From the "Rochester Review" as Recommended by Mary Rack

The Mystery of 'The Shaking Palsy'

For 150 years after James Parkinson described it as the shaking
palsy, nobody knew what to do for the illness to which he gave
his name. Then, in the 1960s, came L-Dopa, an as-yet imperfect
answer. The disease still has its mysteries--but neurological
scientists are beginning to unravel the puzzle.

By Tom Rickey

"Touch your nose and then my finger."

"Hold your hands in front of you and then relax."

"Point your toes toward the ceiling."

"OK, now tap your index finger and your thumb together as fast as you can."

The scene is the University Medical Center's mind unit (that's short for
Movement and Inherited Neurological
Disorders). Taking time out of her busy schedule, Doris Hammer has stopped in to
engage in a kind of
diagnostic Simon Says game with nurse Nancy Pearson.

"All right, now walk back and forth in front of me," Pearson
tells Hammer. Then she grabs her from behind to see if she
can put her off balance. Hammer holds steady. "Solid as a
rock," Pearson pronounces.

Then the encounter begins to get rough: Numbers--lots of
them, one after another. Nancy peppers Hammer with
seven-digit numbers, asking her not only to repeat the digits
but to put them in order from lowest to highest. Hammer aces
most of them, prompting an observer who finds the task
difficult to ask her how she does it. "Oh, you just rearrange
them in your head as they come up," Hammer explains,
looking like, "Well, can't everybody do that?"

Hammer was diagnosed three years ago with Parkinson's
disease. How she responds to each of the nurse's requests
helps doctors precisely assess the progress of the disorder.

Today Hammer has just one complaint to report: a recent
bout of light-headedness, which she attributes to 18 holes of
golf in the hot midsummer sun. In fact, the only sign that
something is amiss in the brain of this sharp, cheerful
70-year-old is a slight, but constant tremor in her right hand,
often the first sign of the disease.

"I tell myself it's not going to interfere with my golf game,"
says Hammer, who sports a deep tan from regular rounds on
the links. The toll of the disorder on her life thus far? "I don't
run down stairs as fast as I once did."

Hammer's good report today is not unusual for patients with
Parkinson's, says Dr. Roger Kurlan '74, chief of the mind unit.
Although the illness is chronic and progressive with no cure
yet in hand--and the effectiveness of currently available
treatment wanes as time passes--the life span of someone
with Parkinson's is nearly average. Further, patients usually
are able to live normal lives for years after diagnosis, just as
Hammer is doing.

That's despite the fact that deep in her brain, in the
substantia nigra--a tiny black region smaller than a pea--lies
a tangle of several hundred thousand dopamine-producing
neurons, many of which, in her case, have died.

No one knows why neurons die here in the brain's
motor-control center, nor does anyone know how to keep it
from happening. But scientists do know that this cell death is
what causes the symptoms collectively known as Parkinson's
disease, a disorder first described in an essay on "The
Shaking Palsy," written in 1817 by the English physician
James Parkinson. Some years later, a baffled French
neurologist wrote that the disease "remains so utterly
inexplicable that we are constantly drawn to it by the lure of
the mysterious." It was not until the 1960s, with the advent of
l-dopa, that researchers even began to get a handle on
effective treatment.

Parkinson's affects about 1 million people in North America,
and every day more than 100 others are diagnosed with it.
By the time a patient first feels symptoms--movement
problems like slowness, rigidity, and tremors--about 80
percent of the neurons in the substantia nigra are already
gone. And by the time of death, in many patients, virtually all
have been destroyed. The average age of onset is 57,
although a few people get it earlier. Janet Reno suffers from
the disease. So does Billy Graham. The Pope reportedly
does also. And some have even speculated that the Good
Samaritan in Rembrandt's famous etching embodies a
classic Parkinson's patient.

Without the crucial brain messenger dopamine produced by
the neurons in the substantia nigra, critical brain signals go
awry, resulting in a litany of symptoms that vary widely from
individual to individual. Besides the symptoms mentioned
above, about one in three patients also experiences
depression, and nearly three of every four ultimately see
some decline in their cognitive skills. Stooped posture,
shuffling gait, loss of balance, fatigue, and difficulty speaking
and swallowing are common. Tasks like brushing one's teeth,
handwriting, shaving, fastening small buttons, and stirring
coffee gradually become more and more difficult, and
patients may end up in a wheelchair, or bedridden.

