The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid.
The stiff-person syndrome, a rare and disabling disorder, is characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. Continuous contraction of agonist and antagonist muscles caused by involuntary motor-unit firing at rest are the hallmark clinical and electrophysiologic signs of the disease. Except for global muscle stiffness, results of neurologic examination are usually normal. Results of conventional computed tomography and magnetic resonance imaging of the brain are also normal. The cause of the stiff-person syndrome is unknown; however, an autoimmune pathogenesis is suspected because of 1) the presence of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA); 2) the association of the disease with other autoimmune conditions; 3) the presence of various autoantibodies; and 4) a strong immunogenetic association. Anti-GAD antibodies, which are found in high titers in most patients, seem to be directed against conformational forms of GAD. New evidence suggests that these antibodies may be pathogenic because they interfere with the synthesis of GABA. In addition, a reduction in brain levels of GABA, which is prominent in the motor cortex, has been demonstrated with magnetic resonance spectroscopy in patients with the stiff-person syndrome. The stiff-person syndrome is clinically elusive but potentially treatable and should be considered in patients with unexplained stiffness and spasms. Drugs that enhance GABA neurotransmission, such as diazepam, vigabatrin, and baclofen, provide mild to modest relief of clinical symptoms. Immunomodulatory agents, such as steroids, plasmapheresis, and intravenous immunoglobulin, seem to offer substantial improvement. Results of an ongoing controlled trial will elucidate the role of these agents in the treatment of the disease.
Levy
L M
LM
Neuroimaging Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. levy@codon.nih.gov
Dalakas
M C
MC
Floeter
M K
MK
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000627:therapeutic use; D004576:Electromyography; D018757:GABA Modulators / Q000627:therapeutic use; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D016750:Stiff-Person Syndrome / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D018757:GABA Modulators; D005680:gamma-Aminobutyric Acid; D003975:Diazepam