Parkinson disease is an idiopathic, slowly progressive, degenerative disorder characterized by resting tremor, stiffness (rigidity), slow and decreased movement (bradykinesia), and gait and/or postural instability. Diagnosis is clinical. Treatment aims to restore dopaminergic function in the brain with levodopa plus carbidopa and/or other drugs (eg, dopamine agonists, MAO type B [MAO-B] inhibitors, amantadine). For refractory, disabling symptoms in patients without dementia, stereotactic deep brain stimulation or lesional surgery may help.
Parkinson disease (PD) 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, PD begins during childhood or adolescence (juvenile parkinsonism). Onset between ages 21 and 40 yr is sometimes called early-onset PD. Genetic causes are more likely in juvenile and early-onset PD; these forms may differ from later-onset PD because they progress more slowly and are very sensitive to dopaminergic treatments and because most disability results from nonmotor symptoms such as depression, anxiety, and pain.
Secondary parkinsonism is brain dysfunction that is characterized by basal ganglia dopaminergic blockade and that is similar to PD, but it is caused by something other than PD (eg, drugs, cerebrovascular disease, trauma, postencephalitic changes). Atypical parkinsonism (see Secondary and Atypical Parkinsonism) refers to a group of neurodegenerative disorders that have some features similar to those of Parkinson disease but have some different clinical features and a different pathology (eg, neurodegenerative disorders such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration).
Synuclein is a neuronal and glial cell protein that can aggregate into insoluble fibrils and form Lewy bodies. The pathologic hallmark of PD is synuclein-filled Lewy bodies in the nigrostriatal system. However, synuclein can accumulate 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 PD is a relatively late development in a systemic synucleinopathy. Other synucleinopathies (synuclein deposition disorders) include dementia with Lewy bodies and multiple system atrophy. PD may share features of other synucleinopathies, such as autonomic dysfunction and dementia.
Rarely, PD occurs without Lewy bodies.
In PD, pigmented neurons of the substantia nigra, locus ceruleus, and other brain stem dopaminergic cell groups degenerate. Loss of substantia nigra neurons results in depletion of dopamine in the dorsal aspect of the putamen (part of the basal ganglia) and causes many of the motor manifestations of PD.
A genetic predisposition is likely, at least in some cases. About 10% of patients have a family history of PD. Several abnormal genes have been identified. Inheritance is autosomal dominant for some genes and autosomal recessive for others. In genetic forms, age at onset tends to be younger, but the course is typically more benign than that of later-onset, presumably nongenetic PD.
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:
Usually, the hands or feet are affected first, most often asymmetrically. The jaw and tongue may also be affected, but not the voice. Tremor may become less prominent as the disease progresses.
Rigidity develops independently of tremor in many patients. When a clinician moves a rigid joint, semirhythmic jerks due to variations in the intensity of the rigidity occur, producing a ratchet-like effect (cogwheel rigidity).
Slow movements (bradykinesia) are typical. Movement also becomes decreased in amplitude (hypokinesia) and difficult to initiate (akinesia).
Rigidity and hypokinesia may contribute to muscle aches and sensations of fatigue. The face becomes masklike (hypomimic), with an open mouth and reduced blinking. Excessive drooling (sialorrhea) may contribute to disability. Speech becomes hypophonic, with characteristic monotonous, sometimes stuttering dysarthria. Hypokinesia and impaired control of distal muscles 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 of gait).
Postural instability may develop, resulting in falls, which occur later in PD. Patients have difficulty starting to walk, turning, and stopping. They shuffle, taking short steps, holding their arms flexed to the waist, and swinging their arms little or not at all with each stride. Steps may inadvertently quicken, while stride length progressively shortens; this gait abnormality, called festination, is often a precursor to freezing of gait. 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, usually late in PD. Early predictors of its development are visuospatial impairment (eg, getting lost while driving) and decreased verbal fluency.
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 (RSD); in this disorder, violent bursts of physical activity occur during REM sleep because the paralysis that normally occurs during REM sleep is absent. Sleep deprivation may exacerbate depression and cognitive impairment, as well as contribute to excessive daytime sleepiness. Recently studies have shown that REM sleep behavior disorder is a marker of synucleinopathies and indicates higher risk of developing Lewy body dementia or Parkinson disease dementia.
