parkinsons disease

Parkinson’s disease is an idiopathic, slowly progressive, degenerative CNS disorder characterized by resting tremor, muscular rigidity, slow and decreased movement, and postural instability. Diagnosis is clinical. Treatment is with levodopa plus carbidopa, other drugs, and, for refractory symptoms, surgery.

Parkinson’s disease affects about 0.4% of people > 40 yr, 1% of people ≥ 65 yr, and 10% of people ≥ 80 yr. The mean age at onset is about 57 yr. Rarely, Parkinson’s disease begins in childhood or adolescence (juvenile parkinsonism).

Parkinsonism refers to symptoms that are similar to those of Parkinson’s disease but caused by another condition.


Synuclein is a presynaptic neuronal and glial cell protein, which can form insoluble fibrils in Lewy bodies. Although there are rare cases of Parkinson’s disease without Lewy bodies, the pathologic hallmark of Parkinson’s disease remains synuclein-filled Lewy bodies in the nigrostriatal system. However, synucleinopathy can occur in many other parts of the nervous system, including the dorsal motor nucleus of the vagus nerve, basal nucleus of Meynert, hypothalamus, neocortex, olfactory bulb, sympathetic ganglia, and myenteric plexus of the GI tract. Lewy bodies appear in a temporal sequence, and many experts believe that Parkinson’s disease is a relatively late development in a systemic synucleinopathy, which may also include Lewy body dementia. Patients with Parkinson’s disease may also have Alzheimer’s disease. Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease share several features (see Delirium and Dementia: Dementia); further research is needed to clarify their relationship to each other, including the relative contributions of synucleinopathy.

In Parkinson’s disease, pigmented neurons of the substantia nigra, locus ceruleus, and other brain stem dopaminergic cell groups are lost. Loss of substantia nigra neurons, which project into the caudate nucleus and putamen, depletes dopamine

in these areas.

A genetic predisposition is likely, at least in some cases. About 15 to 20% of patients have a family history of Parkinson’s disease. Several abnormal genes have been identified. Inheritance is autosomal dominant for some genes and autosomal recessive for others.

Symptoms and Signs

In most patients, the disease begins insidiously.

A resting tremor of one hand is often the first symptom. The tremor is characterized as follows:

Slow and coarse

Maximal at rest, lessening during movement, and absent during sleep

Amplitude increased by emotional tension or fatigue

Often involving the wrist and fingers in movements similar to those used to manipulate small objects or pills (pill-rolling tremor)

Usually, the hands, arms, and legs are most affected, in that order. The jaw and tongue may also be affected, but not the voice. Tremor may become less prominent as the disease progresses.

Rigidity develops without tremor in many patients. When a clinician moves a rigid joint, sudden, rhythmic jerks due to variations in the intensity of the rigidity occur, producing a ratchet-like effect (cogwheel rigidity).

Slow movements (bradykinesia) are typical as rigidity progresses. Movement also becomes decreased (hypokinesia) and difficult to initiate (akinesia).

Rigidity and hypokinesia may contribute to muscular aches and sensations of fatigue. The face becomes masklike, with an open mouth, drooling, and reduced blinking. Early on, patients may appear depressed because facial expression is lacking and movements are decreased and slowed. Speech becomes hypophonic, with characteristic monotonous, stuttering dysarthria. Hypokinesia and impaired control of distal musculature cause micrographia (writing in very small letters) and make activities of daily living increasingly difficult. Without warning, voluntary movement, including walking, may suddenly halt (called freezing).

Postural instability develops, resulting in gait abnormalities. Patients have difficulty starting to walk, turning, and stopping; the gait becomes shuffling with short steps, and the arms are held flexed to the waist and do not swing with the stride. Steps may inadvertently quicken, and patients may break into a run to keep from falling (festination). A tendency to fall forward (propulsion) or backward (retropulsion) when the center of gravity is displaced results from loss of postural reflexes. Posture becomes stooped.

Dementia can occur.

