INTRODUCTION — Parkinsonism is a clinical syndrome presenting with any combination of bradykinesia, rest tremor, rigidity, and postural instability. The most common form of parkinsonism is Parkinson disease (PD), a chronic, progressive disorder caused by degenerative loss of dopaminergic neurons in the brain and characterized clinically by asymmetric parkinsonism and a clear, dramatic, and sustained benefit from dopaminergic therapy.
Because no diagnostic tests have been developed to distinguish PD from other forms of parkinsonism in vivo, PD remains a clinical diagnosis, based on the clinician's ability to recognize its characteristic signs and associated symptoms, especially in the early stages. An accurate clinical diagnosis is fundamental to the expectation that pharmacotherapy of PD will be effective. In general, the other forms of parkinsonism respond poorly to antiparkinson drugs.
This topic will review the diagnosis and differential diagnosis of PD. Other aspects of PD are discussed separately. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease" and "Clinical manifestations of Parkinson disease" and "Initial pharmacologic treatment of Parkinson disease" and "Nonpharmacologic management of Parkinson disease" and "Medical management of motor fluctuations and dyskinesia in Parkinson disease" and "Device-assisted and lesioning procedures for Parkinson disease".)
General approach — The diagnosis of PD during life is based upon its distinctive clinical features discerned from the history and neurologic examination. At a minimum, bradykinesia plus either tremor or rigidity must be present to consider the diagnosis of PD [1,2]. In addition, an unequivocal, beneficial response to dopaminergic therapy is an important supportive feature of the diagnosis, while the absence of an observable response to high-dose levodopa therapy (>1000 mg daily) in patients with at least a moderate severity of parkinsonism makes the diagnosis of PD extremely unlikely. (See "Clinical manifestations of Parkinson disease".)
Postural instability is also a feature of PD but usually does not appear until later in the course of the disease. Thus, patients with parkinsonian signs who exhibit postural instability early in the course of the illness most likely have another form of parkinsonism.
There are no physiologic, radiologic, or blood tests for confirming the clinical diagnosis of PD. Magnetic resonance imaging (MRI) is reasonable to perform to exclude rare, unexpected mimics of PD, such as stroke or hydrocephalus, but it is not necessary in a patient with a classic presentation of PD, no other neurologic signs, and a good response to levodopa therapy. Striatal dopamine transporter imaging (DaTscan) may be useful for occasional patients for whom the clinical diagnosis is unclear. (See 'Conventional MRI' below and 'DaTscan' below.)
While the true "gold standard" for a definitive diagnosis is neuropathologic examination, the gold standard for a clinical diagnosis according to criteria from the Movement Disorder Society (MDS) is an expert clinician (see 'Diagnostic criteria' below). Referral to a specialist or center with expertise in movement disorders is advised for patients with parkinsonian signs and symptoms when the diagnosis is uncertain.
Diagnostic criteria — Clinical diagnostic criteria for PD from the MDS (table 1) require the presence of motor parkinsonism (bradykinesia plus tremor or rigidity) as the central and essential feature of the disease (see 'Parkinsonism' below) . The determination that PD is the cause of motor parkinsonism requires the presence of supportive criteria (see 'Supportive criteria' below) to counterbalance the presence of any "red flags" (see 'Red flags' below) and requires the absence of absolute exclusion criteria. (See 'Absolute exclusion criteria' below.)
The MDS diagnostic criteria for PD specify that the examination of all cardinal manifestations of PD should be performed according to instructions in the MDS-Unified Parkinson Disease Rating Scale (MDS-UPDRS) .
Parkinsonism — Motor parkinsonism is an essential criterion of PD and requires both of the following :
●Rest tremor or rigidity
Bradykinesia is defined as slowness of movement plus a decrement in amplitude/speed or progressive hesitations/halts as movements are continued . Rigidity is a velocity-independent resistance (sometimes referred to as "lead-pipe resistance") to passive movement of the major joints while the patient is in a relaxed position. Rest tremor is a 4 to 6 Hz tremor that is observed in a fully resting limb and is suppressed when initiating movement. (See "Clinical manifestations of Parkinson disease", section on 'Cardinal features'.)