Neurologic symptoms unrelated to parkinsonism commonly develop because synucleinopathy occurs in other areas of the central, peripheral, and autonomic nervous systems. The following are examples:
In some patients, some of these symptoms occur before the motor symptoms of PD.
Seborrheic dermatitis is also common.
Diagnosis is clinical. PD 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.
Slowed and decreased movement due to PD must be differentiated from decreased movement and spasticity due to lesions of the corticospinal tracts. Unlike PD, corticospinal tract lesions cause
The diagnosis of PD is supported by the presence of other signs such as infrequent blinking, lack of facial expression, impaired postural reflexes, and gait abnormalities. In the elderly, other possible causes of decreased spontaneous movements or a short-stepped gait, such as severe depression, hypothyroidism, or use of antipsychotics or certain antiemetics, must be excluded before PD is diagnosed.
To help distinguish PD from secondary or atypical parkinsonism, clinicians often test responsiveness to levodopa. A large, sustained response strongly supports PD. A modest or no response to levodopa at doses of at least 1200 mg/day suggests another form of parkinsonism. Causes of secondary or atypical parkinsonism can be identified by
Many oral drugs are commonly used to relieve symptoms of PD (see see Some Commonly Used Oral Antiparkinsonian Drugs). Levodopa is the most effective treatment. However, when PD is advanced, sometimes soon after diagnosis, response to levodopa can wear off, causing fluctuations in motor symptoms and dyskinesias (see see Levodopa). To reduce the time levodopa is taken and thus minimize these effects, clinicians can consider treating younger patients who have mild disability with MAO-B inhibitors (selegiline, rasagiline), dopamine agonists (eg, pramipexole, ropinirole, rotigotine), or amantadine (which is the best option when trying to decrease peak-dose dyskinesias). However, if these drugs do not sufficiently control symptoms, clinicians should promptly initiate levodopa because it can usually greatly improve quality of life. Evidence now suggests that levodopa becomes ineffective because of disease progression rather than cumulative exposure to levodopa, as was previously believed, so early use of levodopa probably does not hasten the drug's ineffectiveness.
Doses are often reduced in the elderly. Drugs that cause or worsen symptoms, particularly antipsychotics, are avoided.
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 from being decarboxylated into dopamine outside the brain (peripherally), thus lowering the levodopa dosage required to produce therapeutic levels in the brain and minimizing adverse effects due to dopamine in the peripheral circulation.
Levodopa is most effective at relieving bradykinesia and rigidity, although it often substantially reduces tremor.
Common short-term adverse effects of levodopa are
Common long-term adverse effects include
Hallucinations and paranoia occur most often in the elderly and in patients who have cognitive impairment or dementia.
The dose that causes dyskinesias tends to decrease as the disease progresses. Over time, the dose that is needed for therapeutic benefit and the one that causes dyskinesia converge.
Dosage of carbidopa/levodopa is increased every 4 to 7 days as tolerated until maximum benefit is reached or adverse effects develop. The risk of adverse effects may be minimized by starting at a low dose, such as half of a 25/100 mg of carbidopa/levodopa tablet tid or qid (12.5/50 mg tid), and increasing slowly to about one, two, or three 25/100-mg tablets qid. Preferably, levodopa should not be given with food because protein can reduce absorption of levodopa. If peripheral adverse effects of levodopa (eg, nausea, vomiting, postural light-headedness) predominate, increasing the amount of carbidopa may help. Carbidopa doses up to 150 mg are safe and do not decrease the efficacy of levodopa. Most patients with PD require 400 to 1200 mg/day of levodopa in divided doses every 2 to 5 h, but some patients with malabsorption require up to 3000 mg/day.
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 nondissolvable immediate-release carbidopa/levodopa. A controlled-release preparation is available but is usually used only to treat nighttime symptoms.
Occasionally, levodopa must be used to maintain motor function despite levodopa-induced hallucinations or delirium. Psychosis can sometimes be treated with oral quetiapine or clozapine; these drugs, unlike other antipsychotics (eg, risperidone, olanzapine, all typical psychotics), do not aggravate parkinsonian symptoms. Quetiapine can be started at 25 mg at night and increased in 25-mg increments every 1 to 3 days up to 400 mg at night or 200 bid. Although clozapine is most effective, its use is limited because agranulocytosis is a risk (estimated to occur 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 for another 6 mo and then every 4 wk thereafter. However, the frequency may vary depending on the WBC count.
