Idiopathic Parkinson disease (PD) is a progressive neurodegenerative synucleinopathy clinically characterized by parkinsonism. The latter is defined by the presence of bradykinesia plus either resting tremor or rigidity.

• PD
• Paralysis agitans

• •Prodromal symptoms during 3 yr before patients receive a diagnosis of PD include problems with working, lifting heavy objects, and balance.²
• •Tremor (Fig. E1 and Fig. E2 ): Typically, a resting tremor with a frequency of 4 to 6 Hz that is often first noted in the hand as a pill-rolling tremor (thumb and forefinger). Can also involve the leg and lip. Tremor improves with purposeful movement. Usually starts asymmetrically. A subset of patients may develop postural and/or kinetic tremor during the course of illness.³
• •Rigidity (Fig. E3 ): Increased muscle tone that persists throughout the range of passive movement of a joint. Rigidity, like resting tremor, is usually asymmetric at onset.
• •Akinesia/bradykinesia (Fig. E4 and Fig. E5 ): Slowness in initiating movement and decrement with repeated movements. Slowness may also affect speech (hypophonia) and thinking (bradyphrenia). Combination of rigidity and bradykinesia may result in worsening of handwriting, usually characterized as micrographia (small letter sizes).
• •Postural instability: Tested by “pull test.” Ask patient to stand in place with back to examiner. Examiner pulls patient back by the shoulders, and proper response would be to take no steps back or very few steps back without falling. Retropulsion is a positive test, as is falling straight back. Postural instability is usually mild early in the disease course but can be significant in later stages. If falls and postural reflexes are greatly impaired early on, then consider other disorders, such as progressive supranuclear palsy (PSP).
• •Masked facies (hypomimia) (Fig. E6 ): Face seems expressionless, giving the appearance of depression. Decreased blink; often there is excess drooling.
• •Gait disturbance: Patients usually have a stooped posture and often walk slowly with short steps and reduced arm swing. As the disease advances, patients may develop festination, which is characterized by difficulty initiating the first step and small shuffling steps that increase in speed (Fig. E7 ). Steps become progressively faster and shorter while the trunk inclines further forward.
• •Nonmotor symptoms in PD include neuropsychiatric (depression, apathy, impulse control disorders, hallucinations), cognitive, dysautonomia (especially orthostatic hypotension, sexual dysfunction, and anosmia), and sensory abnormalities. These symptoms also may be subject to fluctuations during “on” vs. “off” states.
• •Common premotor symptoms of PD include constipation, anosmia, depression, and REM sleep behavior disorder (Table 1 ).

• •Most cases are sporadic. Age is the most common risk factor, although a combination of both environmental and genetic factors likely contributes to disease expression.
• •Both pesticides and drinking well water are factors correlated with a higher incidence of PD.
• •10% to 15% have a genetic etiology. Several different genes have been identified; these include the parkin gene (a significant cause of early-onset autosomal recessive PD), LRRK2 (the most common cause of familial and sporadic parkinsonism associated with later onset of PD), SNCA (codes for protein alpha synuclein), DJ1, and PINK1 (associated with early-onset PD).^{1 , 4}

Other diseases that cause parkinsonism:

• •Multiple system atrophy (MSA): Distinguishing features include early autonomic dysfunction (including urinary incontinence, orthostatic hypotension, and erectile dysfunction), symmetric parkinsonism, cerebellar signs, and normal cognition. MSA usually results in faster disease progression and early death.
• •Dementia with Lewy bodies (DLB): Parkinsonism with concomitant dementia; patients often have early visual hallucinations and fluctuations in level of alertness and mental status (often worse in the evening and night).
• •Corticobasal syndrome (CBS): Often begins asymmetrically with apraxia, dystonia, cortical sensory loss in one limb, and, sometimes, alien limb phenomenon.
• •Progressive supranuclear palsy (PSP): Tends to have axial rigidity greater than appendicular (limb) rigidity. These patients have early and severe postural instability. Hallmark is supranuclear gaze palsy that usually involves vertical gaze (especially downward) before horizontal.
• •Essential tremor: Bilateral postural and action tremor. Although controversial, there is some evidence suggesting that a subset of patients may develop PD in the future.⁶
• •Normal pressure hydrocephalus (NPH): Parkinsonism with gait impairment characterized by slow, shuffling gait with very low ground clearance (“magnetic gait”) along with cognitive impairment and urinary incontinence.
• •Secondary (acquired) parkinsonism (Box 1 ):
  1. 1.Iatrogenic: Many, including any of the neuroleptics and antipsychotics. The high-potency D₂-blocker neuroleptics are most likely to cause parkinsonism. Metoclopramide can also cause parkinsonism. Abuse of methamphetamine has been linked to risk of PD.
  2. 2.Postinfectious parkinsonism: Von Economo encephalitis.
  3. 3.Chronic traumatic encephalopathy (dementia pugilistica): Parkinsonism and dementia after repeated head trauma.
  4. 4.Toxins (e.g., MPTP, manganese, carbon monoxide).
  5. 5.Cerebrovascular disease: “Vascular parkinsonism” (basal ganglia infarcts); often lower limbs (especially gait) affected more than upper extremities.
  6. 6.Red flags suggesting a diagnosis other than PD are summarized in Box 2 .

