, continued activity of inflammatory cells creates a multi-layered immunologic environment for myelin destruction and disease progression. This immunologic paradigm forms the foundation for the use of immunomodulating and immunosuppressive therapies. Recent clinical trials, however, have produced mixed results for such therapies in SPMS. While interferon beta-1b slowed progression and reduced relapses in the European trial, the North American trial did not duplicate the overall positive results. SPMS patients still having relapses, however, may have a more favorable response, therefore, beta-interferon may be effective in a subset of progressive patients with more active disease, Dr. Richert said.

Betaseron® (Interferon Beta-1b) in SPMS

John R. Richert, MD, Professor of Neurology, Georgetown University Medical Center, Washington, DC; Hillel Panitch, MD, Professor of Neurology, University of Maryland School of Medicine, Baltimore; and Patricia K. Coyle, MD, Professor of Neurology and Director of the Stony Brook MS Comprehensive Care Center, State University of New York School of Medicine, Stony Brook

Hillel Panitch, MD, remarked at the symposium, "The drug [Betaseron® (interferon beta-1b, Berlex)] seems [to improve] parts of the MS picture reflecting acute changes-gadolinium-enhancing MRI and relapse rate." MRI showed important treatment effects as seen in large decreases in T2-weighted lesion areas and newly enhancing lesions in SPMS patients.

Investigators are attempting to understand the factors that could have contributed to the different outcomes in the European and North American trials. One explanation is that the European trial included more patients with apparently more active disease at entry, Dr. Panitch noted. Patients in the European trial had 1.74 relapses in the two years prior to the trial, versus 0.82 for patients in the North American trial. Mean gadolinium-enhancing lesions numbered 2.6 versus 1.5, respectively, at entry.

"This [may] account for much of the difference in outcome.... We are beginning to realize that beta-interferon is effective in SPMS patients who are [at] the relapsing-remitting end of the spectrum," Dr. Panitch said.

Dr. Richert agreed in his presentation, "The drug still [may be] somewhat effective [in SPMS], so rather than switch agents you could add-on a pulse steroid." For the treatment of SPMS with relapses, Dr. Richert said class 1 evidence supports the use of beta-interferon off-label, while class 2 evidence supports the use of adding either methotrexate, glatiramer acetate, pulse IV methylprednisolone, or intravenous immunoglobulin.

New agents may soon help in SPMS, he said. Mitoxantrone in a recent Phase III European trial (Mitoxantrone In MS-MIMS), significantly decreased the progression to disability, number of relapses, time to relapse, and lesions on MRI.

Patricia Coyle, MD, reiterated that the transition to SPMS indicates that disease-modifying therapy may need to be revised. While disease-modifying agents are of proven benefit in relapsing-remitting MS (RRMS), "the picture changes when patients develop SPMS," she said. Treatment failure may occur as the RR patient makes the transition, which is often marked by three or more relapses, accentuated disease course, lack of response to glucocorticoids or disease-modifying agents, and changes in MRI burden and activity (smaller T2-weighted lesion burden, and increased periventricular, spinal cord, and posterior-fossa involvement). Functional changes in T cells, interferon gamma, interleukin-2, and other immunologic factors may also herald SPMS, Dr. Coyle said.

"Nonetheless, it is possible to treat SPMS," she emphasized, by combining a disease-modifying agent with either methylprednisolone, methotrexate, mitoxantrone, or cyclophosphamide. "Early treatment in milder, relapsing periods may also help delay the transition to SPMS. And in the earlier stages [of SPMS] when patients still have relapses, anti-inflammatory therapies may still work."

Psychosocial Issues of the SPMS Patient

Rosalind Kalb, PhD, Clinical Psychologist, Special Projects Consultant, National MS Society, New York, New York

When patients evolve from RRMS to SPMS, as 50 percent or more do, they experience profound changes in their sense of self and their attitudes toward their disease. SPMS triggers a variety of irrational, but nonetheless powerful, beliefs about oneself and one's choices, Rosalind Kalb, PhD, told listeners at the symposium.