Supportive criteria — Supportive criteria are features that increase confidence in the diagnosis of PD :
●A clear benefit from treatment with dopaminergic drugs, especially if the response is dramatic. During initial treatment, the patient returns to normal or near-normal level of function. (Note that tremor may not respond to levodopa in some patients, but bradykinesia and rigidity should improve.) In the absence of clear documentation of initial response, a dramatic response can be classified as one of the following:
•A marked improvement with dose increases or marked worsening with dose decreases (mild changes do not qualify), documented either objectively (ie, by a >30 percent increase in the MDS-UPDRS part III motor score with change in treatment) or subjectively (ie, by a clear history of marked changes from a reliable patient or caregiver).
•Unequivocal and marked on-off fluctuations, which must have at some point included predictable end-of-dose wearing off.
●The presence of levodopa-induced dyskinesia.
●Rest tremor of a limb (usually unilateral at onset), documented on previous or current clinical examination.
●The presence of either olfactory loss or cardiac sympathetic denervation on metaiodobenzylguanidine (MIBG, iobenguane I-123) scintigraphy.
Red flags — Red flags are potential signs of alternate pathology, although with a low or uncertain specificity; these features argue against a diagnosis of PD :
●Rapid progression of gait impairment requiring the regular use of a wheelchair within five years of onset.
●A complete absence of progression of motor symptoms or signs over five or more years unless stability is related to treatment.
●Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, nasogastric tube feeding, or gastrostomy feeding) within the first five years.
●Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs.
●Severe autonomic failure in the first five years of disease. This can include:
•Orthostatic hypotension, defined as an orthostatic decrease of blood pressure within three minutes of standing by at least 30 mmHg systolic or 15 mmHg diastolic, in the absence of dehydration, medication, or other diseases that could plausibly explain autonomic dysfunction, or
•Severe urinary retention or urinary incontinence in the first five years of disease (excluding long-standing or small amount stress incontinence in females) that is not simply functional incontinence. In males, urinary retention must not be attributable to prostate disease, and must be associated with erectile dysfunction.
●Recurrent (more than once a year) falls because of impaired balance within three years of onset.
●Disproportionate anterocollis (involuntary flexion of the neck) (figure 1) or contractures of hand or feet within the first 10 years.
●Absence of any of the common nonmotor features of PD despite five years' disease duration. These include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of rapid eye movement sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations).
●Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response).
●Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination.
Absolute exclusion criteria — Absolute exclusion criteria are specific signs of alternate diagnoses incompatible with a diagnosis of PD; the presence of any of these features rules out PD :
●Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (eg, sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades).
●Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades.
●Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia (see "Frontotemporal dementia: Clinical features and diagnosis", section on 'Diagnostic criteria for PPA' and "Frontotemporal dementia: Clinical features and diagnosis", section on 'Diagnostic criteria for bvFTD') within the first five years of disease.
●Parkinsonian features restricted to the lower limbs for more than three years.
●Treatment (currently or within the past year) with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time course consistent with drug-induced parkinsonism. (See "Drug-induced parkinsonism".)
●Absence of observable response to high-dose levodopa despite at least moderate severity of disease.
●Unequivocal cortical sensory loss (ie, agraphesthesia, astereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia.
●Either documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient's symptoms, or the expert evaluating clinician, based on the full diagnostic assessment, thinks that an alternative syndrome is more likely than PD.
Applying the criteria — The MDS criteria distinguish clinically established PD, which maximizes specificity over sensitivity, and clinically probable PD, which attempts to balance sensitivity and specificity .
The diagnosis of clinically established PD requires all of the following :
●The presence of parkinsonism (see 'Parkinsonism' above)
●No absolute exclusion criteria (see 'Absolute exclusion criteria' above)
●At least two supportive criteria (see 'Supportive criteria' above)
●No red flags (see 'Red flags' above)
The diagnosis of clinically probable PD requires :
●The presence of parkinsonism (see 'Parkinsonism' above)
●No absolute exclusion criteria (see 'Absolute exclusion criteria' above)
•If one red flag is present, there must also be at least one supportive criterion
•If two red flags, at least two supportive criteria are needed
•No more than two red flags are allowed for this category
Response to dopaminergic therapy — A clear benefit from dopaminergic therapy is an important supportive feature for establishing the diagnosis of PD, especially if the response is dramatic (table 1). In some patients, tremor may not show significant improvement with levodopa, but bradykinesia and rigidity should improve. 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 multiple system atrophy (MSA) may respond initially to levodopa , as may a substantial proportion of those with vascular parkinsonism .
