Parkinson disease (PD) is a neurodegenerative condition that involves the progressive depletion of dopaminergic neurons in the basal ganglia, particularly the substantia nigra. The disease most commonly manifests at approx. 60 years of age. PD is predominantly considered an idiopathic disease but genetic factors play a role in approx. 10–15% of cases and, accordingly, familial clustering has been observed. A core clinical feature of PD is parkinsonism, a syndrome that comprises bradykinesia along with resting tremor and/or rigidity. Postural instability is a common finding in later stages of PD. Parkinsonism that results from medication, intoxication, or traumatic brain injury is referred to as secondary parkinsonism. Parkinsonism due to neurodegenerative disorders other than PD is called atypical parkinsonism and manifests with features that are not characteristic of PD, such as vertical gaze palsy in progressive supranuclear palsy and apraxia and agnosia in corticobasal degeneration. The diagnosis is clinical; diagnostic testing may be considered to rule out alternative diagnoses. There is currently no cure for PD. Symptomatic treatment includes physical therapy and, depending on patient factors and individual symptoms, certain medications (e.g., levodopa, dopamine agonists). Deep brain stimulation surgery may be beneficial in specific cases.
- Prevalence: second most common neurodegenerative disorder following Alzheimer disease 
- Age of onset: ∼ 60 years in sporadic cases 
- Risk factors
Epidemiological data refers to the US, unless otherwise specified.
- Contributing genetic factors include:
- α-Synuclein (SNCA)
- Glucocerebrosidase (GBA): A mutation in the GBA gene (the same gene associated with Gaucher disease) is the most common genetic risk factor for PD. GBA mutations are associated with altered autophagy and lysosomal function, potentially resulting in impairment of α-synuclein clearance.
- Dardarin (LRRK2): A mutation in LRRK2 gene is the most common cause of dominantly inherited PD.
- Parkin (PARK2): A mutation in PARK2 gene is the most common cause of recessively inherited PD.
Medication (drug-induced parkinsonism or pseudoparkinsonism)
- Most frequent cause of secondary parkinsonism 
- Frequent use of drugs with considerable antidopaminergic effects: typical antipsychotics (e.g., haloperidol), some antiemetics (e.g., metoclopramide), some calcium channel blockers (e.g., flunarizine), amiodarone, valproate, and lithium 
- MPTP: an illegal drug that metabolizes to MPP+, damaging the substantia nigra
- Metabolic disorders: e.g., , hemochromatosis, Niemann-Pick disease
- Toxins: e.g., manganese, carbon monoxide, carbon disulfide
- Cerebrovascular disease (vascular parkinsonism): subcortical arteriosclerotic encephalopathy
- CNS infections
- : depends on the underlying disease (e.g., genetic abnormalities in )
- Progressive dopaminergic neuron degeneration in the substantia nigra (part of the basal ganglia) and the locus coeruleus → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of PD 
- Indirect pathway of the basal ganglia is affected (see “Basal ganglia” in “ ”)
- Serotonin and noradrenaline depletion (in the raphe nuclei): likely cause of depressive symptoms
- Acetylcholine surplus (in the nucleus basalis of Meynert): likely cause of dyskinesia
- Signs of PD gradually progress over time: The course is usually > 10 years.
- Motor signs are unilateral at onset but may progress to the contralateral side.
- Motor signs are asymmetrical (i.e., more pronounced on one side than on another).
- Preclinical (prodromal) stage with nonmotor signs may precede the onset of motor signs (clinical phase).
Preclinical stage 
- Sleep disturbances
- Mood disorders (most commonly depression, apathy, and/or anxiety)
Motor signs 
Parkinsonism: a syndrome comprising bradykinesia and either resting tremor or rigidity (or both) and that is consistent with impairment of the extrapyramidal system
- A core feature of PD
- Can be also seen in a variety of other disorders, e.g., multiple system atrophy, corticobasal degeneration (see “ ”)
- Bradykinesia: slowed movements in combination with decreased amplitude/speed when moving
- (4–6 Hz)
Rigidity: increased and persistent resistance to passive joint movement that is independent of speed
- Froment maneuver: patient is asked to perform repetitive movements in the contralateral extremity (e.g., opening and closing of the left fist if the right side is examined) → subclinical rigidity becomes more pronounced and may be detected
- A phenomenon caused by the overlay of increased muscle tonus and resting tremor in patients with PD
- May manifest before tremor becomes clinically apparent
- Muscles in an extremity (most commonly the arms) are passively stretched, eliciting a jerking-like motion.
- Muscle tone should be tested with at least two joints.
- Imbalance and tendency to fall
- Evaluated with the pull test
- Parkinsonian gait: shuffling gait with quickened and shortened steps
- Freezing: sudden inability to start or continue movements
- Festination: gait pattern characterized by small, increasingly quick steps
- Propulsion: forward-leaning gait with a risk of a patient falling forward
- Decreased arm swing
- Other motor findings
Parkinsonism is required for the diagnosis of Parkinson disease. Unilateral onset is characteristic of Parkinson disease.
- Autonomic symptoms
- Neuropsychiatric symptoms
- Cognitive problems, e.g., decreased attention and concentration, executive dysfunction, impaired memory (Parkinson dementia): develop in advanced disease 
- Behavioral changes (e.g., irritability, impulsivity)
- Disordered sleep (sleep fragmentation, vivid dreams)
- Hyposmia, anosmia
- Consider PD in patients with parkinsonism.
