Parkinson Puzzle
By: Source: AARP Bulletin Today Date Posted: 2003-09-02 15:40:00-04:00
The messages flit through cyberspace from computer keyboards worldwide. Sent to the Internet's Neurology WebForum, where patients and their families share concerns, they vividly convey the multifaceted, baffling aspects of Parkinson's disease.
There's the bewilderment of newly diagnosed patients and their families ("Need advice quickly on Dad's decline") and the pain experienced by patients ("Here be dragons"). But, increasingly, there's hope, expressed in the sharing of good news ("The surgery has been the answer to our prayers") and excited questions ("Can new brain cells be created?").
Yes, here be dragons; but can they be slain?
The answer is: probably so, but perhaps not for several years.
Parkinson's is a highly complex brain disease that affects physical movement. It has no known cause or cure. The course of the condition, the nature and severity of its symptoms, and the response to treatment can vary so widely that what works for one patient may not for another.
Yet recent research has already yielded improved drugs and surgical techniques that give people with Parkinson's better-than-ever chances of keeping their symptoms in check so they can stay active longer.
On the horizon, too, are experimental approaches in brain cell regeneration which, experts say, promise to revolutionize treatment.
"Parkinson's disease may be the first chronic nervous degenerative disease where we'll see a major breakthrough, with a really significant reversal of symptoms," says Gerald Fischbach, M.D., director of the National Institute for Neurological Disorders and Stroke (NINDS) of the National Institutes of Health. "I don't think it's too ambitious to talk about stopping the process entirely."
Abraham Lieberman, M.D., medical director of the National Parkinson's Foundation, is hopeful that research will find the cause and then "a cure within the next decade."
Optimism has been a long time coming. In 1817 an astute English doctor, James Parkinson, studied some patients in London and decided that their symptoms—a variety of movement disorders that had baffled doctors for centuries—were actually a distinct disease. Parkinson guessed, brilliantly, that it arose from a "disordered state" in the brain. But it took scientists another 150 years, until the 1960s, to identify the problem—loss of the brain cells, or neurons, that produce dopamine, a chemical messenger that controls movement—and to develop the first medication.
Today, 30 years later, Parkinson's remains a puzzling disease. By the time patients notice symptoms, they have already lost about 80 percent of their dopamine-producing cells, but no one knows why. Some patients improve dramatically after surgery—some rising from their wheelchairs to walk again—but, still, it's not clear why. Nor can anyone explain why treatments help some but not others.
More than 1 million Americans have Parkinson's, and 50,000 more are diagnosed each year. Most are over 50 years old, like U.S. Attorney General Janet Reno and evangelist Billy Graham. But increasingly, younger people are diagnosed: Actor Michael J. Fox was only 30 when his symptoms began. The disease has even been detected in two children, ages 11 and 12. In general though, it's a disease of age, affecting three out of 100 people over 65.
The first sign is usually a slight tremor in the hands. As the disease advances—probably because dopamine loss triggers a cascade of reactions in the central nervous system—the shaking worsens, and other symptoms may develop: rigid limbs, loss of facial expression, slow movements, poor balance, speech problems, memory loss. At worst, the individual is unable to move, swallow or speak.
Until 1969, there was no relief. Then came the first breakthrough—the "miracle drug" levodopa, which converts to dopamine in the brain, delaying the onset of severe symptoms and allowing most patients extra years of relatively normal life.
Although still the most effective treatment for Parkinson's, levodopa can cause side effects, like severe nausea and adverse interactions with certain foods and drugs. It has two other big drawbacks. After five to seven years its benefit wears off for most patients, and symptoms recur sooner between doses, causing a daily roller coaster of highs and lows. Long term, the drug can trigger involuntary movements. In severe cases, the problems combine—patients cannot control wild limb jerks during the drug's "on" period but are immobile during the "off."
Efforts to combat these effects have led to new drugs. Some boost dopamine levels and may help protect remaining healthy neurons. Others modify levodopa's effect in the brain, for a smoother ride through the day.
Help Yourself
Exercise may benefit some people with Parkinson's disease, as Janet Reno can attest.
The U.S. attorney general was diagnosed with Parkinson's disease three years ago, but this hasn't kept her from doing long-distance hiking and biking. "She's very active physically, and that's good for patients," says her neurologist, William J. Weiner, M.D., director of the Parkinson's Disease and Movement Disorder Center at the University of Miami School of Medicine in Florida.
Exercise may not help all people with Parkinson's, but many find that regular physical activity—such as walking 20 minutes a day—helps them maintain mobility and balance.
Ask your doctor about an exercise program tailored to your particular symptoms. Ask about nutrition, too, since diet can influence the effectiveness of Parkinson's drugs or ease their side effects.
(One drug, Tasmar, was withdrawn in Europe last fall after three users, of about 60,000 worldwide, died from liver disease. In the United States, the Food and Drug Administration (FDA) issued warnings but did not take it off the market.)
Many patients maintain active lives using a combination of drugs. But for those no longer responding to medications, modern neurosurgery has brought help. In 1990 Mahlon DeLong, M.D., chairman of the neurology department at Emory University School of Medicine in Atlanta, invented a sophisticated mapping procedure to guide surgeons through the brain to a site triggering Parkinson symptoms. Doctors can even listen to the sound of neurons firing to navigate to the exact spot, where the malfunctioning cells are destroyed.
Some of the thousands of patients who have had this surgery, known as pallidotomy, have had excellent results. One of DeLong's patients was so changed that "it was as though I just woke up." Retiring her wheelchair, she was able to play tennis, ride a bike and drive a car for the first time in years.
