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Motor Neuron Disease (MND) - FCPS / MRCP Examination Notes

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1. DEFINITION & CLASSIFICATION

MRCP Tip: ALS = "Charcot's Disease." PLS is the most indolent, PBP the worst prognosis (death within 1-3 years).

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2. EPIDEMIOLOGY

• Incidence: ~2/100,000/year; Prevalence: 6-8/100,000
• Mean age of onset: 55-60 years (middle-aged and elderly)
• Male > Female (ratio ~1.6:1); in familial cases, equal sex distribution
• 5-10% familial (mostly autosomal dominant); 90% sporadic
• High-incidence foci: Guam and Kii peninsula, Japan (ALS-Parkinsonism-Dementia complex)
• Only proven risk factors: increasing age, male sex, genetic susceptibility
• Prognosis: death in 2-5 years from diagnosis; bulbar onset = worse prognosis

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3. GENETICS & PATHOGENESIS

Key Genetic Mutations (MRCP High-Yield)

Pathogenic Mechanisms

• Oxidative stress (SOD1)
• Protein aggregation and misfolding
• Mitochondrial dysfunction
• Excitotoxicity (glutamate)
• Impaired axonal transport
• Neuroinflammation (toxic astrocyte-microglia interactions)
• RNA processing defects (C9ORF72, TDP-43, FUS)

Pathology

• Gross: Atrophy of precentral gyrus; pallor and sclerosis of lateral corticospinal tracts; thin hypoglossal nerves; thinned ventral roots
• Micro: Loss of anterior horn cells (≥50% lost by symptomatic stage); astrocytic gliosis; TDP-43-positive ubiquitinated inclusions (cardinal finding); neurogenic muscle atrophy
• Spared: Onuf's nucleus (pelvic floor - bladder/bowel continence preserved); cranial nerve nuclei III, IV, VI (eye movements spared); sensory neurons

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4. CLINICAL FEATURES

Onset Pattern

• 75% limb onset: Asymmetric distal weakness - foot drop (lower limb) or clumsy hand / wasting of intrinsic hand muscles (upper limb)
• 25% bulbar onset: Slurring of speech (dysarthria), initially when tired; more common in elderly women
• Muscle cramps may precede weakness; fasciculations prominent in large proximal muscles

UMN Signs

• Spasticity, hyperreflexia, upgoing plantar (Babinski sign)
• Jaw jerk brisk (pseudobulbar)
• Emotional lability (pseudobulbar affect)
• Strained, effortful speech (spastic dysarthria)

LMN Signs

• Wasting, weakness, fasciculations
• Hyporeflexia/areflexia
• Flaccid dysarthria, nasal speech, tongue wasting + fasciculations
• Dysphagia (liquids before solids initially)

Classic Exam Finding (MRCP Favourite)

Bulbar Features

• Mixed spastic-flaccid dysarthria (tight strangled + nasal quality)
• Weak, wasted, fasciculating tongue
• Dysphagia (liquids > solids)
• Drooling, aspiration pneumonia
• Brisk jaw jerk, emotional lability

Respiratory Features

• Diaphragm weakness: orthopnoea, paradoxical abdominal wall movement
• Nocturnal CO₂ retention: morning headache, daytime somnolence, interrupted sleep
• Paradoxical decline in FVC when supine (diaphragmatic involvement)

Cognitive Features

• ~5% develop overt frontotemporal dementia (FTD)
• Up to 50% show subtle frontal lobe dysfunction without overt dementia
• C9ORF72 variant associated with cognitive disturbance + family history of dementia/psychosis

What is SPARED (MRCP High-Yield)

• Sensation (no sensory loss)
• Eye movements (III, IV, VI nuclei spared)
• Bladder/bowel continence (Onuf's nucleus preserved)
• Pressure sores rare (patients remain mobile until late)
• Cognitive function (mostly preserved except FTD subset)

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5. SUBTYPES IN DETAIL

Amyotrophic Lateral Sclerosis (ALS)

