Parkinson Disease

Meet the patient

A 68-year-old retired headmaster has noticed for a year that his right hand shakes when he is resting in his chair, watching television. His handwriting has got smaller, his wife says he has stopped swinging his right arm when they walk, and last week he froze in a doorway at the supermarket. He has no tremor when he reaches for his teacup. He smells nothing at all these days, and his GP put it down to old age.^[1]

Two exam questions are now live. Is this idiopathic Parkinson disease, or one of its mimics? — and what will you start, what will you never give him, and what must you warn him about? The asymmetric rest tremor that vanishes on action, the micrographia, the reduced arm swing, the loss of smell — this is the fingerprint of idiopathic PD. Get the diagnosis right and the whole algorithm opens.^[2]

What PD is — a synucleinopathy of the nigrostriatal pathway

Parkinson disease (PD), first described by James Parkinson in 1817 as the Shaking Palsy, is a chronic, progressive neurodegenerative disorder of the central nervous system characterised by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, with intracytoplasmic alpha-synuclein aggregates — Lewy bodies and Lewy neurites. The resulting dopamine depletion in the striatum (dorsolateral putamen) disinhibits the indirect basal ganglia pathway and disrupts the direct pathway, producing the cardinal motor triad of bradykinesia, rigidity and resting tremor, with postural instability developing later.^[1][4]

The clinical skill in PD is threefold. First, recognise parkinsonism (bradykinesia plus tremor or rigidity) and distinguish idiopathic PD from its mimics — drug-induced, vascular, the atypical parkinsonisms (PSP, MSA, DLB), essential tremor and Wilson disease. Second, time and select symptomatic therapy and manage the motor fluctuations and dyskinesia of long-term levodopa. Third, never omit dopaminergic medication in a hospitalised patient and never give dopamine-blocking drugs.^[2]

There is no cure and no proven disease-modifying therapy; treatment is lifelong, symptomatic and individualised, with the goal of maintaining function and quality of life for as long as possible.^[1]

Classification — aetiology, phenotype, severity

PD is classified in three useful ways — by aetiology, by motor phenotype, and by Hoehn and Yahr severity.^[1]

^[2]

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By motor phenotype (prognostically useful):^[1]

• Tremor-dominant — prominent resting tremor, less rigidity and bradykinesia; slowest progression, best prognosis, least cognitive decline.
• Akinetic-rigid (postural-instability or gait difficulty, PIGD) — dominant bradykinesia, rigidity, gait freezing and falls; faster progression, more dementia and disability.
• Mixed or indeterminate — features of both.^[1]

By severity — Hoehn and Yahr staging (1967):^[4]

^[1]

How common, how fast-growing

PD is the second commonest neurodegenerative disease after Alzheimer disease and the fastest-growing neurological disorder worldwide in prevalence and disability.^[1]

Established risk factors: age (the strongest; rare before 40), male sex (1.4 to 2 times the risk of women), genetics (family history; LRRK2, GBA, SNCA, Parkin, PINK1, DJ-1 mutations; first-degree relative risk about 2 to 3 times), and environmental exposures — pesticides and herbicides (paraquat, rotenone — both inhibit complex I), the MPTP discovery (a meperidine-analogue contaminant that caused acute parkinsonism in drug users and proved a toxin can selectively destroy the SNpc), rural living, well water, farming, and manganese, carbon monoxide and carbon disulfide toxicity. Repeated head trauma causes pugilistic parkinsonism.^[1]

Reported protective factors (examinable, controversial): caffeine and coffee (adenosine A2A antagonism is the rationale for istradefylline), cigarette smoking (the strongest and most reproducible inverse association — perhaps nicotine is neuroprotective, or smoking behaviour is itself reduced early in prodromal PD — reverse causation), higher serum urate (antioxidant; slower progression in men), and physical activity. These associations do not justify recommending smoking or treating with urate — the data are observational and confounded.^[1][4]

The prodrome — motor symptoms arrive a decade late

Motor symptoms are preceded by a prodromal phase of 10 to 20 years during which non-motor features accumulate — idiopathic REM sleep behaviour disorder (RBD), hyposmia or anosmia, constipation, depression and anxiety, orthostatic intolerance, and subtle motor signs. Probable RBD confers a very high (over 80% over 14 years) risk of converting to an alpha-synucleinopathy (PD, DLB or MSA).^[3]