Patients may view SPMS as a sign of poor choice of treatment, poor choice of doctor, or retribution for not listening to the advice of others. Common emotional reactions to SPMS include the continuation of normal grieving, anxiety, resentment, guilt, and embarrassment. Thus, as their denial is shattered and they must come to terms with SPMS, patients face a host of psychosocial challenges that require them to redefine their illness, their goals, their priorities, and themselves.

"At the most basic level, patients ask the question, 'Who am I now?' as they embark on a process of redefining self. Getting comfortable with these difficult choices and changes comes at a time when patients are least equipped to do so because of their grief, as well as their possible depression and cognitive dysfunction," Dr. Kalb explained.

"Depression in MS may be a reaction to the losses and challenges of the illness, as well as a symptom of the disease process itself. We have to identify it and offer treatment. Depression is an unnecessary extra burden and prevents patients from participating actively in their own care," she said.

All these psychosocial issues challenge the healthcare team to "tell it like it is," while still conveying hope to patients. The team must frankly discuss the long-term and short-term benefits and side effects of treatment, while addressing the fact that there are no guarantees for the patient's future.

"Patients need to know what's in store. We don't want patients to lose hope, get depressed, or give up yet. Without information they cannot create the safety net they need," she said. "I tell them it's planning for the worst while hoping for the best."

"Fortunately, this transition time is also a time when people who were unwilling to take advantage of support services will make use of them now. We need to be ready to provide these services," she said. "The education and support provided by the healthcare team will be critical to their compliance and well-being."

THE ROLE OF COMBINATION THERAPIES IN MS

Trials of Combination Therapy

Michael Kaufman, MD, Carolinas Medical Center, Charlotte, North Carolina

Since combination therapy has been a successful approach in a number of conditions, such as hypertension and cancer, there is optimism that it may also prove effective in MS. Several trials are now underway to evaluate various agents in combination with Avonex® (interferon beta-1a, Biogen, Inc.), which were described at a session on combination therapy.

Michael Kaufman, MD, concluded after the following presentations that there is nothing yet in the data to dictate a specific change in practice, however, these are preliminary studies that may eventually show improved outcomes with some of the combinations.

Avonex® (Interferon Beta-1a) Plus Copaxone® (Glatiramer Acetate)

Fred Lublin, MD, Mount Sinai School of Medicine, New York, New York

Fred Lublin, MD, is the principal investigator of a new trial evaluating the safety of combining Avonex® (interferon beta-1a, Biogen, Inc.) with Copaxone® (glatiramer acetate, Teva Marion Partners) in RRMS patients. In vitro evidence suggests these agents in combination may be additive in their ability to diminish lymphocyte proliferation. The current study, which will add Copaxone® after six months on Avonex®, seeks to confirm safety of this combination and to evaluate for possible unexpected interference with the drugs' mechanisms of action (by one agent acting against the other).

"Anecdotally, probably hundreds of patients have been treated with this combination, and we know of no adverse effects," Dr. Lublin said.

In addition to safety profile, the other primary outcome measure is MRI gadolinium activity. Since Avonex® and Copaxone® each reduce the number of enhancing lesions, an increase in gadolinium enhancement with combination therapy will be considered evidence of drug interference, i.e., a negative outcome. The study will also evaluate EDSS and MS Functional Composite (MSFC) scores, relapse rate, development of neutralizing antibodies, and other MRI measures.

The study has enrolled 28 patients. Interim safety analysis at three months demonstrated no evidence of drug interference or safety concerns.

Regarding combination therapy in general, Dr. Lublin commented that agents thought to be only partially effective at this point may perform better in combination. "Once one of these combinations succeeds in showing proof of principle-a suggestion of efficacy-without combined toxicity or interference with mechanism of action, I think we will move toward a placebo-controlled, blinded study."

Avonex® (Interferon Beta-1a) Plus Methotrexate

Peter Calabresi, MD, University of Maryland, Baltimore

Peter Calabresi, MD, reported encouraging results from an open-label trial of Avonex® (interferon beta-1a, Biogen, Inc.) plus 20 mg of oral methotrexate weekly in 15 RRMS patients. This study appears to be the first to evaluate the use of methotrexate in patients who have continuous disease activity.

