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Parkinson's Disease: Aetiopathology and Management

1. Overview

• Harrison's Principles of Internal Medicine 22E (2025)

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2. Aetiopathology

2.1 Pathological Hallmarks

1. Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) - visible grossly as pallor of the substantia nigra and locus coeruleus
2. Reduced striatal dopamine - causing the characteristic motor features
3. Lewy bodies and Lewy neurites - intraneuronal proteinaceous inclusions in cell bodies and axons that stain positive for alpha-synuclein (α-syn)

• Cholinergic neurons of the nucleus basalis of Meynert (NBM)
• Noradrenergic neurons of the locus coeruleus (LC)
• Serotonergic neurons in the raphe nuclei
• Neurons of the olfactory system, cerebral cortex, spinal cord, and peripheral autonomic nervous system

• Robbins & Kumar Basic Pathology, p. 854
• Harrison's Principles of Internal Medicine 22E (2025), p. 3537

2.2 Braak Staging

• Stages 1-2: Pathology confined to the dorsal motor nucleus of the vagus and olfactory bulb (explaining premotor features: REM sleep behaviour disorder, anosmia, constipation)
• Stages 3-4: Involvement of the substantia nigra and amygdala (onset of motor symptoms)
• Stages 5-6: Spread to neocortex (cognitive impairment, dementia, hallucinations)

2.3 Molecular Pathogenesis

• Robbins & Kumar Basic Pathology
• Harrison's Principles of Internal Medicine 22E (2025)

2.4 Genetics

2.5 Environmental Factors

• MPTP (contaminant in illicit "synthetic heroin") selectively destroys SNpc neurons - a key experimental model
• Pesticides (rotenone, paraquat) - epidemiological associations with PD
• Head trauma, rural living, well-water drinking have been proposed as risk factors
• Cigarette smoking and caffeine consumption are inversely associated with PD risk (exact mechanism unknown)

2.6 Basal Ganglia Circuit Dysfunction

• Loss of dopamine from SNpc reduces activity in the direct pathway (which normally facilitates movement) and increases activity in the indirect pathway (which inhibits movement)
• Net result: overactivity of the subthalamic nucleus (STN) → excessive inhibition of the thalamus → reduced cortical activation → bradykinesia, rigidity
• Pathological beta-band oscillations (~13-30 Hz) in the STN and motor cortex characterize this state
• Bradley and Daroff's Neurology in Clinical Practice

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3. Clinical Features

Cardinal Motor Features (the "TRAP" mnemonic)

• Tremor - rest tremor, typically "pill-rolling," 4-6 Hz; improves with action
• Rigidity - cogwheel or lead-pipe; throughout range of motion
• Akinesia/Bradykinesia - slowness and reduced amplitude of movements; the most disabling feature
• Postural instability - late feature; contributes to falls

Other Motor Features

• Micrographia, masked facies (hypomimia), reduced blinking, hypophonia, drooling, dysphagia, freezing of gait, festination

Non-Motor Features

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4. Diagnosis

• Bradykinesia + at least one of: rest tremor, rigidity
• Exclusion of alternative causes (drug-induced, vascular, normal pressure hydrocephalus, etc.)
• Supportive features: unilateral onset, persistent asymmetry, rest tremor, levodopa responsiveness

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5. Management

5.1 Pharmacological - Motor Symptoms

Levodopa (Gold Standard)

• Converted to dopamine in the CNS; most effective drug for motor symptoms
• Always combined with a peripheral dopa decarboxylase inhibitor (carbidopa or benserazide) to reduce systemic side effects and improve CNS bioavailability
• Long-term complications (typically after 5+ years): wearing-off, on-off fluctuations, levodopa-induced dyskinesias (LID)
• Does not slow disease progression

Dopamine Receptor Agonists (DRAs)

• Non-ergot: pramipexole, ropinirole, rotigotine (patch)
• Ergot: bromocriptine, cabergoline (less used due to fibrosis risk)
• Preferred as initial therapy in younger patients (lower dyskinesia risk) or as adjuncts to levodopa for wearing-off
• Avoid in elderly patients (hallucinations, cognitive impairment, daytime somnolence) and those with impulse control disorder history
• Per 2021 AAN guidelines, oral pramipexole is among the most effective DRAs; apomorphine (injectable/subcutaneous) is the most effective for managing levodopa motor fluctuations