Pathophysiology — Lewy bodies, Braak, and the direct or indirect balance

PD is a synucleinopathy — the pathological hallmark is the misfolding and aggregation of alpha-synuclein into Lewy bodies (intracytoplasmic eosinophilic inclusions) and Lewy neurites (in neuronal processes).^[1][4]

Site of degeneration. The vulnerable neurons are the melanin-pigmented dopaminergic neurons of the substantia nigra pars compacta — specifically the calbindin-negative neurons in the ventrolateral tier that project to the dorsolateral putamen (the nigrostriatal pathway). About 60 to 80% of these neurons (and a comparable fraction of striatal dopamine) must be lost before motor symptoms appear — the threshold that explains the long prodromal phase and the brain's capacity to compensate.^[1]

Braak staging (2003). Lewy pathology spreads caudal-to-rostral in a predictable six-stage sequence — beginning in the enteric nervous system and dorsal motor nucleus of the vagus (stages 1 to 2), ascending through the medulla, pons and locus coeruleus (stage 2), the midbrain and substantia nigra (stage 3 — onset of motor symptoms), the basal forebrain and limbic cortex (stage 4), and finally the neocortex (stages 5 to 6 — dementia). This is the anatomical basis for the prodromal non-motor symptoms preceding motor disease and for late cognitive decline — and underpins the gut-brain hypothesis (alpha-synuclein propagating via the vagus) and prion-like cell-to-cell spread.^[4]

Basal ganglia circuitry — the mechanism of the motor signs

The basal ganglia normally facilitate wanted movement (direct pathway) and suppress unwanted movement (indirect pathway). Both originate from corticostriatal glutamatergic input to medium spiny neurons of the striatum and act on the thalamus, which then excites the motor cortex.^[1]

• Direct pathway: cortex excites striatum then D1-dopamine-receptor MSNs which inhibit the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr), which themselves inhibit the thalamus — so disinhibiting the thalamus and facilitating movement. Dopamine stimulates D1, enhancing the direct pathway.
• Indirect pathway: cortex excites striatum then D2-MSNs which inhibit the external globus pallidus (GPe), which normally inhibits the subthalamic nucleus (STN), which excites the GPi and SNr — so the indirect pathway, when active, ultimately increases thalamic inhibition and suppresses movement. Dopamine stimulates D2, which inhibits the indirect pathway.^[1]

In PD, loss of dopamine simultaneously weakens the direct pathway (less facilitation of movement) and removes inhibition of the indirect pathway (excess suppression of movement). The net effect is overactivity of the GPi and SNr (excessive thalamic inhibition), producing the hypokinetic features — bradykinesia and rigidity. This is the rationale for STN or GPi deep brain stimulation and for levodopa or dopamine agonist therapy.^[4]

^[1]

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Clinical presentation — the TRAP tetrad

PD is insidious and asymmetric in onset; symptoms group into motor and non-motor, the latter increasingly recognised as the dominant source of disability.^[1]

^[1]

Other motor signs: hypomimia (masked face), hypophonia (soft voice), hypersalivation or sialorrhoea (reduced swallow, not excess saliva), micrographia (small handwriting that gets smaller), reduced arm swing, festination (accelerating shuffling steps), freezing of gait (feet glued to floor, especially at turns, doorways, on starting — "off" freezing), camptocormia (stooped posture), Pisa syndrome (lateral trunk flexion), blepharospasm and dystonia (often a foot in young-onset disease).^[1]

Non-motor features — often precede motor disease and dominate late

^[1]

The mimics — six questions that sort parkinsonism

The discriminator questions are: Is the levodopa response clear and sustained? Is it asymmetric? Is there early dementia, early falls, gaze palsy, autonomic or cerebellar involvement? Is a drug responsible? Is the patient young (Wilson)?^[1]

^[1]

Essential tremor (the commonest mimic): postural or action tremor (not resting), 4 to 12 Hz, bilateral, hands and head (yes-yes), improves with alcohol, family history in over half, no bradykinesia or rigidity, normal gait. DAT-SPECT is normal (essential tremor) versus reduced (PD). Treat with propranolol or primidone.^[1]