Sleep disorders are common. Insomnia may result from nocturia or from the inability to turn in bed. Rapid eye movement (REM) sleep behavior disorder may develop; in it, violent bursts of physical activity occur during REM sleep. Sleep deprivation may contribute to depression, exacerbate cognitive impairment, or cause excessive daytime sleepiness.

Neurologic symptoms unrelated to parkinsonism commonly develop because synucleinopathy occurs in other areas of the central, peripheral, and autonomic nervous systems. It may have the following effects:

Almost universal sympathetic denervation of the heart, contributing to orthostatic hypotension

Esophageal dysmotility, contributing to dysphagia and increased risk of aspiration

Lower bowel dysmotility, contributing to constipation

Urinary hesitancy and/or urgency (common)

Anosmia (common)

Seborrheic dermatitis is also common.

Postencephalitic parkinsonism causes forced, sustained deviation of the head and eyes (oculogyric crises), other dystonias, autonomic instability, depression, and personality changes.


Mainly by clinical evaluation

Diagnosis is clinical. Parkinson’s disease is suspected in patients with characteristic unilateral resting tremor, decreased movement, or rigidity. The tremor disappears (or attenuates) during finger-to-nose coordination testing.

During the neurologic examination, patients cannot perform rapidly alternating or rapid successive movements well. Sensation and strength are usually normal. Reflexes are normal but may be difficult to elicit because of marked tremor or rigidity. Patients may not suppress eye closure when the frontal muscle is tapped between the eyes (glabellar reflex; if persistent, called Myerson’s sign).

Slowed and decreased movement due to Parkinson’s disease must be differentiated from decreased movement and spasticity due to lesions of the corticospinal tracts. Unlike Parkinson’s disease, corticospinal tract lesions cause paresis (weakness or paralysis), preferentially in distal antigravity muscles; hyperreflexia; and extensor plantar responses (Babinski’s sign). Spasticity due to corticospinal tract lesions increases muscle tone and deep tendon reflex responses; muscle tone increases in proportion to rate and degree of stretch placed on a muscle until resistance suddenly melts away (clasp-knife phenomenon). Rigidity in Parkinson’s disease differs because resistance does not change through the entire range of motion (moving the limb is similar to bending a lead pipe).

Diagnosis is confirmed by the presence of other characteristic signs (eg, infrequent blinking, lack of facial expression, impaired postural reflexes, characteristic gait abnormalities). Tremor without other characteristic signs suggests early disease or another diagnosis. In the elderly, decreased spontaneous movements or a short-stepped gait may result from depression or dementia; such cases may be difficult to distinguish from Parkinson’s disease.

To differentiate Parkinson’s disease from secondary parkinsonism, clinicians note whether levodopa results in dramatic improvement, suggesting Parkinson’s disease. Causes of parkinsonism can be identified by the following:

Taking a thorough history, including occupational, drug, and family history

Checking for neurologic deficits characteristic of disorders other than Parkinson’s disease (such as neurodegenerative disorders)

Neuroimaging when indicated



(mainstay of treatment)


, monoamine oxidase type B (MAO-B) inhibitors, or anticholinergic drugs
used first as monotherapy or late with levodopa


agonists at any stage

Catechol O-methyltransferase (COMT) inhibitors sometimes used with levodopa

Surgery if drugs are ineffective

Exercise and adaptive measures

Many oral drugs are commonly used to relieve symptoms of Parkinson’s disease (see Table 3: Movement and Cerebellar Disorders: Some Commonly Used Oral Antiparkinsonian Drugs). Traditionally, levodopa has been the first drug used. However, some experts believe that early use of levodopa hastens development of adverse effects and inconsistency of drug response; they prefer to delay levodopa, particularly in younger patients, if possible and to use MAO-B inhibitors, anticholinergic drugs, amantadine

, or dopamine

agonists first if drug treatment
is necessary. Levodopa is then delayed until symptoms interfere with daily activities despite use of other treatments.

Doses are often reduced in the elderly. Drugs that cause or worsen symptoms, particularly antipsychotics, are avoided.

