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The ultimate goals of multiple sclerosis therapy are to stop ongoing inflammatory and degenerative processes that lead to central nervous system damage and to repair the existing damage responsible for impairment, disability, and handicap. Unfortunately, there do not yet exist treatments that fully address these goals. In their absence, however, there are treatments that can reduce disease activity, delay the progression of disability, and ameliorate symptoms that affect quality of life. This chapter describes the benefits of the currently available course-modifying therapies (Table 78-1) and symptomatic treatments as demonstrated by rigorous clinical trials.

TABLE 78-1 U.S. Food and Drug Administration–Approved Course-Modifying Therapy for Multiple Sclerosis

Disease Type Drug
Relapsing Interferon β-1a (Avonex, Rebif)
Interferon β-1b (Betaseron)
Glatiramer acetate (Copaxone)
Secondary progressive Mitoxantrone (Novantrone)
Primary progressive None approved


Since the early 1950s, neurologists have used corticosteroids to treat acute exacerbations.1 Placebocontrolled clinical trials25 have demonstrated that short-term corticosteroid treatment hastens recovery from a relapse, but the optimal treatment regimen remains unclear. Results of head-to-head comparisons of intravenous methylprednisolone and subcutaneous adrenocorticotrophic hormone have been mixed. One study of 25 patients with clinically definite multiple sclerosis6 revealed that patients receiving intravenous methylprednisolone had more rapid improvement than patients receiving intramuscular adrenocorticotrophic hormone. But this difference, seen at days 3 and 28, was no longer apparent after 3 months. Other studies were not able to demonstrate any significant difference between the agents.79 Typically, patients begin experiencing improvement between the first and third days of steroid treatment, and improvement continues for 15 to 45 days before symptoms stabilize clinically.4

The Optic Neuritis Treatment Trial, assessing recovery of vision in patients with their first episode of acute optic neuritis, provided further insight into the short- and long-term effects of corticosteroids on demyelination. Study patients (N = 457) received (1) intravenous methylprednisolone plus a prednisone taper, (2) prednisone alone, or (3) oral placebo. As in the earlier studies in patients with multiple sclerosis exacerbations, patients receiving steroids recovered faster, especially those receiving intravenous treatment.10 But the differences in visual acuity between the treatment and placebo recipients seen at days 4 and 15 were no longer apparent by 6 months,10 which, again, indicates that steroids affect the timing of recovery from an attack but not the extent of the recovery.11

In general, for treatment of an acute relapse, higher doses of steroids are more effective. For example, in a study of 32 patients with relapse who were randomly assigned to receive 1000 mg of intravenous methylprednisolone per day for 1 day or 5 days, disability scores at 1 month improved more after the extended treatment.12 In another study, 2g/day of intravenous methylprednisolone was compared with 0.5g/day, both for 5 days, in a randomized, doubleblind study of 31 patients with relapsingremitting multiple sclerosis. Although the average improvement in disability scores was comparable between the groups, the higher dose recipients had fewer contrast-enhancing lesions on magnetic resonance imaging (MRI) at 30 and 60 days, respectively, which indicates more thorough reduction in ongoing inflammation.13 The rate of occurrence of side effects was similar in the two groups. The Optic Neuritis Treatment Trial showed that high-dose, intravenous steroid administration is more beneficial than low-dose prednisone.10 The effects of high doses of steroids given orally, however, may be more comparable. A small (N = 35) randomized, doubleblind trial in which 500 mg of oral methylprednisolone was compared with 500 mg given intravenously, both for 5 days, revealed no difference in disability score at 5 and 28 days.14 The safety of oral prednisone, 1250 mg/day, has been demonstrated15; the efficacy of this approach is being studied.

In rare cases, serious side effects have been reported with high-dose methylprednisolone therapy, including fatal arrhythmias,16,17 anaphylaxis,18 anaphylactoid reactions,19 and seizures.20 Although pulse-administered steroids have also been shown to transiently depress some markers of bone growth,21 a prospective study of the effect of sporadic methylprednisolone pulse treatment on bone density did not demonstrate bone loss 6 months after treatment.22 As with any intervention, these risks must be weighed against the potential benefits of treatment.

Despite treatment with corticosteroids, relapses frequently leave patients with permanent deficits,23 a fact that has prompted researchers to seek additional therapies. Intravenous immunoglobulin (IVIg) infusions were shown to improve functional outcome in a small study of patients with acute disseminated encephalomyelitis refractory to intravenous steroids.24 However, in a randomized, doubleblind, placebocontrolled pilot study of 19 patients with multiple sclerosis relapse, in which IVIg infusions were added to treatment with intravenous methylprednisolone, there was no difference in disability after 4 weeks; this suggests that the benefit of adding IVIg infusions to intravenous methylprednisolone is minimal at best.

