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PARKINSON'S DISEASE - Study Notes
Source: Boloor's Textbook of Medicine + Marrow v5.0/8.0
1. DEFINITIONS
- Parkinsonism = Syndrome of Tremor + Rigidity + Bradykinesia + characteristic disturbance of gait and posture (many causes)
- Idiopathic PD (Paralysis Agitans) = Chronic, progressive disorder; idiopathic parkinsonism without widespread neurologic involvement; 2nd most common neurodegenerative disease
Classification
| Category | Examples |
|---|---|
| Primary | Idiopathic PD (80% tremor-predominant), Akinetic-rigid (20%) |
| Secondary | MPTP/Mn toxin, Encephalitis lethargica, Wilson's disease, Head injury, Drugs (dopamine receptor blockers), Vascular, HIV |
| Parkinson-Plus (Atypical) | PSP, MSA (P/C/A), Corticobasal degeneration, DLB, Guadeloupean parkinsonism |
80/20 Rule: 80% = Tremor-predominant (age 60-75, slower progression) | 20% = Akinetic-rigid (>75 yr, faster, poor prognosis)
2. ETIOLOGY
Epidemiology: Onset avg. 60 yr | Males > Females (1.5:1) | Majority sporadic
Environmental Factors:
- Rural living, well water, pesticide exposure = increased risk
- Nonsmokers > higher risk than smokers
- MPTP - potent mitochondrial toxin - oxidative stress - death of dopaminergic neurons
Genetic Factors:
| Gene | Chromosome | Inheritance |
|---|---|---|
| PARK 1 (α-Synuclein) | Chr. 4 | Autosomal dominant |
| PARK 2 (Parkin) | Chr. 6 | Autosomal recessive |
Genetic forms = early onset PD (<45 yr)
3. PATHOLOGY
HALLMARK: Degeneration of dopaminergic neurons in Substantia Nigra pars compacta (SNc) → reduced striatal dopamine → Lewy bodies (intracytoplasmic eosinophilic inclusions of α-synuclein + ubiquitin)
| Feature | Detail |
|---|---|
| Primary site | SNc |
| Also affected | Basal ganglia, brainstem, cortex, dorsal vagal nucleus, locus coeruleus |
| Threshold | Symptoms appear when >80% neurons lost |
| Prodrome | REM sleep disorder, erectile dysfunction - 5-10 yr BEFORE clinical PD |
| MRI sign | Absent "swallow tail sign" at midbrain |
Extrapyramidal Lesion Sites:
| Sign | Site |
|---|---|
| Resting tremor | Substantia nigra, red nucleus |
| Muscular rigidity | Substantia nigra, putamen |
| Hypokinesia | Substantia nigra, globus pallidus |
| Chorea | Caudate nucleus |
| Hemiballismus | Subthalamic nucleus |
| Dystonia/Athetosis | Putamen |
4. CLINICAL FEATURES
Timeline: REM/ANS symptoms (-5 to -10 yr) → TRA (Tremor, Rigidity, Akinesia) → PIGA (Postural Instability + Gait Abnormalities, 5-10 yr later) → Dementia
Always asymmetrical in onset → bilateral within a year
A. MOTOR SYMPTOMS
i. Tremor (presenting in 70%)
- 4-6 Hz, resting, worsens with emotional stress
- "Pill-rolling" - rhythmic flexion-extension of fingers + pronation-supination
- Affects jaw/chin but NOT the head
- Disappears on voluntary movement and sleep
ii. Rigidity
- Lead pipe (at elbow): uniform resistance throughout range - NOT speed-dependent
- Cogwheel (at wrist): tremor superimposed on rigidity = ratchet-like
- Froment's sign: activity-induced increase in contralateral rigidity
iii. Akinesia / Bradykinesia
- Hypomimia - mask-like face, widened palpebral fissures, infrequent blinking
- Glabellar tap (Myerson's sign) - sustained blink response (no fatiguing)
- Micrographia - small tremulous handwriting
- Hypophonia - soft, monotonous, stuttering speech
iv. Gait Changes
- Shuffling gait - short steps, stooped, flexed hips/knees
- Festinant gait - short quick steps, tendency to accelerate, freezing episodes
- Freezing - feet "glued to floor"; triggered by narrow spaces/doorways; disappears stepping over objects
