Stiff man syndrome

Rare Disease May Offer Clues to MS

An Italian investigator at Yale University School of Medicine has a pilot grant from the Society to study an autoimmune central nervous system disease few doctors have ever seen. It is called Moersch-Woltman syndrome, "stiff-man syndrome," or SMS. (Actually it affects women more often than men.) He hopes that his immunologic approach to this disease will open doors to better understanding of another disease thought to be auto-immune: multiple sclerosis.

The cause of SMS is unknown. Its symptoms, which include muscle rigidity and spasms -- a duo typical of tetanus -- were first described by Drs. Frederick P. Moersch and Henry W. Woltman at the Mayo Clinic in 1956 after they had spent a long 32 years observing only 14 patients. (The New England Journal of Medicine called their article "an almost unduplicated instance of self-restraint in medical reporting.") The rarity of SMS has made research on it very difficult.

Dr. Peitro DeCamilli and colleague Michele Solimena at Yale first observed SMS when they worked with a team of clinicians at the University of Milan in Italy. They published a first report on their findings in the April 21, 1988 New England Journal of Medicine. Physicians around the world wrote to the team, informing them of additional cases and asking them to test blood and spinal fluid samples from their patients. By the time the Italian team had moved to Yale that same year, they had begun to collect a file of patients referred from neurologists in Europe, Africa and Central and North America. Today the total stands at 29, the largest collection of such patients ever examined.

This year the team reported to the American Academy of Neurology that of the patients studied, 19 had in their blood autoantibodies directed against certain synapses in their brain and spinal cord. (Synapses are points where two nerve cells meet.) These were synapses that use gamma-aminobutyric acid, or GABA, as a chemical transmitter.

When the brain gives an order to a muscle, it does so using electrochemical signals which transmit information from one nerve cell to the next. GABA is one of the chemicals, called neurotransmitters, which flow across the gaps between nerve cells and synapses.

"We have both excitatory and inhibitory synapses," Dr. DeCamilli explains. "Every healthy person's muscle action is controlled by the right mix of excitatory and inhibitory signals. When there is an imbalance of signals, a patient may develop abnormal muscle function, such as incoordination, rigidity or even paralysis.

"Electromyograms show that nerve cells of patients with SMS fire at a much higher rate than those of healthy people. This means that inhibition of firing in nerve cells controlling muscle activity has been diminished in these patients. The resulting higher firing causes repeated uncontrolled contraction, in which the muscles become stiff."

The antibodies found by DeCamilli and his colleagues in the patients' fluids proved to be directed against enzymes in the neurons that produce GABA. This explained why the inhibitory function had dwindled; less GABA was actually being produced.

"Not only does this define SMS as an autoimmune disease," he says, "but it suggests a way of treating this illness. We have on hand a variety of drugs that increase or enhance the action of GABA, to compensate for the loss due to the autoantibodies. Some drugs have been found partially effective in reducing the severity of the symptoms, though they do not abolish them."

In a letter to the June 1 New England Journal of Medicine, the team reported the effects of plasma exchange (a method of removing toxic elements including autoantibodies from the blood) combined with steroids on a patient with SMS. After five sessions, the patient was free from muscle rigidity for about seven months. The fact that such therapy caused improvement had added to the evidence that SMS is an autoimmune disease.

Dr. DeCamilli thinks discoveries about SMS will go hand in hand with findings on MS observed, "We think that getting a handle on the mechanism of SMS may provide important clues about how an aggressive autoimmune response against central nervous system antigens is mounted by the body. If we can pinpoint the mechanism the body uses to develop autoimmunity to the nerve cells that make GABA, we might find it has resemblance to the mechanism by which a person develops autoimmunity against his own myelin in multiple sclerosis."

A final link between SMS and at least some cases of MS may be the symptom of spasticity. Dr. DeCamilli comments, "We don't know what causes spasticity in either disease. Again, if we can identify the mechanism in SMS, it might lead to a better understanding of how it starts in MS. This could generate ways of treating the symptom."

COPYRIGHT 1989 National Multiple Sclerosis Society
COPYRIGHT 2004 Gale Group