• •Identification of clinical signs and symptoms associated with PD (see “Physical Findings & Clinical Presentation”) and elimination of conditions that may mimic it with a comprehensive history and physical examination.
• •Routine genetic testing is not recommended but should be considered in young patients (<40 yr) or in those with a strong family history of PD.
• •Can evaluate for response to carbidopa/levodopa (C/L) to differentiate PD from other causes of parkinsonism such as PSP, MSA, CBD.
• •Biomarkers for abnormal alpha-synuclein can distinguish persons with clinically defined Parkinson disease, dementia with lewy bodies, or REM sleep behavior disorder from healthy controls and from persons with other neurologic disease with high sensitivity and specificity.⁷

• •MRI of the head may sometimes distinguish between idiopathic PD and other conditions that present with signs of parkinsonism (see “Differential Diagnosis”).
• •Dopamine transporter imaging (DaTscan with [¹²³I]β-CIT SPECT) evaluates the level of dopamine in the striatum and can be used to confirm parkinsonism in atypical cases. Normally there is dopamine reuptake in the caudate and putamen that can light up to look like a comma. If there is poor reuptake in the putamen as seen in PD, only the caudate lights up, similar to a period on imaging. DaTscan is approved to distinguish essential tremor from parkinsonism but cannot distinguish between different causes of parkinsonism.⁵ Interpretation can be tricky, and routine use is not recommended at this time.

• •High-intensity aerobic exercise (heart rate target: 80% of the maximum heart rate for age) 4 to 5 times/week (30 to 40 min daily) has shown to have neuroprotective potential.⁸
• •Physical therapy (to help with exercise and help in evaluation of safe equipment to use), speech therapy, swallow evaluation. ^8-10
• •Avoidance of drugs that can induce or worsen parkinsonism: Neuroleptics (especially high potency), certain antiemetics (prochlorperazine, trimethobenzamide), metoclopramide, nonselective MAO inhibitors (MAO-Is) (may induce hypertensive crisis), reserpine, methyldopa.

• •Levodopa is the gold standard, but patients <65 can be started on agonists if preferred.¹⁰
• •It is appropriate to initiate pharmacotherapy when required by symptoms. Fig. 8 describes treatment of motor symptoms in patients with parkinsonism.
• •Motor complications do develop during the course of the disease and likely reflect the combination of disease progression and the side effects of dopaminergic medications.

Figure 8 Treatment of motor symptoms of Parkinson disease.

Algorithm for the treatment of Parkinson disease (PD). BoNT, Botulinum neurotoxin; DA, dopamine agonist; DAT, dopamine transporter; DBS, deep brain stimulation; Dx, diagnosis; FUS, focused ultrasound; MAOB-1, monoamine oxidase inhibitor type 1; MAOI, monoamine oxidase inhibitor; Rx, treatment; VMAT2, vesicular monoamine transporter 2.

(From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia, 2022, Elsevier.)