Drug-induced parkinsonism (always reversible, always asked): caused by dopamine D2 antagonists — typical antipsychotics (haloperidol, chlorpromazine), atypicals (risperidone, olanzapine — less with quetiapine or clozapine), metoclopramide, prochlorperazine, antinauseants (promethazine), cinnarizine or flunarizine (calcium-channel blockers), valproate (high dose), tetrabenazine, reserpine. Symmetric, less tremor-dominant, develops over weeks to months of the drug, and is reversible on stopping. DAT-SPECT is normal. The trap: it coexists with idiopathic PD and unmasks a hidden parkinsonism.^[1]

Vascular parkinsonism: multi-infarct state; lower-body predominant ("parkinsonism of the feet"), prominent gait disturbance (broad-based, marche à petits pas), pyramidal signs (hyperreflexia, Babinski), stepwise course, vascular risk factors, poor levodopa response, white-matter or lacunar infarcts on MRI.^[2]

Wilson disease — an inherited disorder of copper metabolism that must be excluded in young patients with new parkinsonism: caused by mutations in ATP7B, which encodes a copper-transporting ATPase, producing copper overload in the liver, brain and other organs. Presentation can be neurological (including parkinsonism), psychiatric or hepatic — progressive liver disease is a common feature. Diagnosis uses algorithms combining clinical features, measures of copper metabolism and ATP7B DNA analysis; treatment — chelation therapy or zinc salts, which reverse copper overload by different mechanisms — is effective, so recognising it early is the challenge.^[8]

The bedside exam and the scales

Bradykinesia (obligatory): finger tapping (thumb and index repeatedly), hand pronation-supination, foot tapping, hand opening-closing. Look for decreasing amplitude and speed, hesitation or arrest, fatiguing over 10 to 15 seconds. Observe spontaneous movement — hypomimia, reduced blink rate (normal 12 to 20 per minute, reduced in PD), reduced gesture.^[2]

Tone (rigidity): examine wrist, elbow, shoulder and neck by slow passive movement through full range. Lead-pipe is uniform; cogwheel is a ratchet superimposed on tremor. The activation manoeuvre (Froment) — ask the patient to move the contralateral limb — augments rigidity on the tested side.^[1]

Tremor: observe at rest in hands (pill-rolling), lips, jaw, lower limbs and head. PD rest tremor is suppressed by action; essential tremor is worst with action. Postural tremor in PD re-emerges after seconds ("re-emergent tremor").^[1]

Postural stability (pull test): stand behind the patient; give a quick backward pull on both shoulders and be ready to catch. Normal recovery takes one to two steps. Abnormal (retropulsion): more than two steps, or a fall with no corrective step.^[2]

Standardised scales: the MDS-UPDRS (four parts — I non-motor aspects of daily living, II motor aspects of daily living, III motor examination, IV motor complications) is the gold-standard rating scale. Hoehn and Yahr (1 to 5) is coarse functional staging. The Non-Motor Symptoms Scale (NMSS) quantifies non-motor burden; Schwab and England rates percentage independence.^[1]

Investigations — clinical diagnosis, then exclude mimics

PD is a clinical diagnosis — there is no confirmatory test in life. Investigations exclude mimics and, in selected cases, support the diagnosis.^[2][3]

• Atypical features (early falls, rapid progression, symmetric onset, early dementia, poor levodopa response, pyramidal, cerebellar or autonomic signs) → imaging and secondary-cause work-up.
• Young onset (under 50) → exclude Wilson disease (ceruloplasmin, 24-hour urinary copper, slit-lamp for Kayser-Fleischer rings) and consider genetic testing.
• Diagnostic uncertainty (PD versus drug-induced parkinsonism or essential tremor) → DAT-SPECT.^[1]

MRI brain is usually normal in PD. Its role is to exclude vascular disease, hydrocephalus and tumour, and to show pattern signs of atypical parkinsonism — hummingbird sign (midbrain atrophy in PSP), hot-cross-bun sign (pontine cruciform hyperintensity in MSA), putaminal atrophy (MSA-P), asymmetric frontoparietal atrophy (CBD).^[2]

DAT-SPECT (DaTscan) shows the density of presynaptic dopamine transporters in the striatum. Reduced, asymmetric putaminal uptake in PD, MSA, PSP and DLB (all have nigral degeneration); normal in essential tremor and drug-induced parkinsonism (no structural degeneration). It does not distinguish PD from atypical parkinsonisms. Olfactory testing (UPSIT or Sniffin' Sticks) — hyposmia is present in over 90% of PD and helps distinguish PD from MSA, PSP, CBD and drug-induced parkinsonism (often normal smell).^[2]