In practice, when patients have mild parkinsonian symptoms that do not interfere with daily activities, it may not be advisable to institute dopaminergic therapy purely for diagnostic purposes. When symptoms begin to limit a patient's quality of life, a sustained long-term trial of levodopa or dopamine agonist therapy is appropriate for both diagnostic and therapeutic purposes. Dopamine agonists should be used with caution if at all in older adults. (See "Initial pharmacologic treatment of Parkinson disease".)
The majority of patients with idiopathic PD will enjoy a significant therapeutic response to an adequate long-term trial of moderate doses of levodopa (eg, 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. In accordance with this, the absence of an observable response to high-dose levodopa despite at least moderate severity of parkinsonism is considered an absolute exclusion criterion for the diagnosis of PD . (See 'Absolute exclusion criteria' above.)
An acute dopaminergic challenge test (as opposed to a sustained long-term trial) consists of rater-blinded assessment of parkinsonian symptoms using the MDS-UPDRS part III motor score before and after a dose of levodopa (eg, carbidopa-levodopa 25/250 mg) or subcutaneous apomorphine (usual dose, 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 MDS-UPDRS motor score (usually in the range of 15 to 30 percent or more) one hour after levodopa administration or 20 minutes after apomorphine injection [6,7].
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, and some expert consensus guidelines now advise against it in favor of a sustained (chronic) trial . 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
Diagnostic accuracy — While the clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis at initial visit can be suboptimal. In a systematic review and meta-analysis that included 11 studies using neuropathologic findings as the diagnostic gold standard, the pooled diagnostic accuracy of PD was approximately 80 percent . The most likely explanation for diagnostic error is that other parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and 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' below.)
The diagnostic accuracy for PD is higher in patients who have a clear response to dopaminergic medications, motor fluctuations, dyskinesia, or a longer duration of disease at the initial clinical visit, compared with those who lack these characteristics . In the 2016 systematic review and meta-analysis, the diagnostic accuracy of PD for patients followed by movement disorders specialists was 84 percent , and accuracy may be even higher when patients are followed closely throughout the long course of illness.
Ancillary tests — Neurodiagnostic testing is almost always unnecessary in the evaluation of suspected PD, and the diagnosis is primarily clinical. In specific circumstances, ancillary testing is used to rule out alternative disorders or clarify the diagnosis when clinical symptomatology is atypical.
Conventional MRI — While neuroimaging is usually nondiagnostic in the evaluation of suspected PD, MRI of the brain may 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 [14-16], and MRI may show atrophy of the brainstem and cerebellum in MSA, as well as putaminal hypointensity with a slit-like hyperintensity of the outer margin of the putamen on T2-weighted imaging [17,18]. However, the sensitivity of conventional MRI is suboptimal for distinguishing other parkinsonian syndromes from PD [19,20].
Nevertheless, brain MRI is not necessary in a patient with a classic presentation of PD, no other neurologic signs, and a good response to levodopa therapy.
Advanced MRI techniques — More advanced MRI techniques, including magnetic resonance (MR) volumetry, MR spectroscopy (MRS), magnetization transfer imaging, diffusion-weighted MRI, diffusion tensor MRI, and high-resolution imaging (eg, MRI at 7 Tesla), are methods that may offer higher sensitivity than conventional MRI for detecting the neuroimaging correlates of PD neurodegeneration and for separating idiopathic PD from atypical parkinsonian syndromes [21-29]. As an example, loss of dorsolateral nigral hyperintensity on iron-sensitive MRI sequences at 3 and 7 Tesla is observed in neurodegenerative parkinsonian disorders, including PD, MSA, and PSP, compared with healthy controls [30-32]. Further study is needed to establish the diagnostic utility of these methods.
DaTscan — Striatal dopamine transporter imaging using 123I-FP-CIT single-photon emission computed tomography (DaTscan) can reliably distinguish patients with PD and other parkinsonian syndromes associated with nigrostriatal degeneration (ie, MSA, PSP, and corticobasal degeneration [CBD]) from controls or patients with essential tremor (ET), but it cannot differentiate PD and the other parkinsonian syndromes from one another [19,33-35]. The available evidence suggests that the overall accuracy of DaTscan for parkinsonian syndromes is equal to but not better than the accuracy of a carefully obtained clinical diagnosis .
