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When Is It Not Parkinson's Disease?

Roger L. Albin, MD, Anne B. Young Collegiate Professor of Neurology, University of Michigan Medical School, Past MPF Advisory Board Member

The evaluation and diagnosis of Parkinson's disease (PD) and related conditions is based almost completely on a careful history and physical examination. There are no radiological or laboratory measures that contribute significantly to the evaluation of PD and related disorders. The point of departure for establishing a specific diagnosis is identification of the syndrome of parkinsonism.

A syndrome is a constellation of related symptoms and examination findings that point to dysfunction of a specific organ or part of an organ. Syndromes usually have several causes. In the case of parkinsonism, all the key features stem from impaired production or action of the brain chemical dopamine. Parkinsonism can result from degeneration of dopamine producing nerve cells, blockade of dopamine action by certain types of drugs, or loss of the nerve cells that are the targets of dopamine action.

The key clinical features of parkinsonism are bradykinesia (slow movement), rigidity (an increase in the resistance of an affected body part to passive movement of that body part by an examiner), resting tremor (rhythmic involuntary movements when the affected body part is relaxed), and loss of postural reflexes (impairment of the body's ability to maintain an erect posture when displaced rapidly by an examiner) (Table 1). Discovery of two or more of these findings by a competent examiner indicates an abnormality of dopamine mediated signaling within the brain. If these features are not present, then PD and related disorders are excluded. An important corollary point is that these clinical features and symptoms should exhibit insidious onset and slow worsening. Sudden onset of these features would be very unusual for PD or any related disorder.

Difficulties with diagnosis of PD arise in two specific contexts; (1) initial diagnosis, and (2) individuals thought to have PD whose clinical course is atypical. When an individual is initially found to have parkinsonism, there are 3 major possible explanations.

  • The first is PD itself.

  • The second is drug-induced parkinsonism, a situation in which a prescribed drug impairs the action of dopamine and results in parkinsonism. Many drugs used in psychiatric practice have this side effect. Some drugs used for treatment of nausea can also have this side effect. These side effects do not usually occur after short-term use of these drugs but generally follow weeks to months of administration.

  • The third possible explanation is one of the PD related disorders (see below).

A fourth possibility that should be mentioned is Benign Essential Tremor (ET), even though this disorder does not exhibit parkinsonism. ET is a very common entity among older Americans. It is distinct from parkinsonism in that the tremor is not present at rest but occurs with use of the arms and there is no bradykinesia, rigidity, or loss of postural reflexes. Inexperienced physicians sometimes confuse these entities.

A definite diagnosis of PD is possible only after death with pathologic examination of the brain and detection of characteristic abnormalities. Clinical diagnosis of PD is based on the presence of two or more features of parkinsonism, the exclusion of other causes of parkinsonism (such as drug-induced parkinsonism), and the presence of significant improvement with a dopamine-like drug, either in the form of an L-dopa preparation or a dopamine agonist. PD responds well to treatment with these agents while the other neurologic diseases causing parkinsonism do not. Despite the apparent imprecision of this approach, it is actually very successful and studies comparing clinical diagnosis by expert clinicians with pathological diagnosis have shown clinical diagnosis to be quite accurate.

If these conditions are satisfied, the diagnosis is almost certainly PD. Difficulties occur in diagnosis when one of the other neurologic disorders causing parkinsonism is present.

Table 1: Parkinsonism: The Dopamine Deficiency Syndrome

Resting Tremor
Loss of Postural Reflexes

Table 2: Differential Diagnosis of Parkinsonism

Drug Induced
Dopamine Antagonists; Anti-Psychotics, Anti-Emetics
Catecholamine Depleters; Reserpine, Tetrabenazine
False Transmitters; a-Methyl-Tyrosine
Essential Tremor - Not Really a Mimic
Other Neurodegenerations Affecting the Basal Ganglia
Progressive Supranuclear Palsy
Multiple Systems Atrophy
Corticobasal Degeneration
Idiopathic Parkinson's Disease

Table 3: Discordant Features

Atypical Presenting Features
- Lack of Tremor
- Symmetrical Onset
- Early Autonomic Dysfunction
- Early Cognitive Dysfunction
- Unusual Eye Movement Findings on Examination
- Atypical Movement Control Problems of Affected Limbs
Rapid Progression
Lack of Response to Dopamine Replacement

Table 4: PD-Like Syndromes

Progressive Supranuclear Palsy (PSP)
Multiple System Atrophy (MSA)
Corticobasal Degeneration (CBD)
Lewy Body Dementia (LBD, DLB)


Clues indicating the symptoms are not PD

The most important clue that another neurologic disorder is present is lack of significant response to a dopaminelike drug. These drugs must, however, be tried at adequate doses and for proper lengths of time. A short trial at a low dose may simply not be adequate to assess response.

Some other clinical features may point away from PD. Most, but not all PD patients, have resting tremor. The PD-like disorders usually lack tremor. PD typically begins on one side of the body where most of the PD-like disorders have symmetric onset (for an important exception, see below). Rapid progression of parkinsonism is another important clue. We expect PD patients (with appropriate treatment) to do well and progress slowly for at least 3-5 years after diagnosis. Finally, each of the PD-like disorders has characteristic features that assist in the diagnosis.

Other Disorders

The four major disorders that can mimic PD are Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD), and Lewy Body Dementia (LBD).

PSP is characterized by certain types of eye movement abnormalities, particularly difficulty with voluntary movements of the eyes in the vertical plane.

MSA is distinguished by difficulties with the autonomic system, the part of the nervous system responsible for maintaining blood pressure and similar functions. MSA patients frequently have difficulties with maintaining an appropriate blood pressure when standing, have problems with control of their bladders, may have sweating changes, and in men, impotence is common.

CBD is a rare disorder which typically presents with asymmetric abnormalities of limb function. There may be a combination of clinical findings suggesting parkinsonism and abnormalities of limb use reflecting dysfunction of the cortex; the so called thinking part of the brain.

LBD is quite common but does not usually present with parkinsonism, but rather with dementia. Dementia is uncommon in patients with early PD but when dementia occurs prior to or approximately coincident with the development of parkinsonism, LBD is the likely diagnosis.

These PD-like disorders are individually rare but their aggregate prevalence is significant. Perhaps as many as 15% of patients presenting to Movement Disorder Clinics for evaluation of parkinsonism turn out to have one of these PD-like disorders. Making a specific diagnosis of one of these disorders is often quite difficult. The characteristic clinical features may not appear until months to years after the emergence of parkinsonism and prolonged clinical follow-up is necessary often to confirm a specific diagnosis. There is no effective primary medical or surgical therapy for any of these disorders. The emphasis is on assistive care with physical therapy, occupational therapy and interventions that palliate some of the symptoms. Making a specific diagnosis as early as possible is important to improve patient and family comprehension, reduce unnecessary medication trials and diagnostic studies, and to focus attention of appropriate assistive interventions.



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