"Methotrexate has something of a track record, and it is efficacious in other autoimmune diseases," Dr. Calabresi pointed out. "Even in SPMS, there is some reduction in deterioration of upper extremity dysfunction, and a subtle MRI effect [with treatment]."

At study entry, the patients had a mean EDSS of 2.5, a mean duration of treatment of 2.2 years, and had experienced at least one clinical exacerbation after a year of Avonex® therapy. The study's outcome measures were safety and tolerability, and reduction in gadolinium-enhancing lesions. This was determined by triple-dose gadolinium scans, which detect more lesions than conventional gadolinium MRI protocols.

Twelve patients have completed treatment. The main side effect has been nausea, but only one patient has been unable to tolerate more than 10 mg of methotrexate. There have been no serious adverse events or significantly altered lab values.

Dr. Calabresi said he is cautious interpreting the available data because the study was small; however, a number of encouraging results have emerged. In the 12 patients, EDSS scores decreased and the number of exacerbations was reduced from a total of eight for the group in the six months prior to the study to three exacerbations during treatment. As well, steroid use dropped from three to zero.

The MS Functional Composite score stabilized and showed a trend toward improvement. Mean number of gadolinium-enhancing lesions pre-treatment was five, which dropped to 2.73 with treatment (p = 0.0486). "Some patients had a dramatic change in lesions," he said, "but there is still smoldering activity, which I believe indicates that triple dose scanning is a very sensitive method of detection."

Avonex® (Interferon Beta-1a) Plus Cyclophosphamide

Michael D. Kaufman, MD, of Carolinas Medical Center, Charlotte, North Carolina

Michael D. Kaufman, MD, described a double-blind, placebo-controlled study underway combining Avonex® (interferon beta-1a, Biogen, Inc.) with weekly cyclophosphamide (125-150 mg/m2/week with monthly increases to a maximum of 250-500 mg/m2).

The study includes 24 patients with RRMS or SPMS who have been on Avonex® for at least six months and have progressed or relapsed in the previous two years. The average age is 45, which is somewhat older than most MS study populations since many younger women were concerned about possible infertility from cyclophosphamide.

Treated patients are paired with placebo-treated patients according to a randomized scheme, primarily as a blinding technique. The primary outcome measure is a derived cytokine ratio, which reflects the relative activities of TH1 and TH2 lymphocyte populations. There is evidence that a change in this ratio in favor of TH2 may be favorable in MS, and that cyclophosphamide produces this change and may be specifically cytotoxic for cells that are directed against myelin basic protein. Secondary measures of potential efficacy are the MS Functional Composite score and number of relapses.

The blind has been broken on nine pairs of patients (18 total), however, cytokine levels and functional composite scores have not been evaluated. The major adverse events have been decreases in white blood count and lymphocyte count.

"The summary of this study, to date, without the primary outcome data, is that oral cyclophosphamide can be given safely. We have used it in combination with interferon beta for as long as six years in some patients [off study], without much difficulty. But there are challenges for clinical use," he said, noting that only half the patients who received the study drug have elected to continue on it. (Dr. Kaufman discontinues the drug at a lifetime cumulative dose of 50 mg.) "It's not a drug that many patients will necessarily want to take, although I guess this depends on how successful it turns out to be."

"I have seen patients who seem to do better on cyclophosphamide, and we are hoping to have a similar outcome in the study. But I don't think the data suggest a very strong clinical effect at this time," Dr. Kaufman concluded.

Avonex® (Interferon Beta-1a) Plus Intravenous Immunoglobulin (IVIG)

Saud Sadiq, MD, St. Luke's-Roosevelt MS Center, New York, New York

Saud Sadiq, MD, reported his observations in 115 patients receiving Avonex® (interferon beta-1a, Biogen, Inc.) plus intravenous immunoglobulin (IVIG) 1.5 g/kg administered for five hours a day for two consecutive days. The combination therapy was given for six to 18 months to patients with disease activity while on therapy with an IMA.

Of 115 patients observed, 66 have shown clinical evidence of disease stabilization or improvement. Of the 29 patients with relapsing-remitting MS, 26 have stabilized and none have had significant relapses; among these 26 responders, 21 were receiving the combination therapy. Of 86 patients with secondary progressive MS, 40 have stabilized, and approximately half of these responders and over two thirds of the nonresponders were receiving the combination therapy.

