Abstract & Commentary
Source: Gustavo De Feo LC, et al. Use of intravenous pulsed cyclophosphamide in severe generalized myasthenia gravis. Muscle Nerve. 2002;26:31-36.
Twenty-three patients, aged 21-65 years, with severe generalized myasthenia gravis inadequately controlled with steroids, or experiencing significant steroid side effects, were randomized into a prospective, double-blind, placebo-controlled trial of high-dose pulsed cyclophosphamide (CP) to determine its efficacy and safety. Diagnosis of myasthenia was confirmed by positive antibody titers, decremental response on repetitive motor nerve stimulation, or positive Tensilon test. All patients were steroid dependent for 6 months, unable to taper below 10 mg/d, or were experiencing side effects including hypertension, glaucoma, osteoporosis, diabetes, pseudotumor cerebri, or psychiatric difficulties. Inadequate control of myasthenia was defined as forced vital lung capacity < 60% of predicted, voice or swallowing impairment, or pronounced limb muscle weakness. CP, 500 mg/m2 of body surface, or placebo, was administered monthly for 6 months and then bimonthly for an additional 6 months. Each subsequent CP dose was increased 25% by an unblinded investigator if no improvement was observed, no complications were experienced, and the white blood cell count and polymorphonuclear cell count exceeded 3000/mm3 and 2000/mm3, respectively. Study end points included changes in muscle strength, steroid or pyridostigmine requirements, frequency of ventilatory failure (forced vital lung capacity < 30%), or swallowing impairment requiring feeding tube placement. ANOVA, Student’s t-test, Wilcoxon’s rank sum, and chi-square or Fisher’s exact test were used for statistical analysis.
Five of 12 CP-treated patients were able to discontinue steroid treatment by 12 months compared to none of the 11 placebo-treated patients. By 36 months following study completion, 4 CP patients required no steroids and 3 additional CP patients required no pyridostigmine. Muscle strength was significantly improved at 12 months in the CP group compared to placebo, particularly in bulbar and extraocular muscles. Bronchopneumonia resulted in ventilatory failure in 1 CP patient whereas 2 placebo patients developed respiratory failure due to muscle weakness. Side effects were not significantly increased in the CP group, including hematological and infectious complications, nausea, vomiting, abdominal pain, diarrhea, akathisia, or fasciculations. One CP patient developed bladder cancer 2 years after study completion but had other risk factors associated with this complication (smoking, age > 65 years).
Commentary
Intravenous pulsed CP can be used safely and effectively for refractory severe generalized myasthenia gravis.
Other recent offerings in the treatment of myasthenia include tacrolimus (FK-506), a calcium-calcineurin inhibitor, which was reported to be effective as the sole immunosuppressant in a patient who developed myasthenia during interferon alpha treatment for hepatitis C (Muscle Nerve. 2002;25:111-114).
Intravenous immunoglobulin (IVIG) therapy is another safe and effective adjunct for myasthenia gravis, although randomized trials are lacking (Neurol Sci. 2002;23(Suppl 1);S9-S24). IVIG results in rapid improvement, lacks any long-term toxicity, and may reduce the need for other immunosuppressive agents. Presently, IVIG is useful for the management of myasthenic crisis, particularly where plasma exchange is not feasible, including the elderly, the young, and the septic patient. IVIG may also be used for chronic maintenance therapy when other agents have failed. Monthly or bimonthly infusion may stabilize chronic refractory patients. —Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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