At 23:01 29/01/1999 -0700, you wrote:
> Any assistance would be welcome....thanks, Pam
This is long. It comes from the Merck Manual. Hope it helps.
A syndrome characterized by tremor, muscular rigidity, akinesia, and loss
of postural reflexes.
Parkinsonism, one of the most frequently encountered disorders of the basal
ganglia, is a prominent cause of disability in those > 50 yr of age. Its
prevalence is estimated at about one million cases in the USA; 50,000 new
cases occur each year. The incidence increases with age, peaking at about
75 yr. While < 1% of those < 50 yr develop parkinsonism, the incidence
exceeds 2% in those > 50 yr. The estimated overall lifetime risk is 2.5%
among whites. Though similar data are unavailable for blacks and Orientals,
prevalence rates in both groups are lower than those in whites.
Classification and Etiology
The constellation of symptoms described below occurs in both primary
parkinsonism (Parkinson's disease) and secondary parkinsonism (Parkinson's
Primary parkinsonism: When no cause can be distinguished, the condition is
designated as primary parkinsonism. Most cases of parkinsonism belong in
this category. The disease most frequently appears between the ages of 50
and 79 yr, but the incidence declines beyond the eighth decade. A rare
juvenile form has been described in persons < 30 yr of age. The disease
affects both sexes and all races. No evidence exists to indicate a
hereditary factor, although a familial incidence is claimed by some
Secondary parkinsonism: Secondary parkinsonism is distinguished from
primary parkinsonism by having a known cause. In many conditions, a
parkinsonian syndrome is the predominant clinical manifestation.
The parkinsonian syndrome is occasionally seen during the acute phase of
several types of viral encephalitis, although permanent extrapyramidal
residua are rare. The exception is the parkinsonian syndrome that developed
after the epidemic of encephalitis lethargica from 1915 to 1926; sporadic
cases still occur occasionally.
Cerebral atherosclerosis with multi-infarcts of the cerebrum produces
parkinsonism. Typically, akinesia and gait disturbances occur and are more
properly classified as pseudoparkinsonism. These symptoms rarely respond to
therapeutic measures effective for Parkinson's disease. Parkinsonism has
been reported after carbon monoxide poisoning. Usually occupationally
related, chronic manganese intoxication produces a parkinsonian syndrome
accompanied by dystonia and mental changes.
Parkinsonism may appear as a side effect of drugs that deplete or block the
action of cerebral monoamines, most commonly various antipsychotic drugs
such as the phenothiazines and butyrophenones. Metoclopramide and some
antihypertensive agents (eg, reserpine and methyldopa) may also induce
parkinsonism. Some reactions are dose dependent; others are related to
individual susceptibility (eg, risk increases with age and in women). Once
the drugs are withdrawn, symptoms usually disappear within a few days,
although occasionally they persist for months or even years; sometimes
symptoms begin or worsen when the drugs are stopped. A meperidine analog,
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), occasionally injected
by IV drug abusers, can induce irreversible parkinsonism.
Hypoparathyroidism is associated with calcification of the basal ganglia,
which produces parkinsonism (rarely) as well as chorea and athetosis. A CT
scan may demonstrate small calcium deposits in the basal ganglia. Patients
with brain tumors near the basal ganglia may present with hemiparkinsonism,
ie, parkinsonian symptoms restricted to one side of the body. Frontal lobe
tumors occasionally produce gait and movement abnormalities that mimic
parkinsonism. Other disorders that may be confused with parkinsonism
include myxedema, normal-pressure hydrocephalus, hepatic encephalopathy,
A parkinsonian syndrome may occur to varying degrees in several so-called
degenerative diseases of unknown cause that involve multiple areas of the
CNS (eg, progressive supranuclear palsy, olivopontocerebellar atrophy, and
the Shy-Drager syndrome).
Primary and secondary parkinsonism do not seem to differ in pathophysiology
or even in pathogenetic mechanisms for symptom production. Striatal
dopamine deficiency is common to all types of parkinsonism. Invariably in
primary parkinsonism, cell loss is noted in the substantia nigra in
association with formation of an intracellular inclusion body--the Lewy
body. In secondary parkinsonism, there may be loss of substantia nigra
cells, impairment of the nigral striatal pathway, or loss of striatal
cellular elements, but Lewy bodies do not form. The loss of nigral cells
with destruction of the nigrostriatal pathway results in the decreased
level of striatal dopamine.
The cause of the selective nigral cell destruction is unknown; however,
several pathogenetic mechanisms have been suggested. The most acceptable,
though not proved, concerns cellular damage by the oxidative production of
toxic free radicals. It is postulated that a relative excess of free
radicals develops in nigral cells caused by oxidative stress, leading to
increased oxidative degradation of dopamine and the accumulation of toxic
metabolic products. The factors that cause oxidative stress are not known.
