Dream Robber: Living with Parkinson's disease

As a boy, John Kuhn dreamed of becoming a pilot. Mechanically minded and good with his hands, he earned his first "wings" at 16. At 26, he became a commercial airline pilot, eventually rising to captain on the strength of his experience and finely honed motor skills.

Now 65, he has been permanently grounded by Parkinson's disease, unable, due to the loss of motor control in his right hand and leg, to qualify for the special license he needs to fly the sleek kit airplane he dreamed of building and taking to the skies in retirement.

"Except for having to give up flying, Parkinson's hasn't changed my life much," he says bravely, but a little wistfully.

Diagnosed with the disease in 1998, actor Michael J. Fox perhaps best captured the dramatic impact it can have when he said, "Parkinson's forced me to make a fundamental life decision: adopt a siege mentality—or embark upon a life journey."

Fox since has become one of the nation's foremost advocates for finding a cure for the disease, which was first described in 1817 by English physician James Parkinson as "the shaking palsy." In the early 1960s, researchers identified a fundamental brain defect that is the hallmark of PD: the loss of brain cells, or neurons, in an area known as the substantia nigra that produce dopamine, a chemical that helps direct smooth, purposeful muscle activity.

Like Kuhn, Fox, Muhammad Ali and former U.S. Attorney General Janet Reno, some 50,000 Americans from all walks of life are diagnosed each year with Parkinson's, and more than onehalf million people are affected at any one time. Respecter of neither fame nor fortune, PD strikes all over the world, affecting men at a slightly higher rate than women.

Subtle onset of classic symptoms

Parkinson's disease—the most common form of parkinsonism, a group of disorders with similar features—produces a wide range of problems that appear and progress at different rates and to varying degrees from individual to individual. Early symptoms are often subtle and may include mild shaking of the limbs (tremor), slowness of movement or stiffness.

Often, family or close friends may notice other changes in the person with PD, including decreased facial expression, increasingly soft voice or progressively more illegible handwriting. As the disease Advancess, four classic clinical signs typically appear:

• Tremor—rhythmic, back-and forth trembling of the hands, arms, legs, jaw or face
• Rigidity—stiffness of the limbs and/or trunk
• Bradykinesia—the slowing down and loss of spontaneous and automatic movement, particularly frustrating because it may be unpredictable, and what once was routine, like washing or dressing, may take significantly longer
• Instability—impaired balance and stooped posture

Other clinical features sometimes present include depression; emotional problems, such as anxiety; loss of motivation; difficulty swallowing; urinary problems or constipation; oily skin and scalp; excessive sweating and a variety of sleep difficulties.

Difficult to diagnose

Typically a disease of late middle age, Parkinson's usually affects people over the age of 50, with 60 being the average age of onset—just what happened to John Kuhn two months after his mandatory 60th birthday retirement as a commercial pilot. However, research over the last several years has demonstrated that as many as 10 percent of Parkinson's patients may experience onset before 40, like Michael J. Fox when he was diagnosed.

Even for experienced neurologists, accurately diagnosing Parkinson's in its early stages can be difficult in some cases. No blood or laboratory tests are available, so physicians may have to observe patients for some time until it is apparent that clinical signs and symptoms are consistent with a diagnosis of PD.

Effective drug relief

Although there currently is no cure, various medications can provide dramatic relief from many of Parkinson's debilitating motor (movement-related) symptoms. Physicians tailor treatment to a patient's particular condition since no two people react the same way to a given drug.

The primary therapy for PD is replacement of dopamine via levodopa (also called L-dopa, from the full name L-3,4-dihydroxyphenylalanine), a simple chemical found in plants and animals with which neurons can make dopamine to replenish the brain's dwindling supply; dopamine agonists, which mimic the role of dopamine in the brain; or a combination of both.

Introduced in the 1960s, levodopa relieves many troublesome symptoms of PD, extending the time in which the majority of patients—who would otherwise be very disabled—can lead relatively normal, productive lives. (Dopamine itself cannot be given because it doesn't cross the blood-brain barrier, the elaborate meshwork of fine blood vessels and cells that filters blood reaching the brain.)

Levodopa is combined with the drug carbidopa, which delays the conversion of levodopa into dopamine until it reaches the brain; prevents or diminishes some of its common side effects, such as nausea, vomiting and low blood pressure; and reduces the amount of levodopa needed.

Levodopa does not, however, replace lost nerve cells or stop Parkinson's progression. Bradykinesia and rigidity respond best, while tremor may be less responsive. Problems with balance and other symptoms are often not responsive to dopaminergic therapy. Recent studies show that adding certain medications, either tolcapone or entacapone, can prolong the relief gained from levodopa-carbidopa.

There are other medications for particular symptoms or stages of Parkinson's, including:

• Apomorphine, bromocriptine, pergolide, pramipexole, ropinirole—which mimic dopamine and can be given alone or with levodopa, may be used in the disease's early stages or started later.
• Selegiline—also known as deprenyl, selegiline provides some benefit for the symptoms of PD and may prolong the effect of levodopa
• Anticholinergics—initially the principal treatment for Parkinson's prior to levodopa, the benefit of these drugs is limited but they may help to control tremor and rigidity
• Amantadine—an antiviral drug often used alone in the early stages of the disease, or with an anticholinergic or levodopa. Amantadine is sometimes also used to treat side effects of levodopa called dyskinesias.

Surgery to relieve symptoms

Prior to the development of levodopa, treating Parkinson's with surgery was common but it is currently reserved primarily for those patients with Advanced PD. Today's preferred surgical approach is deep brain stimulation (DBS), which uses a surgically implanted, batteryoperated medical device called a neurostimulator—similar to a heart pacemaker and approximately the size of a stopwatch—to deliver targeted electrical stimulation to block the abnormal nerve signals that generate Parkinson's symptoms.

Unlike previous surgeries, DBS does not damage healthy brain tissue by destroying nerve cells. The advantage to DBS as compared with lesion surgery is that the stimulation settings can be adjusted by a physician in the office, and to some extent by patients in particular cases.

Although most patients still need to take medication after undergoing DBS, many experience considerably reduced symptoms and some are able to lower their doses. This helps reduce side effects, such as involuntary movement, associated with the longterm use of levodopa.

Fighting for future health

As a world leader in research on neurological disorders, the National Institute of Neurological Disorders and Stroke (NINDS) supports twelve Morris K. Udall Parkinson's Disease Research Centers of Excellence throughout the country. Much of the recent progress on Parkinson's has been funded through the Centers and many other NIH grants.

New studies have identified several genes that cause or contribute to PD and some potential environmental risk factors. These findings are improving our understanding of the processes that cause cell death in PD. In addition, a number of promising therapies are now being tested. And continuing research into the underlying biology of the disease is certain to lead to better ways of relieving Parkinson's debilitating symptoms and, ultimately, to halting or preventing the disease itself.