• •Levodopa therapy:
  1. 1.The gold standard is levodopa with a peripheral dopa decarboxylase inhibitor (carbidopa) to minimize side effects (nausea, light-headedness, postural hypotension).¹¹ The combination of the two drugs is marketed under the trade name Sinemet. Levodopa therapy has been found to reduce morbidity and mortality in PD patients.
  2. 2.Usual starting dose is 25/100 mg (C/L) tid 1 h before meals (can be given after meals if there is nausea). There is no official upper limit of the dose. Controlled-release (CR) tablets are usually preferred (given at bedtime) if patients have a lot of nighttime stiffness.
  3. 3.Stalevo (combination Sinemet and entacapone, a COMT inhibitor). Useful for patients with motor fluctuations (wearing off); has no role in treating patients with early PD.
  4. 4.Duopa (C/L), administered by a 16-h infusion to the jejunum through either a nasojejunal tube (short-term) or PEG-J tube (long-term), is used for treating motor fluctuations in patients with advanced PD.
  5. 5.Inbrija (levodopa inhalation powder) is used to treat “off” periods in patients taking C/L, but does not replace taking regular C/L. It works quickly and is easy to carry. It cannot be used if an MAO-I was used in the past 2 wk.
  6. 6.Treatment of levodopa-related motor complications in PD are summarized in Fig. 9 .
• •Dopamine receptor agonists (ropinirole, pramipexole, rotigotine) are not as potent as levodopa, but they are often used as initial treatment in younger patients in an attempt to delay the onset of complications (dyskinesias, motor fluctuations) associated with levodopa therapy.^10,11 In general, they cause more side effects than levodopa, including nausea, vomiting, light-headedness, peripheral edema, hallucinations, confusion, and somnolence. They can also cause impulse control behaviors such as hypersexuality, binge eating, and compulsive shopping and gambling. Presence of these must be assessed at each visit as the appearance of these side effects is often underreported and their consequences can be severe. Dopamine agonists also can be associated with a prolonged withdrawal syndrome.
  1. 1.Ropinirole: Initial dose is 0.25 mg tid but must be titrated over the course of 4 wk to 1 mg tid and then may be increased by 1.5 mg/wk to a maximum of 24 mg/day. An extended-release formulation is also available.
  2. 2.Pramipexole: Initial dose is 0.125 mg tid but must be titrated over the course of weeks to 1.5 to 4.5 mg/day in three doses. An extended-release formulation is also available.
  3. 3.Rotigotine: 2 mg to 6 mg/24 h as transdermal patch.
  4. 4.Apomorphine: A dopamine agonist used for acute, intermittent treatment of unpredictable “off” episodes with advanced Parkinson disease.
• •COMT inhibitors (entacapone, opicapone, and tolcapone) are used as adjunct to levodopa therapy to treat end-of-dose wearing off.
• •MAO-B inhibitors can be used as monotherapy early in the disease or as adjunctive therapy in later stages; they have been shown to have milder symptomatic benefit than dopamine agonists or levodopa.^11,12 They are well tolerated and easy to titrate. Concurrent use of stimulants and sympathomimetics should be avoided. Certain food restrictions may apply.
  1. 1.Rasagiline: Initial dose is 0.5 mg/day, then 1 mg/day. The ADAGIO study suggests that 1 mg rasagiline may have disease-modifying benefits, but results must be interpreted with caution.
  2. 2.Selegiline: Usual dose, 5 mg bid with breakfast and lunch. Has amphetamine by-product, so has mild stimulant-like effects, which can be beneficial in some patients.
  3. 3.Safinamide: FDA approved as add-on therapy for C/L that reduces “off time” and increases “on time” with fewer dyskinesias. Starting dose is 50 mg/day for 2 wk, which can be increased if needed to 100 mg/day.
• •Istradefylline is the first FDA-approved adenosine A 2A receptor agonist for use as an adjunct to C/L in adults with PD experiencing “off” episodes.
• •Amantadine (unclear mechanism of action, but reported to modulate the dopamine and glutamate systems in the CNS) can be used alone early in the disease. Later in the disease, it is especially useful in the treatment of dyskinesias. Dosage is 100 mg tid (titrate weekly from 100 mg daily). Must adjust for elderly and renal impairment. The most notable side effect, especially in the elderly, are confusion and hallucinations. Rarely, it leads to leg edema and pigmentation (classically described as “livedo reticularis”). Extended-release amantadine (Gocovri) may have fewer side effects.
• •Anticholinergic agents are only helpful in treating tremor but may be more effective than levodopa for tremor in some circumstances. They can also be used to treat drooling in patients with PD. However, their use is restricted largely due to frequent side effects such as constipation, urinary retention, memory impairment, and hallucinations. They should be avoided in the elderly.
  1. 1.Trihexyphenidyl: Initial dose, 1 mg PO tid
  2. 2.Benztropine: Usual dose, 0.5 to 1 mg daily or bid
• •Treatment of nonmotor symptoms⁹: Nonmotor symptoms such as depression, anxiety, irritability, dementia, psychosis, constipation, urinary and sexual dysfunction, sleep disturbances such as REM behavior disorder, decreased sense of smell, and impulsive behavior, among others, often cause a great deal of distress for patients and caretakers alike. Treatable symptoms should be addressed pharmacologically using medications appropriate for elderly patients sensitive to antidopaminergic medications.
• •Psychosis: Dopamine agonists, anticholinergics, and amantadine can cause hallucinations, so adjustment of these medications should be the first step. Pimavanserin (Nuplazid) is FDA approved for the treatment of PD psychosis and has been shown effective for the treatment of hallucinations and delusions associated with PD psychosis. The medication is an inverse agonist of 5-HT_2A and 5-HT_2C receptors without any evidence of dopamine blockade. Quetiapine is also very effective in managing hallucinations in PD patients.
• •PD dementia: Rivastigmine (Exelon), a cholinesterase inhibitor available both orally and transdermally as a patch (with few GI side effects), is approved to treat not only Alzheimer disease but also PD dementia.
• •There are monoclonal antibody therapies against alpha synuclein in the pipeline to help with treatment of motor symptoms and cognitive symptoms in PD; however, thus far trials have been unsuccessful.¹³