Some reported adverse effects associated with the use of IVIG were headache, few allergic skin reactions, and reductions in sedimentation rate, mentioned Dr. Sadiq.

Other studies of this combination have shown improvements in EDSS scores, significant reductions in relapses, and prolonged time to relapses. Because of these encouraging results, further study is planned with a similar patient group.

Stem Cell Transplantation

Richard Burt, MD, of Northwestern University Medical School, Chicago, Illinois

Richard Burt, MD, reported on ten patients with progressive forms of MS (mostly SPMS) and EDSS of 6.0-8.5 who have been treated with high-dose chemotherapy plus autologous stem cell transplant and followed up to five years in a Phase I trial. In nine evaluable patients, four improved by 0.5 points and two worsened by 0.5. Seven of the nine patients were stable or mildly improved on EDSS at their most recent follow-up.

No patient has had new enhancing lesions on MRI, eight were unchanged on T2 lesion burden, and one patient had progression of disease burden. According to Dr. Burt, they have not reported any serious adverse events, although thrombocytopenia requiring platelet transfusion was common.

While this was an observational pilot trial only, Dr. Burt says there is now an NIH grant for a controlled study of stem cell transplantation, with crossover, in 96 patients with EDSS of three to five.

COMBINED TREATMENT OF RELAPSING MS WITH INTERFERON BETA-1a (AVONEX®), PREDNISONE, AND AZATHIOPRINE

Oldrich Kolar, MD, Indiana Center for MS and Neuroimmunopathologic Disorders, Indianapolis

Continuous, combined immunomodulating and immunosuppressive therapy (IMIS) may be the most effective way to treat patients in the early stage of multiple sclerosis, according to Oldrich Kolar, MD, who routinely uses this approach.

In view of the essentially continuous course of MS, ongoing pulse therapy may be superior to episodic treatment for several weeks at the time of relapse, maintained Dr. Kolar and colleagues, at a poster session. "The current practice to use pulse therapy with IV steroids in patients showing relapse of neurological symptoms on monotherapy with ABC drugs is suboptimal," he said.

Their open-label study included 181 patients with RRMS (EDSS 0.0-8.0) who experienced relapses or neurological worsening on interferon beta. They were started on continuous combined therapy with Avonex® (interferon beta-1a, Biogen, Inc.) 30 mcg IM weekly-three patients received Betaseron® (interferon beta-1b, Berlex)-and prednisone 7.5-15 mg daily for eight to 216 weeks (median 104 weeks). With prednisone, patients also received calcium 1000-1800 mg/d with vitamin D, and when indicated by bone density studies, alendronate (Fosamax®, Merck) and/or raloxifene (Evista®, Lilly). The patients were followed every two to four months.

After subtracting the 23 pseudo-relapses, the mean annual relapse rate for the 178 patients receiving Avonex® and for the three patients on Betaseron® was comparable to the mean rates reported with the earlier clinical studies. This is much lower than the mean rates reported for monotherapy with Avonex® (0.61), Betaseron® (0.85), Rebif®1 (0.62), and Copaxone® (0.58), the investigators emphasized.

There were no dropouts due to systemic side effects of interferon beta. Traumatic fractures were established in 14 patients, and stress fractures in two patients. New onset hypertension was established in 13 patients.

In 32 patients experiencing relapse on IMIS therapy, additional treatment with azathioprine (1-3 mg/kg/d) was initiated, for a median treatment duration of 20 months. In two patients, azathioprine was discontinued because of idiosyncratic reactions. Among the 30 remaining patients, eight patients demonstrated an improvement in EDSS, and eight showed neurological stabilization.

MANAGEMENT OF MULTIPLE SCLEROSIS-RELATED FATIGUE

Overview and Current Management Approach

R. Philip Kinkel, MD, Medical Director, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

Fatigue may be the most common symptom in multiple sclerosis, affecting an estimated 75-95 percent of all patients and reported by over half these patients to be their worst problem. Fatigue can influence functional outcomes and can have a devastating impact on quality of life, leading to unemployment in otherwise minimally disabled persons, said R. Philip Kinkel, MD, in a symposium on fatigue.