The MDS clinical diagnostic criteria (2015) — reproduced

The MDS 2015 criteria replaced the 1992 UK Parkinson's Disease Society Brain Bank criteria and are the current international standard.^[3]

Step 1 — Diagnose parkinsonism: bradykinesia (obligatory) PLUS either rest tremor or rigidity.^[1]

Step 2 — Absolute exclusions (any one excludes PD): clear cerebellar signs; downward vertical supranuclear gaze palsy or selective slowing of downward saccades; a diagnosis of frontotemporal dementia, primary progressive aphasia or dementia with Lewy bodies within 5 years; parkinsonism restricted to the lower limbs for more than 3 years; treatment with a dopamine blocker or dopamine-depleting drug at onset or within 5 years of starting; absence of response to high-dose levodopa (despite at least 400 mg per day); cortical sensory impairment; severe dysautonomia with intact sphincters; normal DAT-SPECT; a proven alternative cause (Wilson, structural lesion).^[3]

Step 3 — Supportive criteria (any one supports PD): clear dramatic beneficial response to dopaminergic therapy; marked levodopa-induced dyskinesia; rest tremor of a limb documented; olfactory loss or cardiac sympathetic denervation on MIBG.^[1]

Step 4 — Red flags (warn against PD): rapid gait impairment within 3 years; no progression; early bulbar dysfunction within 5 years; early severe dysautonomia within 5 years; falls within 3 years; anterocollis or contractures within 10 years; absence of common non-motor features despite 5 years; bilateral pyramidal signs; bilateral ptosis or vertical gaze restriction.^[1]

Step 5 — Final categories: clinically established PD = no absolute exclusions, at least 2 supportive criteria, no red flags. Clinically probable PD = no absolute exclusions, at least 2 supportive criteria, fewer red flags than supportive criteria.^[3]

The two inviolable rules — never omit, never block

There is no disease-modifying therapy; the goal is symptomatic control of motor and non-motor function and preservation of quality of life.^[1]

Rule 1 — never omit or delay dopaminergic medication. PD drugs are time-critical. Missing doses (especially levodopa, which has a short half-life of 60 to 90 minutes) precipitates wearing-off, akinesia, and — in severe withdrawal — parkinsonism-hyperpyrexia syndrome. In hospital, chart levodopa at the patient's home timing (often every 3 to 4 hours), not at standard drug-round times.^[2]

Rule 2 — never give dopamine-blocking drugs. Metoclopramide, prochlorperazine, haloperidol, chlorpromazine, risperidone and olanzapine cross the blood-brain barrier, block D2 receptors, and worsen parkinsonism or precipitate a crisis. Safe antiemetics: domperidone (does not cross the BBB) and ondansetron (5-HT3).^[1]

Nil by mouth (perioperative or acutely ill): convert levodopa to enteral (NG or NJ) administration if the gut is working — levodopa can be given via NG tube (crushed dispersible levodopa or carbidopa). If the gut is not working (postoperative ileus, severe vomiting), use a transdermal rotigotine patch as a bridge. Apomorphine (subcutaneous) is another parenteral option.^[1]

Acute precipitants of sudden deterioration in a known PD patient (the "sick parkinsonian"): infection (urinary tract infection is commonest; chest infection or aspiration pneumonia), drug omission, dehydration, constipation or faecal impaction, metabolic disturbance, new medication interaction, aspiration. Always dipstick the urine and examine the chest.^[2]

Parkinsonism-hyperpyrexia syndrome (PHS)

A rare, life-threatening emergency analogous to neuroleptic malignant syndrome, triggered by abrupt withdrawal or rapid reduction of dopaminergic therapy (also by adding a dopamine blocker). Features: fever, marked rigidity, altered consciousness or stupor, autonomic instability (tachycardia, labile BP, diaphoresis), elevated creatine kinase, leucocytosis. Rhabdomyolysis may cause acute kidney injury.^[1]

