Parkinson Disease

Background

• Parkinson disease (PD) is a progressive movement disorder characterized by bradykinesia, resting tremor, muscular rigidity, and the loss of postural reflexes.
  • Nonmotor symptoms include pain, fatigue, hyposmia, and constipation.
  • It also is associated with cognitive complications including dementia, depression, sleep disorders, and psychosis.
• The prevalence of Parkinson disease increases with age, with the highest prevalence in adults who are ≥ 80 years old.
• Parkinson disease is due to a loss of dopaminergic neurons in the substantia nigra, as well as other dopaminergic and nondopaminergic areas of the brain.
• Motor fluctuations include "on" and "off" time, as well as medication-induced dyskinesias.
  • "Off" time refers to periods of decreased responsiveness to levodopa resulting in a return of symptoms.
  • Dyskinesias are involuntary movements (chorea and/or dystonia) which occur at peak-dose or during transitions between "off" and "on states.
  • Patients can fluctuate between "on" and "off" states several times during the day.
• Patients with Parkinson disease are at an increased risk of falls, poor nutrition, weight loss, and a loss of muscle mass.
• Levodopa is a metabolic precursor of dopamine. Carbidopa is a decarboxylase inhibitor that inhibits peripheral conversion of levodopa to dopamine, reducing the side effects of levodopa. More of the levodopa is available for central nervous system conversion to dopamine, allowing a lower levodopa dose.

Evaluation

• The diagnosis of Parkinson disease (PD) is clinical and is based on historical information and classic physical exam findings.
• Consider single photon emission computed tomography (SPECT) with DaTscan to help differentiate Parkinson disease from essential tremor. DaTscan is FDA approved for this purpose, and "off-label" use may also help differentiate Parkinson disease from drug-induced Parkinsonism and other conditions.
• Patients usually present with an insidious onset of difficulty performing activities of daily living due to stiffness, problems with dexterity, slowness, tremor, and fatigue.
• Classic exam findings include a resting "pill-rolling" tremor, slow and shuffling gait, "cog-wheel" muscle rigidity, expressionless "masked" facies, and micrographia (tiny handwriting).
• The Movement Disorder Society (MDS) Clinical Diagnostic Criteria for Parkinson Disease can be used to make the diagnosis. The key elements of the criteria include:
  • bradykinesia with at least 1 of
    • muscular rigidity (such as cogwheeling)
    • resting tremor of 4-6 hertz
  • clinically established PD requires
    • absence of absolute exclusion criteria such as unequivocal cerebellar abnormalities, downward vertical supranuclear gaze palsy, treatment with dopamine receptor blocker or dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism, absence of observable response to high-dose levodopa despite at least moderate severity of disease, normal functional neuroimaging of the presynaptic dopaminergic system, and others.
    • at least 2 supportive criteria - clear and dramatic beneficial response to dopaminergic therapy, presence of levodopa-induced dyskinesia, rest tremor of limb documented on clinical exam (past or current), and presence of olfactory loss or cardiac sympathetic denervation on metaiodobenzylguanidine (MIBG) scintigraphy.
    • no red flags such as rapid progression of gait impairment, absence of progression of motor symptoms or signs over 5 years (unless stability is related to treatment), early bulbar dysfunction, severe autonomic failure in first 5 years, recurrent falls due to impaired balance during first 3 years, otherwise unexplained pyramidal weakness or clear pathologic hyperreflexia, bilateral symmetric parkinsonism , and others.
  • clinically probable PD requires
    • absence of absolute exclusion criteria
    • presence of red flags counterbalanced by supportive criteria
      • if 1 red flag is present there must be at least 1 supportive criterion
      • if 2 red flags, at least 2 supportive criteria are needed
      • no more than 2 red flags are allowed for this category
• Major differential diagnostic considerations include:
  • other neurodegenerative disorders causing parkinsonism, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and normal pressure hydrocephalus
  • essential tremor
  • severe depression causing psychomotor slowing
  • medications causing parkinsonism, such as antipsychotics and antiemetics
  • toxins causing parkinsonism, such as carbon monoxide and methanol
• Clinical features which are suggestive of other parkinsonian syndromes distinct from Parkinson disease include (Strong recommendation):
  • falls at presentation and early in the disease course
  • a poor clinical response to L-dopa
  • symmetry at the onset of presentation
  • rapid progression of the syndrome
  • lack of a tremor
  • significant dysautonomia
  • see Parkinsonism for details