Levodopa: Levodopa, the metabolic precursor of dopamine

, crosses the blood-brain barrier
into the basal ganglia, where it is decarboxylated to form dopamine

. Coadministration of the
peripheral decarboxylase inhibitor carbidopa prevents levodopa catabolism, thus lowering the levodopa dosage requirements and minimizing adverse effects. Levodopa is most effective at relieving bradykinesia and rigidity, although tremor is often substantially reduced. Mildly affected patients who take levodopa may return to nearly normal, and bedbound patients may become ambulatory.

Levodopa has central adverse effects; occasional hallucinations or delirium occurs, most often in the elderly and patients with dementia. The dose that causes dyskinesias tends to decrease as treatment continues. In some patients, the lowest dose that reduces parkinsonian symptoms also causes dyskinesias.

Dosage of carbidopa/levodopa

is increased every 4 to 7 days as tolerated until maximum
benefit is reached. Adverse effects may be minimized by increasing the dose gradually and by giving the drug with or after meals; however, high-protein meals may impair absorption of levodopa. If peripheral adverse effects predominate, increasing the amount of carbidopa may help. Most patients with Parkinson’s disease require 400 to 1000 mg/day of levodopa in divided doses every 2 to 5 h. A dissolvable immediate-release oral form of carbidopa/levodopa

can be taken without water; this form is useful for patients who have difficulty
swallowing. Doses are the same as for immediate-release carbidopa/levodopa


Occasionally, levodopa must be used to maintain motor function despite levodopa-induced hallucinations or delirium. Psychosis can sometimes be treated with oral quetiapine


; these drugs aggravate parkinsonian symptoms much less than other
antipsychotics (eg, risperidone

, olanzapine

) or not at all. Haloperidol

should be
avoided. Quetiapine

can be started at 25 mg once/day or bid and increased in 25-mg
increments every 1 to 3 days up to 800 mg/day as tolerated. Use of clozapine

is limited
because agranulocytosis occurs in 1% of patients. When clozapine

is used, the dose is
12.5 to 50 mg once/day to 12.5 to 25 mg bid. CBC is done weekly for 6 mo and every 2 wk thereafter.

After 2 to 5 yr of treatment, most patients experience fluctuations in their response to levodopa (on-off effect). Whether dyskinesias and the on-off effect result from levodopa or the underlying disease is controversial. Eventually, the period of improvement after each dose shortens, and drug-induced dyskinesias result in swings from intense akinesia to uncontrollable hyperactivity. Traditionally, such swings are managed by keeping the levodopa dose as low as possible and using dosing intervals as short as every 1 to 2 h. Alternative methods include adjunctive use of dopamine

-agonists, controlled-release levodopa/
carbidopa, COMT and/or MAO inhibitors, and amantadine


Amantadine: This drug is useful as monotherapy for early, mild parkinsonism in 50% of patients and later can be used to augment levodopa’s effects. It may augment dopaminergic activity, anticholinergic effects, or both. If used as monotherapy, amantadine

often loses its
effectiveness after several months. Amantadine

may ameliorate dyskinesias secondary to
long-term use of levodopa.

Dopamine agonists: These drugs directly activate dopamine

receptors in the basal ganglia.
Oral drugs include bromocriptine

, pramipexole

, and ropinirole


Oral dopamine

agonists can be used as monotherapy but, as such, are rarely sufficient for
more than a few years. They may be useful at all stages of the disease. Using these drugs early in treatment, with small doses of levodopa, may delay emergence of dyskinesias and on-off effects, possibly because dopamine

agonists stimulate dopamine

receptors longer
than levodopa does. This type of stimulation is more physiologic and may better preserve the receptors. Dopamine

agonists are particularly useful in later stages when response to
levodopa decreases or on-off effects are prominent.


was recently withdrawn from the market because of problems with consistent
drug delivery.