MAO-B Inhibitors

• Selegiline, rasagiline, safinamide
• Inhibit MAO-B, which degrades dopamine in the CNS
• Improve motor symptoms; may be used as monotherapy in early PD or as adjuncts
• Possible neuroprotective effect debated (DATATOP trial: selegiline delayed need for levodopa but confounded by symptomatic effect)

COMT Inhibitors

• Entacapone, opicapone, tolcapone (tolcapone - hepatotoxicity risk)
• Inhibit catechol-O-methyltransferase, prolonging levodopa effect
• Used as adjuncts to reduce wearing-off in levodopa-treated patients

Amantadine

• NMDA receptor antagonist
• Mild antiparkinsonian effect; particularly useful for treating levodopa-induced dyskinesias (unique indication)

Anticholinergics

• Trihexyphenidyl, benztropine
• Useful for tremor in younger patients
• Avoid in elderly (cognitive impairment, confusion, urinary retention)

5.2 Advanced Therapies for Motor Fluctuations

• Gold standard surgical option for advanced PD with motor fluctuations uncontrolled by optimal medication
• STN DBS: Greater medication reduction possible; slightly larger off-state benefit; higher neuropsychiatric risk
• GPi DBS: Better dyskinesia suppression; better long-term flexibility; safer neuropsychiatric profile; preferred for "brittle" dyskinesia
• Not a cure; does not slow disease progression
• Bradley and Daroff's Neurology in Clinical Practice, p. 652

5.3 Non-Motor Symptom Management

5.4 Non-Pharmacological Management

• Exercise and physiotherapy: High-intensity aerobic exercise, balance training, and treadmill therapy improve motor function. A 2025 network meta-analysis confirmed exercise as beneficial for motor symptoms, with intensity being a key variable
• Speech therapy: For hypophonia (LSVT LOUD program) and dysphagia management
• Occupational therapy: Adaptive strategies for ADLs
• Nutritional support: Protein distribution advice to improve levodopa absorption; PEG tube for severe dysphagia
• Multidisciplinary team care: Neurologist, physiotherapist, speech therapist, occupational therapist, neuropsychologist, specialist nurse

5.5 Emerging and Investigational Therapies

• Alpha-synuclein-targeted therapies: Monoclonal antibodies (prasinezumab, cinpanemab) to reduce α-syn aggregation - trials ongoing
• GLP-1 receptor agonists: Semaglutide and liraglutide showing neuroprotective signals in early trials
• Gene therapy: Adeno-associated virus (AAV)-mediated delivery of AADC, GDNF/neurturin
• Stem cell therapy: iPSC-derived dopaminergic neuron transplants; Phase 1/2 trials ongoing in Japan, US, and Europe (2023); early safety data encouraging
• LRRK2 inhibitors: Targeting the most common autosomal dominant PD mutation
• Virtual reality rehabilitation: 2025 meta-analysis confirms VR combined with conventional therapy improves balance in PD
• Harrison's Principles of Internal Medicine 22E (2025)

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6. Prognosis

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 446
• Robbins & Kumar Basic Pathology, p. 854
• Bradley and Daroff's Neurology in Clinical Practice
• Recent evidence: 2025 exercise network meta-analysis (PMID 39880702) confirms exercise dose-response benefit for motor symptoms; IHS April 2025 formulary brief aligns with 2021 AAN guidelines for dopaminergic therapy.

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Headache, Migraine, and Stroke: Aetiopathology and Management

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PART 1: HEADACHE

1.1 Classification (ICHD-3)

• Migraine (with and without aura)
• Tension-type headache (TTH)
• Trigeminal autonomic cephalalgias (TACs) - cluster headache, paroxysmal hemicrania, SUNCT/SUNA, hemicrania continua
• Other primary headaches (cough, exercise, thunderclap, hypnic)

• Intracranial hypertension/hypotension, subarachnoid haemorrhage, meningitis, brain tumour, sinusitis, medication overuse, cervicogenic

Red Flags ("SNOOP4")

Tension-Type Headache (TTH)

• Most common headache type overall
• Bilateral, pressing/tightening (non-pulsating), mild-to-moderate intensity, not aggravated by routine physical activity
• No nausea, no vomiting; may have photophobia or phonophobia (but not both)
• Pathophysiology: central sensitisation of pain pathways, myofascial trigger points
• Management: acute - simple analgesics (paracetamol, NSAIDs, aspirin); prevention - amitriptyline (first-line), relaxation therapy, biofeedback

