This article was sent to me by Sarita Agarwal, one of our members in
India, and I think it would be useful to add to our archives--an excellent
overview.
Camilla Flintermann
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FOCUS ON . . . PARKINSON'S DISEASE
by Lynn Wilson

Understanding Parkinson's disease

Parkinson's disease (PD) is a progressive neurological
disorder that results from the degeneration of dopamine-
containing neurons that project from the substantia nigra to
the striatum in the region of the brain (the basal ganglia)
involved in motor control. Symptoms -- tremor, muscular
rigidity, and bradykinesia (slowness of movement) -- don't
develop until the dopamine level has dropped to only 20% of
normal. Approximately 500,000 Americans have been diagnosed
with PD, and 40,000 new patients are diagnosed each year.
Probably a million or more people actually have the disease;
in many cases the general "slowness" attributed to old age
may be an early symptom of PD.

The average age of onset of PD is 57 years, although the
distribution of onset follows a bell-shaped curve, with one-
third of patients diagnosed before age 50, one-third between
50 and 60, and one-third over age 60. The disease typically
starts with weakness in an arm or leg or a slight hand
tremor, then progresses inexorably over the next few decades,
to end in paralysis and often dementia, with early death.
Classic signs include lack of facial expression, weak voice,
drooling and choking due to difficulty swallowing, and
festination (walking with small, shuffling steps). Patients
also suffer from severe muscle pain (due to rigidity),
gastrointestinal disturbances, insomnia, depression, and
nightmares.

Although PD was first identified in 1817, the cause is still
unknown. People in rural areas are at higher risk of
developing the disease than those in urban areas, perhaps
because of exposure to pesticides, fungicides or herbicides
through contaminated well water. There is also a
microorganism in the soil -- Nocardia -- that may damage
dopaminergic neurons. Other high-risk environments include
regions surrounding petroleum plants and pharmaceutical
manufacturing plants. Epidemiologists have noted that most PD
patients have never smoked, and at least one study found a
marked increase in the incidence of the disease among
individuals with a history of mumps compared with those who
never had mumps. PD is not generally regarded as a genetic
disease, although patients may inherit a predisposition. Some
14% of PD patients have one or more first-degree relatives
who have the disease or a related disorder, compared to 5% of
controls. Onset before age 40 is more often associated with a
family history.

Disorders that may confuse the diagnosis include benign
essential or familial tremor, a slowly progressive condition
that usually develops in the fourth and fifth decades.
Symptoms include a tremulous voice and shaky hands and/or
head (the head may bob side to side or up and down). The
typical parkinsonian rigidity, stiffness and bradykinesia do
not occur. Hyperthyroidism can also cause tremor. Other more
serious conditions that may mimic PD include Progressive
Supranuclear Palsy, Shy-Drager Syndrome, and a series of
strokes.

Drugs that can induce parkinsonism include the antiemetic
metoclopramide, the antiarrhythmic amiodarone, the
antipsychotic agents haloperidol and chlorpromazine, and the
antihypertensive agents reserpine, methyldopa, and certain
calcium channel blockers (in particular cinnarizine and
flunarizine, which are not available in the US). There was
one case of captopril-induced parkinsonism that resolved on
drug withdrawal. (Quinn N. Br Med J 1995;310:447-452. Calne
DB. Calne DB. N Engl J Med 1993;329:1021-1027. Ed. UPF Newsl.
1995[1]:3.)

---------------------
Pharmacotherapy of PD

The mainstay of therapy for PD is levodopa combined with
carbidopa (Sinemet/MSD); levodopa is converted into dopamine
within the brain, while carbidopa prevents the peripheral
breakdown of levodopa, thus effectively extending the
duration of drug action. (Two related compounds in clinical
trial -- entacapone and tolcapone -- also prolong the
duration of levodopa action.) Unfortunately, levodopa almost
always loses its efficacy over time (primarily because of
disease progression) and administration is associated with
significant side effects, including response fluctuations
("on-off" phenomenon), involuntary movements, peak-dose
chorea, severe end-of-dose symptoms, and psychosis and
hallucinations. The timed-release preparation of levodopa
(Sinemet CR/MSD) helps smooth the response, although poor
absorption of the first dose in the morning is not uncommon.
Using the regular (short-acting) Sinemet in the morning
followed by Sinemet CR later in the day may circumvent this
problem.