Fatigue remains poorly understood in MS. It has not demonstrated a relationship to disease duration, gadolinium-enhancing activity, patient age or patient gender, though it may be weakly related to disease type since it is more common among SPMS than RRMS. It is not related to EDSS, after adjusting for depression, nor to depression, after adjusting for EDSS.

Fatigue does, however, appear to be a distinct symptom of MS and can even predate other symptoms. The optimal management of fatigue remains unclear, but the aim of management is to reduce fatigue severity, to reduce the impact of fatigue (even if severity cannot be diminished), and to improve quality of life. Because of the multi-dimensional nature of fatigue, management is best undertaken through a multidisciplinary approach.

First, the clinician should "follow common sense" and look for non-primary causes of fatigue, such as other medical conditions, medication side effects, depression, and sleep disorders. In more disabled persons, fatigue can be caused by significant mobility disturbances and respiratory impairment. If such causes can be excluded, or if fatigue persists in spite of their effective management, then one can consider the diagnosis of primary MS-related fatigue.

Treatment combines self-help education, pharmacologic management, energy effectiveness strategies, aerobic exercise, and environmental and equipment modifications. First-line pharmacologic management, at this point, is amantadine. Four controlled trials have found it effective in 20-40 percent of mildly to moderately disabled MS patients, at least in the short-term reduction of self-reported fatigue; fewer than ten percent experience adverse events on this dopaminergic agent.

Second-line therapy is generally with the CNS stimulant pemoline, however, it is not as well-tolerated and its true efficacy is debatable. Expert consensus is that pemoline should not be a first-line agent. The aminopyridines and SSRI class of antidepressants should be further studied before they can be recommended for this purpose, Dr. Kinkel commented.

Encouraging new data are emerging, however, on modafinil (Provigil®, Cephalon, Inc.). Studies are suggesting that this agent may be quite effective in battling fatigue, and it has already entered the armamentarium of many clinicians (topic discussed below).

"Pharmacotherapy is effective in the short-term management of MS-related fatigue, but long-term management requires not only pharmacotherapy but individualized approaches to education, energy conservation, aerobic exercise, and environmental modifications," Dr. Kinkel said. "And since the ABC drugs have shown treatment effects, one would hope they are also positively affecting fatigue."

New Therapeutic Venues

Kottil W. Rammohan, MD, Ohio State University, Columbus

Modafinil (Provigil®, Cephalon, Inc.), which is being used successfully in the treatment of narcolepsy, has been shown to significantly improve fatigue, with good tolerability, in a group of 72 patients treated in a single-blind, placebo-controlled trial.

Kottil W. Rammohan, MD, reported significant improvements on the Fatigue Severity Scale (the primary outcome measure), as well as several other scales that served as secondary outcome measures. Modafinil 200 mg daily significantly improved fatigue, daytime sleepiness, and patients' perceptions of the drug's efficacy.

The study included 72 patients (most with RRMS; some with SP or primary progressive MS), with mild to moderate MS severity (EDSS = 6.0), and moderate to severe fatigue (= 4 on the Fatigue Severity Scale). Patients taking any medications that could affect fatigue were excluded, as were those with high caffeine intake.

During the nine-week study, patients received placebo run-in at weeks one to two; modafinil 200 mg/day plus placebo at weeks three to four; modafinil 400 mg/day at weeks five to six (two tablets); placebo washout at weeks seven to nine. Data were analyzed by intention-to-treat using a repeated-measures ANOVA model, and active treatment periods were compared to the placebo wash-in phase.

The primary outcome measure was the self-reported, seven-point Fatigue Severity Scale, which asks patients to rank such statements as "Fatigue is among my three most disabling symptoms." On this outcome measure, patients receiving 200 mg of modafinil had a significant reduction from 5.5 at the placebo wash-in phase to 4.7 with treatment (p < 0.001), Dr. Rammohan reported.