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PART 2: MIGRAINE

2.1 Epidemiology

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 441

2.2 Aetiopathology

Trigeminal Vascular (Trigeminovascular) System

1. Cortical spreading depression (CSD) - a wave of neuronal/glial depolarisation travelling at 3-5 mm/min across cortex, triggering the aura and activating trigeminal afferents
2. Trigeminal nucleus activation → release of vasoactive neuropeptides, principally:
   • CGRP (calcitonin gene-related peptide) - potent vasodilator and pain sensitiser
   • PACAP (pituitary adenylate cyclase-activating polypeptide)
3. Neurogenic inflammation around meningeal vessels - plasma protein extravasation, mast cell degranulation
4. Central sensitisation via second-order neurons crossing midline → ventrobasal thalamus → cortex
5. Descending pain modulation from periaqueductal grey (PAG), locus coeruleus (LC), and hypothalamus is impaired in migraine

Neurotransmitters

• Serotonin (5-HT): Central to pathogenesis; migraine attacks associated with platelet 5-HT release followed by depletion. 5-HT1B/1D receptors on trigeminal terminals mediate triptans' action
• Dopamine: Many premonitory symptoms (yawning, nausea, food cravings) are dopaminergic in origin; explains why dopamine antagonists (metoclopramide, prochlorperazine) are effective
• CGRP: Now the central therapeutic target; serum levels elevated during attacks; normalise with triptan treatment

Brain Sensitivity and Triggers

• Altered sleep (too much or too little)
• Hormonal fluctuations (especially peri-menstrual)
• Hunger/dehydration
• Stress let-down (weekend migraine)
• Weather/barometric pressure changes
• Bright lights, strong smells
• Alcohol (especially red wine/beer - histamine, tyramine)
• Some triggers may actually be early prodromal features (e.g. light sensitivity, food cravings) rather than true external triggers

Genetics

• Migraine has a strong genetic component; ~50% heritability
• Familial hemiplegic migraine (FHM) - rare autosomal dominant; mutations in CACNA1A (P/Q Ca2+ channel), ATP1A2 (Na+/K+-ATPase), SCN1A (Na+ channel)
• Common migraine: polygenic; GWAS identified loci near TRPM8, LRP1, PRDM16

2.3 Clinical Features

Subtypes

• Migraine without aura (formerly "common migraine") - most frequent
• Migraine with aura (formerly "classic migraine") - ~25% of migraineurs
• Chronic migraine - ≥15 headache days/month for >3 months, of which ≥8 are migrainous
• Hemiplegic migraine - motor aura (must exclude stroke)
• Basilar/posterior circulation migraine - diplopia, dysarthria, ataxia, altered consciousness
• Status migrainosus - attack lasting >72 hours
• Vestibular migraine - episodic vertigo with migrainous features

MIDAS Score

2.4 Management of Migraine

Acute (Abortive) Treatment

1. NSAIDs

• First choice for mild-moderate attacks
• Ibuprofen 400-600 mg, naproxen 500-1000 mg, aspirin 900 mg
• FDA-approved combination: paracetamol + aspirin + caffeine (Excedrin) for mild-moderate migraine
• Most effective when taken early in the attack

2. Triptans (5-HT1B/1D agonists)

• Gold standard for moderate-severe attacks
• Promote cranial vasoconstriction AND arrest trigeminal nociceptive signalling
• Sumatriptan (oral 50/100 mg, SC 6 mg, nasal 10-20 mg) - fastest onset via SC route
• Others: rizatriptan, eletriptan, zolmitriptan, almotriptan, frovatriptan, naratriptan
• Contraindications: ischaemic heart disease, stroke/TIA, uncontrolled hypertension, Prinzmetal angina, concurrent ergotamine/MAO-I
• Repeat dosing at 2 hours is not effective for triptans (unlike gepants)

3. Gepants (CGRP receptor antagonists)

• Ubrogepant, rimegepant, zavegepant (nasal spray)
• Effective acutely; rimegepant can also be taken every other day for prevention
• No vasoconstriction - safe in cardiovascular disease
• Repeat dosing at 2 hours is effective (unlike triptans)

4. Ditans (5-HT1F agonists)

• Lasmiditan - acts only at neural targets (no vasoconstriction)
• Safe in cardiovascular disease
• Main side effect: dizziness, somnolence; no driving for 8 hours

