Immune Drug Eases Rare Spasm Disorder

Protein used for multiple sclerosis may also help 'stiff-person syndrome,' study shows

WEDNESDAY, Dec. 26, 2001 (HealthDayNews) -- A potent immune-suppressing protein used to treat patients with multiple sclerosis may also help people with a rare rigidity disorder known as "stiff-person syndrome," government scientists say.

Regular infusions of the drug, called immune globulin, helps the majority of patients with the neurological condition move much more fluidly. Some even shed the walkers they otherwise need, according to researchers at the National Institute of Neurological Disorders and Stroke, who conducted the study.

That it works so well confirms a theory that stiff-person syndrome is an auto-immune disease in which the body's defense system turns on cells in the brain and spinal cord, the scientists say.

"It's the first drug that has shown efficacy in this disease, and it's the first time patients with such a disabling disease can improve and maintain the improvement over time," says Dr. Marinos Dalakas, the NINDS research who led the work. A report on the findings appears this week in The New England Journal of Medicine.

Stiff-person syndrome (which also goes by its less inclusive name, stiff-man syndrome) causes debilitating muscle spasms and rigidity. Odors, touches and other sensations can trigger the balkiness, which in turn can lead to dangerous falls.

The force of the spasms has been known to break bones, and in some cases can even be fatal. Patients are often so afraid of having an attack outside the safety of their home that they seldom, if ever, leave.

Although it has been estimated that one in a million Americans suffers from the disorder, researchers say it's frequently confused with other conditions, including Parkinson's disease, multiple sclerosis, phobias and psychosomatic symptoms, and is probably more common than generally believed.

Little is known about how stiff-person syndrome starts, but it typically appears between the ages of 30 and 60. Scientists in the 1980s discovered that most patients had abnormally high blood levels of immune proteins, or antibodies, that target an enzyme called glutamic acid decarboxylase (GAD65). This molecule helps create a crucial brain chemical called gamma-aminobutyric acid (GABA), which in turn controls the activity of messenger molecules that signal muscles to move.

Thus, too many antibodies attacking GAD65 depletes GABA, and too little GABA means the floodgates open for the messenger molecules to overstimulate muscles, sending them into lockup.

While doctors haven't found a cure for stiff-person syndrome -- the best treatment so far has been the sedative Valium -- recent case studies have suggested that drugs to pacify the immune system may help relieve spasms and stiffness. One of these compounds is immune globulin (IVIg), a protein that muzzles over-reactive immune cells.

To test that theory, Dalakas and his colleagues gave 16 men and women who had the disease and also the GAD65 antibodies three-month courses of IVIg infused over several hours twice each month, at high doses of 2 grams per kilogram of body weight. They also received three months of dummy injections as a comparison.

In the "crossover" trial, some patients received IVIg first, while others were started on placebo infusions. The groups then switched after a one-month washout period.

When on the active drug, patients' stiffness eased significantly. Not so when they took the placebo infusions, the researchers say. And for 11 patients, the immune therapy produced marked improvements in their ability to walk, keep their balance and perform routine tasks at home and at work.

The benefits of IVIg varied, lasting as short as six weeks or as long as a year, but Dalakas says fine-tuning the therapy might produce more consistent results. Even so, he says, IVIg far outperforms Valium -- which requires high doses that knock patients out -- and carries few side effects.

At $75 to $80 a gram, a month's worth of the drug can easily cost $10,000 or more, a price tag some insurance companies may balk at. On the other hand, Dalakas says, when the NIH trial ended, some patients asked their personal physicians for prescriptions of IVIg and were able to obtain them, presumably with the help of their health care plans.

About 80 percent of people with stiff syndrome have antibodies against GAD65, and Dalakas says it's not clear whether IVIg would work equally well in those without the blood proteins. Still, conclusively linking the disease to the immune system should broaden the therapies available to patients, Dalakas adds, because doctors will now be encouraged to test new and highly effective immune-modulating drugs against the disorder.

Dr. Robert Layzer, a neurologist at the University of California at San Francisco and an expert in stiff-person syndrome, agrees that the latest work will be "very helpful."

The study "showed pretty convincingly that immune globulin therapy can be effective, and that would encourage people to pursue other treatments more rigorously," Layzer says.

What To Do

The National Institute of Neurological Diseases and Stroke and the Medical College of Wisconsin have more information on the disease.

You can also get additional insight at the National Organization for Rare Disorders.

SOURCES: Interviews with Marinos C. Dalakas, M.D., chief, neuromuscular diseases section, National Institute of Neurological Disorders, Bethesda, Md.; Robert B. Layzer, M.D., professor of neurology emeritus, University of California at San Francisco School of Medicine; Dec. 27, 2001, The New England Journal of Medicine
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