Second-line PD therapy involves the use of dopamine receptor
agonists--bromocriptine (Parlodel/Sandoz), pergolide
(Permax/Lilly)--which act directly on dopamine receptors.
These agents may reduce the on-off oscillations, although
therapeutic efficacy starts to decline in about six months,
particularly in patients with more advanced disease. Using an
agonist early in the course of disease allows dosage
reduction and helps delay the onset of levodopa side effects.
Several dopamine agonists are under clinical investigation,
including ropinirole, terguride, talipexole, and cabergoline.
Cabergoline is an exceptionally long-acting agonist in Phase
III trials. It reduces the dose of dopamine required, and
appears to be as effective as bromocriptine or pergolide,
possibly with fewer associated side effects. Other dopamine
agonists under investigation are  (Am Acad Neurology 47th
Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4.
Calne DB. N Engl J Med 1993;329:1021-1027.)

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Pharmacotherapy of ancillary PD symptoms

PD patients have trouble with muscular function in general,
which contributes to a variety of symptoms other than tremor,
rigidity and bradykinesia. PD patients are particularly
bothered by dysphagia (drooling, difficulty swallowing),
nausea, delayed gastric emptying, and constipation. Foot
cramps are another debilitating condition. There are a number
of remedies for these problems, some pharmacologic, some not.
For drooling and difficulty swallowing, sucking hard candy or
chewing gum may facilitate the swallow reflex.
Anticholinergics are not recommended because they make the
saliva sticky. Nausea, delayed gastric emptying and
constipation may respond to cisapride (Propulsid/Janssen), a
prokinetic agent that accelerates gastric emptying and
colonic transit. Exercise and a high-fiber diet also help.
There are dopamine receptors in the gut, so delayed
gastrointestinal transit may be due the same disease process
on a local level.

For foot cramps, muscle relaxants such as cyclobenzaprine
(Flexeril/Merck) and baclofen (Lioresal/Geigy) may ease the
pain. Since cramping can be due to either too much or too
little dopamine (a peak-dose dystonia or a wearing-off
effect), changing the Sinemet dose or dosage schedule or
using the sustained release formulation may help. Some
patients respond to the monoamine-oxidase B inhibitor
selegiline (Eldepryl/Somerset) or to the dopamine agonists
bromocriptine or pergolide. Injections of botulinum toxin
(Botox/Allergan) into the cramping muscle can provide months
of relief.

Another common, and disabling, condition is depression. Some
40% of PD patients develop depression, whether endogenous
(due to an imbalance of neurotransmitters) or exogenous (due
to the stress of having a chronic debilitating illness).
While often responsive to antidepressants, the drug of choice
may be the antischizophrenic agent clozapine
(Clozaril/Sandoz). Clozapine has proved to be highly
effective in PD patients, reducing not only depression but
also hallucinations and confusion. The drug is a dopaminergic
antagonist but does not appear to interfere with
antiparkinson drugs;, its antipsychotic effect is thought to
be due to the blockade of a different configuration of the
dopamine receptor than the one involved in PD. Side effects
include sedation and orthostatic hypotension. Clozapine also
causes bone marrow suppression (in 2% of patients), so weekly
blood counts are necessary. Dosage reduction will reduce the
risk of blood disorders, and low-dose therapy is still
effective for psychotic depression. (Am Acad Neurology 47th
Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4.
Pfeiffer RF. UPF Newsl. 1994[4]:5-6. LeWitt PA. UPF
Newsl.1993[3]:3-4. Gonski PN. Aust NZ J Med 1994;24:585.
Gonski P. Lancet 1995 345:516-517.)

