Parkinson Disease - MBBS Final Year Medicine

Definition & Epidemiology

• Prevalence: ~1 in 1000 in the general population; at least 1% of persons >65 years
• Mean age of onset: ~60 years
• Men affected slightly more than women (3:2)
• Estimated 10.8 million people worldwide with PD
• Lifetime risk: ~3% for men, 2% for women
• First described by James Parkinson in 1817 ("An Essay on the Shaking Palsy")
• Goldman-Cecil Medicine, p. 3726; Harrison's Principles, p. 3537

Etiopathogenesis

Genetic Causes (~10% of cases)

Environmental Factors

• Pesticide and heavy metal exposure
• MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine): accidental exposure selectively destroys dopamine neurons in SNc - key evidence for the "environmental hypothesis"
• MPTP is oxidized to MPP+, which inhibits complex I of the mitochondrial electron transport chain, implicating oxidative stress and mitochondrial dysfunction

Pathogenetic Mechanisms

1. Loss of dopaminergic neurons in the SNc (>60% must be lost before motor symptoms appear)
2. Reduced dopamine in the neostriatum (especially the putamen)
3. Abnormal aggregation of alpha-synuclein protein
4. Formation of Lewy bodies (intraneuronal cytoplasmic inclusions composed chiefly of aggregated alpha-synuclein)
5. Oxidative stress, protein misfolding, mitochondrial dysfunction, excitotoxicity, inflammation, and apoptosis

The Braak Hypothesis

• Goldman-Cecil Medicine, p. 3731-3733; Harrison's Principles, p. 3542

Pathology

• Loss of pigmented dopaminergic neurons in the SNc
• Reactive gliosis
• Lewy bodies - eosinophilic, intracytoplasmic inclusions with a dense pink centre and a pale halo, found in surviving neurons
• Lewy bodies stain positive for alpha-synuclein and ubiquitin
• Pathological changes extend to: locus coeruleus (norepinephrine), nucleus basalis of Meynert (acetylcholine), raphe nuclei (serotonin), olfactory system, cortex, and peripheral autonomic neurons

Note: The widespread extranigral changes account for the many nonmotor features of PD.

• Harrison's Principles, p. 3537; Goldman-Cecil Medicine, p. 3738-3740

Clinical Features

Cardinal Motor Features (TRAP)

Other Motor Features

• Micrographia (small handwriting)
• Masked facies (hypomimia) - reduced facial expression
• Hypophonia (soft voice)
• Drooling (sialorrhea)
• Festinating gait (short, shuffling steps with forward lean; difficulty starting/stopping)
• Freezing of gait (episodic inability to initiate walking)
• Dysphagia
• Reduced eye blinking

Nonmotor Features

Premotor symptoms (constipation, anosmia, RBD) may precede motor features by years to decades

• Harrison's Principles, p. 3537-3538 (Table 446-1)

Diagnosis

UK Brain Bank Criteria (classic, widely tested)

• History of repeated strokes, head injury, or encephalitis
• Oculogyric crises
• Negative response to levodopa
• Cerebellar signs
• Early severe autonomic involvement
• Strictly unilateral features after 3 years
• Babinski sign
• CT evidence of cerebral tumor or communicating hydrocephalus
• Use of neuroleptic drugs at onset

• Unilateral onset
• Rest tremor present
• Progressive disorder
• Persistent asymmetry
• Excellent response to levodopa (>70-100%)
• Severe levodopa-induced dyskinesia
• Response to levodopa for >5 years
• Clinical course of >10 years

Investigations

• Clinical diagnosis - no definitive test required
• DaTscan (dopamine transporter SPECT/PET): Reduced asymmetric uptake in striatum, especially posterior putamen; helps differentiate PD from essential tremor
• MRI brain: Usually normal; may show midbrain atrophy in atypical parkinsonism
• Routine bloods: rule out Wilson disease (serum ceruloplasmin, copper in young patients)
• CSF alpha-synuclein seed amplification assay (SAA): Emerging biomarker with high sensitivity
• Harrison's Principles, p. 3539-3540

Differential Diagnosis of Parkinsonism

Red Flags (suggesting NOT idiopathic PD)

• Early falls, early dementia, early prominent autonomic failure
• Vertical gaze palsy (PSP)
• Cerebellar signs, ataxia
• Poor or no response to levodopa
• Symmetric onset
• Pyramidal signs (Babinski positive)
• No tremor
• Goldman-Cecil Medicine, p. 3743-3796 (Table 378-1, Table 378-3)

Basal Ganglia Circuitry - Key for Exams

• SNc dopamine activates direct pathway (D1 receptors - stimulatory) → facilitates movement
• SNc dopamine inhibits indirect pathway (D2 receptors - inhibitory) → further facilitates movement

• Direct pathway underactive → less facilitation of movement
• Indirect pathway overactive → more inhibition of movement
• Net result: overactivity of the subthalamic nucleus (STN) → excessive inhibitory output from GPi to thalamus → reduced thalamocortical drive → bradykinesia and rigidity