Management: dopaminergic drug replacement — reintroduce the antiparkinson medication — together with supportive measures and active treatment of complications (acute renal failure, aspiration pneumonia, deep-venous thrombosis or pulmonary embolism, and disseminated intravascular coagulation). Prognosis improves with early recognition and management, but even then mortality of up to 4% is reported and about one-third of survivors are left with permanent sequelae — which is why patients and physicians are explicitly warned never to reduce or stop antiparkinson drugs suddenly.^[9]

Levodopa — the gold standard

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Levodopa combined with a peripheral dopa-decarboxylase inhibitor (carbidopa or benserazide) is the most effective symptomatic therapy for PD. The decarboxylase inhibitor prevents peripheral conversion of levodopa to dopamine (which causes nausea, hypotension, and is wasted peripherally), allowing more levodopa to reach the brain, where surviving nigral neurons convert it to dopamine.^[1]

• Preparations: oral carbidopa-levodopa is the standard fixed-combination preparation; pharmacological substitution of striatal dopamine anchors treatment of the motor symptoms.^[1]
• Goal of dosing: treatment is symptomatic, focused on improvement in motor and non-motor signs and symptoms; dopamine-based therapies typically help the initial motor symptoms.^[2]
• Long-term complications: as the disease progresses, patients develop "off periods" (worsening symptoms and functional impairment when a medication dose wears off) and dyskinesias — complications that benefit from advanced treatments such as levodopa-carbidopa enteral suspension or deep brain stimulation.^[2]

Dopamine agonists — and the impulse-control confession

Non-ergot agonists (preferred — no fibrotic or valvular risk) — ropinirole, pramipexole, rotigotine (transdermal) — act directly on D2 or D3 receptors. Use first-line in younger patients (to delay levodopa and dyskinesia) or as adjuncts in advanced disease.^[1]

• Early disease: non-ergot dopamine agonists (pramipexole, ropinirole, rotigotine), oral levodopa preparations, selegiline and rasagiline are all rated clinically useful as monotherapy in early PD by the MDS evidence-based medicine review.^[6]
• Adjunct and fluctuating disease: non-ergot dopamine agonists and rasagiline are clinically useful adjuncts in early or stable PD; for motor fluctuations, non-ergot dopamine agonists, levodopa extended-release, entacapone, opicapone, rasagiline, safinamide, levodopa intestinal infusion and bilateral STN or GPi deep brain stimulation are all clinically useful.^[6]

Ergot agonists (bromocriptine, pergolide, cabergoline) are largely abandoned because of cardiac valve fibrosis and pulmonary or retroperitoneal fibrosis; echocardiographic monitoring if used.^[1]

MAO-B inhibitors, COMT inhibitors and amantadine

MAO-B inhibitors (selegiline, rasagiline) — the MDS evidence-based review rates selegiline and rasagiline clinically useful as monotherapy in early PD, and rasagiline clinically useful as adjunct therapy for early or stable disease and for motor fluctuations. Monotherapy with rasagiline 1 or 2 mg once daily significantly attenuated the worsening of symptoms versus placebo in early PD; unlike selegiline, rasagiline has no amphetamine-like metabolites.^[6][12]

COMT inhibitors (entacapone, opicapone) — for motor fluctuations, the MDS evidence-based review rates entacapone and opicapone clinically useful, alongside rasagiline, safinamide, levodopa extended-release and deep brain stimulation.^[6]

Amantadine — for levodopa-induced dyskinesia, the MDS evidence-based review lists amantadine, clozapine, and bilateral STN and GPi deep brain stimulation as the clinically useful interventions.^[6]

Advanced therapies — when oral optimisation is exhausted

^[1]

DBS selection criteria: clear levodopa-responsive idiopathic PD; motor fluctuations or dyskinesia despite optimised oral therapy; no dementia or major psychiatric illness; realistic expectations. Follett (2010, NEJM) showed STN and GPi stimulation were similarly effective on motor scores at 2 years; GPi may be preferable when dyskinesia control is paramount or cognitive risk exists.^[7]

