Parkinson disease
Description
- Progressive alpha-synucleinopathy: nigrostriatal dopaminergic loss + widespread Lewy pathology
- Cardinal features: bradykinesia (mandatory) + resting tremor and/or rigidity
- Postural instability comes later - early falls point away from PD
- Bradykinesia = slowness with decrement in amplitude/speed on repetition (finger tap, hand open-close, foot tap)
- Tremor - 4-6 Hz, rest, pill-rolling, asymmetric, suppressed on action, worse with distraction/walking
- Re-emergent tremor after a latency on posture is still PD tremor
- Rigidity - lead-pipe, cogwheel when tremor superimposed; enhanced by contralateral voluntary movement
- Gait: stooped, shuffling, reduced arm swing, festination, freezing at turns and doorways; retropulsion on the pull test
- Other motor: hypomimia, hypophonia, micrographia, dysphagia, drooling
- Asymmetry at onset is the rule - symmetrical disease should make you doubt the diagnosis
Non-motor - often precede motor onset by years
- REM sleep behaviour disorder (the strongest prodromal marker of any synucleinopathy)
- Hyposmia, constipation, depression, anxiety
- Later: orthostatic hypotension, urinary urgency, erectile dysfunction, cognitive impairment, psychosis, pain, fatigue
Epidemiology
- Second commonest neurodegenerative disease after Alzheimer disease
- Prevalence ~1% over 60, ~3% over 80; ~80,000-100,000 Australians
- Mean age of onset ~60; ~5-10% onset before 50 (young-onset - test for genes)
- M>F ~1.5:1
- Motor signs appear once ~50-70% of nigral dopaminergic neurons (and ~80% of striatal dopamine) are lost
- Risk factors: age, family history, pesticide/herbicide exposure, head injury, rural living, well water
- Smoking and caffeine are inversely associated (epidemiological, not protective advice)
Aetiopathogenesis
Pathology
- Depigmentation of the substantia nigra pars compacta + Lewy bodies (intracytoplasmic alpha-synuclein inclusions) and Lewy neurites
- Braak staging: pathology begins in the olfactory bulb and dorsal motor nucleus of the vagus, ascends the brainstem to the midbrain (motor onset), then to cortex (dementia)
- Explains why hyposmia, constipation and RBD precede the tremor by a decade
- Cholinergic (nucleus basalis) and noradrenergic (locus coeruleus) loss -> cognitive decline, depression, fatigue
- Circuit consequence: dopamine loss -> inc indirect pathway, dec direct pathway -> inc GPi/SNr output -> thalamic inhibition -> hypokinesia
Genetics
- ~5-10% monogenic; a further large fraction has genetic risk
- GBA1 variants are the commonest genetic risk factor overall - more common than LRRK2; reduced penetrance, not dominant inheritance
- Associated with earlier onset, faster progression and more cognitive decline
- LRRK2 - commonest autosomal dominant cause; phenotype often benign and levodopa-responsive
- PRKN (parkin), PINK1, DJ-1 - autosomal recessive, young onset, slow, dystonia, excellent levodopa response but early dyskinesia
- SNCA duplication/triplication - dominant, aggressive, early dementia
Secondary parkinsonism - always exclude
- Drug-induced - the commonest mimic: metoclopramide, prochlorperazine, typical and most atypical antipsychotics, sodium valproate, lithium, amiodarone, flunarizine
- Symmetric, tremor may be postural, no hyposmia; may take 6-12 months to resolve after withdrawal
- Vascular - lower-body parkinsonism, gait apraxia, brisk reflexes, poor levodopa response, small vessel disease on MRI
- Normal pressure hydrocephalus, repeated head trauma, Wilson disease (<50, check caeruloplasmin), manganese, carbon monoxide, post-encephalitic
Diagnosis
- Clinical diagnosis (MDS criteria): bradykinesia PLUS rest tremor or rigidity, then apply supportive features, exclusions and red flags
- Supportive: clear and dramatic response to dopaminergic therapy, levodopa-induced dyskinesia, rest tremor, hyposmia, cardiac MIBG denervation
Red flags against idiopathic PD
- Symmetrical onset; no tremor
- Early falls (<3 years), early dementia (<1 year), early severe autonomic failure
- Poor or absent levodopa response despite adequate dose (>=600-1000 mg/day trial)
- Supranuclear vertical gaze palsy, apraxia, alien limb, pyramidal or cerebellar signs
- Rapid progression to wheelchair within 5 years