In two randomized, blind, controlled studies, researchers have examined the value of plasma exchange for acute exacerbations. In the first, 116 patients with an acute multiple sclerosis relapse were treated with intramuscular adrenocorticotrophic hormone plus oral cyclophosphamide, and then randomly assigned to receive 11 plasma exchange treatments or 11 sham treatments, administered over 8 weeks.25 Although patients receiving plasma exchange experienced moderately enhanced improvement after 2 weeks in comparison with the sham-treated patients, and although the median time to recovery of disability status before attack was significantly shorter in the plasma exchange recipients, there was no difference between groups at 12 months.

The second controlled plasma exchange study included only patients with severe deficits from a recent demyelinating event that did not improve with intravenous corticosteroids.26 Of the 22 patients studied, 12 had multiple sclerosis; the others had an acute demyelinating syndrome such as acute disseminated encephalomyelitis, neuromyelitis optica, or transverse myelitis. Patients receiving plasma exchange were more likely to have a “moderate or greater” improvement in their primary disability score than were those receiving sham treatment (42% versus 66%), which supports the use of plasma exchange for severe multiple sclerosis exacerbations refractory to steroids.


Relapsing-Remitting Multiple Sclerosis

Interferon β

Interferons are cytokines normally produced by the immune system in response to viral infection. In 1993, the IFNB Study Group reported the first multicenter, randomized, placebocontrolled, doubleblind study to clearly demonstrate that interferon β-1b (IFN β-1b) can modify the course of multiple sclerosis.27 Patients with relapsingremitting multiple sclerosis (N = 372) received 1.6MIU or 8MIU of IFN β-1b (Betaseron) or placebo, by subcutaneous injection, every other day for up to 5 years. The primary outcome measure, annual relapse rate, was reduced by 31% in the high-dose recipients in comparison with the placebo recipients, and there was a consistent dose response for all endpoints. MRI, used innovatively, demonstrated a pathological basis for the observed clinical benefits, confirming that they reflected a persistent, profound effect on the inflammatory process.28 Reduction in the rate of accumulation of disability, however, could not be demonstrated in the post hoc analysis.

In 1996, another large (N = 301), randomized, doubleblind, multicenter study confirmed and extended these observations by demonstrating that IFN β—in this case, 30μg of weekly intramuscular IFN β-1a (Avonex)—delayed the time to sustained progression of disability, defined as a one-point worsening of the Expanded Disability Status Scale (EDSS) score.29 Over 2 years, 21.9% of patients receiving interferon experienced progression of disability, in comparison with 34.9% of placebo recipients. Post hoc analysis showed that over the course of 2 years, fewer treated patients progressed to EDSS scores of 4 (moderate disability) or 6 (requiring a cane).30

The largest placebocontrolled study of IFN β in relapsing multiple sclerosis included 560 patients randomly assigned to receive 22 or 44μg of subcutaneous IFN β-1a (Rebif) or matching placebo three times per week for 2 years. The study demonstrated that IFN β decreased the annual relapse rate by 27% to 33%, in comparison with placebo31; delayed progression of disability, as measured by the EDSS31; and prevented the accumulation of new and enlarging lesions, as demonstrated on T2-weighted MRI.32 After the 2-year placebocontrolled phase of the study, 79% of the participants continued in a 2-year extension phase, in which patients originally randomly assigned to receive active treatment continued with their assigned interferon dose, whereas patients originally assigned to receive placebo were randomly reassigned to receive either 22 or 44μg of IFN β-1a three times weekly.33 The change to active drug decreased the relapse rate and the MRI parameters of disease of those who had initially received placebo, but they continued to have more rapid progression of disability and more MRI lesions over the entire study period than did those who had received IFN β from the start. These observations, combined with studies demonstrating significant benefits in patients treated with low doses of IFN β at the time of their first clinically apparent demyelinating event,34,35 suggest that early treatment is appropriate for preventing as much central nervous system damage and resulting disability as possible.

To determine the relative benefits of different interferon formulations and dosing regimens, head-to-head studies are needed. In the largest and most rigorous of these studies to date, 677 patients with relapsingremitting multiple sclerosis were randomly assigned to receive either subcutaneous IFN β-1a (Rebif), 44μg three times weekly, or intramuscular IFN β-1a (Avonex), 30μg once weekly for a year. The relapse rate in the high-dose, high-frequency recipients was 21% lower than that in the low-dose, weekly recipients.36 Participants on the high-dose high-frequency interferon regimen also had better control of MRI disease activity. The increase in efficacy in the high-dose recipients was associated with more frequent injection site reactions and (asymptomatic) elevations in liver enzyme levels. At the end of this comparative phase of the study, most participants continued into a crossover phase in which all patients received the high-dose, high-frequency IFN β-1a regimen. Patients who had crossed over from low-dose, weekly IFN β-1a experienced significant reductions in relapse rates and MRI activity, in comparison with those who had continued the high-dose treatment from the start of the study.37 A smaller study in which patients were randomly assigned to receive high-dose, high-frequency IFN β-1b (Betaseron) or low-dose weekly IFNβ-1a (Avonex) yielded similar results.38

