Goal: Restore dopaminergic tone in the striatum. Drug selection depends on age, symptom severity, and side-effect profile.

Motor complications develop in ~50% of patients after 5 years and up to 80% after 10 years of levodopa therapy. They result from progressive nigrostriatal degeneration and pulsatile dopamine receptor stimulation.

Types of Motor Fluctuations

• Wearing off (end-of-dose deterioration): Predictable return of symptoms before next dose — most common motor complication; managed by increasing dose frequency, adding COMT inhibitor (entacapone), MAO-B inhibitor, or dopamine agonist
• On-off fluctuations: Unpredictable, sudden switches between “on” (mobile) and “off” (immobile) states — not related to dosing schedule; may require apomorphine rescue injections, Duopa pump, or deep brain stimulation
• Delayed-on / dose failure: Delayed or absent onset of effect — often due to protein competition for absorption; take levodopa 30–60 min before meals
• Freezing of gait: Sudden inability to initiate or continue walking — occurs in both on and off states; may worsen with levodopa

Levodopa-Induced Dyskinesias

• Peak-dose dyskinesias: Choreiform movements at peak plasma levels — most common type; reduce individual levodopa dose, add amantadine
• Diphasic dyskinesias: Occur at rising and falling drug levels (beginning and end of dose); often dystonic/ballistic in legs — more difficult to treat
• Off-period dystonia: Painful dystonia (often foot) in early morning before first dose — treat with controlled-release levodopa at bedtime or early-morning dose

Management Strategies for Motor Complications

• Fractionate levodopa doses (smaller, more frequent dosing)
• Add entacapone or opicapone (COMT inhibitor) to extend “on” time
• Add MAO-B inhibitor (rasagiline, safinamide) for wearing off
• Amantadine — first-line for levodopa-induced dyskinesias
• Apomorphine — SC injection (Apokyn) and sublingual film (Kynmobi) for OFF rescue; pretreat with trimethobenzamide for nausea
• Duopa (carbidopa-levodopa intestinal gel) — continuous jejunal infusion for advanced fluctuations
• Deep brain stimulation (STN or GPi) — for medically refractory motor fluctuations and dyskinesias
• MR-guided focused ultrasound (MRgFUS) Vim thalamotomy for tremor-dominant PD (FDA-approved); GPi pallidotomy newer FDA approval for dyskinesia

• Impulse control disorders (ICDs): Pathological gambling, hypersexuality, compulsive shopping, binge eating — occur in ~15–20% of patients on dopamine agonists; screen regularly; treatment = dose reduction or discontinuation
• Dopamine agonist withdrawal syndrome (DAWS): Anxiety, panic, depression, dysphoria, diaphoresis upon abrupt discontinuation — taper slowly
• Hallucinations: More common than with levodopa — visual hallucinations; reduce agonist before reducing levodopa
• Excessive daytime somnolence / sleep attacks: Sudden onset of sleep without warning — especially pramipexole and ropinirole; counsel about driving
• Peripheral edema: Lower-extremity swelling, may be bilateral
• Orthostatic hypotension: Common across all dopaminergic agents
• Retroperitoneal/pulmonary/cardiac valve fibrosis: Historically with ergot agonists. Pergolide withdrawn (US 2007); bromocriptine and cabergoline rarely used for PD due to fibrosis risk (cabergoline remains for prolactinoma). Non-ergot agonists (pramipexole, ropinirole, rotigotine) do NOT cause valvular fibrosis and don't require echocardiographic monitoring

• Second most common cause of parkinsonism after idiopathic PD
• Caused by dopamine receptor blockade in the striatum
• Typically symmetric (unlike idiopathic PD) and may lack rest tremor
• Usually develops within weeks to months of starting the offending agent
• DaTSCAN is normal in drug-induced parkinsonism (vs. abnormal in PD) — helpful for distinguishing the two

Common Offending Agents

• Typical antipsychotics: Haloperidol, chlorpromazine (highest risk)
• Atypical antipsychotics: Risperidone, olanzapine (moderate risk)
• Antiemetics: Metoclopramide, prochlorperazine (cross BBB)
• VMAT2 inhibitors: tetrabenazine > deutetrabenazine > valbenazine (tetrabenazine carries the highest risk; valbenazine and deutetrabenazine less commonly implicated)
• Other board-tested causes: Valproate (board-tested), amiodarone, reserpine
• Note: Lithium causes tremor, not classic parkinsonism

Safe Medications in PD Psychosis

• Quetiapine: Low D2 affinity — most commonly used; does NOT significantly worsen parkinsonism
• Clozapine: Off-label in US (strongest efficacy data); pimavanserin is the only FDA-approved agent for PD psychosis. REMS: weekly ANC × 6 months → every 2 weeks for months 7–12 → every 4 weeks after 12 months
• Pimavanserin: Selective 5-HT2A inverse agonist — FDA-approved for PD psychosis; NO dopamine receptor blockade; Onset ~2 weeks; full effect by 4–6 weeks; QT prolongation risk