If one assumes that the detection of a striatal dopamine deficiency by DaTscan is the diagnostic gold standard for parkinsonian syndromes, then the sensitivity of the clinical diagnosis is high in both early and advanced PD. However, the specificity varies with the duration of the illness; the clinical diagnosis in advanced PD has a high specificity, while the clinical diagnosis in early PD has a specificity of only 67 percent . (See "Glossary of common biostatistical and epidemiological terms", section on 'Measures of diagnostic test performance'.)
Based upon the data [36,37] and our clinical experience, we suggest the use of DaTscan for the following scenarios:
●Patients for whom the diagnosis is unclear after serial clinical evaluations, such as those with long-standing ET whose tremor evolves to have characteristics of PD but fails to respond unequivocally to levodopa
●Patients suspected of having drug-induced parkinsonism (striatal uptake of the isotope should be normal in this setting) (see "Drug-induced parkinsonism")
●Patients who are possible candidates for deep brain stimulation but for whom the diagnosis of ET versus PD versus some other cause (eg, dystonia) is unclear and where an accurate diagnosis determines the target of deep brain stimulation (eg, thalamic ventral intermediate nucleus versus subthalamic nucleus/globus pallidus interna)
●To firmly establish the presence of nigrostriatal dopamine deficiency when recruiting for a clinical trial, particularly if the focus is neuroprotection
The widespread availability of DaTscan outside of specialized medical centers has led to instances of misinterpreted results because of inaccurate clinical diagnosis and/or inexperienced nuclear medicine practitioners. Therefore, consultation with a movement disorders specialist is recommended to determine the utility of ordering a DaTscan [36,38].
Of note, the use of DaTscan led to the discovery of patients who had "scans without evidence of dopaminergic deficits" (SWEDD). These patients typically have a relatively isolated upper extremity resting and postural tremor resembling early PD but fail to evolve over time into more generalized PD. (See 'Scans without evidence of dopaminergic deficit (SWEDD)' below.)
PET — Positron emission tomography employs several different types of ligands that can assess the integrity of dopaminergic neurons, including ligands that bind to the dopamine transporter and vesicular monoamine transporter, as well as [18F]-fluorodopa, a marker of striatal aromatic amino acid decarboxylase (AADC) activity. All of these ligands show decreased uptake in the caudate and putamen in patients with early PD compared with controls [39-41].
With 18-F fluorodeoxyglucose-PET (FDG-PET), which reveals regional cerebral glucose metabolism, patients with PD have a relative increase in metabolism of the pallidum, posterior putamen, and pons along with a relative decrease in metabolism of certain frontal and parieto-occipital regions.
The results of several studies suggest that the diagnostic accuracy of FDG-PET is greater than that of striatal dopamine transporter imaging for discriminating PD from atypical parkinsonian syndromes  and that FDG-PET has a good specificity for distinguishing the different atypical parkinsonian syndromes [42-44]. However, these studies generally rely on computer-assisted comparisons and are not optimized for clinical decision-making using visual scan inspection in individual patients.
Sonography — Brain parenchyma sonography (also called transcranial ultrasound) is being studied for its potential role in the diagnosis of PD [45,46]. Prospective studies in patients with early parkinsonism suggest that hyperechogenicity of the substantia nigra is predictive of the clinical diagnosis of PD . Hyperechogenicity of the substantia nigra has been reported in approximately 90 percent of patients with clinical PD compared with approximately 10 percent of patients with MSA, PSP, or SWEDD (see 'Scans without evidence of dopaminergic deficit (SWEDD)' below) [48,49]. These data suggest that sonography could be a useful tool to distinguish between PD and other parkinsonian syndromes. In addition, in studies of subjects older than age 50 years without evidence of PD or other neurodegenerative disease, hyperechogenicity of the substantia nigra appears to be a risk marker for the development of PD [50,51]. However, further research is necessary to establish the utility and diagnostic accuracy of this technique .
Olfactory testing — Olfactory testing is considered useful for differentiating PD from other parkinsonian disorders [1,53-57]. Olfactory dysfunction is common in PD (see "Clinical manifestations of Parkinson disease", section on 'Olfactory dysfunction') but is not associated with CBD, PSP, or ET and is mild or nonexistent in MSA . Furthermore, it is not associated with vascular parkinsonism .
