Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome

Abstract

Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period, using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calcium-channel antibodies were measured by radioimmunoassay using 125I-omega-conotoxin MVIIC. Direct anti-idiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks. Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic neutralization by immunoglobulin was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated disorders may similarly be associated with decline in levels of pathogenic autoantibodies.

Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders [RETIRED]

“…One Class II placebocontrolled crossover study evaluated IVIg efficacy in 10 patients with Lambert-Eaton myasthenic syndrome (LEMS). 31 As compared with placebo, IVIg showed a modest benefit on vital capacity, limb strength, drinking time, and antibody titer. There are no controlled studies evaluating the effects of IVIg on polymyositis, diabetic polyradiculoplexoneuropathy, or Miller Fisher syndrome.…”

Lambert-Eaton myasthenic syndrome: report of two cases

“…Others require drugs such as guanidine and 3,4-diaminopyridine that increase the pre-synaptic calcium influx and the acetylcholine release 5,33 . Patients unresponsive to these treatments may respond to corticoids, azathioprine, plasmapheresis and, most recently, endovenous gammaglobulin therapy [34][35][36][37] .…”

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

“…The simulation showed that for the lower pair, mean endogenous IgG concentration decreased from 12.1 mg/ml at the start of the simulation to a minimum value of 5.3 mg/ml before returning to baseline values; while with the higher pair of values less competition between endogenous IgG and mAb for FcRn binding was seen such that mean endogenous IgG concentration decreased from 12.1 mg/ ml at the start of the simulation to a minimum value of 11 mg/ml before returning to baseline values (data not shown). Data in subjects with calcium-channel autoantibodies showed a 35% decrease in levels of the autoantibodies 4 weeks after a total dose of 2 g/kg of IVIG (34).…”