After 2 to 5 yr of treatment, most patients experience fluctuations in their response to levodopa, and symptom control may fluctuate unpredictably between effective and ineffective (on-off fluctuations), as response to levodopa starts to wear off. Symptoms may occur before the next scheduled dose (called off effects). The dyskinesias and off effects result from a combination of the pharmacokinetic properties of levodopa, particularly its short half-life, and disease progression. Dyskinesias result mainly from disease progression, rather than cumulative exposure to levodopa, as previously believed. Eventually, the period of improvement after each dose shortens, and drug-induced dyskinesias result in swings from akinesia to dyskinesias. 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, which are highly impractical. Alternative methods to decrease the off (akinetic) times include adjunctive use of dopamine agonists, as well as COMT and/or MAO inhibitors; amantadine can reliably manage dyskinesias.
A formulation of levodopa/carbidopa intestinal gel (available in Europe) can be given using a pump connected to a feeding tube inserted in the proximal small bowel. This formulation is being studied as treatment for patients who have severe motor fluctuations or dyskinesias that cannot be relieved by drugs and who are not candidates for deep brain stimulation. This formulation appears to greatly reduce the off times and increase quality of life.
This drug is most often used to ameliorate dyskinesias secondary to levodopa and to lessen tremors. Amantadine is useful as monotherapy for early, mild parkinsonism and later can be used to augment levodopa's effects. It may augment dopaminergic activity, anticholinergic effects, or both. Amantadine is also an NMDA (N-methyl-d-aspartate)-receptor antagonist and thus may help slow the progression of PD and dyskinesias. If used as monotherapy, amantadine often loses its effectiveness after several months. Amantadine is most often used to ameliorate dyskinesias secondary to long-term use of levodopa and to relieve tremors.
These drugs directly activate dopamine receptors in the basal ganglia. They include pramipexole (0.75 to 4.5 mg/day po) and ropinirole (3 to 6 mg/day po up to 24 mg/day), rotigotine (given transdermally), and apomorphine (given by injection). Bromocriptine may still be used in some countries, but in North America, its use is largely limited to treatment of pituitary adenomas because it increases the risk of cardiac valve fibrosis and pleural fibrosis. Pergolide, an older ergot-derived dopamine agonist, was taken off the market because it increased the risk of cardiac valve fibrosis.
Oral dopamine agonists can be used as monotherapy but, as such, are rarely effective for more than a few years. Using these drugs early in treatment, with small doses of levodopa, may be useful in patients at high risk of dyskinesias and on-off effects (eg, in patients < 60 yr). However, dopamine agonists may be useful at all stages of the disease, including as adjunctive therapy in later stages. Adverse effects may limit the use of oral dopamine agonists. In 1 to 2% of patients, these drugs may cause compulsive gambling, excessive shopping, hypersexuality, or overeating, requiring dose reduction or withdrawal of the causative drug and possibly avoidance of the drug class.
Rotigotine, given transdermally once/day, provides more continuous dopaminergic stimulation than drugs given via other routes. It was recently reintroduced in the US after technical problems with the patch technology were resolved. Dose starts at 2 mg once/day and is usually increased to 6 mg once/day. Outside the US, higher doses may be recommended.
Apomorphine is an injectable dopamine agonist used as rescue therapy when off effects are frequent and severe. Onset of action is rapid (5 to 10 min), but 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 supine and standing 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 trimethobenzamide 300 mg po tid 3 days before apomorphine and continuing it for the first 2 mo of treatment.
Selective MAO-B inhibitors:
These drugs include selegiline and rasagiline.
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 off effects, selegiline helps prolong levodopa's effectiveness. Used initially as monotherapy, selegiline controls mild symptoms; as a result, use of levodopa can be delayed by about 1 yr. A dose of 5 mg po bid does not cause hypertensive crisis, which is sometimes triggered when patients taking a nonselective MAO inhibitor consume tyramine in foods (eg, some cheeses). 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).
Rasagiline is effective and well-tolerated in early and late disease; uses of rasagiline 1 to 2 mg po once/day are similar to those of selegiline.
These drugs can be used as monotherapy in early disease and later to supplement levodopa. They are most effective for tremor. Doses are increased very slowly. Adverse effects may include cognitive impairment and dry mouth, which are particularly troublesome for the elderly and may be the principal problem with its use. Thus, these drugs are usually used only in young patients with tremor-predominant PD or with some dystonic components. Rarely, they are used as adjunctive treatment in elderly patients without cognitive impairment or psychiatric disorders.