The presence of olfactory loss is one of the supportive criteria in the MDS clinical diagnostic criteria for PD (table 1), though olfactory testing is seldom used in clinical practice. However, test materials such as the University of Pennsylvania Smell Identification Test and Sniffin Sticks are commercially available.
Autonomic testing — Cardiac sympathetic denervation, as documented on MIBG myocardial scintigraphy, is relatively sensitive and specific for distinguishing PD from other neurodegenerative causes of parkinsonism . Cardiac sympathetic denervation documented by MIBG scintigraphy is one of the supportive criteria in the MDS clinical diagnostic criteria for PD (table 1).
Other tests 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, have been examined as potential tools for differentiating PD from other parkinsonian syndromes, especially MSA . These tests are not widely available, and there is insufficient evidence to recommend their routine use as diagnostic tests for PD.
Role of genetic testing — Molecular genetic testing is available for many of the monogenic forms of PD, including synuclein alpha (SNCA), parkin (PRKN), PTEN-induced putative kinase 1 (PINK1), Parkinsonism associated deglycase (DJ-1 or PARK7), and leucine rich repeat kinase 2 (LRRK2) . Although identification of a genetic variant of PD does not change symptomatic management, there are ongoing clinical trials of therapies for specific genetic forms of parkinsonism [10,62,63]. We therefore discuss and offer genetic testing in the following individuals with PD: those with early-onset PD (younger than 40 years of age), those who have a first-degree relative with PD, and those from a population with a higher prevalence of a monogenic form of PD, such as Ashkenazi Jewish or North African Berber .
DIFFERENTIAL DIAGNOSIS — 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 (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) (table 2) [19,64]. Furthermore, parkinsonism is seen in a wide variety of other conditions (secondary parkinsonism) [19,64]. Distinguishing PD from these parkinsonian syndromes can be difficult, particularly in the early stages of disease. Essential tremor (ET) may also be confused with PD because tremor is a key feature of both disorders.
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 "Essential tremor: Clinical features and diagnosis".)
ET usually affects both hands and arms, and it can also involve the head, voice, chin, trunk, and legs. Isolated tremor of the chin or lips is more likely to be a manifestation of PD. ET typically becomes immediately apparent in the arms when they are held outstretched or when they are engaged in activities such as writing or eating. ET is most often symmetric but can be asymmetric or, rarely, unilateral, particularly early in the course of ET.
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, and patients with severe ET may have a rest component to their tremor. Furthermore, some patients with PD may have a re-emergent tremor: a postural tremor that manifests after a latency of several seconds with a frequency typical of the rest tremor in PD [65,66]. This distinction is important, as patients with a re-emergent rest tremor may be misdiagnosed as having ET .
The presence of subtle bradykinesia, rigidity, or micrographia in older adults with a diagnosis of ET may support the diagnosis of PD, although these signs may also be a nonspecific accompaniment of aging. (See "Overview of tremor", section on 'Essential tremor'.)
Scans without evidence of dopaminergic deficit (SWEDD) — The term "scans without evidence of dopaminergic deficit" (SWEDD) has been used to designate patients with relatively isolated upper extremity resting and postural tremor resembling early PD who fail to evolve over time into more generalized PD . Unlike patients with typical PD, these individuals lack evidence for nigrostriatal dopamine deficiency on dopamine transporter imaging (see 'DaTscan' above). Patients with SWEDD, estimated to represent approximately 10 percent of people with a diagnosis of parkinsonism, sometimes exhibit reduced arm swing and mild focal dystonia on the affected side, and they may have jaw or head tremor or facial hypomimia, but no signs of parkinsonian akinesia . Some affected individuals may have dystonic tremor or monogenic forms of adult-onset myoclonus-dystonia [68-70].
In a longitudinal study of 91 patients with newly-diagnosed PD who had SWEDD, the diagnosis was changed from PD to another neurologic disorder in almost half after 22 months (compared with only 4 percent of patients with a dopaminergic deficit) because of lack of clinical progression and no change in striatal dopamine binding on follow-up scans . A systematic review concluded that the term "SWEDD" does not represent a single clinical entity; most cases labeled as SWEDD have a variety of other clinical conditions misdiagnosed as PD, but a small proportion may have PD based upon evidence including a positive response to levodopa, clinical progression characteristic of PD, or other imaging or genetic evidence .