-----------------------------------------------
Surgery: the remarkable efficacy of pallidotomy

The most promising approach to the management of PD since the
advent of levodopa therapy is a stereotactic surgical
procedure called a pallidotomy. It involves destroying a
sliver of neural tissue in the globus pallidus, a paired
structure that serves as a relay station deep within the
brain, coordinating signals from various parts of the brain
that control movement and sensation. The globus pallidus on
the left side of the brain controls the right side of the
body, while the right pallidus controls the left side of the
body. Decades ago, physicians noted that patients with tremor
who suffered from a stroke located near a globus pallidus
showed relief of tremor. An early pioneer, Russell Meyers,
tried to treat 38 PD patients by severing nerve tracts near
the globus pallidus; 25 patients showed improvement in PD
symptoms, and six died. During the 1950s, Swedish
neurosurgeon Lars Leksell found that by threading a probe
into a specific part of the globus pallidus he could markedly
improve all PD symptoms.

Leksell did not publish his findings, but his protege Lauri
Laitinen did. In 1992 Laitinen reported in the Journal of
Neurosurgery  that 92% of 38 patients who underwent
pallidotomy had complete or almost complete relief of
rigidity, while 81% had excellent or good long-lasting relief
of tremor. (Laitinen LV et al. J Neurosurg 1992;76:53-61.)
The report was enthusiastically received by the PD community
and dozens of patients flew to Sweden for the operation. By
mid-1995, Laitinen had performed more than 350 pallidotomies,
with similar excellent results, particularly among the
younger patients. A recent follow-up of Laitinen's first ten
pallidotomy patients from 1985-1986 showed that nine were
doing well.

Recently, neurosurgeons in centers across the United States
have begun offering pallidotomies, at a cost of $20,000 to
$40,000 per operation (not covered by major Medicare
contractors or HMO insurers). Despite the cost, there are
year-long waiting lists at many centers. Robert Iacono of
Loma Linda University in California has done around 500
operations, and reports restoring almost complete function to
dozens of totally disabled patients. In an informal interview
of 113 Iacona patients, 80% reported marked improvement after
pallidotomy, with symptoms reduced by up to 100%. Only nine
patients showed no response.

Surgery is remarkably safe, recovery is rapid (1-2 days in
hospital), and benefits are seen immediately. For the
procedure, the head is immobilized in a cage-like frame, the
globus pallidus is located by brain scan, the scalp is
anesthetized, the skull is opened at the top through a hole
in the frame, and a probe is inserted deep into the brain. An
ultrashort-acting anesthetic is used for the mechanical
portions of the procedure, but for the most part the patient
is awake. Various techniques are used to pinpoint the globus
pallidus. One technique uses sound. The patient is asked to
make a movement (arm, hand or leg) that sounds a note through
a loudspeaker. The sounds tell the neurosurgeons when they
have hit the target, a bundle of neurons that connect the
globus pallidus with the thalamus. (The thalamus is another
relay center that directs signals to various regions of the
brain and spinal cord. Thalamotomy is also an effective
surgical procedure for PD, although benefits appear to be
limited to tremor). When the probe is on target, the tip is
electronically heated and it burns a tiny hole, producing an
immediate improvement in symptoms. During surgery patients
report that they feel a sudden release after being in a state
of total rigidity, or that limbs that flopped continuously
are suddenly stilled.

Risks include brain hemorrhage (2-5% incidence), loss of
speech, full or partial loss of vision (the lesion must be
placed near to the visual tract), paralysis, and death. Not
all patients respond to surgery, and in some patients the
improvement is only temporary. Often symptoms are reduced
rather than eliminated. Because the operation takes such a
long time (up to 10 hours) pallidotomy is performed on one
side at a time. Interestingly, 75% of patients report that a
pallidotomy on one side of the brain benefits both sides of
the body. However, patients are usually so pleased with
results from unilateral pallidotomy that they opt to have
surgery on the other side as well.

