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treatment offers little bene t in our experience However, pulses of high-dose intravenous steroids, as described above, administered once each month, seem to keep some patients from having relapses and are better tolerated than the continuous administration of oral medication It must be acknowledged that the corticosteroid regimens and dosages in common use are derived from anecdotal experience (the Optic Neuritis Treatment Trial being an exception) and that certain patients appear, at least for a period of time, to respond better to one or another method of treatment Treatment of Optic Neuritis The Optic Neuritis Treatment Trial, reported by Beck and colleagues, cautioned against the use of oral prednisone in the treatment of acute optic neuritis (see also Lessell) In this study it was found that the use of intravenous methylprednisolone followed by oral prednisone did indeed speed the recovery from visual loss, although at 6 months there was little difference between patients treated in this way and those treated with placebo They reported that treatment with oral prednisone alone slightly increased the risk of new episodes of optic neuritis In a subsequent randomized trial conducted by Sellebjerg and colleagues, it was found that methylprednisolone 500 mg orally for 5 days had a bene cial effect on visual function at 1 and 3 weeks However, at 8 weeks, no effect could be shown (compared with the placebotreated group), nor was there an effect on the subsequent relapse rate Interferon Beta and Copolymer I These forms of treatment for patients with relapsing-remitting MS modestly alter the natural history of the disease IFN- 1b (Betaseron), a nonglycosylated bacterial cell product with an amino acid sequence identical to that of natural IFN- , was the rst of these agents to be tested (see Arnason) Several trials have now shown that the subcutaneous injection of this agent every second day for up to 5 years decreases the frequency and severity of relapses by almost one-third and also the number of new or enlarging lesions ( lesion burden ) in serial MRIs A large-scale trial (European Study Group) has extended the observations with IFN- 1b to patients with the secondarily progressive type of MS; progression of the disease was delayed for 9 to 12 months in a study period of 2 to 3 years The treatment of relapsing-remitting MS with IFN- 1a (a glycosylated mammalian-cell product, Avonex) is equally effective and has the advantage that it may be taken once weekly as an intramuscular injection (PRISMS Study Group) The dose currently used is 30 mg, or 66 million units Copolymer I (glatiramer acetate; Copaxone), which was synthesized to mimic the actions of myelin basic protein, a putative autoantigen in MS, is given daily in subcutaneous doses of 20 mg Glatiramer acetate may be particularly useful in patients who become resistant, ie, develop serum antibodies to IFN- (Rudick et al) The rate of such antibody emergence varies directly with the frequency of use of interferon: after a period of years, 30 percent of patients demonstrate antibodies with daily administration, 18 percent with alternate-day use, and less than 5 percent with weekly use More recent changes in the preparation of interferon have led to reported rates of only 2 percent with antibodies after 1 year of use There is some evidence that the presence of these antidrug antibodies diminishes the effectiveness of interferon Antibodies do not develop to glatiramer acetate, and this has been emphasized as a relative advantage of the latter drug Overall, the side effects of these interferon agents are modest, consisting mainly of u-like symptoms, sweating, and malaise beginning several hours after the injection and persisting for up to 14 h; they are reduced by nonsteroidal anti-in ammatory drugs and tend to abate with continued use of the agents Nevertheless, some
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patients cannot tolerate them A few migraineurs complain of exacerbation of their headaches There may also be a tendency to depression in susceptible patients treated with interferon, and in our experience, this information, when openly discussed with the patient, has sometimes in uenced the decision regarding choice of treatment A rare but notable problem is the induction of a systemic capillary leak syndrome in patients with a monoclonal gammopathy who receive interferon With more than weekly use, there may be an increase in liver function enzymes Patients receiving glatiramer acetate should be warned of an infrequent complication consisting of ushing, chest tightness, dyspnea, palpitations, and severe anxiety Injection site reactions occur with both classes of drugs but are rarely troublesome if the sites are rotated The salutary effects of treatment are de nite though not overly impressive These issues have been summarized by Hughes and Sharrack Treatment is somewhat disruptive and quite expensive Although most writers on the subject indicate that virtually all patients with proven MS should be treated soon after the diagnosis is established, the long-term effects on the illness still remain to be clari ed Nonetheless, the consistency with which various studies have demonstrated a reduction in relapses and in the accumulation of MRI lesions is notable From these studies, the concept has emerged that subclinical lesions are of importance and that, over time, cognitive decline and neurologic de cits are more likely to occur if the rate of progression is not reduced by treatment There are few circumstances where such treatment is mandated immediately and we allow enough time for the patient to consider the alternatives The endless discussions about the superiority of weekly, every-other-day, or daily medications cannot be resolved except to say that more frequent administration is probably marginally better In the case of interferon, however, it leads to a higher rate of antibody production over years With all of these treatments it should be acknowledged that there is no certain correlation between the number of relapses and the ultimate disability despite authoritative statements to the contrary (see Confavreux et al, 2000) The need to treat patients with optic neuritis alone with interferon has not been satisfactorily resolved We have generally avoided this approach except in a few patients with repeated episodes involving both eyes at various times Some guidance is given by the CHAMPS trial, which examined the effect of interferon (weekly) in patients with a rst episode of optic neuritis and at least two lesions on MRI that were compatible with MS Over 3 years, there was a modest reduction in clinical progression or relapse from 37 percent to 28 percent; if further MRI lesions were included, the difference from placebo treatment was even greater If nothing else, this points to the value of a cerebral MRI in patients who have their rst optic attack Immunosuppressive Drugs A number of agents that modify immune reactivity have been tried, with limited success Drugs such as azathioprine and cyclophosphamide, as well as total lymphoid irradiation, have been given to small groups of patients and seem to have improved the clinical course of some (Aimard et al, Hauser et al, Cook et al) However, the risks of prolonged use of immunosuppressive drugs, including a chance of neoplastic change, will probably preclude their widespread use The careful study by the British and Dutch Multiple Sclerosis Azathioprine Trial Group attributed no signi cant advantage to treatment with this drug For the chronic, progressive phase of the disease, an MS study group has reported a modest delay in the advance of the disease after a 2-year trial of prednisolone and cyclophosphamide They caution,
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