Dementia with Lewy bodies — DLB is the second most common cause of neurodegenerative dementia after Alzheimer disease and is characterized clinically by dementia with visual hallucinations, fluctuating cognition, rapid eye movement sleep behavior disorder, and parkinsonism. Other associated symptoms include repeated falls, syncope, autonomic dysfunction, neuroleptic sensitivity, delusions, hallucinations in nonvisual modalities, and depression. (See "Clinical features and diagnosis of dementia with Lewy bodies".)
The majority of patients with PD eventually develop dementia (see "Cognitive impairment and dementia in Parkinson disease", section on 'Incidence and prevalence'). The differentiation of PD dementia (PDD) from DLB is arbitrary, based on criteria (table 3) established by a consensus conference . According to these criteria, dementia in PDD occurs in the setting of well-established parkinsonism more than a year after onset of motor symptoms, while in DLB, dementia usually occurs concomitantly with or before the development of parkinsonian signs or no more than a year after onset of motor symptoms. Thus, patients are classified as having PDD if parkinsonism is present for more than one year before the onset of dementia. The overlap between these two clinical entities and the uncertainty of the one-year rule continue to provoke debate about the validity of existing nomenclature . Intraneuronal aggregation of alpha-synuclein is the underlying pathology of PD and DLB. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Pathology' and "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies", section on 'Pathology'.)
Multiple system atrophy — MSA is a neurodegenerative disorder that encompasses syndromes previously known as olivopontocerebellar atrophy, striatonigral degeneration, and Shy Drager.
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 and poor response to levodopa suggests this diagnosis rather than PD. However, early in the course, some cases of MSA may resemble typical PD in every way, including responsiveness to levodopa along with the presence of motor fluctuations and dyskinesia, only to evolve into the more typical profile of MSA later. Cognitive function in MSA tends to be relatively well preserved compared with PD and other parkinsonian syndromes, probably reflecting a lesser degree of cortical involvement. (See "Multiple system atrophy: Clinical features and diagnosis".)
Aggregation of alpha-synuclein is also the underlying pathology of MSA, except that it affects oligodendroglia instead of neurons . In addition, subtle differences exist in the conformation of alpha-synuclein aggregates in the two disorders, which may eventually be leveraged diagnostically . (See "Multiple system atrophy: Epidemiology, pathology, and pathogenesis", section on 'Pathology'.)
Corticobasal degeneration — CBD (also known as corticobasal syndrome [CBS] when applied to clinical diagnoses) is a rare but usually distinctive form of degenerative parkinsonism, which can mimic PD in its early phase largely based on the asymmetric onset of motor symptoms.
The classic description of CBD is that of a progressive asymmetric movement disorder with symptoms initially affecting one limb, including various combinations of akinesia and extreme rigidity, dystonia, focal myoclonus, ideomotor apraxia, and alien limb phenomenon (table 4). Cognitive impairment is a common manifestation of CBD and may be a presenting feature, while the parkinsonian motor features may emerge later as the disease progresses. Important cognitive features of CBD include executive dysfunction, aphasia, apraxia, behavioral change, and visuospatial dysfunction, with relatively preserved episodic memory. The distinctive clinical phenotype and the lack of clear response to an adequate trial of levodopa are typical for CBD and help to distinguish it from PD. (See "Corticobasal degeneration", section on 'Clinical features' and "Corticobasal degeneration", section on 'Diagnosis'.)
The underlying pathology of CBD is an intracellular aggregation of the microtubule-associated protein, tau (picture 1). Because the cognitive and motor features considered characteristic of CBD are not specific to CBD, the term CBS is used for cases with a clinical diagnosis, while CBD is reserved for cases with neuropathologic confirmation. (See "Corticobasal degeneration", section on 'Pathology and pathophysiology' and "Corticobasal degeneration", section on 'History and nomenclature'.)
Progressive supranuclear palsy — PSP is an uncommon but not rare parkinsonian syndrome that can mimic PD in its early phase.
PSP has several distinct clinical phenotypes. The phenotype known as PSP-parkinsonism, characterized by asymmetric onset of limb symptoms, tremor, and a moderate initial therapeutic response to levodopa, may be confused with idiopathic PD early in the course, before characteristic vertical gaze abnormalities emerge . With the most common "classic" phenotype of PSP, known as Richardson syndrome, the typical initial feature is a disturbance of gait resulting in falls. Supranuclear vertical ophthalmoparesis or ophthalmoplegia is the hallmark of PSP (table 5A-B). Dysarthria, dysphagia, rigidity, frontal cognitive abnormalities, and sleep disturbances are additional common clinical features. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Clinical characteristics' and "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Variant phenotypes'.)