On the 21-item Modified Fatigue Impact Scale, modafinil 200 mg significantly improved fatigue, for a score of 37.7, versus 44.7 for placebo wash-in (p < 0.001). This scale ranks from zero to four items such as, "I have limited my physical activities," and "I have been clumsy and uncoordinated." All subscales of the Modified Fatigue Impact Scale-physical, cognitive, and psychosocial-were significantly improved by 200 mg of modafinil, he added. The 400 mg dose was not different than placebo in most outcome measures.

The results were also analyzed according to whether the improvements were "clinically significant," shown by magnitude of change in scores. By this definition, over half the patients reported clinically significant improvements on the two scales, the study found.

Likewise, the Visual Analog Scale for Fatigue exhibited a significant benefit for modafinil 200 mg (p = 0.003), as did the Epworth Sleepiness Scale, which found both dosages significantly effective (p < 0.001). The drug was well-tolerated, and no serious adverse events were reported.

Lauren R. Krupp, MD, Professor of Neurology at the State University of New York, Stony Brook, who has contributed a substantial body of research in the area of fatigue, commented, "I interpret this study as saying the drug was very effective. I use this drug and I think it works. The question now is when to use it. My approach is to use this drug first with people for whom fatigue is a big issue and who are fairly mobile and minimally impaired. [For these patients,] this is the drug to go with."

Efficacy of an Energy Conservation Course

Virgil Mathiowetz, PhD, OTR, University of Minnesota, Minneapolis

A study involving 54 persons with fatigue secondary to MS found that a formal energy conservation educational course had a significant impact on fatigue, self-efficacy, and quality of life. Subjects in the control group, who were exposed only to a support group, had no improvement, according to the principal investigator Virgil Mathiowetz, PhD, OTR.

The study (in press, Archives of Physical Medicine and Rehabilitation) utilized a six-session course developed by Packer et al. in 1995 (taught for two hours a week by occupational therapists to groups of eight to ten). The format included lectures, discussions, practical activities, and homework assignments, which Dr. Mathiowetz judged to be critical to the success of the program. The participants learned to integrate energy conservation principles into daily activities, and they received reinforcement through weekly support groups.

Significant improvements were seen in scores of the Fatigue Impact Scale, Self-Efficacy Gauge, and Health Status Survey SF-36. The score of the Fatigue Impact Scale, for example, was reduced from 70 at baseline to 55 at week 19. The improvements were being maintained by 86 percent of subjects six weeks after the conclusion of the course.

"We think the group format was important-coming together and finding that others were struggling with fatigue," Dr. Mathiowetz said. "The participants got peer support for behavior changes, and there was a lot of creative problem-solving together."

COGNITIVE DYSFUNCTION

Jill S. Fisher, PhD, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

Cognitive impairment in multiple sclerosis is common and can have devastating functional consequences. While memory impairment and information processing are the most likely deficits, cognitive impairment in MS is not limited to these functions, according to Jill S. Fisher, PhD, a researcher in the field.

"The key is to try to prevent these things before they occur, to advocate for early treatment," Dr. Fisher told attendees at a Consortium workshop. She noted that interferon beta-1a has demonstrated to have beneficial effects in delaying brain atrophy measured by MRI.

Several studies have reached the same conclusion regarding prevalence of memory impairment. About one-quarter to one-third of MS patients appear to have intact memory, about one-half have evidence of very subtle memory deficits that may not meet the strict definitions of impairment, and the remainder have striking difficulties, she reported.

"We looked at cognition broadly in the Avonex® (interferon beta-1a, Biogen, Inc.) pivotal trial, in relapsing patients with relatively low levels of physical disability. We used a variety of measures in different domains and found one third to be intact or better, up to 20 percent to have impairment in multiple domains, and about one-half to have circumscribed deficits, such as memory or information processing."

These deficits have functional consequences. Studies have shown that cognitively impaired MS patients are less likely to be employed, less able to perform activities of daily living, and less able to carry out routine household tasks, despite having comparable physical ability.

For example, a 1995 report by Beatty et al. showed the best predictor of employment status to be ambulation and scores on information processing and memory. A 1999 report by Langdon and Thompson showed that cognition affected patients' ability to benefit from in-patient rehabilitation.