Figure 9 Treatment of levodopa-related motor complications in Parkinson disease.

A2A, Adenosine A2A receptor; COMTI, catechol-o-methyl-transferase inhibitor; CR, controlled release; DA, dopamine agonist; DBS, deep brain stimulation; ER, extended release; GPi, globus pallidus interna; LCIG, levodopa-carbidopa infusion gel; MAOI, monoamine oxidase inhibitor; SC, subcutaneous; STN, subthalamic nucleus.

(From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia, 2022, Elsevier.)

• •Deep brain stimulation of the globus pallidus interna (GPi-DBS) and subthalamic nucleus (STN-DBS) are currently the surgical options of choice for PD patients with motor fluctuations. Similar improvement in motor function and adverse effects have been reported after either procedure.^14-16 STN-DBS has the benefit of possible medication lowering compared to pallidal targets. Compared to ablative procedures, DBS has the advantage of being reversible and adjustable. DBS is useful for the treatment of tremor refractory to levodopa. It improves the cardinal motor symptoms, extends medication “on” time, and reduces motor fluctuations during the day. In general, patients are likely to benefit from this therapy if they show a clear response to levodopa. Therefore when considering DBS, patients should be evaluated for motor response to levodopa by stopping levodopa overnight and evaluating motor response before and after a dose of levodopa.
• •Focused ultrasound (FUS) is a MRI-guided an imaging-guided method for creating therapeutic lesions in deep brain structures, including the subthalamic nucleus. FUS subthalamotomy in one hemisphere improved motor features of PD in selected patients with asymmetric signs.¹⁷ At 3 mo, patients who were most likely to benefit were younger, had lower motor severity scores, or had higher dyskinesia scores.¹⁸ Longer and larger trials are required to determine the effect and safety of FUS in persons with Parkinson disease. DBS is currently favored over FUS as it can be continually reprogrammed to account for worsening disease and does not cause a permanent lesion.
• •Surgery is often limited to patients with disabling, medically refractory problems, and patients must still have a good response to l-dopa to undergo surgery. Yet for many patients, earlier stimulation might provide an improved motor benefit before disability from other symptoms has occurred and should be considered at an earlier stage of PD. DBS results in decreased dyskinesias, fluctuations, rigidity, and tremor.

PD usually follows a slowly progressive course leading to disability over the course of several years. However, every patient will progress individually, and patients should be reassured that this diagnosis does not, by definition, result in being either wheelchair or bed bound.

• •Neurology consultation is recommended at initial diagnosis of PD.
• •Moderate- to high-intensity aerobic exercise is important for all patients with PD.
• •Participation in outpatient physical and speech therapy program is recommended for patients with moderate to advanced disease.
• •Neuropsychology testing in patients considering DBS.

• Parkinson Disease (Patient Information)