Adverse effects may limit use of dopamine

agonists. Reducing the levodopa dose may
minimize adverse effects of dopamine

agonists. Agonists can cause compulsive gambling,
hypersexuality, or overeating in 1 to 2% of patients, requiring a change in drug or a reduction in dose. Bromocriptine

is rarely used because cardiac valvular fibrosis and pleural fibrosis
are concerns. Pergolide

, another dopamine

agonist, was recalled because it increases
risk of cardiac valvular fibrosis.


is an injectable dopamine

agonist used as rescue therapy when off effects
are severe. Onset of action is rapid (5 to 10 min), and duration is short (60 to 90 min). Apomorphine

2 to 6 mg sc can be given up to 5 times/day as needed. A 2-mg test dose is
given first to check for orthostatic hypotension. BP is checked in the standing and supine positions before treatment and 20, 40, and 60 min afterward. Other adverse effects are similar to those of other dopamine

agonists. Nausea can be prevented by starting

300 mg po tid 3 days before apomorphine

and continuing it for the first
2 mo of treatment.

Selective monoamine oxidase type B (MAO-B) inhibitors: Selegiline

inhibits one of the 2
major enzymes that break down dopamine

in the brain, thereby prolonging the action of
each dose of levodopa. In some patients with mild on-off effects, selegiline

helps prolong
levodopa’s effect. Used initially as monotherapy, selegiline

can delay the initiation of
levodopa by about 1 yr. Selegiline

may slow progression of Parkinson’s disease by
potentiating residual brain dopamine

in early disease or by reducing oxidative metabolism of
brain dopamine

. A dose of 5 mg po bid does not cause hypertensive crisis (sometimes
triggered by consuming tyramine in foods, such as some cheeses, during MAO inhibitor therapy); this adverse effect is common with nonselective MAO inhibitors, which block A and B isoenzymes. Although virtually free of adverse effects, selegiline

can potentiate levodopa-
induced dyskinesias, mental and psychiatric adverse effects, and nausea, requiring reduction in the levodopa dose. Selegiline

is also available in a formulation designed for buccal
absorption (zydis-selegiline



, an MAO-B inhibitor that is not metabolized to amphetamine, is effective and
well-tolerated in early and late disease. Whether rasagiline

‘s effects are purely symptomatic
or also neuroprotective is unclear, but recent studies suggest rasagiline

may alter disease

Anticholinergic drugs: These drugs can be used as monotherapy in early disease and later to supplement levodopa. Commonly used anticholinergic drugs include benztropine


. Antihistamines with anticholinergic effects (eg, diphenhydramine

25 to 50
mg po bid to qid, orphenadrine

50 mg po once/day to qid) are occasionally useful for
treating tremor. Anticholinergic tricyclic antidepressants (eg, amitriptyline

10 to 150 mg po
at bedtime), if used for depression, may be useful as an adjunct to levodopa. Doses of anticholinergic drugs are increased very slowly. Adverse effects are particularly troublesome in the elderly; if possible, they should not be given anticholinergic drugs.

Catechol O-methyltransferase (COMT) inhibitors: These drugs (eg, entacapone


) inhibit the breakdown of dopamine

and therefore appear to be useful adjuncts to
levodopa. A combination of levodopa, carbidopa, and entacapone

can be used. For each
dose of levodopa taken, 200 mg of entacapone

is given, to a maximum of 200 mg 8 times/
day. Tolcapone

, a potent COMT inhibitor, is less commonly used because of rare reports of
liver toxicity.