Tardive Dyskinesia — Additional Details

• Risk factors: Older age, female sex, longer duration of D2 blocker use, higher doses, mood disorders, diabetes
• Mechanism: Dopamine receptor supersensitivity from chronic blockade
• Valbenazine: Selective VMAT2 inhibitor; once daily; well-tolerated; FDA-approved 2017
• Deutetrabenazine: Deuterated form of tetrabenazine; better tolerability (longer half-life, less peak-dose side effects); twice daily; FDA-approved for TD and Huntington chorea
• Do NOT treat TD with anticholinergics (may worsen it) — unlike acute dystonic reactions
• TD may be irreversible even after stopping the causative agent

• Chorea: VMAT2 inhibitors are first-line
  • Tetrabenazine: First FDA-approved drug for Huntington chorea (2008); depletes presynaptic monoamines; short half-life (3x/day dosing); causes depression, parkinsonism, akathisia — BLACK BOX warning for suicidality; CYP2D6 genotyping required for doses >50 mg/day (to identify poor metabolizers); not required to start drug
  • Deutetrabenazine: Deuterated tetrabenazine with longer half-life (2x/day); better tolerability; also FDA-approved for Huntington chorea
• Antipsychotics for chorea + psychosis/behavioral disturbances — olanzapine, risperidone, aripiprazole (atypicals preferred); typical antipsychotics like haloperidol generally avoided due to EPS and worsening late-stage motor symptoms
• Benzodiazepines may help chorea and associated anxiety
• Depression: SSRIs/SNRIs (extremely common in HD, screen regularly)
• Irritability/aggression: SSRIs, atypical antipsychotics
• No disease-modifying therapy currently available

Focal Dystonia

• Botulinum toxin injections: First-line for cervical dystonia, blepharospasm, spasmodic dysphonia, writer’s cramp
• Botulinum toxin blocks presynaptic acetylcholine release at the NMJ
• Effect onset: 2–5 days; peak: ~2 weeks; duration: 3–4 months
• Antibodies to botulinum toxin can develop → switch serotype (type A → type B)

Generalized Dystonia

• Anticholinergics (trihexyphenidyl): Most effective oral agent, especially in children and young adults; titrate slowly; adults tolerate less well
• Baclofen: GABA-B agonist; helpful adjunct
• Benzodiazepines: Clonazepam for adjunctive benefit
• Deep brain stimulation (GPi): Highly effective for DYT1 dystonia; can help other generalized forms

Dopa-Responsive Dystonia (DRD / Segawa Disease)

• Always trial levodopa in any child or young adult with unexplained dystonia
• Autosomal dominant; GCH1 gene (GTP cyclohydrolase I deficiency) — most common cause
• Diurnal fluctuation: symptoms worse in the evening, improve with sleep
• Dramatic, sustained response to LOW-dose levodopa — hallmark of the disease
• Unlike PD, does NOT develop motor complications with chronic levodopa use
• DaTSCAN is normal (intact presynaptic dopamine terminals)

• First-line agents:
  • Propranolol: Non-selective beta-blocker; 60–320 mg/day; most evidence; also available as long-acting formulation; avoid in asthma, bradycardia, diabetes (masks hypoglycemia)
  • Primidone: Anticonvulsant (metabolized to phenobarbital and PEMA); start at very low dose (25 mg at bedtime) to avoid initial “first-dose phenomenon” (severe sedation, nausea, ataxia); equally effective as propranolol
• Second-line agents:
  • Topiramate: Modest benefit; weight loss side effect may be beneficial or detrimental
  • Gabapentin: Mild benefit as monotherapy; may be used as adjunct
  • Benzodiazepines (alprazolam, clonazepam): For refractory or situational tremor
• Botulinum toxin: Useful for head/voice tremor that does not respond well to oral medications; hand tremor treatment limited by weakness side effect
• Surgical: DBS (VIM thalamus) or MRI-guided focused ultrasound thalamotomy for medically refractory cases

• Orthostatic hypotension: midodrine, droxidopa, fludrocortisone
• Constipation: PEG, senna, lubiprostone
• REM behavior disorder: melatonin first-line (3–18 mg HS); clonazepam (with caveats — sedation, falls, cognitive impairment in elderly)
• Drooling (sialorrhea): glycopyrrolate, atropine drops, BoNT to parotids/submandibular glands

• Iron first-line if ferritin <75: IV ferric carboxymaltose; oral iron + vitamin C; check transferrin saturation
• Alpha-2-delta ligands now FIRST-LINE per AAN 2024: gabapentin enacarbil (Horizant, FDA-approved), pregabalin, gabapentin
• Dopamine agonists (pramipexole, ropinirole, rotigotine) — now second-line due to augmentation risk; if used, keep doses low
• Opioids (low-dose methadone, oxycodone) for refractory cases
• Avoid: caffeine, alcohol, antihistamines; SSRI/SNRI worsen RLS

• Alpha-2 agonists first-line: clonidine, guanfacine (Intuniv ER)
• Aripiprazole (FDA-approved for Tourette syndrome)
• Pimozide, fluphenazine, risperidone (D2 antagonists — effective but carry EPS/TD risk)
• VMAT2 inhibitors: valbenazine, deutetrabenazine
• CBIT (Comprehensive Behavioral Intervention for Tics) — non-pharmacologic, evidence-based first-line

• Levetiracetam — broad utility for cortical and post-anoxic myoclonus
• Clonazepam — effective across cortical, subcortical, spinal myoclonus
• Valproate — particularly useful for cortical myoclonus
• Piracetam — adjunct for cortical myoclonus (limited US availability)
• Primidone — consider for essential/cortical myoclonus