• Combined UMN + LMN degeneration
• Triad: atrophic weakness of hands/forearms + fasciculations + corticospinal signs - all WITHOUT sensory change
• Upper limb: thenar + intrinsic hand muscles severely affected; triceps and finger flexors relatively spared until late
• Lower limb: pyramidal pattern (flexors weaker than extensors), hip flexion + ankle dorsiflexion affected early

Progressive Bulbar Palsy

• Lower brainstem cranial motor nuclei affected (V, VII, IX, X, XII)
• Presents as dysarthria, dysphagia, dysphonia
• Usually progresses to full ALS
• Death in 1-3 years, most rapid progression

Progressive Muscular Atrophy (PMA)

• Pure LMN; 5-10% of MND patients
• Weakness and atrophy without UMN signs
• Slower progression than ALS

Primary Lateral Sclerosis (PLS)

• Pure UMN degeneration confined to corticospinal pathways
• Spastic paraparesis, hyperreflexia, Babinski without atrophy
• Most benign, decades-long course

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6. INVESTIGATIONS

Diagnosis is CLINICAL - supported by investigations

El Escorial Diagnostic Criteria (Revised)

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7. DIFFERENTIAL DIAGNOSIS

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8. MANAGEMENT

Disease-Modifying Treatment (MRCP Critical)

Symptomatic Management

Respiratory Management

• Non-Invasive Ventilation (NIV/BiPAP): when FVC <50% predicted or symptoms of respiratory failure - improves survival and quality of life
• Respiratory muscle training: recent meta-analysis (PMID: 40488544) supports benefit in pulmonary function
• Mechanical insufflation-exsufflation (cough assist device) for secretion clearance
• Invasive ventilation (tracheostomy) - patient's individual choice; continues neurological decline

Nutritional Support

• Dietitian referral early
• PEG feeding: ideally when FVC >50% (anaesthetic risk if lower); improves nutrition and quality of life but does not prolong survival significantly

Multidisciplinary Team (MDT) - Essential

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9. KENNEDY DISEASE (SBMA) - MND Mimic (High-Yield)

• Spinal and Bulbar Muscular Atrophy (SBMA)
• X-linked; CAG trinucleotide repeat expansion in androgen receptor gene (Chr X)
• Pure LMN: distal limb amyotrophy, bulbar signs (tongue atrophy, fasciculations, dysphagia)
• Gynecomastia, testicular atrophy, infertility (androgen insensitivity)
• Sensory neuropathy (mild, subclinical)
• Very slow progression - decades; not fatal
• Differentiator: no UMN signs, androgen-receptor gene mutation

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10. SPINAL MUSCULAR ATROPHY (SMA) - Paediatric/Young Onset

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11. PROGNOSIS

• Median survival: 3 years from symptom onset
• 10% survive >10 years (Stephen Hawking being a famous example)
• Poor prognostic factors:
  • Bulbar onset (1-3 year survival)
  • Older age at onset
  • Rapid rate of progression in first year
  • FVC <50% at diagnosis
  • Low body weight
  • C9ORF72 mutation (associated with cognitive involvement)
• Best prognosis: PLS (decades); PBP/ALS with bulbar onset (worst)
• Cause of death: Respiratory failure (most common) or aspiration pneumonia

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12. KEY MRCP/FCPS EXAM MNEMONICS & PEARLS

• Sensation (preserved)
• Sphincters (bladder/bowel)
• Sex muscles (extraocular - eye movements)

• C9ORF72 = most Common familial cause
• SOD1 = SODium dismutase = oxidative stress = chromosome 21

• EMG = confirms LMN degeneration (widespread active denervation)
• MRI = rules out structural mimics (must be done)
• El Escorial criteria = 3 regions (bulbar + cervical + thoracic/lumbosacral) for Definite ALS

• Cervical myelopathy + radiculopathy (most common mimic; get MRI C-spine)
• Multifocal motor neuropathy (anti-GM1 Ab; responds to IVIG - TREATABLE!)

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13. SUMMARY TABLE

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