Yet, its effect can be counteracted by inhibiting monoamine oxidase (MAO),
thereby limiting the catabolism of dopamine and accumulation of toxic
metabolic products. Selegiline (L-deprenyl), a selective MAO-B inhibitor,
may protect the brain cells involved in Parkinson's disease. This agent is
discussed under Treatment, below.
Symptoms and Signs
The disease begins insidiously; any of its cardinal manifestations may
appear alone or in combination. The most common initial symptom is tremor,
usually in one hand or sometimes in both and involving the fingers in a
pill-rolling motion. The tremor is present at rest (resting tremor), may be
accentuated by posture, and usually decreases with active, purposeful
movement. It disappears with sleep. The tremor is rhythmic, low in
frequency, generally low in amplitude (alternately affecting flexor and
extensor muscles), and may involve upper or lower limbs, lips, tongue, or
Muscular rigidity is usually readily evident on passive movement of a limb.
Passive movement may demonstrate a smooth resistance (like trying to bend a
lead pipe--lead-pipe rigidity), sometimes with superimposed ratchet-like
jerks (cogwheel phenomenon). The patient may be slow to initiate movement
(bradykinesia) and while carrying out routine tasks may find his volitional
movement suddenly and unexpectedly halted; the patient may be unable to
follow through to complete the action. Bradykinesia is especially evident
in writing and feeding and can be striking when the patient attempts to
walk and finds that his feet are suddenly "frozen to the ground.'' However,
bradykinesia may not be present at the onset of the disease. Rapidly
alternating movements are very difficult to perform.
Gait becomes shuffled with short steps, and the arms fail to swing. The
steps may inadvertently quicken, and the patient may break into a run to
keep from falling (festination). Postural abnormalities are evident in the
erect and sitting positions; an erect posture is not readily assumed or
maintained. The head tends to fall forward on the trunk, and the body falls
forward or backward unless supported. The tendency to fall forward
(propulsion) or backward (retropulsion) results from the loss of postural
reflexes. Bradykinesia prevents the patient from stopping the fall, by
either taking a step or moving the arms. Kyphotic deformity of the spine,
causing a stooped posture, is a hallmark of the disease, a result of
altered striatal activity with imbalance between right and left.
The face can become masklike, with lack of expression and diminished eye
blinking. Blepharospasm can be readily induced when the frontal muscle is
tapped (Meyerson's sign). Micrographia and difficulty with activities of
daily living (eg, tying shoes) often develop. Speech becomes slow and
monotonous. The patient has difficulty swallowing and tends to drool. The
skin has an oily quality and may be afflicted with seborrheic dermatitis.
Mood abnormalities, usually depression or anxiety, are common and may be
the heralding symptoms. Sometimes bradykinesia and decreased facial
expression make a person appear depressed, even when mood is unaffected.
Although intellectual impairment does occur, whether it is intrinsic to the
disease or associated with a superimposed but unrelated dementing illness
Although parkinsonism is invariably progressive, the rates at which
symptoms develop and disability ensues are extremely variable. Sometimes
the disease progresses rapidly, and patients become disabled within 5 yr.
More often, the course is slower and more protracted, and patients remain
functional for many years.
Parkinsonism is diagnosed on the basis of the symptoms and signs. Early
signs include infrequent blinking and lack of facial expression, loss of
voice volume, poverty of movement, impaired postural reflexes, and the
characteristic gait abnormality. About 30% of patients may not have tremor
initially, and it often becomes less prominent as the disease progresses;
this should not obscure the diagnosis. Rigidity of some degree usually
develops, and its absence makes the diagnosis of parkinsonism suspect.
Patients with essential tremor, which is the disorder most commonly
confused with parkinsonism, have animated facies, normal rates of movement,
normal muscle tone, and no gait impairment (see ESSENTIAL TREMOR).
Furthermore, essential tremor occurs as an action tremor rather than a
resting tremor, which is most common in parkinsonism. Parkinsonism may be
more difficult to distinguish in elderly persons with reduced spontaneity
of movement, short-stepped (rheumatic) gait, and mild depression or dementia.
No specific laboratory test can confirm the diagnosis of parkinsonism.
Routine blood, spinal fluid, and urine tests yield normal results. The
disturbance in cerebral dopamine metabolism may result in decreased CSF
levels of homovanillic acid; however, this finding is not reliable in
confirming the diagnosis and testing is not recommended. The EEG is usually
normal, although diffuse slowing may be present and sleep recordings may be
abnormal. Neither CT nor MRI scan of the head shows abnormalities in
primary parkinsonism but may be helpful in diagnosing some of the secondary
forms. When a treatable cause is suspected, a CT or MRI scan should
generally be performed.
