Amyotrophic Lateral Sclerosis (ALS) Treatment

by Food and Drug Administration (FDA)

Sunday, May 2, 1939, will be forever remembered in the annals of baseball as the day New York Yankees' first baseman Lou Gehrig voluntarily benched himself, ending a streak of 2,130 consecutive games.

For months the once-great player's game had been in decline. His reflexes were off. He stumbled, fumbled, and struggled to hit or catch the ball. No one understood why, least of all Gehrig himself.

A few weeks after Gehrig benched himself, doctors diagnosed his illness as amyotrophic lateral sclerosis (ALS), a progressive disease of the central nervous system that remains incurable to this day.

Two years later, on June 2, 1941, Gehrig died at the age of 37. The disease that took his life became known to Americans as Lou Gehrig's disease. His consecutive games record stood for 56 years until it was broken by the Baltimore Orioles' Cal Ripken Jr. on Sept. 6, 1995.

In the years since Gehrig's death, many drugs have been tried for the treatment of ALS. For 54 years, none was found to be effective. But one recent drug approval and the granting of early access to another drug give reason for hope.

The Food and Drug Administration approved Rilutek (riluzole) in December 1995. It was the first drug found to have an effect, albeit a modest one, on the course of ALS. In clinical trials conducted in the United States and Europe, the drug appeared to prolong patients' survival by about three months.

Before the agency approved Rilutek, the drug had been made available to more than 3,000 ALS patients in the United States under the Treatment IND (investigational new drug) program. This program gives patients access, under certain circumstances, to promising investigational new drugs for serious and life-threatening diseases for which there is no adequate treatment.

A second drug, Myotrophin (somatomedin C), was granted a Treatment IND by FDA last June 24. Myotrophin is a recombinant insulin-like growth factor that appears to prevent neuron loss and promote neuron regeneration in animal studies. The drug has been studied in humans since 1992 in two completed international trials and a third ongoing in Japan. FDA granted treatment IND status to Myotrophin based on the results from the drug's first trial in humans, which indicated the drug has a modest effect in reducing the rate of disease progression.

Disabling and Often Deadly

More than 30,000 Americans have ALS, according to the ALS Association, a nonprofit organization that supports ALS research and public and patient education about the disease. Around 3,000 to 5,000 new cases of the disease are diagnosed every year.

Although ALS can strike at any age, it usually appears between the ages of 40 and 70. Men and women of all ethnic and racial groups are about equally affected.

The disease attacks the motor neurons, nerve cells in the brain and spinal cord that control the body's voluntary muscles. As the motor neurons begin to die, the muscles weaken and shrink. Early symptoms of ALS may include unusual fatigue and clumsiness, muscle weakness, slurred speech, and difficulty swallowing.

As the disease progresses, patients gradually lose the use of their hands, arms, legs, and neck muscles, ultimately becoming paralyzed. They can speak and swallow only with great difficulty. However, thinking ability, bladder and bowel function, sexual function, and the senses — sight, hearing, smell, taste, and touch — are unaffected.

About half of people with ALS die within three to five years of diagnosis. In rare cases, a person may survive with the disease for many years (see accompanying article). The usual cause of death is failure of the diaphragm muscles that control breathing. Some individuals with ALS choose to prolong their lives by using a ventilator, but prolonged use of a ventilator may increase the risk of death from an infection such as pneumonia.

No single test can diagnose ALS. Because of the slow onset of the disease, it can be difficult to diagnose in the early stages, said Jeffrey Rothstein, M.D., Ph.D., associate professor of neurology at Johns Hopkins University School of Medicine in Baltimore. Johns Hopkins is one of the nation's leading centers for ALS research.

"We do a number of tests to rule out other diseases that might mimic ALS. Because it's a fatal disease, you want to be absolutely certain of your diagnosis. The patient is generally about 20 to 50 percent into the disease by the time it is diagnosed," he said.

Cause a Mystery

Doctors have known about ALS since 1874 (it was first identified by a French physician, J.M. Charcot), but its cause remains a mystery. Inability to pinpoint the cause of ALS has hindered efforts to find an effective treatment, said Marc Walton, M.D., Ph.D., a medical officer in the clinical trials division of FDA's Center for Biologics Evaluation and Research.

Doctors once thought that ALS might be caused by the same virus that causes polio and that exposure to polio would increase the risk of ALS, said Ralph Kuncl, M.D., Ph.D., associate professor of neurology at Johns Hopkins. However, he said, no evidence has been found to support this theory.

Another conjecture was that an environmental toxin might cause ALS. This theory arose in part because some places — the South Pacific island of Guam and parts of Japan — have somewhat higher than normal rates of ALS.

The cicad nut, a traditional food in Guam, contains toxic substances capable of killing motor neurons, said Kuncl. "But the toxicity level is not enough to cause the degeneration seen in ALS."

The "surprisingly uniform" incidence of ALS in the rest of the world "would not be expected if the disease were caused by an environmental toxin," Kuncl added. However, the reason for the increased rate of ALS in Guam and Japan remains unknown.

Some doctors believe that ALS is an autoimmune disease — that is, a disease in which the body attacks itself with antibodies normally produced to protect against infection. In ALS, according to this theory, antibodies attack and kill the motor neurons. However, "very potent autoimmune therapies have been tried in ALS and have all failed to alter the course of the disease," said Rothstein.

Another theory is that ALS is caused by toxic levels of glutamate in the brain. Glutamate is a constituent of protein that cells in the body use to help break down food and build up body tissues. In the central nervous system, nerve cells (neurons) use glutamate to communicate with one another.

About the Author

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