5. Dopamine antagonists (antiemetics)

• Metoclopramide, prochlorperazine, chlorpromazine
• Both antiemetic and antimigraine; particularly useful parenterally in ED
• 2025 AHS Emergency Department Guideline:
  • Level A "must offer": Prochlorperazine IV, greater occipital nerve block (GONB)
  • Level A "must not offer": Hydromorphone IV (opioids should not be used routinely)
  • Likely effective: chlorpromazine IV, metoclopramide IV, eptinezumab IV, ketorolac IV, sumatriptan SC, supraorbital nerve block
  • 2025 AHS ER Guideline, PMID 41321235

Other acute options

• Ergotamine/dihydroergotamine (DHE): Older agents; effective but significant vasoconstriction risk; IV DHE useful for status migrainosus
• Corticosteroids (dexamethasone 10 mg IV): Reduce recurrence in ED settings
• Valproate IV: Useful in ED for intractable migraine

Preventive Treatment

Medication Overuse Headache (MOH)

• Also called "rebound headache" or analgesic overuse headache
• Occurs with use of acute treatments on ≥10-15 days/month for >3 months (triptans and opioids at ≥10 days; NSAIDs at ≥15 days)
• Results in transformation of episodic to chronic daily headache
• Management: withdrawal of the overused medication (supervised detoxification); bridge with prednisolone or DHE; patient education

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PART 3: CLUSTER HEADACHE (Key TAC)

Aetiopathology

• Cluster headache involves activation of the posterior hypothalamus (the biological "clock" - explains periodicity and circadian pattern) and the trigeminal-autonomic reflex arc
• Cranial parasympathetic activation via the sphenopalatine ganglion causes ipsilateral autonomic features
• Men affected 3x more than women; population prevalence ~0.1%

Clinical Features

• Attacks: Severe, deep, unilateral retroorbital/periorbital pain; excruciating, non-fluctuating, explosive
• Duration: 15-180 minutes; 1-8 attacks/day
• Ipsilateral autonomic features: Lacrimation, conjunctival injection, rhinorrhoea, nasal congestion, miosis, ptosis (Horner's), eyelid oedema
• Patients are restless and agitated during attacks (contrasts with migraine where patients prefer stillness)
• Periodicity: Bouts last 6-12 weeks (episodic); pain-free intervals average ~1 year
• Onset often nocturnal (~50%); ~1 hour after sleep onset (REM-related)

Management

Acute Attack Treatment

Preventive Treatment

• Harrison's Principles of Internal Medicine 22E (2025)

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PART 4: STROKE

4.1 Epidemiology and Classification

• 87% are ischaemic (arterial occlusion)
• 13% are haemorrhagic (10% intracerebral haemorrhage, 3% subarachnoid haemorrhage)

• Rosen's Emergency Medicine

4.2 Ischaemic Stroke - Aetiopathology

TOAST Classification of Ischaemic Stroke

Ischaemic Penumbra

• Core: Irreversibly infarcted tissue (CBF <10 mL/100g/min); necrosis within minutes
• Penumbra: Electrically silent but viable tissue (CBF 10-20 mL/100g/min); can be salvaged with reperfusion
• Time is critical: "Time is brain" - ~1.9 million neurons lost per minute in untreated stroke

Special Causes in Young Patients

• Oral contraceptive pill, pregnancy
• Antiphospholipid syndrome, protein C/S deficiency, factor V Leiden
• Sickle cell anaemia, polycythaemia
• Fibromuscular dysplasia
• Carotid/vertebral dissection (leading determined cause of stroke in young adults)
• Cocaine/amphetamines (vasoconstrictors - both ischaemic and haemorrhagic stroke)
• Migraine-associated stroke (rare; prolonged vasospasm in aura)

4.3 Intracerebral Haemorrhage (ICH) - Aetiopathology

4.4 Transient Ischaemic Attack (TIA)

• New tissue-based AHA definition: Transient neurological dysfunction from focal brain/spinal cord/retinal ischaemia without acute infarction on MRI
• ~240,000 TIAs/year in the US
• 10% risk of stroke within 3 months (50% within first 2 days)
• ABCD2 score (age, BP, clinical features, duration, diabetes) stratifies 2-day stroke risk
• Urgent evaluation and treatment (antiplatelet, statin, carotid imaging, cardiac monitoring) dramatically reduces subsequent stroke risk

