Parkinson disease (PD) is a chronic, progressive neurodegenerative disorder characterized by any combination of four cardinal signs: rest tremor, rigidity, bradykinesia, and gait disturbance. An accurate diagnosis of PD rests on the clinician’s ability to recognize its characteristic signs and associated symptoms, especially in the early stages. Correct diagnosis is fundamental to the appropriate therapy of PD, even though the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes.
This topic will review the diagnosis of PD.
Symptoms and signs of parkinsonism (ie, tremor, bradykinesia, rigidity, and postural instability) can be prominent in neurodegenerative disorders other than idiopathic PD, including dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy [1,2]. Furthermore, parkinsonism is seen in a wide variety of other conditions (secondary parkinsonism) [1,2]. Distinguishing PD from these parkinsonian syndromes can be difficult, particularly in the early stages of disease. Essential tremor may also be confused with Parkinson disease (PD).
Essential tremor (ET) is the most common neurologic cause of action tremor, with an estimated prevalence worldwide of up to 5 percent of the population. The incidence of ET increases with age, although it often affects young individuals, especially when it is familial. The neuropathologic basis for ET is unknown. (See “Overview of tremor”, section on Essential tremor).
Essential tremor is most often symmetric but can be unilateral, particularly early in the course of ET. It usually affects the hands and arms and can also affect the head, voice, chin, trunk, and legs. Tremor typically becomes immediately apparent in the arms when they are held outstretched.
Differentiating the action tremor of ET from the classic resting tremor of PD should be straightforward. However, some patients with PD also have a postural-action tremor indistinguishable from ET. Likewise, patients with severe ET may have a rest component to their tremor.
The presence of subtle bradykinesia or micrographia in early cases of parkinsonian postural tremor may support the diagnosis of idiopathic PD, although these signs may not appear until later on. However, it is important to be aware that elderly patients with ET may have mild bradykinesia and limb rigidity as a nonspecific accompaniment of aging. Head tremor is more likely to be a manifestation of ET, whereas tremor of the jaw or lips is more typically parkinsonian. (See “Overview of tremor”, section on Essential tremor).
Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer disease and is characterized clinically by visual hallucinations, fluctuating cognition, and parkinsonism. Other associated symptoms include repeated falls, syncope, autonomic dysfunction, neuroleptic sensitivity, delusions, hallucinations in nonvisual modalities, sleep disorders, and depression. (See “Clinical features and diagnosis of dementia with Lewy bodies”).
Approximately 40 percent of patients with PD eventually develop dementia, and the differentiation of Parkinson disease dementia (PDD) from DLB is somewhat arbitrary. In PDD, dementia occurs in the setting of well established parkinsonism, while in DLB, dementia usually occurs concomitantly with or before the development of parkinsonian signs. Thus, patients are classified as having PDD if parkinsonism is present for more than one year before the onset of dementia. (See “Clinical features and diagnosis of dementia with Lewy bodies” and see “Parkinson disease dementia”).
Patients with CBD can have asymmetric parkinsonism including bradykinesia, rigidity, and postural instability. More distinctive features can include ideomotor apraxia, alien limb phenomenon, aphasia, and loss of cortical sensory function . Absence of tremor and lack of levodopa response are typical for CBD and help to distinguish it from PD.
Multiple system atrophy
The syndromes of olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager are now collectively known as multiple system atrophy (MSA). Pathologically, MSA is characterized by the presence of alpha-synuclein positive glial cytoplasmic inclusions.
Clinically, MSA commonly presents with parkinsonism, but patients also have varying degrees of dysautonomia, cerebellar involvement, and pyramidal signs . The prominence of these manifestations along with symmetry of onset, absence of tremor, and poor response to levodopa suggest this diagnosis rather than PD . However, some cases of MSA may demonstrate responsiveness to levodopa, including motor fluctuations and dyskinesia, early in the course of the disease, with declining benefit over time . Cognitive function in MSA tend to be relatively well preserved compared with PD and other parkinsonian syndromes, probably reflecting a lesser degree of cortical involvement .
Progressive supranuclear palsy
Progressive supranuclear palsy, also known as Steele Richardson Olszewski syndrome, is an uncommon but not rare parkinsonian syndrome that can mimic PD in its early phase. Characteristic features of PSP include a vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls [7,8]. Bradykinesia and rigidity are typically symmetrical in onset . Apathy, disinhibition, dysphoria, and anxiety are common . The typical rest tremor of PD is rare in PSP.