But the procedure has limits, and its benefits are not always long lasting. Typically performed on one side of the brain, it alleviates symptoms only on the opposite side of the body. This means, explains Harvard neurologist and Parkinson's specialist David Standaert, M.D., that "the symptoms get worse on the unoperated side, and eventually even the operated side shows problems as well. But it can buy people four or five years of very good functions."
Why not operate on both sides? Because for reasons that are unclear, complications shoot up from 2 percent to about 30 percent.
A new surgical technique has emerged out of research linking Parkinson's symptoms to several sites in the brain. Deep brain stimulation (DBS) plants electrodes in the brain where they block the defective nerve signals that cause symptoms. DBS can be turned on and off and does not destroy cells as pallidotomy does.
A thin wire under the skin links the electrodes to a "pacemaker" implanted in the chest. The patient controls the pacemaker's on-off switch; a doctor fine-tunes the stimulation it delivers, tailoring its effects to the patient's needs.
The first form of DBS, which targets the thalamus in the brain, was approved by the FDA in September 1997, but it controls only tremor. The true breakthrough came when neurologists discovered that DBS in another brain structure, a pea-sized organ called the subthalamic nucleus, could control not only tremor but also rigidity and walking and balance problems.
Subthalamic nucleus implants are still regarded as experimental in the United States and don't have FDA approval. Of maybe 150 operations worldwide, only about 30 have been done here. But surgeons in Grenoble, France, who pioneered the technique in 1993, recently reported remarkable improvements in 20 patients up to three years after surgery: Once severely disabled, all are now living independently, their symptoms greatly reduced, their levodopa medication decreased or stopped entirely.
Trials to compare this technique with others—pallidotomy and DBS in other parts of the brain—are just getting under way. "It's a very useful therapy," says Jerrold Vitek, M.D., a neurologist at Emory. "We can do it on both sides of the brain."
But, he adds, a choice of techniques raises a new issue: "Which one is better for which patient? That hasn't been answered yet."
DBS is a real advance but by no means a complete answer to Parkinson's. The risks of brain surgery mean that only people who are severely disabled, but otherwise healthy, are treated. DBS is also expensive, and it doesn't work well for everyone. Finally, like all other existing therapies, DBS can ease symptoms, but it is not a cure.
That is why an even newer, still very experimental, approach is causing excitement. It is based on the discovery that healthy nerve cells can be transplanted into the brain and will then grow and function normally.
In Parkinson's, cells injected into the right spot will start producing dopamine. The approach offers hope not only for reducing symptoms but for stopping the progress of the disease and even preventing it.
Several different cell types are under investigation. Human fetal cells are being tested in Parkinson's patients at three U.S. medical centers, with results expected this spring. At Boston University, neurologists transplanted purified fetal cells from pigs into 12 patients three years ago—the first time animal cells were placed in human brains. Results were mixed, but three patients improved dramatically. Larger trials using more cells—48 million for each person instead of 12 million—have just begun.
The problems inherent in such research range from ethical controversies over using human fetal cells to the risk of transmitting genetic diseases. But the greatest practical issue is the need for vast numbers of cells. This has inspired a lab technology called "expanded" cell production, in which a single brain cell multiplies into hundreds—eventually, maybe into tens of thousands—of cells that retain the ability to grow into dopamine-producing neurons when injected into the brain.
Ron McKay of NINDS has demonstrated this technique in mice. He hopes that within a few years scientists will have "freezers full" of engineered human cells for research and therapies.
Other promising work is going on in this rapidly growing field of neural "repair." Scientists at the Johns Hopkins School of Medicine have developed a drug—GBI-1046—that has successfully regenerated damaged brain cells in research animals. "If we see the effect in humans that we see in animals," Ted Dawson, M.D., says, "it could revolutionize the treatment of Parkinson's disease."
Human trials will not begin for at least a year, and a full assessment of the drug is years away. Yet if it works, the implications are immense. Instead of surgery, a pill. Instead of deterioration, a reversal. The question arises whether GBI-1046 could prevent the loss of dopamine neurons in the first place. But that would require finding a way to diagnose Parkinson's before symptoms develop. No technique exists, although scientists are working on it.
They're also working on other Parkinson's puzzles. Is the condition genetic? Three abnormal genes have been found so far, though only for rare forms of the disease. Is it caused by environmental toxins? Certain chemicals and even well water are suspected but not proved. Why do cigarette smokers rarely get Parkinson's? No one yet knows.
Why don't some patients respond to drugs or surgery? The best guess, ironically, is that Dr. Parkinson was wrong: The symptoms do not belong to a single disease. Autopsies show that one in four diagnoses prove instead to be other, rarer conditions.
But since Parkinson's begins in a well-defined area of the brain—and its symptoms can be reproduced in research animals—it offers a clear focus of study. Therefore, in cutting-edge studies that will eventually benefit many disorders and injuries, Parkinson's is leading the field.
Congress has even recommended $100 million for research into Parkinson's, once an underfunded Cinderella disease, for 1999.
Joan Samuelson, president of the Parkinson's Action Network and a Parkinson's patient, says if the research funds are focused on an all-out effort—"like a moonshot or a Manhattan Project, to take all these ideas from where they are now to fruition"—many patients could be out of their wheelchairs within five years.
Lieberman, of the NPF, believes such an effort could nail down both the cause of the disease and a cure within a decade.
This article previously appeared in the AARP Bulletin. Since its original publication, there may have been some medical developments in this area. Therefore, consult your physician for the latest information and advice on treating this particular condition. The information in this article is intended only to describe this medical issue in general terms. This information should not be used as advice regarding your particular condition. Only your physician can give you proper medical advice.
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