4.5 Clinical Syndromes by Territory

4.6 Investigation

• Door to doctor: 10 min
• Door to CT completion: 25 min
• Door to CT reading: 45 min
• Door to treatment (tPA): 60 min ("door-to-needle") - target <45 min at advanced centres

4.7 Acute Management of Ischaemic Stroke

General Measures

• Airway, Breathing, Circulation - ABC stabilisation
• Oxygen: Only if SpO2 <94%
• Blood glucose: Target 140-180 mg/dL; treat hypoglycaemia (<60 mg/dL) with IV dextrose immediately
• Temperature: Treat fever aggressively (even mild hyperthermia worsens neurological injury)
• NPO until swallowing assessed (aspiration risk)
• ECG monitoring for AF detection

Blood Pressure Management

• Without thrombolysis: Withhold antihypertensives unless SBP >220 or DBP >120 mmHg (permissive hypertension maintains penumbral perfusion)
• Pre-thrombolysis: Must achieve SBP <185 / DBP <110 mmHg
• Agents: IV labetalol 10-20 mg bolus, or nicardipine infusion 5 mg/h (titrate to 15 mg/h max)
• Post-thrombolysis: Monitor BP every 15 min x 2h, then 30 min x 6h, then hourly x 16h; treat if SBP 180-230: labetalol or nicardipine

Reperfusion Therapy

IV Thrombolysis (tPA)

• Haemorrhage on CT
• Previous ICH
• Recent surgery/trauma/GI bleeding
• Platelets <100,000, INR >1.7
• Blood glucose <50 or >400 mg/dL
• Active anticoagulation (DOAC within 48h unless levels normal)
• SBP >185/110 despite treatment
• Recent LMWH within 24h (full treatment dose)

Mechanical Thrombectomy (MT)

• For large vessel occlusions (ICA, M1/M2 MCA, basilar artery)
• Standard window: Up to 6h from onset
• Extended window (6-24h): With CT perfusion or DWI-FLAIR mismatch imaging showing viable penumbra (DAWN, DEFUSE-3 trial criteria)
• Can be combined with IV tPA (not required before MT)
• 2025 meta-analysis (PMID 40245349): MT effective even in large ischaemic core strokes that were previously excluded from intervention
• Stent retrievers and aspiration catheters are the primary devices

Secondary Prevention of Ischaemic Stroke

4.8 Management of Intracerebral Haemorrhage (ICH)

Acute Phase

• Haematoma expansion prevention is the primary goal in the first hours
• Reverse anticoagulation urgently:
  • Warfarin: 4-factor PCC (prothrombin complex concentrate) + IV vitamin K
  • Dabigatran: Idarucizumab (specific reversal agent)
  • Xa inhibitors: Andexanet alfa or 4-factor PCC
  • LMWH: Protamine sulfate
• Blood pressure: Target SBP <140 mmHg acutely (if SBP 150-220 mmHg) - reduces haematoma expansion (ATACH-2, INTERACT2 trials)
• Platelet transfusion: Only if platelet count <10,000; NOT routinely for antiplatelet users (PATCH trial: worse outcomes)
• ICP management: HOB 30°, IV mannitol or hypertonic saline for herniation
• Seizure: AEDs only if seizure occurs (not prophylactically)
• Glucose: Maintain normoglycaemia

Surgical Treatment

• Cerebellar haematoma >3 cm with neurological deterioration: Urgent surgical evacuation (life-saving)
• Supratentorial ICH: Conventional open surgery does not improve functional outcome (STICH I/II trials)
• Minimally invasive surgery (MIS): MISTIE III and ENRICH trials show selective benefit; emerging approach
• EVD (external ventricular drain): For obstructive hydrocephalus from intraventricular haemorrhage

ESO/EANS 2025 Guideline (PMID 40401775) on spontaneous ICH covers BP management, haemostasis, and surgical decision-making.

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Summary Table: Key Drug Targets

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• Harrison's Principles of Internal Medicine 22E (2025), Chapters 441 (Headache & Migraine) and Chapter 446
• Rosen's Emergency Medicine: Concepts and Clinical Practice (Chapter 87: Stroke)
• 2025 AHS Emergency Department Migraine Guideline - PMID 41321235
• 2025 ESO/EANS ICH Guideline - PMID 40401775
• Endovascular thrombectomy for large core stroke 2025 meta-analysis - PMID 40245349