BASICS
DESCRIPTION
- Parkinson disease (PD) is a progressive neurodegenerative disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta.
- Cardinal symptoms include resting tremor, rigidity, bradykinesia, and postural instability.
- Diagnosis is based primarily on history and examination.
EPIDEMIOLOGY
Incidence
- Average age of onset: ~60 years
- Slightly more common in men than women
Prevalence
- Second most common neurodegenerative disease after Alzheimer disease
- 0.3% of general population and 1 " 2% of those ≥60 years of age and up to 4% of those ≥80 years of age
- Affects approximately 1 million people in the United States and 5 million worldwide
ETIOLOGY AND PATHOPHYSIOLOGY
Dopamine depletion in the substantia nigra and the nigrostriatal pathways results in the major motor complications of PD.
- Pathologic hallmark: selective loss of dopamine-containing neurons in the pars compacta of the substantia nigra
- Loss of neurons accompanied by presence of Lewy bodies, pale bodies (predecessor of the Lewy body), and Lewy neuritis
Genetics
Mutations in multiple autosomal dominant and autosomal recessive genes have been linked to PD/parkinsonian syndrome particularly when the age at symptom onset is <50 years. Genes investigated in PD include SNCA, Parkin, Pink-1, DJ-1and LRRK2.
RISK FACTORS
- Age and family history of PD or tremor are the greatest risk factors.
- History of smoking as well as coffee and caffeine intake may reduce risk.
- Weak association with exposure to toxins (herbicides and insecticides); however, relationship is not clear.
COMMONLY ASSOCIATED CONDITIONS
Non " motor-associated symptoms include cognitive abnormalities, autonomic dysfunction (e.g., constipation, urinary urgency), sleep disturbances, mental status changes (depression, psychosis, hallucinations, dementia), orthostatic hypotension, and pain.
DIAGNOSIS
- Diagnosis is based on clinical impression.
- Gold standard for diagnosis is neuropathologic exam.
- Generally, bradykinesia plus either tremor or rigidity must be present in order to make the diagnosis of idiopathic PD.
- Clinical features supportive of the diagnosis include unilateral onset, resting tremor, persistent asymmetry with the side of onset most affected, and significant response to dopaminergic therapy.
HISTORY
Symptoms often subtle or attributed to aging:
- Decreased emotion displayed in facial features
- General motor slowing and stiffness (one or both arms do not swing with walk)
- Resting tremor (often initially one hand)
- Speech soft/mumbling
- Falls/difficulty with balance (tends to occur with disease progression)
PHYSICAL EXAM
- Tremor
- Resting tremor (4 to 6 Hz) that is often asymmetric.
- Disappears with voluntary movement
- Frequently emerges in a hand while walking and may present as pill rolling
- May also present in jaw, chin, lips, tongue
- Bradykinesia
- Rigidity: cogwheel (catching and releasing) or lead pipe (continuously rigid)
- Postural instability
DIFFERENTIAL DIAGNOSIS
- Essential tremor: Bradykinesia is not present; often symmetric and occurs mostly during action or when holding hands outstretched
- SWEDD: scans without evidence of dopaminergic deficit; isolated upper extremity resting and postural tremor resembling PD but failing to progress to generalized PD; no akinesia
- Dementia with Lewy bodies: characterized clinically by visual hallucinations, fluctuating cognition, and parkinsonism, dementia occurs concomitantly with or before the development of parkinsonism
- Corticobasal degeneration: asymmetric parkinsonism, absence of tremor, no response to levodopa
- Multiple system atrophy: presets with parkinsonism but with varying degrees of dysautonomia, cerebellar involvement, and pyramidal signs
- Progressive supranuclear palsy: impairment in vertical eye movements (particularly down gaze), hyperextension of neck, and early falling; pseudobulbar palsy
- Idiopathic basal ganglia calcification
- Associated neurodegenerative disorders: late stages of Alzheimer disease, Huntington disease, frontotemporal dementia, spinocerebellar ataxias
- Secondary parkinsonism
- Drug-induced: reversible; may take weeks/months after offending medication is stopped
- Neuroleptics (most common cause)
- Antiemetics (e.g., prochlorperazine and promethazine), metoclopramide
- SSRIs
- Calcium channel blockers (e.g., flunarizine and cinnarizine) metoclopramide
- Amiodarone
- Lithium
- Cholinergics
- Chemotherapeutics
- Amphotericin B
- Estrogens
- Valproic acid
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Diagnosis is mainly clinical and there are no physiologic or blood tests to confirm the diagnosis.
- Excellent response to an acute dopaminergic challenge test supports the diagnosis
- MRI of brain is nondiagnostic but can be used to rule out structural abnormalities.
- DaTscan: Striatal dopamine transporter imaging can distinguish PD and other parkinsonian syndromes but cannot differentiate between them.
- PET and single-photon emission CT may be helpful with diagnosis but are not required.