Deficits in memory, which have been the most studied in MS, are not global, that is, not all types of memory are vulnerable to the disease. Impairment is largely related to "explicit memory"-explicitly instructed information meant for learning and remembering. Especially affected is the subtype called episodic memory, which is the memory of events and of information that is read, heard, or seen. Semantic memory-the remembering of previously acquired knowledge (such as words and facts)-may also be impaired. More likely to remain intact is the implicit memory system-learning and remembering without conscious awareness.

Attention and information processing-also called "working memory" and involving the more complex aspects of attention-have been studied less. It is clear, however, that there are deficits in processing speed.

What appears to be most affected is "alternating attention," that is, the ability to shift attention back and forth between two stimuli, and "divided attention," which requires one to simultaneously attend to multiple stimuli (for example, driving a car).

A number of aspects of executive function can be affected as well. One of these is the ability to see common features of an object or deduce words linking items in a series, which reflects reasoning. Planning and sequencing (performing a series of actions in the correct order) are frequently impaired, and problem-solving flexibility may sometimes be diminished, depending on the demands of the task.

Some persons have a decline in visual perception, as well. This includes facial perception ("knowing who"), object/form perception ("knowing what"), and visuospatial perception ("knowing where").

"In other words, there is no uniform pattern of cognitive impairment in MS. There is clinical heterogeneity," Dr. Fisher stated.

Rather than rely on brief assessment tools, Dr. Fisher recommends using a comprehensive measurement in most cases. "The Brief Mental Status Examination has very good specificity, but you really should consider neuropsychiatric screening batteries that have established sensitivity," she told attendees. She also pointed out that patients' perceptions of their own cognitive function might be very different from the results produced on formal testing.

She initially poses a series of ad hoc screening questions to her patients, for example, "Do you have trouble remembering appointments, driving, reading?" Other "flags" of cognitive impairment include recent transition to a secondary progressive course, recent relapse, significant fatigue, cerebellar or brain stem signs, and large T2 lesion load.

Recent attention has been directed toward atrophy-related MRI predictors. A number of factors have been linked to cognitive dysfunction, including periventricular involvement, third ventricle size, confluent lesions, corpus callosum size, and overall cerebral atrophy. Magnetization transfer ratio imaging has suggested that normal-appearing tissue on T2-weighted images is "not necessarily normal," but is producing subtle problems, she added.

While cognitive rehabilitation can be of benefit, and various pharmacologic agents may help some patients, there is little to offer patients in the way of treatment. Dr. Fisher commented that the best approach might be to start immunomodulating agents early. Avonex® showed a statistically significant benefit on memory and information processing at two years (p = 0.011), and a trend toward improvement in visuospatial ability and executive functions.

"It appears Avonex® does have beneficial neuropsychiatric effects," she said. Betaseron® (interferon beta-1b, Berlex) demonstrated some beneficial effects on visual memory, and only a trend towards improvement in information processing.

Since studies are suggesting that few patients remain cognitively stable, especially as they move into a secondary progressive phase, early identification and treatment become very important, Dr. Fisher emphasized.

BLADDER DYSFUNCTION

Scott Litwiller, MD, Urologic Specialists of Oklahoma, Tulsa; Marie Namey, RN, MSN, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

Voiding symptoms are noted in 50-80 percent of all MS patients, and in almost 100 percent of patients who have had MS for ten years or longer. Application of appropriate management strategies, however, often has a favorable outcome in terms of minimizing infections, reducing urinary symptoms, improving continence, and preventing secondary complications.

"With increasing EDSS, bladder dysfunction also increases, in fact, it is almost guaranteed in patients who are using a walker or a wheelchair," noted Scott Litwiller, MD, a urologist with extensive experience treating MS patients. Physiologic effects of MS on the bladder include detrusor hyperreflexia in 60 percent (failure to store syndrome), detrusor sphincter dyssynergia (DSD) in 30 percent (failure to empty syndrome), and impaired contractility in 30 percent (causing "stopping and starting" of urination).