The outlook was woefully dimmer until the 1960s, when
scientists first discovered the dopamine shortage in
Parkinson's brains. Later researchers developed the amino
acid l-dopa as a way to replenish this critical chemical
messenger. Now part of the drug Sinemet (which helps to
buffer unwanted side effects), l-dopa is still the best treatment
for the disease. Its effectiveness, however, drops off over
time, usually waning faster than the 15 years the average
patient lives after diagnosis.

"Before l-dopa, there really was no good treatment," says
Kurlan. "People progressed to death on a fairly short time
frame, and they had nothing to control their symptoms. The
l-dopa era changed that dramatically. Even so, it's like putting
your finger in the hole of a dike. Eventually the pathology of
the disease overcomes the benefit of the medication."

The testing of new medications that might supplement or
replace l-dopa is one of the primary concerns of researchers
at the Medical Center's mind unit, which treats nearly 1,000
Parkinson's patients from throughout New York State and
northern Pennsylvania.

One person who is especially thankful for this work is Dr.
Milton Luria, professor emeritus of medicine, who retired in
1993 after spending 40 years caring for patients at the
Medical Center.

As it happened, many of those patients had Parkinson's
disease, yet Luria (like many others with the illness) let creep
up on him, unheeded, his own similar symptoms. In his case,
it was slower and smaller handwriting and the typical
Parkinson's shuffle. He finally acknowledged his problem
three years ago when a colleague told him, "You know, the
spring has gone out of your step." Luria realized that his
usual five-minute walk from parking lot to office was now taking more like 15,
"and that it was more than pain
that kept me from walking briskly." Shortly after that he was diagnosed with
Parkinson's.

A year ago Luria's symptoms suddenly worsened: It took him more than an hour to
sign a sheaf of 50 letters he
was writing for a committee, and jotting comments on student papers became a
chore. "I thought, 'If I have to go
through the rest of my life at this speed, I'll never make it,'" he says,
smiling a little now at the recollection. Then
one day his sister sent pictures of him she'd taken on a trip. "I looked at
those pictures and I said right away,
'That's the picture of somebody who has classic Parkinson's.'"

He decided he needed more help. So he visited his physician, Dr. Ira Shoulson
'71M (MD). Shoulson offered
him a spot in a two-year trial comparing two drugs, Sinemet (containing the old
standby, l-dopa) and a newer
drug, Mirapex. (As with all such studies, nobody will know which patients got
which until the study code is
broken.) Within a few days, Luria started feeling better, and soon he was back
to his five-minute stride and
enjoying mile-long hikes in Mendon Ponds Park. Teaching again, he is serving as
a mentor to incoming
medical students and is helping teach internal medicine.

"Whatever I'm on is certainly working," he says. " I'm one hundred percent
better than I was before I started the
medication, no question about it."

The current Mirapex study is being coordinated through the University's Division
of Experimental Therapeutics.
The results of its previous study of the drug contributed to its FDA approval.
More than a dozen studies on
Parkinson's are under way or in the pipeline at the division, says Dr. Karl
Kieburtz '85M (MPH, MD), who
coordinates the effort. Especially exciting to the researchers are tests of
remacemide--a completely new type
of drug that targets a different chemical system in the brain--that is being
conducted in studies code-named
ramp and real. (The division gives out gifts like bottles of champagne to the
people who come up with the
snazziest acronyms.) The division is also testing an agent that acts much like
nicotine. (People who smoke, it
seems, are less likely to develop the disease, although no one is recommending
taking up the habit as a
preventive measure.) The Rochester team has so far participated in more than 30
studies of new Parkinson's
drugs, some of them still in progress.

Parkinson's research at the Medical Center rose to prominence in the 1980s when
Shoulson, the Louis
Lasagna Professor in Clinical Pharmacology, founded both the mind unit at the
Medical Center and the
Parkinson's Study Group, a collection of dozens of medical centers nationwide
brought together for multi-center
clinical trials of experimental medications. The multi-center group is best
known for Shoulson's landmark
datatop study, which tested two experimental treatments in 800 patients with
early untreated Parkinson's
disease. The drug study, the largest ever in Parkinson's patients, inaugurated
an era of institutional cooperation
in the quest for new therapies.

People who participate in such clinical research fare better than those who
don't, says Kurlan. Earlier access to
new medicines is of course one of the reasons why, but there are also other,
equally important, factors involved.
Participants meet more regularly with doctors and nurses than those who don't
take part in the studies, and
they're given a thorough battery of tests at each visit. Perhaps the greatest
boost, though, comes from the
psychological benefits.

