Immunotherapy treatment shows dramatic results for rare neurological disorder

December 26, 2001

An immunologic therapy, intravenous immunoglobulin (IVIg), administered to patients suffering from stiff person syndrome (SPS), provides dramatic relief from disabling symptoms, according to a study appearing in the December 27, 2001, issue of The New England Journal of Medicine.* The study's principal author, Marinos C. Dalakas, M.D., chief of the Neuromuscular Diseases Section of the National Institute of Neurological Disorders and Stroke, says that the success of the treatment supports the theory that SPS is the result of an autoimmune response gone awry in the brain and spinal cord.

SPS is characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress that can set off muscular spasms. People with SPS are often too disabled to walk or move, or are afraid to leave the house because of stimuli-triggered spasms and frequent falls. The incidence of SPS has been estimated at one in every one million persons, but according to Dr. Dalakas, "the disorder is so often misdiagnosed - as Parkinson's disease, multiple sclerosis, fibromyalgia, psychosomatic illness, or anxiety and phobia - that its actual incidence is probably much higher."

Researchers have known since the 1980s that people with SPS have elevated circulating antibodies against a particular enzyme, glutamic acid decarboxylase (GAD65), involved in the synthesis of ã-aminobutyric acid (GABA), an inhibitory neurotransmitter that controls muscle movement. Since GABA modulates the action of the excitatory muscular neurotransmitters, lower levels of circulating GABA allow the excitatory neurotransmitters to hijack communications between the brain and the motor system, overstimulating the muscles into stiffness and spasm.

This link between the neurological symptoms of SPS and a potential immunological culprit led to several preliminary but successful attempts to treat the symptoms of the disorder with immuno-modulating therapies, including IVIg. Dr. Dalakas and his colleagues put this anecdotal evidence to the test by designing a double-blind, cross-over study that would measure the effect of immunoglobulin therapy versus placebo in a group of patients with SPS.
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*Dalakas, M; Fujii, M; Li, M; Lutfi, B; Kyhos, J; McElroy, B. "A Randomized Controlled Trial of High-Dose Intravenous Immunoglobulin in the Treatment of Patients with Stiff Person Syndrome." The New England Journal of Medicine, December 27, 2001, Vol. 345, pp. 1870-1876.

The research team selected 16 patients who tested positive for GAD65 antibodies to receive either IVIg or placebo for 3 months. After a 1-month washout period, the patients crossed to the alternative therapy. Results were based on a "stiffness scale" and a "heightened sense scale" devised by Dr. Dalakas and his colleagues to detect changes in the severity of spasms.

Patients treated with IVIg showed a statistically significant decrease in symptoms of stiffness and spasm. The scores of the IVIg-randomized patients dropped significantly from the first month to the fourth, but rebounded when they crossed to placebo. In the placebo group, scores remained constant for the first 4 months, and then dropped after crossing to IVIg. Eleven of the 14 patients who finished the study became less stiff and more mobile, and were able to either walk unassisted, resume work activities, or remain upright without fear of falling.

The current treatment standard for SPS is diazepam, but according to Dr. Dalakas, "most patients require such high dosages that they become overly sedated." IVIg treats symptoms more successfully and comes with no disabling side effects.

The mechanism of action of IVIg is not completely understood. Dalakas proposes that IVIg either blocks production of GAD65 or somehow neutralizes the circulating antibodies. What causes SPS is also uncertain. "We don't know why the body begins to produce these antibodies or how they reach the neuronal cell," says Dalakas. "It could be a virus, or something else that breaks tolerance and induces the autoimmune process. What we do know is that we have a strong indication that SPS is an autoimmune disease. As a result, we may be able to propose and test additional autoimmune modulators."

The Bayer Corporation and Crescent Health donated part of the IVIg used in the study.

The NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of biomedical research on the brain and nervous system. The NINDS is celebrating its 50th anniversary this year.

This release will be posted on EurekAlert! at http://www.eurekalert.org and on the NINDS website at http://www.ninds.nih.gov/news_and_events/index.htm

NIH/National Institute of Neurological Disorders and Stroke

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