Dr. Litwiller and Marie Namey, RN, MSN, another workshop leader, stressed that bladder problems should not be approached in a cursory manner, rather, an entire visit needs to be designated for their evaluation. Proper diagnosis and management depend on obtaining a complete urologic and voiding history that includes detailed fluid intake and voiding characteristics (a voiding diary is very helpful), medication history, and description of MS disease course. A good evaluation will also explore lifestyle and practical issues, such as environmental obstacles to proper voiding.

The post-void residual (PVR) provides essential information. An acceptable amount of PVR, obtained during the evaluation by catheterization or ultrasound, is generally less than 100 ml. Patients with acceptable PVRs can usually be managed with medications, but higher levels may need intermittent catheterization to completely empty the bladder, Ms. Namey commented.

She advised attendees, "If there are 200 cc left on the bladder scan, get another measurement because this may be spurious. You don't base life-altering interventions on one post-void residual."

Treatment of Neurogenic Dysfunction

Scott Litwiller, MD, Urologic Specialists of Oklahoma, Tulsa; Marie Namey, RN, MSN, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

Patients with unacceptable PVRs are candidates for urodynamic testing with or without imaging. A normal urodynamic test tends to exclude the presence of neurogenic voiding dysfunction. Patients with normal tests can then be evaluated for altered mobility, motor dysfunction, and environmental causes of urinary problems.

Abnormal urodynamic tests usually indicate the inability to store urine, inability to empty, or a combination of failure to store or empty. Symptoms of these syndromes can overlap, and can include urgency, frequency, hesitancy, retention, intermittency (double-voiding), dysuria, incontinence, nocturia, and more.

Management of failure to store is usually successful with anticholinergic agents, monitoring of fluid intake, scheduled or prompted voiding, avoidance of caffeine, alcohol and aspartame, and wearing of pads and protective undergarments. Treatment of failure to empty includes timed voids, structured fluid intake, intermittent catheterization, and Foley catheters in some cases. Treatment of combined dysfunction includes anticholinergic medication, intermittent catheterization, protective pads, and, if necessary, Foley catheters.

For complex cases of DSD, Dr. Litwiller often prescribes alpha blockers and muscle relaxants, especially tizanidine (Zanaflex®, Athena). Botulinum toxin can be effective, however, he does not find it suitable for a chronic condition such as MS. While catheterization is preferred over surgery, it is sometimes necessary to endoscopically alter the urinary sphincter in patients who have spasticity or poor hand function and cannot catheterize themselves.

Anticholinergics can be effective in cases of refractory hyperreflexia. Dr Litwiller sometimes instills capsaicin, however, this approach is painful and causes symptoms to worsen for several days. Resiniferatoxin, or RTX 108, a local neurotoxin that acts on sensory nerve endings, is being evaluated in a multicenter study, is 1000 times more potent than capsaicin, but does not produce pain on instillation. It appears to work best in patients with EDSS less than six, commented Dr. Litwiller.

If pharmacologic therapy for complex cases of neurogenic dysfunction fails, surgical procedures can be quite effective in DSD. Options include suprapubic tube placement to provide drainage, surgical augmentation to increase bladder storage (bilateral dexterity is a requirement, since intermittent catheterization will be necessary), and ileovesicostomy to provide bladder drainage while avoiding tubes.

Dr. Litwiller and Ms. Namey reminded clinicians that bladder dysfunction can have a variety of causes, for instance, constipation, immobility (which creates edema) and enlarged prostate. "You can't just treat symptoms, you must investigate," said Ms. Namey.

FOOTNOTES:

1. Rebif® is not approved by the US Food and Drug Administration for use in the United States.

(c) 2000 Millennium Medical Communications, Inc.

Multiple Sclerosis Forum Report™ is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Multiple Sclerosis Forum Report™ is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein as well as the guest editor. The ideas and opinions expressed by the guest editor are those solely of the guest editor and do not necessarily reflect the opinions of Millennium Medical Communications, Inc. or any Sponsor hereto. This Multiple Sclerosis Forum Report™ may contain data on products, product uses, indications, and dosages, which are not approved for use in the USA, Canada and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Multiple Sclerosis Forum Report™ is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from Biogen, Inc. Biogen, Inc. maintains no control, direct or indirect, over the content, substance, or distribution of this report.