MEDICAL PROGRESS

New Hope for Parkinson’s Treatments

Ever since the British doctor James Parkinson first described the disease
that bears his name in 1817, the search for Parkinson’s treatments has been
marked by both hope and disappointment. In the 1940s and 50s, for example,
doctors were optimistic that an operation called pallidotomy could reduce
or halt the tremors, rigidity, and slowed movements that characterize this
degenerative brain disorder. But their hopes were soon tempered by concerns
that the procedure carried too high a risk of inflicting severe
neurological damage.

Because of this, and because of the arrival of the drug levodopa (L-dopa)
in 1968, pallidotomy was subsequently abandoned. With none of the hazards
of surgery, L-dopa could control tremor, relieve painfully slow movements,
and reduce rigidity. Today, the
most widely used and effective form of the drug is Sinemet, a combination
of levodopa and a related substance called carbidopa, which helps prevent
L-dopa from breaking down before it reaches the brain.

However, as more patients were treated with L-dopa over the years, it
became obvious that the drug has its own share of problems. For reasons
scientists don’t understand, the medication’s benefits wane. After about
five years, approximately half of those taking Sinemet fall into an
"on-off" pattern, in which "frozen" periods of impaired movement
(bradykinesia) alternate with intervals of excessive and uncontrolled movement
(dyskinesia).

Now, scientists and doctors have once again emerged from their labs and
clinics with a spate of hopeful discoveries - as well as improvements to
previous therapies. Pallidotomy, for example, has returned in the past few
years as a much safer procedure, and one that is particularly effective at
reducing the dyskinesia caused by long-term Sinemet use. Meanwhile, several
new medications have recently become available that may enhance the
effectiveness of L-dopa or reduce or delay its use.

Parkinson’s disease is one of several illnesses that cause parkinsonism - a
term that refers to any condition marked by slow, trembling, or rigid
movements. But Parkinson’s disease carries a unique neurological signature:
the selective, progressive death of nerve cells in a small area of the
brain called the substantia nigra. These specialized cells manufacture the
chemical messenger dopamine, which is essential for smooth
and normal movement.

Although Parkinson’s is not a terminal illness, its symptoms worsen over
time as more and more nerve cells are destroyed. No one knows what causes
the disease, which affects about 1 million Americans, but older age seems
to be the most important risk factor. The majority of affected individuals
are diagnosed after age 65, although about 10% have a less common,
early-onset form of the disease that strikes before 40.

L-dopa remains the "gold standard" of Parkinson’s treatment; it works by
increasing the amount of dopamine in the brain. However, because the drug’s
effectiveness diminishes over time, most doctors recommend delaying
treatment with Sinemet as long as
possible and starting with other drugs.

In 1997, the U.S. Food and Drug Administration (FDA) approved two new drugs
- pramipexole (Mirapex), manufactured by Pharmacia & Upjohn, and ropinirole
(Requip), from SmithKline Beecham Pharmaceuticals - that may put off the
use of L-dopa. These
medications are the latest additions to an existing class of drugs called
dopamine agonists, which trick the brain into believing there is more
dopamine on hand than there really is.

The new drugs are approved for both early use as single-drug therapies and
to be taken in combination with Sinemet later on. All dopamine agonists can
cause nausea, confusion, and nightmares, but the new drugs are believed to
cause fewer of these side effects than older members of this class.

In early 1998, the FDA approved tolcapone (Tasmar), the first of a new
class of Parkinson’s medications called COMT inhibitors. These drugs
enhance the effectiveness of levodopa by blocking the enzyme
catechol-O-methyltransferase, which causes L-dopa to break down before
reaching the brain. Tasmar was initially intended for individuals who were
responding fairly well to Sinemet as well as those in whom Sinemet’s
effectiveness had waned.

However, in light of a report issued late last year linking Tasmar to three
fatal liver injuries, the medication is now recommended only for people who
do not have severe movement abnormalities and who do not respond to or are
not appropriate candidates for other available treatments. The report,
which was released by the FDA and  Hoffman-LaRoche, Inc., Tasmar’s
manufacturer, also advised anyone taking the drug to have frequent blood
tests to monitor liver function.

Surgery makes a comeback

Pallidotomy has gained new popularity in recent years. A five-year Harvard
study presented at a neurological conference last year indicated that about
70% of 85 Parkinson’s patients who underwent pallidotomy experienced good
to excellent improvements in mobility. Last year, Medicare agreed to cover
the cost of the
surgery, which ranges from $20,000 to $40,000. Only 5%-10% of patients,
whose symptoms can no longer be controlled by Sinemet, are candidates for
pallidotomy. Although the surgery won’t cure the disease, it can improve
slowed movements, rigidity, and
tremor and lessen the uncontrolled movements caused as a side effect of
Sinemet. The operation targets one side of the globus pallidus, an area of
the brain that appears to become overactive in Parkinson’s patients.
Surgeons use magnetic resonance imaging
(MRI) to visualize the globus pallidus and then insert an electrode probe
to destroy a small portion of its cells. Pallidotomy relieves symptoms
mainly on one side of the body, because operating on both sides of the
brain is very risky.

Pallidotomy is safer than it used to be due to improvements in imaging
technology that allow doctors to more accurately target the right area of
the brain. However, it still carries risks; the most serious complication
is stroke, which occurs in about 1%-3%
of cases.