A pseudobulbar palsy with associated dysarthria and dysphagia develops in approximately 80 percent or more of patients with PSP . A frontal lobe-like dementia syndrome occurs in a similar percentage, although the cognitive impairment may be mild in the first few years after clinical disease onset. The overall course is relentlessly progressive, with death occurring at a median of six years after onset .
The response to levodopa in PSP is typically poor, but about 20 percent of patients have some improvement initially or in the early stages of the disease .
Other neurodegenerative disorders
Parkinsonism may develop in late stages of Alzheimer disease. However, the relative timing of the appearance of dementia and parkinsonism is usually obvious, such that the late onset of parkinsonism, in itself, does not lead to confusion about the diagnosis of Alzheimer disease.
Parkinsonism may also occur in several other less common disorders:
- Huntington disease (rigid form). (See “Huntington disease: Clinical features and diagnosis”).
- Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). (See “Dementia syndromes”, section on Frontotemporal dementia).
- Spinocerebellar ataxias and dentatorubral pallidoluysian atrophy. (See “The spinocerebellar ataxias”).
A wide variety of conditions can cause secondary parkinsonism, including the following :
- Drugs (eg, classic and atypical antipsychotic agents, metoclopramide, prochlorperazine, reserpine).
- Toxins (eg, carbon disulfide, carbon monoxide, cyanide, MPTP, manganese, organic solvents).
- Head trauma, isolated or repeated (eg, boxing).
- Structural brain lesions that affect striatonigral circuits (eg, hydrocephalus, chronic subdural hematoma, tumor). (See “Normal pressure hydrocephalus” and see “Clinical presentation and diagnosis of brain tumors”).
- Metabolic and miscellaneous disorders (eg, Wilson’s disease, hypoparathyroidism and pseudohypoparathyroidism, chronic liver failure, extrapontine myelinolysis, neurodegeneration with brain iron accumulation, neuroacanthocytosis). (See “Pathogenesis and clinical manifestations of Wilson’s disease” and see “Clinical manifestations of hypocalcemia” and see “Bradykinetic movement disorders in children”, section on Neurodegeneration with brain iron accumulation, and see “Spiculated cells (echinocytes and acanthocytes) and target cells”).
- Infections (eg, encephalitis lethargica or Economo’s encephalitis, HIV/AIDS, neurosyphilis, prion disease, progressive multifocal leukoencephalopathy, toxoplasmosis). (See “Approach to HIV-infected patients with central nervous system lesions” and see “Neurosyphilis” and see “Diseases of the central nervous system caused by prions” and see “Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis”).
- Small vessel disease (ie, “vascular parkinsonism”), particularly multiple lacunar infarcts in the basal ganglia and/or Binswanger’s disease. It should be noted that this entity is controversial , in part because most basal ganglia infarcts are not associated with parkinsonian signs [13,14]. (See “Lacunar infarcts”).
Generally, the clinical history, associated features, and laboratory or radiologic findings in these cases allow the clinician to distinguish secondary parkinsonism and its underlying cause from PD or other primary parkinsonian syndromes.
Of the conditions causing secondary parkinsonism, drug-induced parkinsonism is the most common, and antipsychotic and antiemetics drugs are the most frequent offenders [1,15]. (See “Antipsychotic medications: Classification and pharmacology” and see “Antipsychotic medications: Treatment issues”).
Movement disorders such as akathisia and orofacial dyskinesia may be associated with chronic neuroleptic use and, if present, can be useful for distinguishing drug-induced parkinsonism from PD [16,17]. However, drug-induced parkinsonism can have clinical features identical to PD, including asymmetric onset with rest tremor . (See “Tardive dyskinesia: Clinical features and diagnosis”).
While drug-induced parkinsonism is usually reversible, persistent or progressive parkinsonism is seen in a minority of cases after drug withdrawal. It is unclear if this persistence is due to ongoing toxicity of the responsible drug or to the presence of an underlying parkinsonian syndrome .
The practical diagnosis of PD during life is based on clinical impression. There are no physiologic tests or blood tests for confirming the diagnosis, and neurodiagnostic testing with computerized imaging is almost always unrevealing. The true “gold standard” for diagnosis is neuropathologic examination.
It is generally accepted that two out of the three cardinal manifestations (tremor, bradykinesia, rigidity) must be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected . (See “Clinical manifestations of Parkinson disease”).