Treatment

Principles

• No disease-modifying therapy currently exists - all treatments are symptomatic
• Goal: maximize quality of life, maintain function, minimize side effects
• Treatment is individualized based on age, disability, cognitive status, and comorbidities

Pharmacological Therapy

1. Levodopa + Carbidopa (Sinemet) - GOLD STANDARD

• Levodopa: precursor of dopamine; crosses blood-brain barrier
• Carbidopa: peripheral DOPA decarboxylase inhibitor - reduces peripheral conversion, increases CNS availability, reduces nausea
• Usual starting dose: carbidopa 25 mg / levodopa 100 mg three times daily
• Most effective for bradykinesia and rigidity; also effective for tremor
• Long-term complications:
  • Wearing off (end-of-dose deterioration): predictable loss of effect before next dose
  • On-off fluctuations: unpredictable motor fluctuations
  • Peak-dose dyskinesias: chorea/athetosis at time of peak drug effect
  • Diphasic dyskinesias: at beginning and end of dose
  • Delayed-on / dose failures

2. Dopamine Agonists (first-line in younger patients)

• Pramipexole, Ropinirole (non-ergot, preferred), Rotigotine (transdermal patch)
• Used as monotherapy in early disease to delay levodopa and its long-term complications
• Side effects: nausea, somnolence, postural hypotension, impulse control disorders (hypersexuality, gambling, binge eating), hallucinations
• Older ergot agonists (bromocriptine, cabergoline): associated with cardiac valvulopathy - less preferred

3. MAO-B Inhibitors (Monoamine Oxidase B Inhibitors)

• Selegiline, Rasagiline, Safinamide
• Inhibit breakdown of dopamine in the brain
• Used as monotherapy in early mild disease, or as adjunct to levodopa
• May have mild neuroprotective effect (still debated)
• Rasagiline has better evidence than selegiline (ADAGIO trial)

4. COMT Inhibitors (Catechol-O-methyltransferase Inhibitors)

• Entacapone (peripheral only), Tolcapone (central + peripheral; hepatotoxic), Opicapone
• Inhibit peripheral breakdown of levodopa and dopamine
• Used as adjunct to levodopa to reduce wearing off
• Entacapone combined with levodopa+carbidopa = Stalevo

5. Amantadine

• Mechanism: NMDA receptor antagonist, increases dopamine release
• Used for mild symptoms and for treatment of levodopa-induced dyskinesias
• Side effects: livedo reticularis, ankle edema, confusion (especially in elderly)

6. Anticholinergics

• Trihexyphenidyl (Benzhexol), Benztropine
• Best for tremor in younger patients
• Avoid in elderly due to cognitive side effects, confusion, urinary retention, constipation

7. Adenosine A2A Receptor Antagonist

• Istradefylline: adjunct to levodopa; improves wearing-off

8. For Non-Motor Features

• Dementia/Cognitive impairment: Rivastigmine (licensed), Donepezil
• Psychosis/Hallucinations: Quetiapine, Clozapine (monitoring required), Pimavanserin (5-HT2A inverse agonist)
• Depression: SSRIs
• Orthostatic hypotension: Fludrocortisone, Midodrine, Droxidopa
• RBD: Clonazepam, Melatonin
• Constipation: Increased fibre, laxatives
• Goldman-Cecil Medicine, p. 3960-3984; Harrison's Principles, p. 3544-3547; Textbook of Family Medicine, p. 65-69

Surgical Treatment

Deep Brain Stimulation (DBS) - Most Important

• Targets: Subthalamic nucleus (STN) or Globus Pallidus pars interna (GPi) - bilateral
• Mechanism: High-frequency electrical stimulation suppresses abnormal neuronal activity
• Indications:
  • Advanced PD with disabling motor fluctuations, dyskinesias, or refractory tremor
  • Good baseline response to levodopa (best predictor of DBS response)
  • Age <70, cognitively intact, no severe psychiatric illness
• STN DBS: Greater medication reduction possible; slightly higher neuropsychiatric risk
• GPi DBS: Better dyskinesia suppression; safer neuropsychiatric profile; more flexible
• Contraindications: Levodopa non-responders (except tremor), significant dementia, severe psychiatric comorbidity, poor general health

Focused Ultrasound (FUS)

• Unilateral thalamotomy for refractory tremor; non-invasive; permanent but unilateral only
• Goldman-Cecil Medicine, p. 3986-3988; Bradley and Daroff's Neurology, p. 3024-3036

Staging and Prognosis

Hoehn and Yahr Scale (classic staging)

Prognosis

• Progressive and inexorable over many years; rate of progression varies widely
• Most patients eventually develop symptoms resistant to medications (falls, dementia, dysautonomia)
• Mean survival ~15 years from diagnosis with modern treatment
• Dementia, falls, aspiration pneumonia are major late complications
• Most important cause of death: pneumonia (aspiration), falls

Summary Table - High-Yield Points for Exam