IMPROVED TREATMENTS, TESTS
FOR MYASTHENIA GRAVIS REPORTED

HONOLULU, April 4, 2003 -- The disease myasthenia gravis (MG), which literally means “grave muscular weakness,” is treatable with medication in most cases. But for some people with the disease, even the most tried-and-true medications don’t seem to work.

At the 55th annual meeting of the American Academy of Neurology in Honolulu Thursday, Donald Sanders, director of the MDA clinic at Duke University in Durham, N.C., discussed new research aimed at better treatment options for MG.

MG is caused by a self-directed attack of the immune system on the connection between nerve and muscle (the neuromuscular junction).

At the normal neuromuscular junction, nerve cells release a chemical signal called acetylcholine (ACh), which attaches to a docking site on muscle cells, called the ACh receptor. Signaling between nerve and muscle is terminated (at least in part) by acetylcholinesterase, an enzyme that breaks down ACh.

In most cases of MG, wayward antibodies — the Y-shaped missiles that the immune system launches against foreign microbes — target and destroy the ACh receptor.

Often, the disease can be treated with drugs that block the action of acetylcholinesterase, or with immunosuppressant drugs such as prednisone. But sometimes, these treatments are ineffective or they have intolerable side effects.

Sanders has been investigating the possibility of treating MG with CellCept (mycophenolate mofetil), a drug originally developed to prevent immune rejection of transplanted organs. In a pilot trial, eight out of 12 patients on CellCept for several months gained strength or were able to reduce their need for prednisone.

At the meeting, Sanders presented a new analysis of MG patients who had been prescribed CellCept at Duke and at Rush-Presbyterian-St. Luke’s Medical Centers in Chicago. Among 92 patients who took the drug for three to 45 months, improvement was seen in 67, including five people who experienced complete remission.

“[CellCept] works in the majority of MG patients,” he said. “Its advantages over other immunosuppressants are that it has a more rapid onset and fewer side effects.” He added that neurologists are starting to test the drug against inflammatory myopathies, a distinct group of muscle diseases that involve an immune attack against muscle.

In another study presented at the meeting, Sanders collaborated with Angela Vincent at Oxford University in England to examine patients with “seronegative” MG, who have no ACh receptor antibodies detectable in their blood. About 15 percent of all MG cases are seronegative.

Out of 35 seronegative patients, Sanders and Vincent identified 10 with antibodies to MuSK, a protein that helps organize ACh receptors (AchR) on the muscle cell surface. Most of the MuSK-positive patients had a distribution of weakness different from that seen in AChR-positive MG. More remarkably, cholinesterase inhibitors were ineffective in three of the patients, and removal of an immune system gland called the thymus — a widely practiced surgical treatment for AChR-positive MG — was ineffective in six.

Detection of MuSK antibodies “is going to be a major clinical tool in evaluating patients with seronegative MG” and might be useful for selecting effective treatments, Sanders said. Athena Diagnostics, a company in Worcester, Mass., is expected to come out with a commercially available test for the antibodies this summer, he said.

Other meeting highlights from Wednesday and Thursday include:

Progress in Tamoxifen Study
Tamoxifen, a drug better known for its use in breast cancer, is being tested against amyotrophic lateral sclerosis (ALS) by Benjamin Brooks, director of the MDA/ALS Clinical Research Center at the University of Wisconsin in Madison. Brooks reported that the drug was well-tolerated by the first 50 patients taking a range of doses, with only one person discontinuing it.

Some significant strength changes could be measured in all patients, but the increase was not enough to affect daily function. The trial is still open for enrollment with an eventual goal of 100 participants.

Predicting the Course of Duchenne MD
Parents of a child found to have Duchenne muscular dystrophy, caused by defects in the dystrophin gene, often want to know how severe the disease will be. Sheila Kumar of Johns Hopkins University in Baltimore demonstrated that a combination of two laboratory techniques can be highly effective at predicting the course of DMD in an individual child.

The first technique, Western blotting, is a way to measure the amount of dystrophin protein present in a tissue extract. The second technique, immunohistochemistry, allows researchers to look at the amount of the protein in a muscle biopsy. Individually, the two techniques were about 60 to 70 percent accurate in predicting the severity of the disease, but together, they were close to 100 percent accurate.

Two Distinct Types of Phosphoglycerate Kinase Deficiency Identified
Ronald G. Haller of the University of Texas Southwestern Medical Center in Dallas presented evidence that phosphoglycerate kinase deficiency, an X-linked metabolic muscle disease, exists as two distinct syndromes: a pure muscle syndrome characterized by recurrent cramps and muscle breakdown in response to intense exercise, and a “muscle plus” syndrome which may feature mental retardation and/or a type of anemia.

Haller, a member of MDA’s Medical Advisory Committee, found that boys with the “muscle plus” syndrome had a much lower capacity for exercise and lower blood enzyme levels when compared to boys with the pure myopathy form.