Parkinson Disease

Definitions

Parkinson disease (Parkinson's disease, PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic nigrostriatal neurons. It is named after James Parkinson, the English physician who described the shaking palsy in 1817.

Parkinsonism, the syndrome, is a common movement disorder. PD is its most common cause.

Illustration of Parkinson's disease by William Richard Gowers from A Manual of Diseases of the Nervous System in 188

Epidemiology
Predominant age: Uncommon before age 40, begins most often between the ages of 45 and 65
Predominant sex: Male > Female; affects all races and ethnic groups
2nd most prevalent neurodegenerative disease after Alzheimer disease
0.3% prevalence in general population; prevalence increases with age.
Affects 1% of population over age 60, 4% over age 80, and about 1 million Americans.

Pathophysiology
Depigmentation, neuronal loss, and gliosis in basal ganglia
Presence of Lewy bodies (round eosinophilic intracytoplasmic inclusions in the nuclei of neurons)

Aetiology
Dopamine depletion in the substantia nigra and the nigrostriatal pathways result in increased inhibition of the thalamus and reduced excitatory input to the motor cortex.
Genetic link:

• Multiple autosomal dominant and recessive genes or gene loci have been linked to PD, but common polymorphism in some of these genetic loci might play a role.
• 10–15% will have affected 1st- or 2nd-degree relative.
• Genetic forms of PD (designated PAK1 through PAK13), related to nuclear and mitochondrial genes, are being identified.

Presentation
Clinical diagnosis: 2 out of 3 signs must be present: tremor, bradykinesia and rigidity

Tremor	Resting tremor (4–8 Hz) in a limb, most commonly 1 hand, that disappears with voluntary movement; frequently emerges in a hand while walking Absent in 20% of cases Tremors affect cranial musculature and present as tongue, jaw, and chin but not as head tremors. Small and irregular handwriting (micrographia)
Bradykinesia	Weakness of hand or leg; normal strength testing; reduced amplitude of movement, especially with repetition; fine movements affected more. Also manifests as low-volume speech, shuffling gait with propulsion and retropulsion, no arm swing, swallowing neglect with drooling, decreased blinking, and blepharospasm.
Rigidity	Stiffness associated with vague aching and discomfort Cogwheel (catching and releasing) or lead-pipe (continuously rigid)
Others	Dysautonomia with constipation, incontinence, and sexual dysfunction Depression, psychosis, hallucinations, delirium, sleep disturbances Loss of olfaction, often early in disease Dementia estimates range from 20–50%. constipation, and urinary urgency dysphagia orthostatic hypotension.

Investigation
Diagnosis is mainly clinical.
MRI of brain to rule out other disorders
PET and SPECT may be helpful in early diagnosis but can't differentiate PD from other parkinsonian syndromes.
Transcranial US; olfactory testing is being studied for early diagnosis.

Ddx

Essential tremors	Generally symmetric tremors in hands with head and voice tremors without rigidity and bradykinesia, large and tremulous handwriting
Spasticity	only increased flexor tone
Drug-induced parkinsonism	although it may take weeks or months after offending medication is stopped
Neuroleptics	antiemetics, calcium channel antagonists (e.g., flunarizine and cinnarizine), amiodarone, lithium, and valproic acid may cause PD.
Parkinsonism-plus syndromes	parkinsonism is a part of another disorder. These have a worse prognosis and poor response to antiparkinsonian medications. Progressive supranuclear palsy: Frequent falls owing to marked postural instability, vertical gaze paralysis Multiple system atrophy: Autonomic and urinary dysfunction in Shy-Drager syndrome, cerebellar dysfunction in olivopontocerebellar atrophy Dementia with Lewy bodies: Hallucinations and episodes of delirium

Consider other conditions if falls or early dementia, symmetric parkinsonism, wide-based gait, marked orthostatic hypotension, urinary retention, abnormal eye movements, Babinski sign, marked disability within 5 years of onset of symptoms, failure to respond to adequate trial of levodopa (occurs in <10% of patients with pathologically proven PD).