- Postural instability - 5-10 yr after onset; Pull test = patient falls backward
B. NON-MOTOR SYMPTOMS
| Category | Features |
|---|---|
| Autonomic | Orthostatic hypotension, urinary incontinence, constipation, sexual problems |
| Sleep | REM sleep behaviour disorder (m/c prodrome), restless legs, insomnia |
| Neuropsychiatric | Depression (>dementia), anxiety, apathy, psychosis, dementia |
| Sensory | Hyposmia/Anosmia (m/c ANS prodrome), pain |
| Rheumatological | Frozen shoulder, periarthritis, swan neck deformity |
5. INVESTIGATIONS
- Diagnosis is clinical
- CT/MRI: usually normal; may show absent swallow tail sign; atrophy in Parkinson-plus
- SPECT/PET: reduced uptake of striatal dopaminergic markers (posterior putamen)
- DaT imaging: shows nigrostriatal cell loss; distinguishes PD from essential tremor or drug-induced PD
6. HOEHN AND YAHR STAGING
| Stage | Features |
|---|---|
| I | Unilateral only; minimal impairment |
| II | Bilateral/midline; no balance impairment |
| III | First sign of impaired righting reflex; mild-moderate disability |
| IV | Fully developed, severely disabling; can still walk/stand unassisted |
| V | Confined to bed or wheelchair |
7. DIFFERENTIAL DIAGNOSIS
Parkinson-Plus Syndromes
| Syndrome | Key Feature |
|---|---|
| PSP (Steele-Richardson) | Downward gaze palsy, reptilian stare; "Hummingbird sign" on MRI |
| MSA-P | Parkinsonism + early prominent autonomic dysfunction |
| MSA-C | Parkinsonism + cerebellar signs; "Hot cross buns sign" on MRI |
| Corticobasal degeneration | Asymmetric dystonia, apraxia, alien limb phenomenon |
| DLB | Early dementia, visual hallucinations, fluctuating alertness |
PD Tremor vs Essential Tremor
| Feature | PD | Essential Tremor |
|---|---|---|
| Type | Resting +/- re-emergent | Postural/kinetic |
| Frequency | 4-6 Hz | 5-8 Hz |
| Distribution | Asymmetric; hands + legs | Symmetric; hands, head, voice |
| Writing | Micrographia | Large and tremulous |
| Family history | Less common | Common (~30%) |
| Relief | Levodopa, anticholinergics | Alcohol, propranolol, primidone |
| Surgery site | Subthalamic nucleus / GPi | Ventral intermediate thalamus |
8. MANAGEMENT
Drug treatment is SYMPTOMATIC, not curative. No neuroprotective drugs currently available.
A. Pharmacological Treatment
| Drug Class | Drugs | MOA | Key Points / ADR |
|---|---|---|---|
| Anticholinergics | Trihexyphenidyl, Benztropine | Muscarinic antagonist | Best for TREMOR; avoid >65 yr; ADR: urinary retention, dry mouth, confusion, hallucinations; Drug-induced PD → Rx = Trihexyphenidyl |
| Levodopa | L-DOPA + Carbidopa (co-careldopa) or + Benserazide | Dopamine precursor; crosses BBB | MOST EFFECTIVE; resolves hypokinesia + rigidity first, tremor later; ADR: postural hypotension, nausea, dyskinesias, behavioural disturbances; "On-Off" effect = late complication |
| MAO-B Inhibitors | Selegiline, Rasagiline | Inhibit MAO-B → reduce dopamine breakdown | Also neuroprotective; enhance levodopa; monotherapy benefit |
| Dopamine Agonists | Pramipexole, Ropinirole, Rotigotine, Apomorphine (non-ergot); Bromocriptine, Pergolide (ergot) | Direct dopamine receptor stimulation | Non-ergot PREFERRED; ADR: impulse control disorders (gambling, hypersexuality), somnolence; Ergot: avoid - cardiac valvular fibrosis |
| COMT Inhibitors | Entacapone, Tolcapone | Inhibit peripheral COMT → prolong levodopa | Tolcapone: hepatotoxicity risk; Entacapone: peripheral only |
| Amantadine | Amantadine | Potentiates dopaminergic function | Short-lived; mild anti-bradykinesia; ADR: livedo reticularis, oedema |