PSP, like CBD, is also a tau disorder (picture 2), and the two entities can resemble each other clinically. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Pathology and pathophysiology'.)
Idiopathic and familial basal ganglia calcification — Idiopathic basal ganglia calcification (IBGC), also known as bilateral striopallidodentate calcinosis, Fahr syndrome, or Fahr disease, is a rare neurodegenerative condition characterized by the accumulation of calcium deposits in the basal ganglia and other brain regions, most easily visualized on computed tomography (CT) scan, and a variable phenotype that can include one or more features of parkinsonism, chorea, dystonia, cognitive impairment, or ataxia [78,79]. Onset of symptoms usually occurs between ages 20 and 60 [78,80].
The familial form of IBGC, now termed "primary familial brain calcification" (PFBC), is usually inherited in autosomal dominant fashion and is genetically heterogeneous [81,82]. Estimated penetrance is variable, ranging from 50 to 85 percent depending on the variant . There are several causative variants for PFBC, listed in approximate order of prevalence:
●The solute carrier family 20 member 2 (SLC20A2) gene on chromosome 8p11.2 
●The xenotropic and polytropic retrovirus receptor 1 (XPR1) gene on chromosome 1q25.3 
●The myogenesis regulating glycosidase (MYORG) gene on chromosome 9p13.3 (autosomal recessive) 
●The platelet-derived growth factor subunit B (PDGFB) gene on chromosome 22q13.1 [87,88]
●The platelet-derived growth factor receptor beta (PDGFRB) gene on chromosome 5q32 
●The junctional adhesion molecule 2 (JAM2) gene on chromosome 21q21.3 (autosomal recessive) [90,91]
The sporadic (IBGC) and familial (PFBC) forms of brain calcification are not associated with disorders of calcium or parathyroid hormone metabolism, such as hypoparathyroidism or pseudohypoparathyroidism. However, these disorders can be associated with intracranial and basal ganglia calcification on imaging, similar to that seen in IBGC and PFBC. More limited basal ganglia calcification is a nonspecific neuroimaging finding seen in a number of infectious, metabolic, and genetic conditions . It is also an incidental finding in approximately 1 percent of head CT scans [93-95].
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 disorders:
●Huntington disease (rigid form) (table 6) (see "Huntington disease: Clinical features and diagnosis")
●Frontotemporal dementia with parkinsonism linked to chromosome 17 (see "Frontotemporal dementia: Clinical features and diagnosis")
Secondary parkinsonism — A wide variety of conditions can cause secondary parkinsonism. Among these, drug-induced parkinsonism is most often encountered. 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 (table 2).
●Drug-induced parkinsonism – A variety of drugs, including first- and second-generation antipsychotic agents, metoclopramide, prochlorperazine, tetrabenazine, and valproic acid (table 8 and algorithm 1), can cause parkinsonism that is clinically indistinguishable from idiopathic PD. Parkinsonism can take up to a year to resolve after discontinuation of an offending agent, and therefore it is important to review both current and past medications. The presence of orofacial dyskinesia or other tardive movements may be a clue to medication exposure.
Persistent or progressive motor symptoms despite drug withdrawal may represent early or "unmasked" PD and are an indication for DaTscan (algorithm 1). Clinical features, diagnosis, and management are reviewed in detail separately. (See "Drug-induced parkinsonism".)
●Toxic exposure – Toxins that can cause parkinsonism include carbon disulfide, carbon monoxide, cyanide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), manganese, and organic solvents.
●Structural or traumatic – Structural lesions can affect striatonigral circuits either directly or via mass effect. Examples include hydrocephalus, chronic subdural hematoma, and primary or secondary brain tumors. (See "Normal pressure hydrocephalus" and "Overview of the clinical features and diagnosis of brain tumors in adults".)
Head trauma, isolated or repeated (eg, boxing), can result in parkinsonism or so-called dementia pugilistica. Parkinsonism has also been described as a feature of chronic traumatic encephalopathy. (See "Sequelae of mild traumatic brain injury", section on 'Chronic traumatic encephalopathy'.)
