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Glimmer of Hope for People with ALS

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.

Because too much glutamate can be toxic, the brain usually regulates the substance, keeping levels to those needed for body functioning. Abnormally high levels of glutamate have been found in the cerebrospinal fluid (the clear watery fluid that surrounds the brain and the spinal cord) of some patients with ALS.

In experiments, scientists have found that a protein responsible for removing excess glutamate from the brain appears not to work properly in people with ALS. They theorize that toxicity resulting from excessive glutamate might be killing motor neurons. The death of these cells leads to progressive muscle wasting in patients with ALS. One of the characteristics of Rilutek is that it inhibits the release of glutamate in the brain.

Rilutek is taken by mouth. Everyone who takes the drug must be monitored regularly for signs of Rilutek's most important side effect, a rise in the level of liver enzymes, which indicates abnormal liver function.

The drug's labeling states that treatment should be discontinued if liver enzymes increase to 10 times their normal level.

About five out of every 100 people who get ALS have an inherited, or familial, form of the disease; that is, one or more of their immediate family members--parents, brothers, sisters, or grandparents--also have the disease. Children of people with familial ALS have a fifty-fifty chance of developing the disease themselves.

In 1993, scientists identified a gene that, when defective, is associated with some cases of familial ALS. This gene carries the operating instructions for a protein whose function is to neutralize cell-damaging substances called free radicals. Some scientists think that when the gene is defective, an excessive buildup of free radicals may kill motor neurons.

However, this genetic mutation is found in only about one-fifth of people with familial ALS, according to Rothstein, and it has not been detected in anyone with the sporadic (noninherited) form of the disease, which is far more common.

Searching for Treatments

Even if the cause of the disease is eventually found, the development of effective treatments presents enormous challenges, said Rothstein. "The drugs have to be potent and they have to get into the nervous system, which has a very tight barrier--the blood-brain barrier--that prevents entry by many drugs."

Some doctors think that neurotrophic growth factors, substances produced by the body that stimulate nerve cells to grow and multiply, may be useful for treating ALS. These substances can now be produced in the laboratory using the techniques of biotechnology. Myotrophin is one such factor.

"No one thinks that neurotrophic factors, or the lack of them, cause ALS," said Rothstein. "But in animal experiments they seem to work quite well in preventing injury to motor neurons."

FDA's Walton said the agency is working with investigators and the drugs' manufacturers to try to design trials "that will tell us as quickly and efficiently as possible whether or not these products can be effective in the treatment of ALS."

Until more effective drugs are developed and approved to treat ALS, measures to improve patients' mobility and quality of life remain the mainstay, said Rothstein. "Nutrition is very important. A recent study in Italy showed increased survival in ALS patients who received good nutrition using a feeding tube.

"There's also a mask that patients can use to assist their breathing, and physical therapy can help to make them more comfortable. A speech pathologist can help them to learn different swallowing techniques as their swallowing muscles become weaker. Support groups for patients and their families are also very important."

On Sept. 6, 1995--the day Cal Ripken Jr. broke Lou Gehrig's record for consecutive games played--the Baltimore Orioles and the Johns Hopkins Medical Institutions announced the launch of the Cal Ripken/Lou Gehrig Fund for Neuromuscular Research.

Ticket sales to the record-breaking game and an Orioles contribution raised $2 million for the fund. Kuncl said the money will support research at Johns Hopkins on neuromuscular diseases, with an emphasis on ALS.

Johns Hopkins' Rothstein said that though the drugs available do not thus far seem to give dramatic improvement, he is not discouraged.

"This is against the background of decades when no drug ever did anything for the disease. Initial therapies for many diseases, like leukemia and other cancers, had the same kind of effect ... a modest increase in survival. But they were followed by better therapies that, over time, increased patients' survival.

"It's a daunting task, but I envision that some day it will be possible to develop drugs that will not only stop motor neurons from dying but replace them and reverse the course of ALS."

Eleanor Mayfield is a writer in Silver Spring, Md.

Exceptional Survivor

Hawking, now 54, was diagnosed with ALS in 1963 when he was a 21-year-old graduate student at Cambridge University in England.

Hawking's life demonstrates that ALS impairs neither intellect nor sexual function. His work on the origin and nature of the universe has been, in the words of biographers Michael White and John Gribbin, "ground-breaking and revolutionary." Hawking also married and fathered three children after his diagnosis.

In 1985, after suffering a windpipe blockage, Hawking had a breathing device surgically implanted in his throat. The surgery resulted in the loss of his voice. He now "speaks" by using a voice synthesizer connected to a computer that he operates by squeezing a switch in his hand.

In Stephen Hawking: A Life in Science, White and Gribbin write that Hawking has a very strong personality and has "never [given] in to the symptoms of ALS more than he is physically compelled to."

--E.L.M.