| PDIs (Peripheral Decarboxylase Inhibitors) | Carbidopa, Benserazide | Block peripheral decarboxylation | Increase plasma levodopa; reduce daily L-DOPA requirement by 75% |
B. Neuroprotective Agents
- MAO-B inhibitors (Selegiline, Rasagiline)
- Riluzole (antiexcitotoxicity)
- Coenzyme Q10 (bioenergetic antioxidant)
- Adenosine A2A antagonist: Istradefylline
C. Surgical Treatment
Indication: Intractable tremor + drug-induced motor fluctuations/dyskinesias
- Stereotactic thalamotomy - unilateral
- Pallidotomy - improves tremor and dyskinesia
- Deep Brain Stimulation (DBS) - best site = Subthalamic nucleus (also GPi); bilateral stimulation; medically refractory cases
- Focused Ultrasound - unilateral STN/thalamus; markedly asymmetric tremor-dominant
D. Experimental Therapies
- Fetal dopaminergic neuron transplants
- Gene therapy: AAV2 encoding AADC into putamen
9. HIGH-YIELD ONE-LINERS (NEET PG)
- Most common cause of parkinsonism = Idiopathic PD
- Hallmark pathology = Lewy bodies (α-synuclein + ubiquitin) in SNc
- Most effective drug = Levodopa
- Drug for tremor = Trihexyphenidyl (anticholinergic)
- Drug-induced parkinsonism Rx = Trihexyphenidyl
- On-Off phenomenon = late complication of Levodopa
- COMT inhibitor with hepatotoxicity = Tolcapone
- DBS best site = Subthalamic nucleus
- Ergot agonists avoided = cardiac valvular fibrosis
- PD tremor = 4-6 Hz resting | ET = 5-8 Hz postural
- Early prodrome = REM sleep disorder + erectile dysfunction (5-10 yr before)
- Myerson's sign (glabellar tap) = positive in PD (no blink fatigue)
- Swallow tail sign = ABSENT in PD on MRI
10. CHOREA - SHORT NOTE
Definition: Irregular, semi-purposeful, abrupt, rapid, brief, jerky movements flowing randomly. Disappear during sleep. Site = Caudate nucleus. When violent = Ballism.
Signs in Chorea
- Jack in the box: involuntary tongue protrusion/retraction
- Pronator sign: palms pronate outward when held above head
- Milkmaid sign: milking action when gripping fingers
- Motor impersistence: inability to sustain eye closure or tongue protrusion
Sydenham's Chorea (Saint Vitus Dance)
- Most common cause of chorea in children
- Nonsuppurative complication of Group A β-haemolytic streptococcal pharyngitis
- Follows acute rheumatic fever by 4-6 months
- Mechanism: molecular mimicry - cross-reactive antibodies - basal ganglia disruption
- Clinical: chorea + weakness + hypotonia + psychiatric (OCD, emotional lability)
- Evaluate for valvular heart disease; ASO + ESR often normal
Treatment:
- 1st line: Sodium valproate 200-600 mg TID
- If fails: Risperidone 1-2 mg BID
- Haloperidol, pimozide, carbamazepine as alternatives
- Penicillin prophylaxis - to prevent future streptococcal infections + cardiac involvement
Huntington's Disease
- Progressive, fatal, autosomal dominant
- Onset: 25-45 years
- CAG repeats >40 in huntingtin gene on short arm chromosome 4
- Earlier manifestation with higher repeat number
Manifestations:
- Early: Focal chorea, dysarthria, gait disturbance, oculomotor abnormalities
- Advancing: Dystonia, rigidity, bradykinesia, myoclonus
- Late: Dementia, depression with suicidal tendencies, psychosis
Treatment:
- Multidisciplinary approach
- Psychosis: atypical neuroleptics
- Depression: antidepressants/anxiolytics
- No adequate treatment for cognitive/motor decline
- Experimental: Ubiquinone, creatine (promitochondrial)
Source: Boloor's Textbook of Medicine (pp.1333-1339) | Marrow v5.0/8.0
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