- Perform a thorough clinical evaluation.
- Consider diagnostic testing to:
- Provide diagnostic certainty if a diagnosis cannot be made based on clinical features alone
- Help rule out alternative diagnoses of parkinsonism
- Refer to a neurologist or movement disorder specialist for diagnostic confirmation.
Parkinson disease is a clinical diagnosis. A definitive diagnosis requires postmortem confirmation of .
Clinical evaluation 
- Evaluate for typical based on:
- Assess for:
- Supportive features of PD
- Atypical features for PD suggesting other causes of parkinsonism
- A diagnosis can be made by a specialist using diagnostic criteria (see “Tips and Links”).
Supportive features 
- A diagnosis of PD requires the presence of parkinsonism (i.e., bradykinesia and either resting tremor, rigidity, or both).
- Supportive features include:
Consider other causes of parkinsonism if any of the following are present :
- Absence of typical nonmotor signs
- Disease trajectory
Distribution of symptoms
- Bilateral symmetric parkinsonism
- Limited to legs
- History suggestive of alternative causes
If patients have atypical features for PD, evaluate for or .
Imaging  
Imaging is not routinely required for diagnosis but can be considered under specialist guidance if the diagnosis is unclear.
- MRI brain: usually no specific changes, nonspecific atrophy of the putamen may be seen in patients with PD
- DaTSCAN: SPECT with visualization of striatal dopamine transporters using 123I-ioflupane
- Iodobenzamide single-photon emission computed tomography (IBZM-SPECT): measures D2-receptor density in the striatum 
Other modalities (rarely used)
- Transcranial sonography
Ancillary tests are not routinely used but can support the diagnosis.
- Levodopa challenge test: performed to support the diagnosis of PD or as part of the evaluation prior to implantation of a deep brain stimulator
- Olfactory testing: to test for hyposmia 
- MIBG myocardial scintigraphy: to test for cardiac sympathetic denervation
- Lewy bodies
- Loss of dopaminergic neurons in substantia nigra pars compacta, causing depigmentation of substantia nigra on gross and microscopic examination
- Reactive gliosis is found within the areas of neural degeneration. 
|Differential diagnoses of Parkinson disease |
|Characteristics||Parkinson disease||Vascular parkinsonism||Multiple system atrophy||Progressive supranuclear palsy||Corticobasal degeneration|
|Usual onset age|| || || || || |
|Average survival|| || || || || |
|First symptoms|| || |
|Symmetricity|| || || || || |
|Tremor|| || || || |
|Postural instability|| || || || || |
|Rigidity|| || |
|Other clinical signs|
|Eye movements|| || || || |
|Bulbar dysfunction|| || || |
|Other specific features|
|Imaging|| || || |
The differential diagnoses listed here are not exhaustive.
General principles 
- Offer supportive care to all patients.
- Initiate pharmacotherapy when symptoms start to cause functional impairment.
- Consult a neurologist or movement disorder specialist before initiating or changing treatment.
- Manage associated symptoms (e.g., major depressive disorder, dementia) as necessary.
Pharmacotherapy does not alter the disease trajectory in PD; initiate when symptoms interfere with quality of life.
Supportive care 
- Fall prevention 
- Sleep hygiene
- Prognosis and end-of-life choices should be discussed early.
- Consider palliative care as needed.
Choose initial therapy based on individual patient factors (e.g., motor symptoms, age, comorbidities). To delay levodopa-based treatment for as long as possible, various age thresholds were previously recommended. 
- Commonly used options for initial monotherapy include levodopa, a dopamine agonist, or an MAO-B inhibitor.
Risk factors for levodopa-induced dyskinesia include: 
- Young age
- Low body weight
- Female sex
- Severe disease
- In patients with refractory symptoms or intolerable adverse effects that require dose reduction, consider:
- Switching monotherapy
- Combination therapy
- Avoid abrupt discontinuation or sudden changes in medication.
- Consider enteral infusion of levodopa or deep brain stimulation for patients with advanced disease and severe motor fluctuations.
- See “” for additional information on mechanisms of action and adverse effects.
Avoid abrupt discontinuation or sudden changes in medication. Consult a specialist if such changes are necessary.
|Pharmacological treatment for PD |
|Levodopa|| || |
|Nonergot dopamine receptor agonists|| |
|COMT inhibitors|| |
Deep brain stimulation (DBS) 
- Severe motor symptoms or refractory tremor
- Decrease in dosage of medication because of adverse effects
- Breakage or displacement of electrodes or leads
Treatment of associated symptoms 
Under specialist guidance, carefully consider the risks and benefits of pharmacological treatment of nonmotor symptoms.
- Major depressive disorder
- Dementia: Consider treatment with rivastigmine.
Autonomic dysfunction 
- Detrusor hyperactivity: Consider medications without significant CNS effects when available (e.g., ).
- Neurogenic orthostatic hypotension: Consider .
- Erectile dysfunction: Consider sildenafil.
- Sialorrhea: Options include botulinum toxin injections, glycopyrrolate, or sublingual atropine.
- Sleep disorders (e.g., RBD)
While improvement of nonmotor symptoms is often crucial for quality of life, treatments often worsen other clinical features of PD.