Parkinson Disease

Essentials of Diagnosis

• Any combination of tremor, rigidity, bradykinesia, and progressive postural instability ("parkinsonism")

• Cognitive impairment is sometimes prominent

General Considerations

• Risk factors

  • Age

  • Family history

  • Male sex

  • Ongoing herbicide/pesticide exposure

  • Significant prior head trauma

• Dopamine depletion due to degeneration of the dopaminergic nigrostriatal system leads to an imbalance of dopamine and acetylcholine

• Exposure to toxins and certain medications can lead to parkinsonism

  • Manganese dust

  • Carbon disulfide

  • Severe carbon monoxide poisoning

  • 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) for recreational purposes

  • Neuroleptic drugs

  • Reserpine

  • Metoclopramide

• Postencephalitic parkinsonism is becoming increasingly rare

• Only rarely is hemiparkinsonism the presenting feature of a space-occupying lesion

Demographics

• Common disorder that occurs in all ethnic groups, with an approximately equal sex distribution

• The most common variety, idiopathic Parkinson disease, usually begins in people between ages 45 and 65 years

• May rarely occur on a familial basis

Symptoms and Signs

• Cardinal features

  • Tremor

  • Rigidity

  • Bradykinesia

  • Postural instability

• Nonmotor manifestations include

  • Affective disorders (depression, anxiety, and apathy)

  • Psychosis

  • Cognitive changes

  • Fatigue

  • Sleep disorders

  • Anosmia

  • Autonomic disturbances

  • Sensory complaints or pain

  • Seborrheic dermatitis

• Dementia or mild cognitive impairment will eventually develop in many patients

• Tremor

  • Four to six cycles per second

  • Most conspicuous at rest

  • Enhanced by stress

  • Often less severe during voluntary activity

  • Commonly confined to one limb or to one side for months or years before becoming more generalized

  • May be present about mouth and lips

  • May be absent in some patients

• Rigidity causes the flexed posture

• Bradykinesia is the most disabling symptom, ie, a slowness of voluntary movement and a reduction in automatic movements such as swinging of the arms while walking

• The face

  • Relatively immobile with widened palpebral fissures

  • Infrequent blinking

  • Fixity of facial expression

  • Seborrhea of scalp and face

• Mild blepharoclonus

• Repetitive tapping (about twice per second) over the bridge of the nose producing a sustained blink response (Myerson sign)

• Other findings

  • Saliva drooling from the mouth

  • Soft and poorly modulated voice

  • Variable rest tremor and rigidity in some or all of the limbs

  • Slowness of voluntary movements

  • Impairment of fine or rapidly alternating movements

  • Micrographia

• Typically no muscle weakness and no alteration in the tendon reflexes or plantar responses

• Difficulty rising from a sitting position and beginning to walk

• Gait

  • Small shuffling steps and a loss of the normal automatic arm swing

  • There may be unsteadiness on turning, difficulty in stopping, and a tendency to fall

Differential Diagnosis

• Different causes of parkinsonism

• Essential tremor

• Depression

• Wilson disease

• Huntington disease

• Normal-pressure hydrocephalus

• Multisystem atrophy (previously called Shy-Drager syndrome)

• Progressive supranuclear palsy

• Corticobasal ganglionic degeneration

• Diffuse Lewy body disease

• Creutzfeldt-Jakob disease

• Drugs causing parkinsonism

  • Antipsychotic agents

  • Reserpine

  • Metoclopramide

• Primarily a clinical diagnosis

Medications

• Amantadine

  • Available in immediate-release (100 mg orally two or three times daily) and extended-release (129–322 mg once daily) formulations

  • May improve all of the clinical features of parkinsonism

  • Ameliorates dyskinesias resulting from prolonged levodopa therapy

• Sinemet

  • A combination of carbidopa and levodopa in a fixed ratio (1:10 or 1:4)

  • Start with small dose, eg, 1 tablet of Sinemet 25/100 (containing 25 mg of carbidopa and 100 mg of levodopa) three times daily orally, and gradually increase depending on the response

• Sinemet CR

  • A controlled-release formulation (containing 25 or 50 mg of carbidopa and 100 or 200 mg of levodopa)

  • Mainly useful when taken at bedtime to lessen motor disability upon awakening

• Rytary

  • Novel formulation of carbidopa/levodopa

  • Contains both immediate- and delayed-release beads

  • Provides a smoother response in patients with fluctuations

  • Continuous infusion of a carbidopa-levodopa enteral suspension through a percutaneous gastrojejunostomy tube by a portable infusion pump reduces "off" time in patients with advanced Parkinson disease

• Stalevo is a commercial preparation of levodopa combined with both carbidopa and entacapone

  • Stalevo 50 (12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone)

  • Stalevo 100 (25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone)

  • Stalevo 150 (37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone)

• Inbrija is an inhaled formulation of levodopa

  • Can be used as a rescue medication for patients developing severe akinesia (off periods)