Several side effects can occur with interferon therapy. Most patients experience flulike symptoms, including myalgia, arthralgia, headache, malaise, and fever for 12 to 24 hours after each injection. This reaction is most common when treatment is initiated and tends to decrease in intensity with continued therapy. It can be minimized with dose titration and concomitant acetaminophen, nonsteroidal antiinflammatory medications, or low doses of prednisone.39 Transient injection site reactions, with focal erythema and skin induration, are also common with subcutaneous interferon injections. Pretreatment of the injection site with a topical anesthetic or ice can ameliorate this symptom. In rare cases, injection site reactions can persist or progress into focal areas of necrosis, necessitating surgical treatment.40 There has been concern that interferons may worsen depression,41 which is common in patients with multiple sclerosis. However, a post hoc analysis of data from the large Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial demonstrated no increase in the frequency of depression in patients treated with interferon in comparison with those receiving placebo.42

Most patients develop antibodies against IFN β during treatment, especially those receiving high-dose, high-frequency treatment by subcutaneous injection. Antibodies generally arise in the first year of treatment and have variable persistence thereafter.43 A subset of these antibodies interferes with the effects of IFN β in in vitro assays; these have been called neutralizing antibodies. Although the results of clinical studies conflict somewhat, most studies suggest that patients with persistent high titers of neutralizing antibodies have increased signs of disease activity, although this may take years to become clinically apparent. For example, in the initial 2-year PRISMS study, antibodies to IFN β-1a did not affect clinical outcome measures,31 but in the subsequent 2-year extension phase of the study, patients with neutralizing antibodies to IFN β-1a had more relapses and MRI activity than did those without antibodies.33 Because the extension phase had no placebo condition, it was not possible to quantify any partial benefit from treatment despite the antibodies.

Glatiramer Acetate

Glatiramer acetate is a mixture of synthetic polypeptides with amino acids in a ratio similar to that in myelin basic protein, a major component of the myelin sheath. In the pivotal trial, 251 patients were treated with glatiramer acetate or placebo for 2 years.44 The primary outcome, relapse rate, was reduced by 29% in those receiving active drug, in comparison to placebo. With regard to disability, those receiving placebo were more likely to experience worsening (by one EDSS point or more) over the course of the study, but the percentages of patients with “sustained disability” (lasting at least 90 days) were comparable in the two groups, as was their ability to ambulate. Most of the initially randomly assigned patients (83%) continued to be monitored in the open-label extension phase of the study,45 in which patients who initially received placebo were offered glatiramer acetate. At 6 years, those remaining in the study had substantially fewer relapses and progression of disability46 than would be predicted by natural history studies.47 At 8 years, 142 (56.6%) of the original patients remained in the study. Those receiving glatiramer acetate from the time of random assignment had a very low rate of relapse, about one every 5 years, and were also about 20% less likely to have worsening of their disability than were those who had initially received placebo.48

A separate MRI study of 239 patients with multiple sclerosis demonstrated that the mean total number of enhancing lesions was 29% lower in patients receiving glatiramer acetate than in those receiving placebo during 9 months of treatment.49 Secondary analysis showed that in patients treated with glatiramer acetate, fewer gadolinium-enhancing lesions became hypointense on T1-weighted MRI, which would indicate the most severe tissue damage.50 Most of these patients were also evaluated for changes in brain volume by MRI, but no difference could be detected between patients receiving glatiramer acetate and those receiving placebo.51

Aside from necessitating a daily injection, glatiramer acetate is generally well tolerated. Common side effects include pain and redness at the injection site, and rarely atrophy of subcutaneous fat. Symptoms resembling panic attack (flushing, palpitations, dyspnea) lasting 15 to 30 minutes occur sporadically in 10% of patients, typically immediately after injection.