Response to dopaminergic therapy
As noted above, an excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of PD. The response to dopaminergic therapy in most parkinsonian syndromes is reduced or absent compared with the response in PD. However, up to 20 percent of patients with parkinsonism due to MSA may respond initially to levodopa , as may a substantial proportion of those with vascular parkinsonism .
An acute dopaminergic challenge test consists of rater-blinded assessment of parkinsonian symptoms using the Unified Parkinson Disease Rating Scale (UPDRS) before and after a dose of levodopa (eg, carbidopa-levodopa 25/250 mg) or subcutaneous apomorphine (1.5 to 4.5 mg). Although there is no standard definition, a challenge is considered positive if there is a clinically significant improvement in the UPDRS score (usually in the range of 15 to 30 percent or more) one hour after levodopa administration or 20 minutes after apomorphine injection [21,22].
A systematic review and practice parameter from the American Academy of Neurology (AAN) published in 2006 concluded that levodopa and apomorphine challenge tests should be considered when the diagnosis of PD is uncertain, as both tests are “probably useful” in distinguishing PD from other parkinsonian syndromes . An earlier systematic review found that both apomorphine and levodopa challenge tests had similar sensitivity and specificity for the diagnosis of idiopathic PD .
However, the exact role of acute levodopa or apomorphine challenge for the diagnosis of PD in clinical practice remains unclear. The problem with challenge testing is illustrated by the following observations :
- Up to 30 percent of patients with PD may not respond to acute dopaminergic challenges
- Approximately 20 to 30 percent of patients with a positive acute dopaminergic challenge will go on to develop another parkinsonian syndrome
n practice, when patients have mild symptoms that do not interfere with daily activities, it may not be advisable to institute dopaminergic therapy purely for diagnostic purposes. When PD symptoms begin to limit a patient’s quality of life, a long-term trial of dopaminergic or levodopa therapy may be just as adequate as an acute dopaminergic challenge.
The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to an adequate trial of moderate doses of levodopa (400 to 600 mg daily). Complete absence of response to a dose of 1000 to 1500 mg/day for at least two months strongly suggests that the original diagnosis of PD was incorrect and that the diagnosis should be revised to one of the other parkinsonian syndromes.
Features suggesting an alternative diagnosis
According to the 2006 AAN systematic review and practice parameter, a number of clinical features in early stages of disease are probably useful for distinguishing other forms of parkinsonism from PD :
- Falls at presentation or early in the course of the disease
- Poor response to levodopa
- Symmetrical motor signs
- Rapid progression to Hoehn and Yahr stage 3 with mild to moderate disease and some postural instability, but physically independent
- Lack of tremor
- Dysautonomia, early in the disease course, as manifested by urinary urgency/incontinence and fecal incontinence, urinary retention requiring catheterization, persistent erectile failure, or symptomatic orthostatic hypotension
Additional historical or clinical features that may suggest a diagnosis other than PD include:
- History of encephalitis
- History of repeated head injury
- History of recurrent strokes and stepwise progression of parkinsonism
- Antipsychotic drug treatment at the onset of symptoms
- Presence of neoplasm or hydrocephalus on neuroimaging
- Cerebellar signs
- Supranuclear gaze palsy
- Dementia preceding or occurring concurrently with parkinsonism
- Babinski sign
- Presence of apraxia
While a clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard [18,25]. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists [26,27].
An early diagnostic error rate of approximately 10 percent has been documented in some long-term studies of the natural history of PD . The most likely explanation is that other parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), can mimic idiopathic PD early in the course of illness, before the later appearance of the signature symptoms, such as disordered eye movements seen with PSP or severe autonomic insufficiency that occurs with MSA . (See “Differential diagnosis” above).
Neurodiagnostic testing is almost always unhelpful in the evaluation of suspected PD. The AAN systematic review and practice parameter published in 2006 found insufficient evidence to support or refute the value of certain ancillary tests for distinguishing PD from other parkinsonian syndromes, including magnetic resonance imaging (MRI), ultrasound of the brain parenchyma, 18F fluorodeoxyglucose (FDG) positron-emission tomography (PET), urodynamics, autonomic testing, and urethral or anal electromyography .
While neuroimaging is usually nondiagnostic in the evaluation of suspected PD, magnetic resonance imaging (MRI) of the brain should be performed to exclude specific structural abnormalities (eg, hydrocephalus, tumor, or lacunar infarcts). Brain MRI may also be helpful in patients with clinical findings that suggest atypical parkinsonism.