- Prominent bulbar dysfunction or inspiratory stridor
Parkinson-plus and other differentials
| Discriminator | |
|---|---|
| MSA | Early severe autonomic failure (orthostatic hypotension, urinary retention/incontinence, ED), symmetric, poor levodopa response, cerebellar signs (MSA-C) or parkinsonism (MSA-P), stridor, antecollis. "Hot cross bun" sign on MRI pons |
| PSP | Early falls (backwards), vertical supranuclear gaze palsy (downgaze first), axial > limb rigidity, frontal cognitive change, "hummingbird sign" on midline sagittal MRI |
| CBD | Markedly asymmetric, apraxia, alien limb, cortical sensory loss, myoclonus, dystonia |
| DLB | Dementia within 1 year of parkinsonism, fluctuating cognition, visual hallucinations, RBD, severe neuroleptic sensitivity |
| Essential tremor | Action/postural tremor, bilateral, head/voice involvement, improves with alcohol, family history, no bradykinesia |
| Drug-induced | Symmetric, temporal relationship, resolves (slowly) on withdrawal |
| Vascular | Lower-body predominant, stepwise, brisk reflexes, extensor plantars |
Investigation
- PD is a clinical diagnosis - there is no confirmatory test in routine use
- MRI brain - to exclude vascular disease, NPH, structural lesions and support Parkinson-plus patterns
- DaTSCAN (dopamine transporter SPECT) - separates degenerative parkinsonism from essential tremor, drug-induced parkinsonism and functional tremor
- It does NOT distinguish PD from MSA/PSP/CBD - all are abnormal
- Caeruloplasmin, serum copper, 24 h urinary copper if age <50 (Wilson disease)
- Alpha-synuclein seed amplification assay (CSF or skin biopsy) - high sensitivity/specificity for synucleinopathy; a research and specialist tool, increasingly used to define disease biologically
- Genetic testing (GBA1, LRRK2, PRKN) if young onset or a positive family history - GBA1 status has prognostic and trial-eligibility relevance
- The most useful single test remains an adequate levodopa trial
Management
A. Early disease - when to start, and with what
- Start when symptoms interfere with function or quality of life - no evidence that delaying preserves anything
- Levodopa (with carbidopa or benserazide) is the recommended initial therapy at any age
- Immediate-release, lowest effective dose, titrate to symptoms
- This supersedes the older practice of levodopa-sparing in younger patients. Dyskinesia is driven mainly by disease duration and total dose, not by starting early
- Take 30-60 min before food; protein competes for the same amino-acid transporter
- *FDA warning (March 2026): carbidopa/levodopa lowers vitamin B6 - seizures reported at levodopa doses >1000 mg/day. Check B6 in high-dose or infusion therapy
- Alternatives where levodopa is not appropriate or as adjuncts:
- Non-ergot dopamine agonists - pramipexole, rotigotine patch (ropinirole where available). *Never ergot agonists (bromocriptine, pergolide, cabergoline) - cardiac valvulopathy and retroperitoneal fibrosis*
- Impulse control disorders in ~15-20% - gambling, hypersexuality, binge eating, punding. Ask about them at every visit and warn the patient and family in advance
- Also somnolence and sudden-onset sleep (driving), hallucinations, oedema, worse in the elderly
- MAO-B inhibitors - rasagiline, selegiline; modest, well tolerated, useful as first agent in mild disease
- Amantadine - mild benefit; its real role is treating dyskinesia
- Anticholinergics (benztropine) - tremor only, in the young; avoid over 65 - confusion, urinary retention, falls
- Non-ergot dopamine agonists - pramipexole, rotigotine patch (ropinirole where available). *Never ergot agonists (bromocriptine, pergolide, cabergoline) - cardiac valvulopathy and retroperitoneal fibrosis*
- Exercise is disease-modifying-adjacent: high-intensity aerobic exercise, and PD-specific physiotherapy (LSVT BIG), speech therapy (LSVT LOUD) for hypophonia and swallow
B. Motor fluctuations and dyskinesia
Develop in ~50% after 5 years of levodopa
- Wearing off -> shorten the interval, increase the frequency (not the dose), then add:
- COMT inhibitor - entacapone with each dose, or opicapone once daily
- MAO-B inhibitor - rasagiline, safinamide
- Dopamine agonist