In August 1997, the FDA approved an implanted electronic brain stimulator
that can reduce tremors in many people with Parkinson’s disease or
essential tremor, a disorder that causes involuntary shaking but no other
symptoms. (For more on essential tremor, see Harvard Health Letter, March
1999.) An electrode is surgically inserted into one side of the thalamus,
the part of the brain believed to cause tremors. A wire attached to the
electrode is threaded just under the scalp and connected to a
pacemaker-like generator implanted near the collarbone. When activated, the
device sends a constant stream of electrical waves to the brain, blocking
tremors.

In the genes

In 1997 and 1998, scientists identified for the first time two gene
abnormalities present in Parkinson’s patients whose families have a high
prevalence of the disease, indicating that at least some cases are
inherited. Both abnormalities cause the body to
produce an altered version of a protein that plays a role in the function
of nerve cells.

A subsequent study in the January 27, 1999, Journal of the American Medical
Association suggested that heredity has a major influence in causing only
the early-onset form of the disease. Researchers led by those at the
Parkinson’s Institute in Sunnyvale, California, contacted 19,842 male twins
age 65 and older and identified 172 twin pairs in which at least one twin
had Parkinson’s.

If the condition is hereditary, the investigators reasoned, the rate of
twins both having the disease should be lower among fraternal twins, who
share some but not all of the same genes, than among identical ones, whose
genetic makeups are exactly alike. In individuals who were diagnosed after
age 50, the rate of twins who both had the disease was similar among
fraternal and identical twins. However, in those diagnosed at 50 or
younger, the rate was much lower in fraternal twins.

Making the diagnosis

Unfortunately, there is no single test that can nail down a Parkinson’s
diagnosis. Instead, doctors make the call based on the presence of tremor,
stiffness, and slowed
movement. However, this often leads to misdiagnosis, since many other
conditions - including essential tremor, drug-induced parkinsonism, and
arthritis - can cause similar symptoms.

For the past ten years, scientists around the world have been working to
find a way to visualize the characteristic loss of dopamine-producing cells
that occurs in the brains of Parkinson’s patients. In one line of research,
Harvard investigators identified a chemical called altropane, which binds
to dopamine nerve cells and lights them up on a special imaging instrument
- a single photon emission computed tomography (SPECT) machine. After being
injected with a small amount of altropane, a person would place her or his
head in the machine, which visualizes the brain. Meanwhile, Yale
researchers have been studying another promising imaging agent, called
beta-CIT, which could also be
used with SPECT to identify Parkinson’s.

SPECT instruments can be found in almost every medical center in the
country, and doctors are currently testing the safety and effectiveness of
altropane and similar agents. Thus, a reliable diagnostic test for
Parkinson’s disease could be a reality within a few years.

On the horizon

Researchers are currently investigating a number of agents that they hope
can somehow prevent dopamine-producing nerve cells from dying. One such
compound, called glial-derived neurotrophic factor (GDNF), is a naturally
occurring substance that has been found to markedly improve Parkinson’s
symptoms in animal studies. GDNF is currently being tested in human trials
of individuals with advanced Parkinson’s.

Another experimental approach involves transplanting dopamine-producing
human or pig fetal cells into the brains of Parkinson’s patients. In
preliminary studies, these transplants improved patients’ symptoms for up
to two years and enabled some of them to lower their dose of L-dopa.
However, this field of inquiry is plagued by controversy; opponents argue
that the use of human fetal tissue is morally wrong and that using pig
cells could pose unknown risks.

Several research teams are currently experimenting with genetically
engineered skin cells and a variety of other human and animal cells that
can be "taught" to produce dopamine. Cell transplantation is a hot area of
investigation, but its benefits
will probably not be available to Parkinson’s patients for many years.

Although doctors still don’t know what causes Parkinson’s or how to cure
it, research efforts to find treatments to slow, halt, or even reverse the
disease’s relentless progression are more active than ever before. There
will be setbacks, of course. But for both investigators determined to find
answers and individuals living with the disease, hope springs eternal.


References:

Lang AE and Lozano AM. Medical Progress: Parkinson's Disease,
First of Two Parts. New England Journal of Medicine, October 8,
1998, 339: 1044-53.

Lang AE and Lozano AM. Medical Progress: Parkinson's Disease,
Second of Two Parts. New England Journal of Medicine, October 15,
1998, 339: 1130-43.

Tanner CM, et al. Parkinson's Disease in Twins: An Etiologic
Study. Journal of the American Medical Association, January 27,
1999, 281: 341-46.

Web sites:

American Parkinson's Disease Association at
     <http://www.apdaparkinson.com>

National Institute of Neurological Disorders and Stroke at
     <http://www.ninds.parkinson.org>

National Parkinson Foundation Inc. at
     <http://www.parkinson.org>


Harvard Health Letter
Volume 24 Number 8 June 1999
Editor-in-Chief Stephen E. Goldfinger, M.D.
Editor Leah R. Garnett
Web related inquiries: [log in to unmask]
<http://www.harvardhealthpubs.org/Ltxt.html>

janet paterson
52 now / 41 dx / 37 onset
PO Box 171  Almonte  Ontario  K0A 1A0  Canada
a new voice http://www.geocities.com/SoHo/Village/6263/
[log in to unmask]