High-Dose Intravenous ImmuneGlobulin for Stiff-Person Syndrome
Marinos C. Dalakas,M.D., Mavis Fujii, M.D., Mian Li, M.D., Bashar Lutfi, M.D., Joan Kyhos, B.S.N.,and Beverly McElroy, C.N.R.N.
Background Stiff-person syndrome is a disabling central nervoussystem disorder with no satisfactory treatment that is characterizedby muscle rigidity, episodic muscle spasms, high titers of antibodiesagainst glutamic acid decarboxylase (GAD65), and a frequentassociation with autoimmune disorders. Because stiff-personsyndrome is most likely immune-mediated, we evaluated the efficacyof intravenous immune globulin.
Methods We assigned 16 patients who had stiff-person syndromeand anti-GAD65 antibodies, in random order, to receive intravenousimmuneglobulin or placebo for three months
Results Among patients who received immune globulin first, stiffnessscores decreased significantly (P=0.02) and heightened-sensitivityscores decreased substantially during immuneglobulin therapy
but rebounded during placebo administration. Eleven patients who receivedimmune globulin became able to walk more easily or without assistance,their frequency of falls decreased, and they were able to performwork-related or household tasks. The duration of the beneficialeffects of immune globulin varied from six weeks to one year.Anti-GAD65 antibody titers declined after immune globulin therapybut not after placebo administration.
Conclusions Intravenous immune globulin is a well-toleratedand effective, albeit costly, therapy for patients with stiff-personsyndrome and anti-GAD65 antibodies.
Stiff-person syndrome is a rare central nervous system disordercharacterized by rigidity of truncal and proximal limb muscleswith intermittent superimposed spasms. Continuous contractionsof agonist andantagonist muscles caused by the involuntaryfiring of motor units at rest are the clinical and electrophysiologichallmarks of the disease. The cause of stiff-person syndromeis autoimmune pathogenesis is suspected forseveral reasons. Circulating antibodies against glutamic aciddecarboxylase(GAD65) are characteristic of the diseaseandhave distinct epitope specificity.These antibodiesare produced intrathecally and may be pathogenic because theyinhibit the activity and may impair the synthesis of the inhibitoryneurotransmitter-aminobutyric acid (GABA), resulting in lowlevels of GABA in the brain and cerebrospinal fluid. Stiff-person syndrome is frequently found in association withother autoimmune disorders, autoantibodies, and certain HLA-DRand DQ
From 1996 to 1999, we enrolled 16 patients with stiff-personsyndrome(9 women and 7 men) who ranged in age from 28 to 59years (mean age,46). All patients had had incomplete responsesto therapies andfulfilled the following strictly defined clinicalcriteria: rigidity of limb and axial (trunk) muscles that wasprominent in the abdominal and thoracolumbar paraspinal areasand made bending difficult; clinical and electrophysiologicalevidence of continuous contraction of agonist and antagonistmuscle; episodic spasms precipitated by unexpected noises,tactile stimuli, or emotional upset; the absence of any otherneurologic disease that could explain the stiffness andrigidity;and anti-GAD65 antibodies, as assessed by immunocytochemicalanalysis,
The protocol specified the intravenousadministration of 2g of immune globulin per kilogram of bodyweight per month, divided into two consecutive daily doses of1 g per kilogram,or placebo, consisting of half-normal saline,once a month for threemonths in random order, followed by aone-month washout period and three months of treatment withthe alternative agent. Immuneglobulin costs $75 to $80 pergram. Thus, for a patient who weighed70 kg, the cost of thedrug would be at least $10,500 per month or$31,500 for thefull three-month course of treatment.
Measurement of Anti-GAD65 Antibody Titers
Anti-GAD65 antibody titers were measured by ELISAin codedspecimens obtained before and after each three-monthtreatmentperiod. Twelve patients had preinfusion and postinfusionserumsamples from both phases of the study.
The primary end point was a change in the scores of thedistribution-of-stiffnessindex and the heightened sensitivity scalefrom base line (month1) to the second and third month of eachtreatment. Secondaryend points were changes in the patients'ability to bend atthe waist, expand their chests, and perform timedactivities,such as walking 9.1 m (30 ft)Student's t-test was used toassess differences in anti-GAD65antibody titers before andat the end of each three-month treatmentperiod.