Management

• Treatment of Parkinson disease (PD) is individualized and aimed at reducing movement dysfunction, tremor, postural instability, while managing cognitive changes and minimizing side effects.
• For early, symptomatic PD, the first-choice options include levodopa, a non-ergot dopamine agonist such as pramipexole, ropinirole, or rotigotine patch, or a monoamine oxidase type B (MAO-B) inhibitor such as selegiline or rasagiline (Strong recommendation). The choice of therapy depends on the priority in the individual patient.
  • Levodopa is better for improving motor impairment but is associated with motor complications such as dyskinesias and motor fluctuations.
  • Dopamine agonists are effective as mono- or add-on therapy for many patients but can have significant side effects such as excessive daytime drowsiness, sleep attacks, nausea, and compulsive behaviors.
  • MAO-B inhibitors may not be as effective for improving motor impairment as other first-line options.
• Other medications that can be considered for early symptomatic disease include amantadine and anticholinergic drugs (Weak recommendation).
• Medications for PD are associated with significant side effects and medication interactions that warrant a regular assessment for new symptoms and attention when starting or changing the dose of a medication.
  • For patients on levodopa who develop motor fluctuations and increased "off" time, consider adjuvant therapy with dopamine agonists, MAO-B inhibitors, or catechol-O-methyltransferase (COMT) inhibitors such as entacapone to help reduce symptoms (Weak recommendation).
  • Amantadine may be used to reduce dyskinesias (Weak recommendation).
• Consider deep brain stimulation for improving motor function in patients with motor fluctuation despite optimal medical treatment, or for patients with poor tolerability to oral medication (Weak recommendation).
• MRI-guided focused ultrasound for targeted tissue ablation is a potential option for patients with medication-resistant symptoms.
• There is insufficient evidence from randomized trials evaluating specific antidepressant treatments for managing depression in patients with PD.
  • Also consider counseling for managing depression.
  • Selection of antidepressants should be guided by comorbidities (such as trazodone for concurrent insomnia).
• Consider managing effects of cognitive impairment (deficits in attention and memory) with lifestyle modification and coaching. Rivastigmine may also be considered (FDA approved for Parkinson disease dementia).
• Management of psychotic symptoms (hallucinations, delusions, paranoia) may include:
  • Removing or reducing dose of anticholinergic medications (or medications with anticholinergic effects) such as trihexyphenidyl and amantadine.
  • Removing or reducing dose of dopamine agonists and other medications other than levodopa.
  • Reducing dose of levodopa.
  • If medication adjustments are not adequate, giving medications aimed at reducing psychotic symptoms such as pimavanserin (FDA approved for psychosis associated with Parkinson disease) or quetiapine.
• For managing orthostatic hypotension (OH), consider:
  • increased dietary salt and fluid intake.
  • compression garments.
  • sleeping with head of bed elevated.
  • reviewing current medication use to address possible pharmacological cause (such as antihypertensives, dopamine agonists, anticholinergics, or antidepressants)
  • medication - droxidopa (FDA approved for OH associated with Parkinson disease), midodrine (FDA approved for OH), and fludrocortisone.
• Dietary considerations include:
  • for significant weight loss, a swallow evaluation and referral to dietitian
  • for constipation due to colonic dysmotility, consider increased dietary fiber and fluid intake
  • For patients experiencing motor fluctuations, consider taking levodopa 30 minutes before a meal (digestion may interfere with levodopa absorption).
• Physical therapy should be available to patients with Parkinson disease (Strong recommendation). Exercise may improve physical function.