●Metabolic disorders – In rare cases, basal ganglia dysfunction or injury can result from hypoparathyroidism, pseudohypoparathyroidism, chronic liver failure, extrapontine myelinolysis, and end-stage kidney disease with diabetes. An increased risk of parkinsonism has also been associated with type 2 diabetes .
●Neurogenetic disorders – Parkinsonism is a prominent feature of Wilson disease, neurodegeneration with brain iron accumulation, and neuroacanthocytosis. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history" and "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation' and "Neuroacanthocytosis".)
●Infections – Infectious causes of parkinsonism include encephalitis lethargica or Economo's encephalitis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), neurosyphilis, prion disease, progressive multifocal leukoencephalopathy, and toxoplasmosis. (See "Approach to the patient with HIV and central nervous system lesions" and "Neurosyphilis" and "Diseases of the central nervous system caused by prions" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
●Cerebrovascular disease ("vascular parkinsonism") – It should be noted that this entity is controversial [19,97-100], in part because most basal ganglia infarcts are not associated with parkinsonian signs [101,102]. Nevertheless, neuropathologic evidence suggests that mild parkinsonian signs in old age, particularly parkinsonian gait, are associated with the presence of macroscopic infarcts, microscopic infarcts, and arteriolosclerosis (ie, small vessel disease) . (See "Etiology, clinical manifestations, and diagnosis of vascular dementia", section on 'Clinical features'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parkinson disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Parkinson disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Parkinson disease symptoms and diagnosis (Beyond the Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Parkinson disease".)
SUMMARY AND RECOMMENDATIONS
•Bradykinesia plus tremor or rigidity – At a minimum, bradykinesia plus either tremor or rigidity must be present. (See 'Parkinsonism' above.)
•Response to dopaminergic therapy – An unequivocal, beneficial response to dopaminergic therapy is an important supportive feature of the diagnosis, while the absence of an observable response essentially rules out the diagnosis of PD. (See 'Response to dopaminergic therapy' above.)
•Other supportive features – Additional supportive features are a marked improvement with dopaminergic dose increases or marked worsening with dose decreases, unequivocal and marked "on-off" fluctuations, the presence of levodopa-induced dyskinesia, rest tremor of a limb, and the presence of either olfactory loss or cardiac sympathetic denervation on metaiodobenzylguanidine (MIBG, iobenguane I-123) scintigraphy. (See 'Supportive criteria' above.)
•Red flags and exclusions – "Red flags" are features that suggest an alternative cause of parkinsonism, while absolute exclusion criteria are signs incompatible with a diagnosis of PD. The determination that PD is the cause of motor parkinsonism requires the presence of supportive criteria (see 'Supportive criteria' above) to counterbalance the presence of any "red flags" (see 'Red flags' above) and requires the absence of absolute exclusion criteria. (See 'Absolute exclusion criteria' above.)
●Role of imaging – There are no diagnostic tests for PD. A brain MRI scan can be helpful to exclude structural lesions but is not necessary in a patient with a classic presentation of PD, no other neurologic signs, and a good response to levodopa therapy. (See 'Conventional MRI' above and 'Advanced MRI techniques' above.)
Striatal dopamine transporter imaging (DaTscan) may also be useful for occasional patients for whom the clinical diagnosis is unclear. (See 'DaTscan' above.)
●Differential diagnosis – The differential diagnosis of PD is extensive (table 2).
•Predominant tremor – Essential tremor (ET) may sometimes be confused with PD when tremor is predominant. Other patients may have relatively isolated upper extremity resting and postural tremor that resemble early PD but do not evolve over time into more generalized PD. (See 'Essential tremor' above and 'Scans without evidence of dopaminergic deficit (SWEDD)' above.)
•Other neurodegenerative disorders – Parkinsonism can be a prominent feature of several other neurodegenerative disorders, the most common of which is dementia with Lewy bodies (DLB) (table 3). Less common are the atypical parkinsonian syndromes, such as multiple system atrophy (MSA), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). (See 'Differential diagnosis' above.)
•Secondary parkinsonism – A wide variety of conditions can cause secondary parkinsonism. Of these, drug-induced parkinsonism is the most common, and antipsychotic and antiemetic drugs are the most frequent offenders (table 8). (See 'Secondary parkinsonism' above.)
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