- Delayed on / dose failure -> erratic gastric emptying; take on an empty stomach, dispersible levodopa, treat constipation and H. pylori, avoid a protein-heavy meal with the dose
- Peak-dose dyskinesia -> reduce individual dose and give more often; amantadine; consider DBS
- Off-period rescue -> subcutaneous apomorphine injection pen; sublingual/inhaled apomorphine
- Freezing of gait -> cueing strategies (metronome, laser cane, stepping over a line), physiotherapy; poorly drug-responsive
C. Device-assisted therapy - advanced disease
Referral criterion: refractory fluctuations or dyskinesia despite optimised oral therapy
- Deep brain stimulation - STN or GPi
- Best candidates: levodopa-responsive symptoms, disease duration >4-5 years, no dementia, no uncontrolled psychiatric illness, biologically fit
- Allows substantial levodopa reduction; reduces dyskinesia and off time; does not help levodopa-unresponsive symptoms (freezing, postural instability, speech, cognition)
- Thalamic (VIM) DBS or focused ultrasound thalamotomy for intractable tremor alone
- Continuous subcutaneous apomorphine infusion
- Levodopa-carbidopa intestinal gel via PEG-J, or subcutaneous foslevodopa/foscarbidopa infusion
D. Non-motor problems - where most of the disability lives
| Problem | Treatment |
|---|---|
| Psychosis / hallucinations | Reduce anticholinergics, amantadine, agonists, then levodopa. Quetiapine or clozapine only - low D2 affinity. Clozapine has the best evidence but needs FBE monitoring, so quetiapine is used first in practice. Never haloperidol, risperidone, olanzapine |
| Dementia | Rivastigmine (also donepezil); avoid anticholinergics |
| Depression / anxiety | SSRI/SNRI; pramipexole has antidepressant effect; CBT |
| Orthostatic hypotension | Stop offending drugs, salt/fluid, compression, head-up tilt at night; fludrocortisone, midodrine, droxidopa |
| Constipation | Macrogol, fluid, exercise |
| REM sleep behaviour disorder | Safety of the bed environment first; melatonin, then clonazepam |
| Drooling | Speech therapy, glycopyrrolate, botulinum toxin to salivary glands |
| Nausea from dopaminergics | Domperidone (ECG - QT) or ondansetron. Never metoclopramide or prochlorperazine |
E. Inpatient rules that matter
- *Never abruptly stop or omit levodopa - risks parkinsonism-hyperpyrexia syndrome* (a neuroleptic malignant-like state)
- Give doses on the patient's own timing, not the ward drug round; use a patch or NG route if nil by mouth
- Contraindicated antiemetics and antipsychotics as above
- Falls, aspiration and delirium risk; involve the PD nurse specialist
- Discuss driving, advance care planning, carer support, Parkinson's Australia
Associations
- REM sleep behaviour disorder - prodromal to PD, DLB and MSA; most isolated RBD phenoconverts within 10-15 years
- Hyposmia, constipation, depression - prodromal
- GBA1 carriage - also causes Gaucher disease when biallelic
- Melanoma - increased incidence (independent of levodopa)
- Osteoporosis and fractures; sarcopenia; malnutrition
- Type 2 diabetes - shared risk, worse motor progression
- Impulse control disorders and dopamine dysregulation syndrome - iatrogenic
- Camptocormia, Pisa syndrome, cervical dystonia
- Inverse association with smoking, caffeine, and (weakly) urate
Natural history & complications
- Slowly progressive over 10-20+ years; the levodopa "honeymoon" of stable response lasts ~3-5 years
- Motor fluctuations and dyskinesia in ~50% at 5 years, most by 10
- Dementia in up to 50-80% with long disease duration - the single strongest predictor of nursing home placement and death
- PD dementia = parkinsonism >=1 year before dementia; DLB = dementia within 1 year (an arbitrary but examinable rule)
- Postural instability, freezing and falls dominate the later years and are levodopa-unresponsive
- Mortality ratio ~1.5-2x age-matched; death usually from aspiration pneumonia, falls/fracture complications, or intercurrent illness
- Faster progression: older onset, akinetic-rigid phenotype, early cognitive impairment, GBA1 variants
- Slower: tremor-dominant, young onset, LRRK2 or PRKN
Monitor
- Motor response and fluctuations; impulse control disorders; cognition and hallucinations
- Orthostatic BP, swallow and weight, falls, mood
- Bone health, driving fitness, carer strain
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