IVIG for Stiff-Person Syndrome
Abstract & Commentary
Source: Dalakss MC, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001;345: 1870-1876.
In this randomized, double-blind, placebo controlled, crossover study, 16 patients with stiff-person syndrome, 9 women and 7 men, mean age 46 years, received 3 months of either placebo or intravenous immunoglobulin (IVIG) followed by a 1-month washout period and 3 months of the alternative therapy. None had any other neurologic disease, none were bedridden, and all were positive for circulating antibodies to glutamic acid decarboxylase (GAD65). IVIG was administered as 1 g/kg/d for 2 consecutive days, once a month for 3 months. Baseline medications were unchanged during the study and included benzodiazepines (n = 16), baclofen (n = 6), gabapentin (n = 3), and valproic acid (n = 1). Primary end points were 2-fold: first, a distribution-of-stiffness index, ranging from 0-6, reflecting stiffness in the upper or lower trunk, legs, arms, face, and abdomen. Second, change in spasm frequency, assessed using the heightened sensitivity scale, which monitors spasms following unexpected noise, visual or somatosensory stimuli, activity, stress or emotional upset, no stimuli, or nocturnal spasms. Anti-GAD65 antibody titers were measured pre- and posttreatment and patients were asked to judge their own response to treatment.
Two patients’ response to treatment could not be obtained, one due to severe rash (n = 1) which precluded masking, and one due to daily fluctuations which precluded data collection. Among the remaining 14 patients, IVIG resulted in significant improvement that was lost when the placebo arm followed active treatment. Conversely, placebo, when administered first, resulted in no significant change in stiffness or spasm frequency, both of which improved when the IVIG arm of therapy was instituted. Ambulation was facilitated, falls less frequent, and household chores surmountable in 11 patients who received IVIG, and the duration of benefit lasted from 6-52 weeks. Twelve patients correctly guessed when they had received IVIG compared to placebo. GAD65 titers dropped with IVIG, and not with placebo, but titers did not correlate with disease severity, nor did reduction correlate with degree of improvement. IVIG is a safe and effective treatment for stiff-person syndrome.
Commentary
In 1956, Moersch and Woltman first described 14 patients, whom they had observed at the Mayo Clinic over a 32-year period, with "progressive fluctuating muscular rigidity and spasm." They termed the disorder stiff-man syndrome, which also bears their name as eponym (Moersch Woltman syndrome) and which, in our age of political propriety, has been modified to stiff-person syndrome (although 4 of the original cases were women). Their original description has not been improved upon. However, 2 significant advances, one regarding disease pathogenesis and one regarding therapy, have occurred. Its pathogenesis remains unknown but is suspected to be autoimmune in nature, based in part on the presence of characteristic antibodies to glutamic acid decarboxylase (GAD) of various sizes, which have been reported by several groups (N Engl J Med. 1988;318:1012-1020; Neurology. 1993;43:114-120). Treatment was uniformly disappointing until diazepam was shown to be symptomatically beneficial, so dramatically in fact that it is a diagnostic criteria (Mayo Clin Proc. 1989;64:629-636). Presently, it appears that prolonged relief of symptoms may be obtained by IVIG infusions. Uncovering and addressing the underlying cause will be necessary before definitive treatment will be available. Meanwhile, the rare but unfortunate patient with this condition may be offered succor and solace with this safe and easily administered remedy. —Michael Rubin, MD. Dr. Rubin, Associate Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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