"One of the biggest problems many patients have when they're diagnosed with a
chronic, progressive
neurologic disease," says Kurlan, "is that their sense of self-worth
deteriorates. Eventually they may lose their
jobs, and their role in the family also changes. Being in a research study
restores some of that self-worth. They
feel good about themselves. If the medicine we're testing doesn't help this
particular patient, maybe someday it
will help a friend or neighbor or a son or daughter. People feel good about
that. It raises their spirits. And that's
a very long-lasting benefit.

"People who were patients in some of our research studies of 10 years ago are
still beaming today because
they contributed to the understanding of a new medication that is now being
prescribed."

While new drugs are the focus of much of the research at Rochester, there is a
variety of other procedures
being developed elsewhere. One is deep-brain stimulation, in which a pacemaker
type of device is implanted
in the brain to help control its errant signals. Another is pallidotomy, a
surgical procedure in which a small part
of the brain is destroyed in an effort to damp down unwanted brain signaling.
While some patients at other
medical centers have shown dramatic results--walking normally for the first time
in years--others have
experienced major problems, including paralysis and blindness, leading Rochester
physicians to adopt a
cautious approach toward the procedure.

For a long-term cure, Kurlan says, two other approaches look more promising:
grafting of fetal dopamine
neurons into the brains of adult patients (a technique pioneered at the Medical
Center) and gene therapy to
protect the dying neurons. Earlier this year University researchers took a
significant step toward achieving the
latter, when they were able to shuttle into rat brains a gene that codes for a
substance that shields dopamine
neurons.

Such a permanent solution would be welcome news to patients like David Carter
(as he would prefer to be
called), an engineer who was diagnosed with the disease 11 years ago, at age 46.
For the first 10 years his
symptoms were almost completely controlled, but last year an outbreak of
problems caused him to take
medical disability from his job.

During a recent interview in which he talked about his disease, Carter's arms
and legs jerked constantly and
randomly. Such movements are due to a condition known as dyskinesia, a side
effect of the l-dopa in Sinemet
that is common in patients who have been on the drug for a few years. Carter
says the movements are tiring,
painful, and distracting, and that he has had to begin eating more to compensate
for the energy these
uncontrollable movements demand.

"Your muscles fight back," says Carter, sitting with one leg tucked under the
other to keep it from straying.
"You're trying to make the muscle do one thing, and it's trying to do something
else at the same time."

When the medicine is not working, Carter is free from the side effects but, he
says, then he's even worse off
than before: He slips from "on" to "off," a condition in which he is nearly
frozen in place and may have to resort
to crawling to move even a short distance. The change is completely
unpredictable and happens several times
a day. "It can switch just like that," he says, eyes lighting up as he suddenly
snaps his fingers smoothly and
quickly. Carter takes about 30 different pills a day, mainly Sinemet, and
carries a small buzzer that reminds him
every two hours to take his next dose.

(His father, like Luria's, also had Parkinson's and was one of the first to
benefit from l-dopa treatment.
Parkinson's, however, is not believed to be an inherited disease in the sense of
hemophilia, for instance,
although it is possible that there is some slight genetic predisposition to it.)

When Sinemet fades in effectiveness, Dr. Kurlan says, there are other steps that
physicians can take--like
trying countless combinations of other drugs. They can also enlist the help of
social workers and physical
therapists to help keep other problems at bay, encourage a healthy lifestyle,
and support the spouse or
caregiver. Emotional support, Kurlan says, is highly important.

"Being able to help the patient or the family at any given point is very
rewarding," he says. "And there's always
something we can do to help these people.

"It sounds pretty bad when you hear that you've been diagnosed with a chronic,
progressive neurodegenerative
disorder. And, yes, there will be difficulties, but, on the other hand, patients
will have many, many, many years of
time to experience the good things in life. We encourage people to stay active,
to play their golf, to do their
traveling, and to keep up with all the other activities they enjoy."

So it is that, as Kurlan and his colleagues here and elsewhere are gradually
closing in on a still-elusive cure,
Hammer is out whacking golf balls, Luria is passing on his art of doctoring to
young physicians, and Carter,
open as ever to new experiences, is learning to express himself in a new way: He
is taking up the study of
Japanese. Hey, you never know when you might need a new skill like that.


Tom Rickey is senior science writer for the Office of University Public
Relations.

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Rochester Review--Volume 60 Number 2--Winter 1997-98
Copyright 1997, University of Rochester
Maintained by University Public Relations (jc)
--

CHARLES T. MEYER, M.D.
Middleton, WI
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