At a recent annual meeting of the American Academy of
Neurology in Seattle, neurosurgeons Enrico Tazzini (New York
University), Jerrold Viteck (Emory University), and Anthony
Lang (Toronto University) agreed that pallidotomy is highly
efficacious, with nearly all patients showing long-lasting
improvement. It is more effective in patients under age 70
who respond to levodopa but show severe fluctuations in
response and disabling dyskinesias. It is less effective for
freezing. One side effect is an increased incidence of falls,
since surgery so improves function in one side of the body
that the patient is assymetrical. Because pallidotomy offers
relief of symptoms but is not a cure, patients remain on
medication, although often at lower doses.

In light of these new findings, researchers have speculated
that dopamine is involved in a complicated inhibitory
feedback loop. Lack of dopamine results in the loss of
inhibition of neurons involved in the control of movement. A
clinical study underway at Emory University will attempt to
evaluate the risk/benefit ratio, determine what part of the
globus pallidus should be destroyed for maximum relief, and
find out how long benefits last. At Stanford University,
researchers are working on a new "spatially correct" magnetic
resonance imaging (MRI) scanner with pinpoint accuracy.
        Pallidotomy has been described as "a miracle." Patients
report that for the first time in years, they can turn over
in bed, shower, dress themselves, and eat normally. Many can
walk, write, drive a car, and even go back to work. (Iacono
RP, Lonser RR. Lancet 1994;343:418-419. Giller CA, Dewey RB.
West J Med 1995;162:255-256. Am Acad Neurology 47th Annual
Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4. Joyce L
Stanford Univ Med Cen Report 1995[3/15]:1,11. Stipp D. WSJ
1995[2/22]:A-1, A-10.)

-------------------------------------------------
New technology: transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a new noninvasive
technique that involves the application of a pulsating
magnetic wave to the brain through the cranium. Alvaro
Pascual-Leone (Spain) and his colleagues at National
Institutes of Health (Washington) are using TMS to improve
motor function in PD patients. The technique is thought to
increase the threshold for activation of neurons, and can be
targeted to a particular area of the brain to relieve
specific motor symptoms. A brief course of TMS has been shown
to improve motor performance in PD patients for up to four
hours. Studies are underway to determine whether continuous
application of TMS can provide sustained control of symptoms.
(Am Acad Neurology 47th Annual Meeting in Seattle, 1995. Ed.
UPF Newsl. 1995([2]:3-4.)

-------------------------------------------------------------
New research: neurotrophic factors, brain implants, apoptosis

PD was the focus of several recent scientific meetings and
conferences. Researchers described their studies with nerve
growth factors, neural tissue implants, progenitor cells,
apoptosis, and genetically engineered cells capable of
making, storing and releasing dopamine. They also reported
the results of experiments to introduce viruses into the CNS
that can infect nerve cells and inject dopamine-coding DNA
into neurons.

Barry Hoffer at the University of Colorado and researchers at
Synergen are studying glial-derived neurotrophic factor
(GDNF), which can protect animals against neurotoxins known
to cause PD. Louis Ptek and Paul Carvey (Rush-Presbyterian-
St. Luke's, Chicago) are studying progenitor cells, cells
that are capable of developing into dopaminergic cells when
given the appropriate signals. Paul Sanberg at the University
of South Florida has implanted Sertoli cells (testicular
cells that provide nutrients and support to developing sperm)
into the striatum of parkinsonian rats. These cells
significantly improved motor function, and improvement was
correlated with sprouting of dopaminergic neurons.

