High-Dose Intravenous ImmuneGlobulin for Stiff-Person Syndrome

High-Dose Intravenous ImmuneGlobulin for Stiff-Person Syndrome

Discussion

Our findings demonstrate that, as used, intravenous immune globulin isa safe and effective therapy for stiff-person syndrome. This conclusionis based on the objective improvement after the administration ofimmune globulin, as compared with placebo, and is supported by theincreased ability of the patients to perform the activities of dailyliving.

Up to 65 percent of patients with stiff-person syndrome cannot performroutine daily activities because of total-body stiffness, fear offalling, anxiety-triggered spasms, and frequent falls.Others use walkers or wheelchairs, and still others are bedridden becauseof severe stiffness. Our results show an improvement in the symptomsof most patients who completed the study, according to objectivedata obtained through reproducible instruments that measurestiffness and sensitivity to stimuli that trigger spasms. Immuneglobulin therapy had a positive effect on the degree of stiffness;the frequency of falls; the ability to walk unaided, showerindependently without spasms, and work or perform household chores;and the number of episodic spasms triggered by unexpected noises,tactile stimuli, fear, or emotional upset.

The role of anti-GAD65 antibodies in the autoimmune pathogenesis of stiff-person syndrome has been questioned because GAD65 is acytoplasmic antigen and the few autopsy studies that have been performeddid not find substantial histologic changes in the brains ofaffected patients.¹¹ However, studies found thatanti-GAD65–specific IgG from patients with stiff-person syndrome(but not from controls) inhibited GAD65 activity in vitro andimpaired the synthesis of GABA without causing identifiable structuralchanges in GABAergic neurons. Furthermore, anti-GAD65 antibodies areproduced intrathecally and suppress GABA levels in the brain andcerebrospinal fluid of affected patients.The predominant inhibitoryneurotransmitter in the brain is GABA, accounting for 25 to 35percent of all synapses; thus, a reduction in GABA due to anti-GAD65antibodies could easily explain the muscle hyperactivity ofstiff-person syndrome. Our finding that intravenous immune globulindecreased the symptoms of the disease supports the view thatstiff-person syndrome is a functional rather than structuraldisorder, with an ongoing immune response that impairs GABAergictransmission without causing structural changes in the brain.Because GABA is involved in many brain circuits that control muscletone, autonomic responses, fear, arousal, and behavior,²⁶increased transmission of GABA as a result of the immunoregulatoryeffects of immune globulin can explain the reduction in both musclestiffness and the frequency of spasms triggered by fear andemotional upsets in our patients.

Although the anti-GAD65 antibodies declined after immune globulin therapywas stopped, the titers did not correlate with either the severityof disease or the magnitude of the clinical response. If anti-GAD65antibodies are pathogenic in stiff-person syndrome, immune globulinmay have inhibited their activity by accelerating the rate of IgGcatabolism,by acting directly on Fc receptorsof B cells to suppress autoantibody production, or by inducing anti-idiotypicantibodies. The concept of a delayed actionof anti-idiotypic antibodies is supported by our preliminary findingsthat anti-GAD65 antibody titers declined within a week after theadministration of immune globulin and reached a nadir within threeweeks. The other immunomodulatory effects of immune globulin on Tcells and cytokines may also have had acomplementary role in suppressing disease activity.

In some of the patients, the efficacy of immune globulin was short-lived(lasting up to six weeks) — a response that is commonly seen inother autoimmune neuromuscular disorders. Insome patients, however, the benefit was sustained, lasting up to ayear. The mechanisms of such a long-lasting effect are unclear. Ifuntreated, stiff-person syndrome can result in total disability and israrely controlled by diazepam or other available agents. Ourfindings indicate that, as used, intravenous immune globulin issafe, well tolerated, and effective, although very expensive, forstiff-person syndrome and significantly improves patients' abilityto perform the activities of daily living and, thus, their qualityof life.

Supported by the National Institutes ofHealth. We are indebted to the patients who participated in the study; to the patient organization for recruiting patients; to the nurses on 5E Neurology Ward for providing excellentcare to our patients; to Drs. Mark Hallett and Camillo Toro for helpful suggestions with the study design; to Judy Starling of theNational Institutes of Health pharmacy for randomization and preparation of the bottles of intravenous immune globulin andplacebo; to Dr. Cristina Mora for helpful advice with the statistics; to Dr. Mary Kay Floeter for performingelectrophysiologic studies; to Drs. Boyd Koffman and Carlos Lucianofor help with the care of some of the patients; to Sherry Vorbaughfor help with videotaping and gait studies; and to Bayer Corporationand Crescent HealthCare for donating part of the intravenous immuneglobulin used in the study.

Source Information From the Neuromuscular Diseases Section,National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.

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