TREATMENT
GENERAL MEASURES
- Multidisciplinary rehabilitation with standard physical and occupational therapy components to improve functional outcomes.
- Physiotherapy to help with gait reeducation, enhancement of aerobic capacity, improvement in movement initiation, improvement in functional independence, and help with home safety
MEDICATION
- PD goal: Improve motor and nonmotor deficits.
- Agents are chosen based on patient age and symptoms present.
- No treatment shown to slow progression
First Line
- 1st-line agents in early PD: levodopa, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors (1)[A]
- Levodopa combined with carbidopa is still the most effective treatment for symptoms of PD, particularly bradykinesia.
- Levodopa versus dopamine agonist is controversial (2)[B]:
- Most patients eventually will develop motor fluctuations with levodopa. Younger patients are more likely to develop motor fluctuations. Some recommend delaying initiation of levodopa to decrease drug-induced motor fluctuations early in the disease.
- Older patients often are less able to tolerate the adverse events of dopamine agonists.
- All patients eventually will require levodopa.
- MAO-B inhibitors (rasagiline) should be considered as initial monotherapy; investigated for potential neuroprotective effects (2)[B]
- Carbidopa + levodopa (carbidopa inhibits peripheral conversion of levodopa)
- Immediate release (Sinemet)
- Tablets (mg): 10/100, 25/100, 25/250
- Usual initial maintenance dose: 25/100 mg PO TID. Most patients require 25 mg of carbidopa to inhibit peripheral conversion of levodopa.
- Watch for nausea/vomiting, orthostatic hypotension, sedation, and vivid dreams.
- Orally disintegrating (Parcopa)
- Tablets (mg): 10/100, 25/100, 25/25
- Sustained release (Sinemet CR):
- Tablets (mg): 25/100, 50/200
- Dose agents initially BID
- Carbidopa + levodopa + entacapone (Stalevo)
- Tablets (mg): 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200
- Addition of entacapone as a single agent should be initiated prior to use of this combination:
- Once-daily dose of carbidopa/levodopa has been identified; may convert to Stalevo
- Dose of levodopa may need to be decreased with the addition of entacapone.
- Side effects are the same, plus diarrhea and brownish orange urine.
- Dopamine agonists (nonergot): side effects: nausea, vomiting, hypotension, sedation, edema, vivid dreaming, compulsive behavior, confusion, light-headedness, and hallucinations:
- Pramipexole (Mirapex): tablets (mg): 0.125, 0.25, 0.5, 1, 1.5
- Start with 0.125 mg TID, gradually increase every 5 to 7 days; usual maintenance of 0.5 to 1.5 mg TID
- CrCl 30 to 59 mL/min 0.125 mg PO BID
- CrCl 15 to 29 mL/min 0.125 mg PO daily
- Pramipexole ER (Mirapex ER): tablets (mg): 0.375, 0.75, 1.5, 3, 4.5; start with 0.375 PO daily
- Ropinirole (Requip): tablets (mg): 0.25, 0.5, 1, 2, 3, 4, 5; start with 0.25 mg TID, increase gradually to 3 to 8 mg TID
- Requip XL: tablets (mg): 2, 4, 6, 8, 12; start at a 2-mg dose once daily, increase in 1 to 2 weeks
- Selective MAO-B inhibitors: side effects: insomnia, jitteriness, hallucinations; mostly found with selegiline; rasagiline similar adverse events as placebo in clinical trials. Rasagiline is metabolized via CYP1A2; caution with other medications using this enzyme system (e.g., ciprofloxacin):
- Both agents contraindicated with meperidine and numerous other agents metabolized via CYP1A2
- At therapeutic doses, unlikely to induce a "cheese reaction " (tyramine storm)
- Selegiline (Eldepryl)
- Tablets: 5 mg; initiate 5 mg PO BID
- Orally disintegrating tablet (Zelapar): 1.25 mg; 1.25 mg PO daily for 6 weeks; increase as needed to max of 2.5 mg daily
- Rasagiline (Azilect): tablets: 0.5 mg, 1.0 mg; initiate 0.5 to 1 mg daily
Second Line
- Second-line agents in early PD: ²-adrenergic antagonists (postural tremor), amantadine, anticholinergics (young patients with tremor); there is lack of good evidence for symptom control (1)[A].
- Dopamine agonists (ergot): increased adverse event profile makes these agents nonpreferred to nonergot dopamine agonists; bromocriptine (Parlodel)
- Treatment of levodopa-induced motor complications
- End of dose wearing off
- Entacapone (with each levodopa dose) or rasagiline preferred (3)[B]
- May also consider dopamine agonist, apomorphine, selegiline (4)[B]
- Dyskinesias
- Typically occur at peak dopamine level
- Amantadine may be considered; however, its efficacy is questionable (1)[B].