Commonly used anticholinergic drugs include benztropine and trihexyphenidyl. 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.
Catechol O-methyltransferase (COMT) inhibitors:
These drugs (eg, entacapone, tolcapone) inhibit the breakdown of levodopa and dopamine and therefore appear to be useful adjuncts to levodopa. They are used commonly in patients who have been taking levodopa for a long time when response to levodopa is progressively wearing off at the end of dosing intervals (known as wearing-off effects),
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 is a more potent COMT inhibitor because it can cross the blood-brain barrier; however, it is less commonly used because rarely, liver toxicity has been reported. It is an appropriate option if entacapone does not sufficiently control off effects. The dose for tolcapone is increased gradually from 100 up to 200 mg tid. Liver enzymes must be monitored periodically. Tolcapone should be stopped if ALT or AST levels increase to twice the upper limit of the normal range or higher, or if symptoms and signs that suggest liver damage develop.
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If drugs are ineffective and/or have intolerable adverse effects, surgery, including deep brain stimulation and lesional surgery, may be 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 to modulate overactivity in the basal ganglia and to thus decrease parkinsonian symptoms in patients with PD. 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 preferred.
Lesional surgery aims to stop overactivity directed to the thalamus from the globus pallidus interna or to control tremor in patients with tremor-predominant PD if thalamotomy is planned. However, lesional surgery is not reversible and cannot be modulated over time; bilateral lesional surgery is not recommended because it can have severe adverse effects such as dysphagia and dysarthria. Lesional surgery involving the subthalamic nucleus is contraindicated because it causes severe ballismus.
Patients with cognitive impairment, dementia, or a psychiatric disorder are not suitable candidates for surgery because neurosurgery can exacerbate cognitive impairment and psychiatric disorders, and the risk of additional mental impairment outweighs the benefits of any improvement in motor function.
Maximizing activity is a goal. Patients should increase daily activities to the greatest 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).
To prevent or relieve constipation (which may result from the disease, antiparkinsonian drugs, and/or inactivity), 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.
Secondary and Atypical Parkinsonism
Secondary parkinsonism refers to a group of disorders that have features similar to those of Parkinson disease but have a different etiology. Atypical parkinsonism refers to a group of neurodegenerative disorders other than Parkinson disease that have some features of Parkinson disease but have some different clinical features and a different pathology. Diagnosis is by clinical evaluation and response to levodopa. Treatment is directed at the cause when possible.
Parkinsonism results from drugs, disorders other than Parkinson disease, or exogenous toxins (see see Some Causes of Secondary and Atypical Parkinsonism). In secondary parkinsonism, the mechanism is blockade of or interference with dopamine's action in the basal ganglia. The most common cause is
These drugs include antipsychotics (eg, phenothiazine, thioxanthene, butyrophenone), antiemetics (eg, metoclopramide, prochlorperazine), and drugs that deplete dopamine (eg, tetrabenazine, reserpine).
Atypical parkinsonism encompasses neurodegenerative disorders such as progressive supranuclear palsy, diffuse Lewy body dementia, corticobasal degeneration, and multiple system atrophy.
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Symptoms and Signs
Parkinsonism causes the same symptoms as Parkinson disease (eg, resting tremor, rigidity, bradykinesia, postural instability—see Symptoms and Signs).
To differentiate Parkinson disease from secondary or atypical parkinsonism, clinicians note whether levodopa results in dramatic improvement, suggesting Parkinson disease. Causes of parkinsonism can be identified by the following:
Deficits that suggest neurodegenerative disorders other than Parkinson disease include gaze palsies, signs of corticospinal tract dysfunction (eg, hyperreflexia), myoclonus, autonomic dysfunction (if early or severe), cerebellar ataxia, prominent dystonia, ideomotor apraxia (inability to mimic hand motions), early dementia, early falls, and confinement to a wheelchair.
The cause is corrected or treated if possible, sometimes resulting in clinical improvement or disappearance of symptoms. Drugs used to treat Parkinson 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 disease). They include physical and occupational therapy, exercise, and use of adaptive devices. Good nutrition is essential.
Last full review/revision January 2013 by Hector A. Gonzalez-Usigli, MD; Alberto Espay
Content last modified May 2013