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Secondary and Atypical Parkinsonism

By

Hector A. Gonzalez-Usigli

, MD, HE UMAE Centro Médico Nacional de Occidente

Last full review/revision May 2020| Content last modified May 2020
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Topic Resources

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.

In secondary parkinsonism, the mechanism is blockade of or interference with dopamine’s action in the basal ganglia.

Atypical parkinsonism encompasses neurodegenerative disorders such as progressive supranuclear palsy, dementia with Lewy bodies, corticobasal ganglionic degeneration, and multiple system atrophy.

Etiology

Parkinsonism results from drugs, disorders other than Parkinson disease, or exogenous toxins.

The most common cause of secondary parkinsonism is

  • Use of drugs that decrease dopaminergic activity

These drugs include antipsychotics (eg, phenothiazine, thioxanthene, butyrophenone), antiemetics (eg, metoclopramide, prochlorperazine), and drugs that deplete dopamine (eg, tetrabenazine, reserpine).

Table
icon

Some Causes of Secondary and Atypical Parkinsonism

Cause

Comments

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 years and death after about 10 years

Responds poorly to antiparkinsonian drugs

Dementia (eg, Alzheimer disease, chromosome 17–linked frontotemporal dementias, diffuse dementia with Lewy bodies)

Parkinsonism often preceded by dementia most typically with

May include prominent autonomic dysfunction (orthostatic light-headedness, urinary or fecal incontinence)

May include prominent cerebellar dysfunction

May include severe parkinsonian features, usually with poor response to levodopa

May include pyramidal signs

Often causes early falls and balance problems

Responds poorly to antiparkinsonian drugs

First manifests with gait and balance problems

In its classic form, causes progressive ophthalmoparesis, starting with impairment of downward gaze

Responds poorly to antiparkinsonian drugs

Spinocerebellar ataxias (usually type 1, 2, or 3)

Usually first manifests with imbalance and poor coordination but may have additional classical symptoms (eg, pyramidal tract signs in type 1, slow saccades and polyneuropathy in type 2, parkinsonism and dystonia in type 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 and symmetric symptoms

Rarely responds to antiparkinsonian drugs and, if it responds, may require high levodopa doses (at least 1000 mg a day)

Brain tumors near the basal ganglia

Manifests with hemiparkinsonism (ie, restricted to the side of the body opposite the lesion)

Often causes dementia (as in dementia pugilistica)

Usually characterized by normal CSF pressure (normal-pressure hydrocephalus) and caused by various mechanisms

Rarely caused by obstructed CSF flow with increased CSF pressure (obstructive hydrocephalus)

Causes calcification of the basal ganglia

May cause parkinsonism, chorea, and athetosis

Viral encephalitis (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

Drugs

Can cause reversible† parkinsonism (drug-induced or pharmacologic parkinsonism)

Meperidine analog (N-MPTP)‡

Can cause sudden, irreversible parkinsonism due to a contaminant in the illicit preparation of meperidine

Occurs in IV drug users

Metoclopramide

Prochlorperazine

Reserpine (not available in the US)

Lithium, long-term use

Can cause reversible† parkinsonism

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

With lithium, sometimes results in cerebellar dysfunction; may occur in patients with serotonergic syndrome

Toxins

Carbon monoxide

Can cause irreversible parkinsonism due to bilateral internal globus pallidus necrosis

Methanol

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

Manganese

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

Usually related to occupation (eg, in miners or industrial workers) but can result from abuse of methcathinone (a metabolite of ephedrine), which causes a form of presumed manganese poisoning that has been reported in IV drugs users who inject self-prepared methcathinone

* Language impairment may involve expressive (nonfluent primary progressive) aphasia or receptive primary progressive semantic) aphasia.

† 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.

CSF = cerebrospinal fluid; N-MPTP = N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Symptoms and Signs

Parkinsonism causes the same symptoms as Parkinson disease (eg, resting tremor, rigidity, bradykinesia, postural instability).

Diagnosis

  • Clinical evaluation

  • Response to levodopa therapy

  • For differential diagnosis, sometimes neuroimaging

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:

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

  • Evaluation for neurologic deficits characteristic of neurodegenerative disorders other than Parkinson disease

  • Neuroimaging when indicated

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.

Treatment

  • Treatment of the cause

  • Physical measures

The cause of secondary parkinsonism 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. However, because these drugs may worsen cognitive decline and possibly increase tau pathology and neurodegeneration, their use should be limited (1, 2).

Physical measures to maintain mobility and independence are useful (as for Parkinson disease). 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, help them make appropriate adaptations in the home (eg, installing grab bars to reduce the risk of falls), and recommend adaptive devices that may be useful.

Good nutrition is essential.

Treatment references

  • 1.. Yoshiyama Y, Kojima A, Itoh K, Uchiyama T, Arai K: Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model. Neurobiol Dis 2012 45 (1):329-336, 2012. doi: 10.1016/j.nbd.2011.08.017.

  • 2.. Yoshiyama Y, Kojima A, Itoh K, et al: Does anticholinergic activity affect neuropathology? Implication of neuroinflammation in Alzheimer's disease. Neurodegener Dis 15 (3):140-148, 2015. doi: 10.1159/000381484.

Key Points

  • Parkinsonism can be caused by drugs, toxins, neurodegenerative disorders, and other disorders that affect the brain (eg, stroke, tumor, infection, trauma, hypoparathyroidism).

  • Suspect parkinsonism based on the clinical evaluation and differentiate it from Parkinson disease by the lack of response to levodopa; neuroimaging may be needed.

  • Check for deficits that suggest a neurodegenerative disorder other than Parkinson disease.

  • Correct or treat the cause if possible, and recommend physical measures to maintain mobility.

Drugs Mentioned In This Article

Drug Name Select Trade
COMPRO
REGLAN
COGENTIN
No US brand name
DEMEROL
Levodopa
LITHOBID
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