Non-motor symptom management

• Depression, anxiety and other psychiatric symptoms — non-motor symptoms require nondopaminergic approaches: selective serotonin reuptake inhibitors help psychiatric symptoms and cholinesterase inhibitors help cognitive problems.^[2]
• Psychosis (hallucinations and delusions) — frequent and debilitating. Pimavanserin 40 mg per day, a selective serotonin 5-HT2A inverse agonist, improved Parkinson disease psychosis on the SAPS-PD scale in a 6-week randomised, placebo-controlled phase 3 trial, was well tolerated and caused no worsening of motor function — an option for patients "for whom few other treatment options exist".^[5]
• Non-motor burden generally — non-motor symptoms add substantially to overall disability in PD and must be treated actively alongside motor therapy; rehabilitative therapy and exercise complement pharmacological treatment, and palliative care is part of Parkinson disease management.^[1][2]

Motor complications — the long-term levodopa story

After 5 years of levodopa, over 50% of patients develop motor complications; higher in young-onset disease.^[1]

Motor fluctuations (wearing-off): the benefit of each levodopa dose shortens from 4 hours to under 2 to 3 hours. Manage with more frequent dosing, controlled-release formulations, a COMT inhibitor (entacapone or opicapone) or MAO-B inhibitor (rasagiline), or a dopamine agonist. Delayed-on or dose failure is often due to protein competition for gut absorption — advise taking levodopa 30 to 60 minutes before high-protein meals. Unpredictable on-off fluctuations indicate advanced therapies (apomorphine, LCIG, DBS).^[1]

Levodopa-induced dyskinesia: involuntary movements complicating long-term dopaminergic therapy. The MDS evidence-based review rates amantadine, clozapine, and bilateral STN and GPi deep brain stimulation as the clinically useful interventions for dyskinesia; the same review rates non-ergot dopamine agonists, levodopa extended-release, entacapone, opicapone, rasagiline, safinamide, levodopa intestinal infusion and DBS as clinically useful for the accompanying motor fluctuations.^[6]

How PD patients come to harm (the preventable list)

• Giving dopamine-blocking drugs (metoclopramide, prochlorperazine, haloperidol) — the single most preventable error^[2]
• Withholding levodopa for fear of dyskinesia — outdated; deprives the patient of the most effective therapy^[2]
• Missing atypical parkinsonism (early falls, gaze palsy, symmetric, poor levodopa response, early dementia) and labelling it "PD that has stopped responding"^[1]
• Missing impulse control disorders on dopamine agonists — ask about gambling, sexuality, spending^[1]
• Abrupt drug withdrawal precipitating parkinsonism-hyperpyrexia syndrome^[1]
• Failing to treat non-motor symptoms — the main driver of quality-of-life loss^[1]
• Forgetting Wilson disease in any patient under 50 with new parkinsonism^[4]
• Omitting the inpatient levodopa dose because "drug round is at 9 and 5"^[1]
• Missing aspiration pneumonia — the leading cause of death in PD^[1]

Prognosis and disposition

PD is progressive but not directly fatal; typical course from diagnosis to death is 10 to 20 years (longer in tremor-dominant and young-onset disease, shorter in PIGD phenotype and with early cognitive or autonomic involvement).^[1]

The leading causes of death are the complications of immobility and neurodegeneration: aspiration pneumonia (the single commonest cause), falls and fractures, sepsis (urinary or chest), and the dementing process.^[1]

No proven disease-modifying therapy. Multiple candidates — selegiline (DATATOP), coenzyme Q10, creatine, vitamin E, inosine, isradipine, exenatide — have been tested and none has shown convincing neuroprotection. Research continues on alpha-synuclein immunotherapy and prodromal early-intervention trials.^[1]

Special populations

^[4]

The 1-year rule and PD psychosis versus dementia

PD dementia (PDD): dementia develops in an established PD patient, at least 1 year after the onset of motor symptoms (the 1-year rule).^[2] Dementia with Lewy bodies (DLB): dementia precedes or occurs within 1 year of parkinsonism. Both are alpha-synucleinopathies on a spectrum; the timing distinguishes them for clinical and research purposes.^[2]

The named evidence — what changed practice

The MDS 2015 clinical diagnostic criteria replaced the 1992 UK Parkinson's Disease Society Brain Bank criteria, formalising the two-step (parkinsonism then exclusions, supportive criteria and red flags) framework and the categories of clinically established and clinically probable PD.^[3]

Levodopa efficacy (ELLDOPA, 2004; PD-MED, 2014): levodopa is more effective than dopamine agonists or MAO-B inhibitors for early PD; long-term levodopa does not appear to accelerate progression. PD-MED found marginally better mobility with levodopa than with levodopa-sparing strategies, at no cost in dyskinesia-related disability.^[2]