- Anticholinergic agents: usually avoided due to lack of efficacy (only useful for tremor) and increased adverse event profile, including blurred vision, confusion, constipation, dry mouth, memory difficulty, sedation, and urinary retention
- Trihexyphenidyl
- Tablets: 2 mg, 5 mg
- Start with 1 to 2 mg daily, increase by 2 mg every 3 to 5 days until usual dose is 6 to 10 mg in 3 to 4 divided doses
- Benztropine (Cogentin)
- Tablets: 0.5 mg, 1 mg, 2 mg
- Start with 0.5 to 1 mg in 1 to 2 divided doses; increase by 0.5 mg every 5 to 6 days; usual dose is 1 to 2 mg/day in divided doses.
- N-methyl-d-aspartic acid antagonist: Exact mechanism is unknown and efficacy is questionable; however, it may be useful for dyskinesias. Side effects include confusion, dizziness, dry mouth, livedo reticularis, and hallucinations:
- Amantadine (Symmetrel)
- Tablets: 100 mg
- Start with 100 mg BID; may increase to 300 mg daily in divided doses; renally adjusted
- Catechol-O-methyl transferase (COMT) inhibitors: entacapone preferred due to hepatotoxicity associated with tolcapone. Adverse events include nausea and orthostatic hypotension:
- Entacapone (Comtan)
- Tablets: 200 mg
- 200 mg with each dose of carbidopa/levodopa; max dose, 1,600 mg/day
- Tolcapone (Tasmar)
- Tablets: 100 mg, 200 mg
- Start 100 mg TID; max dose 600 mg/day; must be taken with carbidopa/levodopa
- Requires LFT monitoring
- Apomorphine (Apokyn): nonergot-derived dopamine agonist given SC for off episodes in advanced disease; adverse events: nausea, vomiting, dizziness, hallucinations, orthostatic hypotension, somnolence
- Only for "off " episodes with levodopa therapy
- Requires initial "test " dose (2 mg); monitor for orthostatic hypotension after initial dose; this is a potent emetic, so initiate an antiemetic (e.g., trimethobenzamide) 3 days prior to start and continue for 2 months. Avoid ondansetron (combination contraindicated due to profound hypotension) and dopamine antagonists, such as prochlorperazine and metoclopramide.
- Effective dose ranges from 2 to 6 mg/injection.
ISSUES FOR REFERRAL
Early specialty referral for patients with suspected PD for an accurate diagnosis and management
ADDITIONAL THERAPIES
- Emotional and psychological support of patient family
- Physical therapy and manual medicine has been shown to improve balance, muscle strength, and walking speed.
- Speech therapy: may be helpful in improving speech volume and maintaining voice quality
SURGERY/OTHER PROCEDURES
Deep brain stimulation (bilateral subthalamic nucleus/globus pallidus interna) is an effective therapeutic option for patients with motor complications refractory to best medical treatment who are healthy, have no significant comorbidities, are responsive to levodopa, and do not have depression or dementia.
ONGOING CARE
DIET
- Increase dietary fluids and fiber and increase activity for constipation.
- For dysphagia, consider soft food, swallowing evaluation, and increased time for meals.
- Avoid large, high-fat meals that slow digestion and interfere with medication absorption.
PATIENT EDUCATION
- www.apdaparkinson.org
- www.parkinson.org
- www.michaeljfox.org
PROGNOSIS
- PD is a chronic progressive disease; prognosis varies based on patient-specific symptoms.
- Increased mortality in PD; on average, PD survival reduced by 5% every year of follow up (4).
COMPLICATIONS
Most commonly the result of adverse effects of medications used to treat
REFERENCES
11 Gazewood JD, Richards DR, Clebak K. Parkinson disease: an update. Am Fam Physician. 2013;87(4):267 " 273.22 Nalls MA, Plagnol V, Hernandez DG, et al. Imputation of sequence variants for identification of genetic risks for Parkinson 's disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377(9766):641 " 649.33 Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):983 " 995.44 Diaz NL, Waters CH. Current strategies in the treatment of Parkinson 's disease and a personalized approach to management. Expert Rev Neurother. 2009;9(12):1781 " 1789.
ADDITIONAL READING
- Macleod AD, Taylor KS, Counsell CE. Mortality in Parkinson 's disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1615 " 1622.
CODES
ICD10
- G20 Parkinson 's disease
- G21.9 Secondary parkinsonism, unspecified
- G31.83 Dementia with Lewy bodies
- G21.11 Neuroleptic induced parkinsonism
- G21.19 Other drug induced secondary parkinsonism
ICD9
- 332.0 Paralysis agitans
- 332.1 Secondary parkinsonism
- 331.82 Dementia with lewy bodies
SNOMED
- 49049000 Parkinson 's disease (disorder)
- 230292008 Secondary parkinsonism (disorder)
- 425390006 Dementia associated with Parkinson 's Disease (disorder)
- 72820004 neuroleptic-induced Parkinsonism (disorder)
CLINICAL PEARLS
- Emphasize the importance of exercise and movement to help preserve function.
- Pharmacotherapeutic regimens need to be individualized based on patient-specific symptoms and age.