Key Facts

PD is a clinical diagnosis based on the presence of bradykinesia plus at least one additional motor feature. Treatment is symptomatic — levodopa remains the gold standard. Management of motor complications and non-motor symptoms is increasingly important as the disease progresses.

Epidemiology

Prevalence ~2 per 1,000 (1% of over-60s); ~150,000 people affected in UK. Incidence ~15-20 per 100,000 per year. M:F 1.5:1. Mean age of onset ~60 years. Young-onset PD (<40 years) accounts for ~5%. Incidence rising (aging population).

Aetiology

• Idiopathic (most common): multifactorial — genetic susceptibility + environmental factors
• Genetic: LRRK2 (commonest genetic cause — autosomal dominant), GBA (glucocerebrosidase — major risk factor), PARK2/Parkin, PINK1, SNCA (α-synuclein)
• Environmental: pesticide exposure, rural living, head trauma; protective factors: smoking (paradoxical), caffeine

Pathophysiology

Progressive loss of dopaminergic neurones in the substantia nigra pars compacta (SNpc) → reduced dopamine in the striatum (caudate + putamen) → disruption of basal ganglia circuitry → motor symptoms. Lewy bodies (intraneuronal inclusions of misfolded α-synuclein) are the pathological hallmark. Symptoms manifest when ~60-70% of SNpc neurones are lost. Non-motor symptoms result from widespread neurodegeneration beyond the SNpc (brainstem, cortex, autonomic nervous system) — Braak staging.

Motor Features

• Bradykinesia: slowness of movement + progressive reduction in speed/amplitude with repetition (essential for diagnosis); difficulty with fine movements (writing — micrographia, buttoning)
• Rest tremor: 4-6 Hz, pill-rolling; present at rest, reduced with action; often asymmetric onset; affects hands/arms first
• Rigidity: lead-pipe rigidity (uniform throughout range); cogwheel rigidity (lead-pipe + superimposed tremor)
• Postural instability: late feature; impaired postural reflexes → falls (pull test positive)
• Gait: shuffling, reduced arm swing, festination (involuntary acceleration), freezing of gait
• Asymmetric onset: characteristically unilateral initially, progressing to bilateral

Non-Motor Features

• Neuropsychiatric: depression (40%), anxiety, apathy, PD dementia (PDD — 50% at 10 years), visual hallucinations, psychosis
• Autonomic: constipation (earliest non-motor symptom), orthostatic hypotension, urinary frequency/urgency, erectile dysfunction, sweating
• Sleep: REM sleep behaviour disorder (prodromal — precedes motor symptoms by years), insomnia, excessive daytime sleepiness
• Sensory: anosmia/hyposmia (early — often prodromal), pain
• Other: fatigue, micrographia, hypomimia (mask-like face), hypophonia (quiet speech)

Red Flags (Suggest Alternative Diagnosis)

• Symmetric onset (MSA, PSP)
• Rapid progression (MSA, PSP, CBD)
• Poor/absent response to levodopa (MSA, PSP)
• Early falls (PSP)
• Prominent autonomic failure (MSA)
• Vertical gaze palsy (PSP)
• Early severe dementia (DLB)
• Cerebellar signs (MSA-C)

Clinical Diagnosis

• Diagnosis is primarily clinical (NICE NG71): bradykinesia + ≥1 of rest tremor, rigidity, postural instability
• Response to levodopa supports diagnosis (but not diagnostic)

Imaging

• DaTSCAN (¹²³I-FP-CIT SPECT): dopamine transporter imaging; reduced uptake in striatum confirms nigrostriatal degeneration; useful to distinguish PD from essential tremor, drug-induced parkinsonism, or psychogenic tremor (DaTSCAN normal in these conditions)
• MRI brain: usually normal in PD; helps exclude vascular parkinsonism, PSP (hummingbird sign), MSA (hot cross bun sign), NPH

Bloods

• Copper/caeruloplasmin: exclude Wilson disease in young-onset (<50)
• TFTs: exclude hypothyroidism

Other

• Olfactory testing: hyposmia supports PD (reduced in ~90%)
• Genetic testing: consider if young-onset (<40) or strong family history (LRRK2, GBA, Parkin, PINK1)

Pharmacological (NICE NG71)

Initial Treatment (choice depends on patient preference, symptoms, lifestyle):

• Levodopa (co-beneldopa 62.5-250 mg TDS or co-careldopa 62.5-250 mg TDS): most effective symptomatic therapy; start low, titrate; always given with dopa-decarboxylase inhibitor (benserazide or carbidopa) to reduce peripheral side effects
• Dopamine agonists: ropinirole 0.25-24 mg/day, pramipexole 0.088-3.3 mg/day, rotigotine patch 2-16 mg/24h; less motor complications than levodopa but less effective; side effects: impulse control disorders (gambling, hypersexuality, compulsive spending — warn patient), somnolence, hallucinations
• MAO-B inhibitors: rasagiline 1 mg OD, selegiline 5-10 mg OD, safinamide 50-100 mg OD; mild symptomatic benefit; may delay need for levodopa

Motor Complications Management:

• Wearing-off: increase levodopa frequency, add COMT inhibitor (entacapone 200 mg with each levodopa dose — Stalevo combination), add MAO-B inhibitor, add dopamine agonist
• Dyskinesias: reduce individual levodopa doses, add amantadine 100 mg BD-TDS
• On-off fluctuations: as above + consider advanced therapies

Advanced Therapies (specialist centre):

• Apomorphine SC infusion: continuous dopamine agonist; for severe motor fluctuations
• Levodopa-carbidopa intestinal gel (LCIG/Duodopa): continuous jejunal infusion via PEG-J; reduces off-time
• Deep brain stimulation (DBS): bilateral subthalamic nucleus (STN) or globus pallidus interna (GPi); for motor fluctuations/dyskinesias refractory to medical therapy; NICE IPG19

Non-Pharmacological

• MDT approach: PD nurse, physiotherapy (gait, balance, falls prevention), occupational therapy, speech and language therapy (LSVT LOUD for hypophonia), dietitian
• Exercise: strong evidence for benefit; tai chi, dance, boxing classes

Non-Motor Symptom Management

• Depression: SSRIs (citalopram, sertraline); avoid TCAs in elderly
• Dementia (PDD): rivastigmine (NICE TA); only cholinesterase inhibitor licensed for PDD
• Psychosis/hallucinations: reduce/stop anticholinergics and dopamine agonists first; quetiapine 12.5-100 mg (first-line — lowest EPS risk); clozapine (if refractory); AVOID typical antipsychotics (worsen parkinsonism)
• Orthostatic hypotension: fludrocortisone 100-300 μg OD, midodrine 2.5-10 mg TDS
• Constipation: macrogol (Movicol), adequate hydration, exercise
• RBD: clonazepam 0.25-2 mg ON, melatonin 2-6 mg ON

Referral Criteria

• All suspected PD: specialist with expertise in movement disorders (NICE NG71) — do not initiate treatment in primary care
• Advanced therapies: tertiary movement disorder centre

PD is progressive; rate varies between individuals. Mean duration from diagnosis to death ~15 years. Dementia develops in ~50% at 10 years (strongest predictor of nursing home admission). Falls and aspiration pneumonia are major causes of morbidity/mortality in advanced disease. Levodopa motor complications affect ~50% at 5 years. Quality of life is significantly affected by non-motor symptoms. DBS and advanced therapies can significantly improve quality of life in selected patients. No neuroprotective therapy has been proven to date.

PD vs Parkinson-Plus Syndromes

Hoehn and Yahr Staging