Table 3

Some Commonly Used Oral Antiparkinsonian Drugs

Starting Dose
Average Daily Dose
Usual Dose Range
Major Adverse Effects



500–1200 mgb
1200 mg
500–6000 mg (total daily), in divided doses
Central: Drowsiness, confusion, orthostatic hypotension, psychotic disturbances, nightmares, dyskinesia

Peripheral: Nausea, anorexia, flushing abdominal cramping, palpitations


25/100, 10/100, or 25/250 mg (immediate-release or dissolvable)
25/100 mg tid
25/100 mg tid to 25/100 mg 6 times/day
25/100 mg tid to 25/250 mg 8 times/day


25/100 or 50/200 mg (controlled-release)
25/100 mg bid
50/200 mg tid to qid
75/300–600/2400 mg (total daily), in divided doses

Antiviral drug


100 mg once/day
100 mg bid
100–200 mg bid to tid
Confusion, urinary retention, leg edema, elevated intraocular pressure, livedo reticularis




1.25 mg bid
10–40 mg once/day
1.25–40 mg once/day
Nausea, vomiting, somnolence, orthostatic hypotension, dyskinesia, confusion, hallucinations, delirium, psychosis


0.125 mg tid
0.5–1 mg tid
1.5 mg tid


0.25 mg tid
3–4 mg tid
0.25–8 mg tid

Anticholinergic drugsd


0.5 mg at night
1 mg bid
0.5 mg at night to 2 mg tid
Dry mouth, urinary retention, constipation, blurred vision

Particularly in the elderly, confusion, delirium, impaired thermoregulation due to decreased sweating


1 mg tid
2 mg tid
2–5 mg tid

Monoamine oxidase-B (MAO-B) inhibitors


0.5 mg once/day
1–2 mg once/day
1–2 mg once/day
Nausea, insomnia, somnolence, edema


5 mg once/day
5 mg bid
5 mg bid
Possible potentiation of nausea, insomnia, confusion, and dyskinesias secondary to levodopa

Catechol O-methyltransferase (COMT) inhibitor


200 mg with each dose of levodopa
800 mg once/day
800–1600 mg once/day
Dyskinesias, nausea, confusion, hallucinations, diarrhea, discoloration of urine
aLevodopa alone is almost never used in a clinical setting.
bLevodopa 1200 mg once/day is equivalent to carbidopa/levodopa

25/100 mg tid.
c Bromocriptine

is rarely used because cardiac valvular fibrosis and pleural fibrosis
are concerns.
dAnticholinergic drugs should be used cautiously in the elderly.
e Selegiline

is also available in a formulation designed for buccal absorption.
f Entacapone

is also available in a triple combination tablet (carbidopa, levodopa,
and entacapone


Surgery: If drugs are ineffective and disease is advanced, surgery is considered. For patients with levodopa-induced dyskinesias or significant motor fluctuations, deep brain stimulation of the subthalamic nucleus or globus pallidus interna is often recommended. For patients with tremor only, stimulation of the ventralis intermediate nucleus of the thalamus is sometimes recommended; however, because most patients also have other symptoms, stimulation of the subthalamic nucleus, which relieves tremor as well as other symptoms, is usually preferable.

Physical measures: Maximizing activity is a goal. Patients should do daily activities to the extent possible. If they cannot, physical or occupational therapy, which may involve a regular exercise program, may help condition them physically. Therapists may teach patients adaptive strategies and help them make appropriate adaptations in the home (eg, installing grab bars to reduce the risk of falls).

Because the disease, antiparkinsonian drugs, and inactivity can lead to constipation, patients should consume a high-fiber diet, exercise when possible, and drink adequate amounts of fluids. Dietary supplements (eg, psyllium) and stimulant laxatives (eg, bisacodyl

10 to 20
mg po once/day) can help.


Parkinsonism refers to symptoms that are similar to those of Parkinson’s disease but caused by another condition.

Parkinsonism results from drugs, disorders other than Parkinson’s disease, or exogenous toxins (see Table 4: Movement and Cerebellar Disorders: Some Causes of Parkinsonism). The mechanism is blockage of or interference with dopamine

‘s action in the basal ganglia.
The most common cause is ingestion of drugs that block dopamine

receptors (eg,
phenothiazine, thioxanthene, butyrophenone, antipsychotic drugs, reserpine


Table 4

Some Causes of Parkinsonism


Neurodegenerative disorders

Amyotrophic lateral sclerosis–parkinsonism-dementia complex of Guam
Responds poorly to antiparkinsonian drugs