Nerve tissue implants -- in the striatum or the substantia
nigra -- have shown some efficacy in animal studies and are
showing promise in clinical studies. Implantation into the
substantia nigra, followed by withdrawal of the needle along
a path from the nigra to the striatum, may be effective for
reconstructing the normal nigrostriatal pathway. Kordower et
al described significant clinical improvement in a 59-year
old patient who received bilateral fetal nigral implants.
Improvement was correlated with enhanced dopaminergic signal
on a PET scan in the months following surgery. The patient
died of unrelated causes 18 months after the procedure, and
autopsy revealed that each implant was viable and dense
clusters of dopaminergic neurons had integrated into the host
striatum. (Kordower JH et al. N Engl J Med 1995;332:1118-
1124. Hoffer BJ, Van Horne C. N Engl J Med 1995;332:1163-
1164.)

One of the most intriguing avenues of research is apoptosis,
or programmed cell death. Early brain development is a
dynamic process with billions of neurons growing rapidly and
competing with other neurons to make connections. Those that
don't make enough connection die. In fact, it appears that
these cells commit suicide. They actually synthesize proteins
that destroy their own DNA. Glial cells promptly engulf the
dying cell, in response to some sort of signal. A number of
studies indicate that apoptosis may play a role in PD.
Several factors thought to be involved in neuron death --
including free radicals, iron, stress, lack of growth factors
-- have been shown to induce apoptosis. Levodopa itself
induces apoptosis in tissue cultures. During fetal
development, apoptosis is important to weed out excess
neurons, but it is disastrous in the aging brain. Researchers
are trying to detect apoptosis in parkinsonian brains (a
difficult task as glial cells eliminate dying cells within 24
hours) and they are trying to determine how to block the
suicide attack. (Winter Conference on Neural Plasticity
[Grenada]; Conference on Neurodegenerative Disorders: Common
Molecular Mechanisms conference [Jamaica]; Annual meeting of
the American Society for Neural Transplantation [Clearwater
Florida].)

Parkinsonism with metoclopramide
--------------------------------
Metoclopramide is a dopamine antagonist approved for treating
gastroesophageal reflux and disorders of gastric emptying
(such as diabetic gastroparesis) and for preventing
chemotherapy-induced nausea and vomiting. Since it blocks
dopamine receptors in the brain, metoclopramide would be
expected to cause extrapyramidal (parkinsonian) side effects.
Yet according to the manufacturer, at usual daily doses of
30-40 mg, parkinsonism occurs only rarely (0.2%), most often
in children and young adults.

Recently Avorn et al published the results of their study of
medication use in 17,000 elderly medicaid patients. They
found that elderly patients who were using metoclopramide for
gastric problems were three times more likely to begin taking
drugs specific for Parkinson's disease (levodopa) than
patients who were not on metoclopramide. The risk of
developing parkinsonian symptoms increased with increasing
doses of metoclopramide (to a five-fold increase in patients
taking more than 20 mg/day.) These results suggest not only
that metoclopramide induces parkinsonism more often than
previously suspected, but also that physicians may be
misdiagnosing patients with parkinsonism and prescribing
drugs for Parkinson's disease, rather than looking at
medication history to rule out drug-induced parkinsonism.
(Avorn J et al. JAMA 1995;274:1780-1782.)

Parkinson's disease and parkinsonism are fairly common in
older people, and may be even more common than suspected.
Bennett et al conducted a community study of common health
problems in the elderly, and found parkinsonian signs in a
substantial number of people over age 65. A total of 464
patients underwent structured neurological examinations,
neuropsychological performance testing, and laboratory
testing. In addition, medications were identified, medical
history taken, and an interview conducted. Almost 15% of
those surveyed in the age group 65-74 had two or more signs
of parkinsonism--bradykinesia, gait disturbances, rigidity,
and tremor--while 29.5% of those aged 75-84 had parkinsonism,
and 52.4% of those 85 and older had parkinsonism. Adjusted
for age and sex, patients with parkinsonism had twice the
risk of death of patients without symptoms of Parkinson's
disease, particularly when a gait disturbance was present.
(Bennett DA et al. N Engl J Med 1996;334:71-76.) It would be
interesting to find out how many patients with parkinsonism
were taking drugs that could induce such symptoms.