No curative therapy is available for primary parkinsonism or for most cases
of secondary parkinsonism. The major exception is secondary parkinsonism
resulting from drugs. Almost all other cases require lifelong treatment
with drugs directed primarily at symptom control. Treatment programs should
be individualized, using as a guide the type and severity of symptoms, the
degree of functional impairment, any associated disease processes, and the
expected benefits and risks of available drugs. This caution applies
especially to the elderly, who have reduced tolerance for dopaminergic and
anticholinergic agents, the mainstays of parkinsonism therapy (see also
Antiparkinsonian Drugs in Ch. 21).
Patients with symptoms of recent onset, especially if tremor predominates
and functional impairment is mild, are best treated with drugs that
centrally inhibit cholinergic activity. However, anticholinergics are often
poorly tolerated by the elderly, producing sedation, confusion, urinary
retention, dry mouth, blurred vision, and orthostatic hypotension. They are
contraindicated in persons with glaucoma, benign prostatic hypertrophy, and
dementia. Diphenhydramine, an antihistamine with anticholinergic action, in
a dose of 25 mg tid may suffice. More effective but more toxic is
trihexyphenidyl 2 mg 3 to 5 times/day; it should be administered cautiously
and usually below the optimal dosage.
Amantadine, another useful drug, is generally prescribed at 100 mg bid.
Amantadine's mode of action in the treatment of parkinsonism is unknown,
but its mild anticholinergic effects appear to play only a small part. It
may promote dopamine release in the corpus striatum or may reduce dopamine
Selegiline (an MAO-B inhibitor) in doses of 5 mg bid may be used in an
early stage to prevent or slow disease progression. The drug inhibits
oxidative metabolism of dopamine. Trials indicate that selegiline can delay
the need for additional antiparkinsonian agents. However, whether
selegiline slows the disease or just suppresses symptoms is controversial.
The drug is generally well tolerated with few side effects. Although
chemically related to other MAO inhibitors, selegiline does not require
Patients with fully established parkinsonian symptoms that impair motor
function should be treated with drugs capable of replenishing or activating
striatal dopaminergic effects. There are as many recent studies supporting
delayed use of dopaminergic agents as there are those that promote early
use. Most experts believe that treatment should not be instituted until
symptoms cause functional impairment. In so doing, the risk of late side
effects of dopaminergic agents, which can be most distressing, is delayed.
The best way to accomplish dopamine replacement is to use levodopa combined
with carbidopa. Levodopa is converted to dopamine in both the CNS and the
periphery. To reduce peripheral conversion, levodopa is combined with
carbidopa (a peripheral decarboxylator inhibitor), which does not cross the
Treatment usually begins with a half tablet of the 25:100 combination (ie,
25 mg carbidopa to 100 mg levodopa) bid or tid. After 1 wk, the dose can be
increased to a full tablet tid if needed and if side effects are tolerable.
After several weeks, the dose can be increased again. Side effects may be
peripheral--such as flushing, abdominal cramping, and anorexia--in which
case increasing the amount of carbidopa may be helpful, or they may be
central--such as anxiety, nightmares, confusion, and hypotension--in which
case decreasing the dose of levodopa may be necessary. A controlled-release
form (50:200) may reduce side effects but generally requires a slightly
higher total daily dose.
Levodopa-carbidopa is often given in combination with other drugs, although
these other drugs may occasionally be used as single therapies. A cautious
induction period with each is required. Bromocriptine is begun with 1.25
mg/day and gradually increased by 2.5-mg increments every 2 days to a total
daily dose of 10 to 15 mg. Pergolide is begun at 0.05 mg/day with
increments of 0.05 mg every 2 or 3 days until a daily dose of 1 to 3 mg is
reached. Selegiline, amantadine, and anticholinergic agents may also be
administered with levodopa-carbidopa. TABLE 93-2 lists the most commonly
used antiparkinsonian drugs and their major side effects.
A new approach to replenishing the dopamine deficit by transplantation or
grafting of fetal nigral cells to the corpus striatum shows promise. Nigral
cells harvested from aborted fetuses are stereotactically inserted in the
striatum, particularly the putamen, of patients with Parkinson's disease.
These cells appear to remain viable, to form neural connections, and to be
capable of producing dopamine. Because selection criteria have been strict
(eg, limiting participation in studies to only those who have developed
difficulties with pharmacotherapy), the usefulness of this approach cannot
yet be fully assessed.
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