Corticobasal ganglionic degeneration
Begins asymmetrically, usually after age 60

Causes cortical and basal ganglia signs, often with apraxia, dystonia, myoclonus, and alien limb syndrome (movement of a limb that seems independent of the patient’s conscious control)

Causes immobility after about 5 yr and death after about 10 yr

Responds poorly to antiparkinsonian drugs

Dementia (eg, Alzheimer’s disease, chromosome 17–linked frontotemporal dementias, diffuse Lewy body dementia)
Parkinsonism often preceded by dementia with prominent memory loss

Multiple system atrophy
May include prominent autonomic dysfunction

May have predominantly cerebellar features

Often causes early falls and balance problems

Responds poorly to antiparkinsonian drugs

Progressive supranuclear palsy
First manifests with gait and balance problems

Causes progressive ophthalmoparesis starting with downward gaze

Responds poorly to antiparkinsonian drugs

Spinocerebellar ataxia 3
Responds poorly to antiparkinsonian drugs

Other disorders

Cerebrovascular disease
Manifests with rigidity and bradykinesia or akinesia (akinetic-rigid syndrome) that predominantly involves the lower extremities, with prominent gait disturbance

Rarely responds to antiparkinsonian drugs

Brain tumors near the basal ganglia
Manifests with hemiparkinsonism (ie, restricted to one side of the body)

Repeated traumatic brain injury
Often causes dementia (described as punch-drunk)

Usually, normal-pressure hydrocephalus; rarely, obstructive hydrocephalus

Causes calcification of the basal ganglia; may cause chorea and athetosis

Viral (eg, West Nile) encephalitis, infectious or postinfectious autoimmune
Can cause parkinsonism transiently during the acute phase or, rarely, permanently (eg, postencephalitic parkinsonism after the epidemic of encephalitis lethargica in 1915–1926)

In postencephalitic parkinsonism, forced, sustained deviation of the head and eyes (oculogyric crises); other dystonias; autonomic instability; depression; and personality changes


Can cause reversible* parkinsonism


analog (N-MPTP)†
Can cause sudden, irreversible parkinsonism

Occurs in IV drug users


Can cause reversible* parkinsonism

May be dose-dependent or related to the patient’s susceptibility (risk factors include older age and female sex)


Same as for methyldopa


Same as for methyldopa


, long-term use
Same as for methyldopa

, often with
cerebellar features


Carbon monoxide
Can cause irreversible parkinsonism

As contaminated moonshine, can cause hemorrhagic necrosis of the basal ganglia

Can cause parkinsonism with dystonia and cognitive changes when toxicity is chronic

Usually occupation-related
*When drugs are withdrawn, symptoms usually resolve within a few weeks, although they may persist for months.
† N-MPTP results from unsuccessful attempts to produce meperidine

for illicit use.
N-MPTP = N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Parkinsonism causes the same symptoms as Parkinson’s disease (eg, resting tremor, rigidity, bradykinesia, postural instability—see Movement and Cerebellar Disorders: Symptoms and Signs).


Clinical evaluation, response to levodopa therapy, and, for differential diagnosis, sometimes neuroimaging

To differentiate Parkinson’s disease from secondary parkinsonism, clinicians note whether levodopa results in dramatic improvement, suggesting Parkinson’s disease. Causes of parkinsonism can be identified by the following:

A thorough history, including occupational, drug, and family history

Evaluation for neurologic deficits characteristic of disorders other than Parkinson’s disease (such as neurodegenerative disorders)

Neuroimaging when indicated


Treatment of the cause

The cause is corrected or treated if possible, sometimes resulting in amelioration or disappearance of symptoms. Drugs used to treat Parkinson’s disease are often ineffective or have only transient benefit. But amantadine

or an anticholinergic drug (eg, benztropine

may ameliorate parkinsonism secondary to use of antipsychotic drugs.

Physical measures to maintain mobility and independence are useful (as for Parkinson’s disease, see Movement and Cerebellar Disorders: Physical measures). Good nutrition is essential.

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