Intravenous Immunoglobulin

After it was demonstrated to have efficacy in the treatment of peripheral demyelinating disease,52,53 IVIg treatment was studied for the treatment of relapsingremitting multiple sclerosis in four randomized, doubleblind studies.5459 Although the dosages of IVIg differed substantially among the studies (0.2 to 2.0g/kg body weight/month), all four studies revealed significant benefits in the patients who received IVIg, in comparison with those receiving placebo. The largest of these studies (N = 150), the Austrian Immunoglobulin in Multiple Sclerosis Study Group,56 compared disability scores and the proportions of patients whose disability had improved, stabilized, or worsened with IVIg, 0.15 to 0.2g/kg/month for 2 years, as opposed to placebo. Disability scores improved more among patients receiving active treatment than among placebo recipients (31% versus 14%) and worsened among fewer treated patients (16% versus 23%).56 The other three studies, which were smaller, also demonstrated differences between treatment and placebo with regard to relapse rate55,57 and number of enhancing lesions on brain MRI.59 One study, in which two dosage conditions (0.2g/kg body weight and 0.4g/kg body weight monthly) were used, demonstrated no differences in relapse rates between low and high doses, but both yielded better results than did placebo.55 The incidence of side effects was comparable with that of placebo in the studies that included the lower doses. High-dose (2.0g/kg body weight/month) IVIg infusions led to adverse events more frequently than did placebo (headache, 26% versus 6%; nausea, 9% versus 0%; and urticaria, 7% versus 1%).59


Corticosteroid pulse treatment clearly shortens the duration of acute relapses, but its long-term effect on disease course is less certain. Treatment of multiple sclerosis with long-term, low-dose corticosteroids has been studied for several decades and has not proved effective.60 In the Optic Neuritis Treatment Trial, patients experiencing their first demyelinating event were less likely to have another attack over the next 2 years if they were treated with intravenous methylprednisolone treatment (7.5%) than if they received oral prednisone (14.7%) or placebo (16.7%).61 The validity of this observation is unclear, however, because group differences were not sustained beyond 2 years,11 and the results have not been replicated in similar studies.62 The benefits of periodic corticosteroid pulse treatment were addressed more directly in a study of 88 patients with relapsingremitting multiple sclerosis randomly assigned to receive a 5-day course of high-dose intravenous methylprednisolone either every 4 months or only at the time of a relapse. After 5 years, the group receiving scheduled treatments had less progression in brain atrophy and lower hypointense lesion volume on T1-weighted MRI.63 The clinical significance of these observations remains to be determined.

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors

3-Hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors (statins) have been known to have antiinflammatory effects for many years64 and have shown benefit in animal models of multiple sclerosis65,66 and in vitro studies.67 Two preliminary, uncontrolled studies of statins have been published to date. The first study (N = 7) showed that 20 mg of lovastatin per day was well tolerated, although no change in multiple sclerosis parameters could be documented. Another study (N = 30) revealed that simvastatin, 80 mg/day, decreased the average frequency of new gadolinium-enhancing lesions in comparison with patients’ pretreatment baselines.68 These preliminary study results suggest that larger controlled studies are warranted.

Clinically Isolated Syndromes Suggestive of Multiple Sclerosis

Patients with a single episode of neurological dysfunction that is probably the result of demyelination, such as optic neuritis, transverse myelitis, or a brainstem syndrome, are at substantial risk for future demyelinating events. If the initial brain MRI shows a clinically silent lesion, the 10-year risk of developing multiple sclerosis is 83%, in comparison with 11% when no such lesion is demonstrated.69 Because of the preventive nature of multiple sclerosis immunotherapy, it is logical to consider treatment in patients as soon as the disease process has been identified. In two randomized, controlled studies, researchers have examined the effect of IFN β-1a on preventing progression to definite multiple sclerosis. Both studies included only patients with one or more asymptomatic brain lesion. The first, a large (N = 383) randomized, doubleblind, multicenter study, showed that patients with a first-ever demyelinating event could decrease the 3-year risk of developing a second demyelinating event by 44% by using weekly intramuscular IFN β-1b (Avonex) injections.34 In addition, treated patients demonstrated improvement in several MRI parameters of disease at 18 months, including a substantial decrease in the median growth (in total volume) of T2-weighted lesions (1% versus 16%) and mean number of enhancing T1-weighted lesions (0.4 versus 1.4).34 In the second study (N = 308), a lower dosage of IFN β-1a (Rebif, 22μg) was administered subcutaneously once a week. At 2 years, this treatment decreased the risk of developing a second exacerbation by 48%.70 Treated patients also had significantly less brain atrophy than did those receiving placebo.35 IVIg has also been studied for treatment of a clinically isolated event. A randomized, doubleblind study (N = 91) of high-dose IVIg (2.0g/kg loading dose, with a 0.4g/kg booster dose every 6 weeks) found that over 1 year, treated patients had a 64% reduction in the risk of progressing to definite multiple sclerosis.71

Secondary Progressive Multiple Sclerosis

Most cases of relapsing multiple sclerosis eventually transition from a course with relapses intermixed with stable deficits to one with progressive deficits and less prominent relapses.72 The pathophysiology underlying this transition is not completely understood, but the transition is believed to be the result of a change in the multiple sclerosis disease process from primarily inflammatory to primarily neurodegenerative.73

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