Pimavanserin (Cummings 2014, Lancet): a selective 5-HT2A inverse agonist — the only drug with positive phase-3 RCT evidence and FDA approval specifically for PD psychosis, with no worsening of motor function.^[5]

Deep brain stimulation (Follett 2010, NEJM): STN and GPi stimulation comparably improve motor function at 2 years in advanced PD; the choice is individualised.^[7]

The mantra, and the mnemonic

The mantra: TRAP with bradykinesia obligatory; never block dopamine, never omit levodopa, ask about gambling.^[2]

Ward-round test — three stems, thirty seconds each

Stem 1 — the headmaster from the top of the topic (answer)ShowHide

The 68-year-old with a right resting tremor that vanishes on action, micrographia, reduced right arm swing, freezing in a doorway, and anosmia. What is the diagnosis, the pathognomonic pathology, and the two drugs you must not give him? Model: Idiopathic Parkinson disease — bradykinesia (obligatory) plus asymmetric rest tremor and rigidity, with supportive anosmia; the pathognomonic pathology is alpha-synuclein Lewy bodies in the substantia nigra pars compacta. First-line is levodopa plus carbidopa when function requires it (the levodopa-sparing doctrine is outdated). The two drugs you must never give: a dopamine blocker (metoclopramide, prochlorperazine, haloperidol — safe antiemetics are domperidone and ondansetron), and — once he is on an agonist — never miss the impulse-control question (gambling, hypersexuality).^[1][2]

Stem 2 — the 45-year-old with new parkinsonism (answer)ShowHide

A 45-year-old presents with a stiff, slow left arm and a slight tremor. What must you exclude before you label this idiopathic PD? Model: Wilson disease — in anyone under 50 with new parkinsonism, send serum ceruloplasmin, 24-hour urinary copper, and slit-lamp examination for Kayser-Fleischer rings, and check liver function. Wilson is treatable (penicillamine, trientine, zinc) and missing it is catastrophic. Also consider genetic PD (Parkin, PINK1, DJ-1, LRRK2, GBA) and drug-induced or toxin exposure. Apply the MDS 2015 criteria — young-onset disease is more often genetic, progresses more slowly, and carries a higher risk of levodopa-induced dyskinesia, so a levodopa-sparing strategy (dopamine agonist or MAO-B inhibitor first) is reasonable.^[4]

Stem 3 — the 'PD that stopped responding' (answer)ShowHide

A 72-year-old labelled with PD now falls several times a week within the first year of symptoms, cannot look down, and has not improved on levodopa 800 mg per day. What have you missed? Model: Stop calling this "PD that stopped responding" — it is atypical parkinsonism: progressive supranuclear palsy (PSP). PSP is defined pathologically by 4-repeat tau neuropathology and is now recognised as a range of motor and behavioural syndromes rather than a single phenotype; new MDS diagnostic criteria capture early and variant presentations. There is no cure and no disease-modifying therapy — standard of care is multidisciplinary, supportive and symptomatic — so shift the focus from escalating levodopa to falls prevention, swallowing and airway safety, and carer support.^[10][11]

References12ShowHide

1. [1]Poewe W, Seppi K, Tanner CM, et al. Parkinson disease Nat Rev Dis Primers, 2017.PMID 28332488
2. [2]Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review JAMA, 2020.PMID 32044947
3. [3]Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease Mov Disord, 2015.PMID 26474316
4. [4]Kalia LV, Lang AE. Parkinson's disease Lancet, 2015.PMID 25904081
5. [5]Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial Lancet, 2014.PMID 24183563
6. [6]Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease Mov Disord, 2018.PMID 29570866
7. [7]Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease N Engl J Med, 2010.PMID 20519680
8. [8]Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers, 2018.PMID 30190489
9. [9]Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care, 2009.PMID 18712508
10. [10]Boxer AL, Yu JT, Golbe LI, et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches Lancet Neurol, 2017.PMID 28653647
11. [11]Coughlin DG, Litvan I. Progressive supranuclear palsy: Advances in diagnosis and management Parkinsonism Relat Disord, 2020.PMID 32487421
12. [12]Siddiqui MA, Plosker GL. Rasagiline. Drugs Aging, 2005.PMID 15663351