As examples, MRI may reveal thinning of the anteroposterior diameter of the midbrain with enlargement of the posterior third ventricle in moderate to advanced-stage PSP [30,31], and MRI may show atrophy of the brainstem and cerebellum in MSA, as well as putamenal hypointensity with a slit-like hyperintensity of the outer margin of the putamen on T2-weighted imaging [32,33]. However, the sensitivity of conventional MRI is suboptimal for distinguishing other parkinsonian syndromes from PD [1,34].
Newer MRI techniques
More advanced MRI techniques, including MR volumetry, MR spectroscopy, magnetization transfer imaging, diffusion-weighted MRI, and diffusion tensor MRI, are promising methods that may offer higher sensitivity than conventional MRI for separating atypical parkinsonian syndromes from idiopathic PD [1,34,35]. Further study is needed to establish the diagnostic utility of these methods.
PET and SPECT
Positron emission tomography (PET) and single photon emission computed tomography (SPECT) may be helpful for the early diagnosis of PD.
- With PET, decreased tracer uptake is seen in the mid- and posterior putamen of patients with early PD when compared with controls [36-38].
- Dopamine transporter imaging using beta-CIT SPECT can reliably distinguish patients with PD and other parkinsonian syndromes from controls or patients with essential tremor, but it cannot differentiate PD and the parkinsonian syndromes from one another . Moreover, the severity of the imaged dopamine transporter abnormality does not correlate with the degree of clinical impairment.
The availability of these tests is generally limited to research centers.
Brain parenchyma sonography (also called transcranial ultrasound) is being studied for its potential role in the preclinical diagnosis of PD [39,40]. Prospective studies in patients with early parkinsonism suggest that hyperechogenicity of the substantia nigra is predictive of the clinical diagnosis of PD . In addition, hyperechogenicity of the substantia nigra has been reported in 96 percent of patients with clinical PD compared with only 9 percent of patients with MSA or PSP , suggesting that sonography could be a useful tool to distinguish between PD and other parkinsonian syndromes. However, further research is necessary to establish the utility and diagnostic accuracy of this technique.
Olfactory testing is another promising method for the early diagnosis of PD , as olfactory dysfunction is common in PD. (See “Clinical manifestations of Parkinson disease”, section on Olfactory dysfunction).
In contrast, olfactory dysfunction is not associated with CBD or PSP, and is mild in MSA . Furthermore, it is not associated with vascular parkinsonism .
The 2006 AAN systematic review and practice parameter concluded that olfactory testing should be considered and is probably useful for distinguishing CBD and PSP from PD, but not PD from MSA . However, olfactory testing is rarely used in clinical practice as a diagnostic test for PD.
Testing of autonomic function, including urodynamic testing, urethral or anal sphincter EMG, sympathetic skin responses, Quantitative Sudomotor Axon Reflex Test, tilt table testing, and heart rate variability during forced respirations, has been examined as a potential tool for differentiating PD from other parkinsonian syndromes, especially MSA . These tests, however, are generally not widely available, and there is insufficient evidence to recommend their routine use as diagnostic tests for PD.
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Summary and Recommendations
An accurate diagnosis of Parkinson disease (PD) rests on the clinician’s ability to recognize its characteristic signs and associated symptoms (rest tremor, rigidity, akinesia, and gait disturbance), especially in the early stages.
- The differential diagnosis of PD is extensive. Essential tremor may be confused with PD. Furthermore, parkinsonism can be a prominent feature of several neurodegenerative disorders in addition to idiopathic PD. The most common of these is dementia with Lewy bodies. Less common are the atypical parkinsonian syndromes, such as corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). (See “Differential diagnosis” above).
- A wide variety of conditions can cause secondary parkinsonism. Of these, drug-induced parkinsonism is the most common, and antipsychotic and antiemetics drugs are the most frequent offenders. (See “Secondary parkinsonism” above).
- The diagnosis of PD during life is based on clinical impression; neurodiagnostic testing is almost always unhelpful. While a clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists. (See “Diagnosis” above and see “Diagnostic accuracy” above).
- Two of the three cardinal manifestations (tremor, bradykinesia, rigidity) must be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected. (See “Diagnosis” above and see “Clinical manifestations of Parkinson disease”).
- Features that are most useful for identifying patients with parkinsonism other than PD are the following:
– Falls at presentation and early in disease – Poor response to levodopa – Symmetry at onset – Rapid progression – Lack of tremor – Dysautonomia
(See “Features suggesting an alternative diagnosis” above).
- While there are no diagnostic tests for PD, we suggest brain MRI scan to exclude structural lesions. (See “Ancillary tests” above).
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