Management

Assess disability	Time how long to walk 10m, dress alone, turn over in bed
First line medication	Start drugs when symptoms interfere with life Levodopa (L-dopa), coupled with a peripheral decarboxylase inhibitor(eg. carbidopa) Example of drugs: Sinemet (immediate release), Sinemet CR (sustained release), Stelavo(contains entacapone, may cause diarrhea) Start at low dose: 50mg/12h PO (with food to avoid nausea & vomitting). Titrated to symptom control. Good response with 400-600mg/d for >3yr Effect wears off with time- switching between times of exaggerated movement and of immobility (‘on-off’/wheelchair sign- sometimes on wheelchair, suddenly can walk and push the wheelchair) treats motor symptoms better than dopamine agonists but has more motor complications s/e: nausea, dyskinesia-unwanted movement (seen after 2y), fluctuation, orthostatic hypotension, GI s/e, arrhytmmias, psychosis, and compulsions(sex, gambling, food) For levodopa-related motor complications, adjuvant therapy with dopamine agonist, MAO-B inhibitor, or a COMT inhibitor Dopamine agonist Nonergot dopamine agonist Ergot dopamine agonist S/e: nausea, vomiting, hypotension, ankle edema, excessive daytime sleepiness, compulsive behavior, confusion, and hallucinations. Side effects the same as pramipexole plus retroperitoneal, pulmonary, and cardiac fibrosis; heart valve dysfunction; Raynaud phenomenon; and erythromelalgia. Avoid in patients with dementia because they can produce hallucinations. Pramipexole (Mirapex): Start with 0.125 mg t.i.d., gradually increase to 0.5–1.5 mg t.i.d. Ropinirole (Requip): Start with 0.25 mg t.i.d., increase gradually to 3–8 mg t.i.d. Requip XL: Start at a 2-mg dose once daily. Rotigotine (Neupro): Available as 2-, 4-, or 6-mg/24 h once-daily patch in Europe; usually started as 2 mg/24 h and titrated weekly by increasing in increments of 2 mg/24 h to a dose of 6 mg/24 h. Pergolide (Premax): Start with 0.05 mg t.i.d., increase up to 1 mg t.i.d. Bromocriptine (Parlodel): Start with 1.25 mg/d or b.i.d., increase by 1.25 mg every 2–5 days up to effective dose 10–30 mg/d. Side effects are much less than with Pergolide. Apomorphine (Apokyn): Start 0.2 mL SC; may increase in 0.1-mL increments every few days. Monitor for orthostatic hypotension is a potent emetic, so initiate an antiemetic Avoid ondansetron (combination causes severe hypotension and unconsciousness) Beneficial in early disease, but insufficient in advanced disease Used in early disease, to delay dyskinesia. (often in young patient)
Second line	Anticholinergic agents: Usually avoided because of side effects, which include impaired memory, confusion, constipation, blurred vision, urinary retention, xerostomia, and angle-closure glaucoma. Eg: Trihexyphenidyl (Artane)- Start with 1 mg t.i.d., increase to 2 mg t.i.d. Benztropine (Cogentin)-Start with 0.5 mg b.i.d., increase to 1 mg b.i.d. Selective MAO-B inhibitors: Side effects include insomnia, nausea, anorexia, hallucinations, and interactions with SSRIs and meperidine. Eg: Selegiline (Eldepryl): Start with 5 mg daily, increase up to 5 mg b.i.d. Rasagiline (Azelex): 0.5–1 mg/d NMDA antagonist: Amantadine: 100 mg b.i.d..Side effects include dizziness, insomnia, livedo reticularis, hallucinations, and confusion. COMT inhibitors: Tolcapone (Tasmar). Start 100 mg t.i.d., maximum dose 600 mg/d. Must be taken with carbidopa/levodopa.Side effect: Hepatotoxicity, monitor LFTs q6mo. Entacapone (Comtan). Start with 200 mg with each dose of carbidopa/levodopa, maximum dose 1,600 mg/d. Side effects: red-brown urine, dyskinesia, ausea and orthostatic hypotension, hallucination, sleep disorder, dry mouth, Hb↓, LFT↑
Multidisciplinary rehabilitation	physical and occupational therapy Emotional and psychological support of patient and family Speech therapy in dysarthria or hypoarthria
Surgery	Subthalamic deep brain stimulation for patients with motor complications refractory to best medical treatment who are healthy, have no significant active comorbidity, are responsive to levodopa, and don't have depression or dementia Others: thalamic, pallidal stimulation. Destruction of targeted areas of the brain Thalamotomy involves destruction of a part of the thalamus, generally the ventral intermediate (VIM) nucleus, to relieve tremor. Pallidotomy- destruction of a part of the GPi, improves tremor, rigidity, bradykinesia, dyskinesia. Subthalamotomy involves destruction of a part of the STN improves cardinal features, motor fluctuations& dyskinesia Neural transplantation is a potential treatment in the future
Other treatment	Repetitive transcranial magnetic stimulation Fava beans and velvet beans acupuncture, Qigong, or Tai chi: weak evidence

Complications
Psychosis can be caused by medication (most common); a decrease in or discontinuation of anticholinergics, dopamine agonists, amantadine, and selegiline; and a decrease in levodopa.

• Clozapine is useful but needs frequent monitoring owing to agranulocytosis.
• Quetiapine (Seroquel) has not been evaluated in trials but is prescribed commonly.
• In dementia, adjust medications as above, and consider cholinesterase inhibitors.

Depression (40%)- tricyclic and selective serotonin reuptake inhibitor (SSRI)
Aspiration pneumonia

Prognosis
1.6 times higher mortality than non-PD patients of same age