  • Benefit occurs about 10 minutes after inhalation

  • Side effects

    • Cough

    • Upper respiratory tract infection

    • Nausea

    • Discolored sputum

• Pramipexole

  • Newer dopamine agonist that is not an ergot derivative

  • Dosage: started at 0.125 mg three times daily orally, and the dose is built up gradually to between 0.5 mg and 1.5 mg three times daily

• Ropinirole

  • Newer dopamine agonist that is not an ergot derivative

  • Dosage: started at 0.25 mg three times daily orally and gradually increased; most patients require between 2 mg and 8 mg three times daily for benefit

• Rotigotine

  • Dopamine agonist absorbed transdermally

  • Dosage: started at 2 mg once daily and increased weekly by 2 mg daily until achieving an optimal response, up to a maximum of 8 mg daily

• Rasagiline, selegiline, safinamide

  • Selective monoamine oxidase B inhibitors

  • Rasagiline (1 mg/day orally taken in morning) may slow progression of disease

  • Selegiline (5 mg orally with breakfast and lunch) or safinamide (50 mg orally daily, increased to 100 mg daily after 14 days) are also approved as adjunctive treatments

• Entacapone and tolcapone, two catecholamine-O-methyltransferase (COMT) inhibitors, may be used as an adjunct to Sinemet when there are response fluctuations or inadequate responses

  • Entacapone is given as 200 mg orally with each dose of Sinemet

  • Entacapone is generally preferred over tolcapone

  • Tolcapone is given in a dosage of 100 mg or 200 mg three times daily orally

  • Tolcapone should be avoided in patients with preexisting liver disease because of rare cases of fulminant hepatic failure following its use

  • With either preparation, the dose of Sinemet taken concurrently may have to be reduced by up to one-third to avoid side effects

• Opicapone

  • Long-acting, peripherally selective COMT inhibitor

  • Taken once daily (50 mg) at bedtime

  • Available in Europe but not yet in the United States

• Anticholinergics are more helpful for tremor and rigidity than bradykinesia

  • Trihexyphenidyl and benztropine are commonly used formulations

  • Start with a small dose

  • Common side effects include dryness of the mouth, nausea, constipation, palpitations, cardiac arrhythmias, urinary retention, confusion, agitation, restlessness, drowsiness, mydriasis, increased intraocular pressure, and defective accommodation

  • Contraindicated in patients with benign prostatic hyperplasia, narrow-angle glaucoma, or obstructive intestinal disease

  • Often tolerated poorly by the elderly

  • Should be avoided when cognitive impairment or a predisposition to delirium exists

• Confusion and psychotic symptoms often respond to antipsychotic agents

  • Olanzapine

  • Quetiapine

  • Risperidone

  • Clozapine

• Clozapine may rarely cause bone marrow suppression, and weekly blood cell counts are therefore necessary

  • Starting dose, 6.25 mg at bedtime orally

  • Dose is increased to 25–100 mg/day as needed

  • In low doses, clozapine may also improve iatrogenic dyskinesias

• Pimavanserin

  • Dose: 34 mg once daily

  • Effective in treating the psychosis of Parkinson disease

Therapeutic Procedures

• Drug therapy may not be required early

• Physical and speech therapy and simple aids to daily living may help

  • Rails or banisters placed strategically about the home

  • Special table cutlery with large handles

  • Nonslip rubber table mats

  • Devices to amplify the voice

• Stimulation and ablative treatments

  • Stimulation is the preferred surgical approach to treatment

  • Advantageous over ablative thalamotomy and pallidotomy procedures because it is reversible and causes minimal or no damage to the brain

  • High-frequency stimulation of the subthalamic nuclei or globus pallidus internus may benefit all the major features of the disease

  • Deep brain stimulation is reserved for patients without cognitive impairment or psychiatric disorder who have a good response to levodopa but in whom dyskinesias or response fluctuations are problematic

  • It frequently takes 3–6 months after surgery to achieve optimal results

  • Side effects include depression, apathy, impulsivity, executive dysfunction, and decreased verbal fluency in a subset of patients

  • Focused ultrasound thalamotomy or stereotactic radiosurgery may help patients with medically refractory tremor-predominant parkinsonism who are reluctant to undergo surgery

Complications

• Levodopa-induced dyskinesias may take any form

  • Chorea

  • Athetosis

  • Dystonia

  • Tremor

  • Tics

  • Myoclonus

• Later complications of the drug include the "wearing off effect" or the "on-off phenomenon"

  • Abrupt but transient fluctuations in the severity of parkinsonism occur unpredictably but frequently during the day

  • The "off" period of marked bradykinesia has been shown to relate in some instances to falling plasma levels of levodopa

  • During the "on" phase, dyskinesias are often conspicuous but mobility is increased

  • Because of this complication, levodopa therapy should be postponed and dopamine agonists used instead, except in the elderly

When to Refer

• All patients

When to Admit

• Patients requiring surgical treatment