Key Facts

MND is a progressive, fatal neurodegenerative condition. Diagnosis is clinical, supported by EMG. Early MDT involvement and palliative care are essential. Riluzole offers modest survival benefit.

Epidemiology

Incidence ~2 per 100,000/year. Prevalence ~5-7 per 100,000. Mean age of onset 55-65 years. M:F 1.5:1. Lifetime risk ~1 in 300. ~90% sporadic; ~10% familial.

Aetiology

• Sporadic (~90%): cause unknown; multifactorial with environmental and genetic contributions
• Familial (~10%): C9orf72 hexanucleotide repeat expansion (commonest — ~40% of familial MND; also causes FTD), SOD1 mutations (~20% of familial), TARDBP (TDP-43), FUS
• Risk factors: increasing age, male sex, smoking, possible military service

Pathophysiology

Selective degeneration of motor neurones in the motor cortex (UMN), brainstem motor nuclei, and anterior horn cells of the spinal cord (LMN). TDP-43 protein inclusions found in >95% of sporadic ALS. Glutamate excitotoxicity (basis for riluzole — glutamate release inhibitor). Protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation all contribute. Eye movements and sphincters are spared because Onuf's nucleus and oculomotor nuclei are resistant.

Typical Presentations

• Limb-onset ALS (~65%): asymmetric weakness/wasting of hand (split hand sign — thenar > hypothenar) or foot drop; mixed UMN + LMN signs
• Bulbar-onset ALS (~25%): dysarthria (slurred speech), dysphagia, tongue wasting/fasciculations; worse prognosis
• Respiratory onset (~5%): dyspnoea, orthopnoea, morning headaches from nocturnal hypoventilation

UMN Signs

• Spasticity, hyperreflexia, upgoing plantars, clonus, brisk jaw jerk, pseudobulbar affect (emotional lability)

LMN Signs

• Muscle wasting, weakness, fasciculations (visible twitching), hyporeflexia/areflexia, muscle cramps

Red Flags

• Sensory involvement → NOT MND (consider cervical myelopathy, CIDP)
• Eye movement abnormality → NOT typical MND
• Early sphincter involvement → NOT MND (consider spinal cord compression)
• Symmetric onset → atypical (consider Kennedy disease, SMA)
• Very slow progression (>5 years) → consider PLS, Kennedy disease

Bedside

• Clinical examination: mixed UMN + LMN signs in multiple regions
• FVC (forced vital capacity): baseline and serial monitoring (respiratory function)

Bloods

• CK: mildly raised in MND (usually <1000 IU/L)
• TFTs, glucose, B12, folate: exclude metabolic causes
• Anti-GM1 antibodies: exclude multifocal motor neuropathy
• Serum protein electrophoresis: exclude paraprotein
• Genetic testing: C9orf72, SOD1 if familial or FTD features

Imaging

• MRI brain + spine: exclude structural causes (cervical myelopathy, foramen magnum lesions); usually normal in MND

Special Tests

• EMG/nerve conduction studies (NCS): essential — shows widespread denervation (fibrillations, positive sharp waves, fasciculations) with preserved sensory nerves; Awaji criteria incorporate EMG findings
• Revised El Escorial criteria: clinical classification (definite, probable, possible MND) based on UMN + LMN signs in multiple body regions
• FVC and SNIP (sniff nasal inspiratory pressure): respiratory muscle strength

Pharmacological

• Riluzole 50 mg BD: only disease-modifying drug; glutamate release inhibitor; extends survival by ~2-3 months; NICE TA20; monitor LFTs
• No cure: all other treatments are symptomatic

Non-pharmacological

• MDT essential: neurology, respiratory, SALT, dietitian, OT, PT, palliative care, MND nurse specialist, social worker, psychology
• Nutrition: SALT assessment for swallowing; high-calorie supplements; PEG/RIG insertion when swallowing unsafe (insert early while FVC >50%)
• Respiratory: NIV (non-invasive ventilation — BiPAP) for respiratory failure; improves survival by ~7 months (NICE); monitor with serial FVC/SNIP; initiate when FVC <50% or symptoms
• Communication: speech aids, eye-tracking technology, letter boards
• Physiotherapy: maintain mobility, prevent contractures

Symptom Management

• Sialorrhoea: hyoscine patches, glycopyrronium 1-2 mg TDS, botulinum toxin to salivary glands
• Spasticity: baclofen 5-80 mg/day, tizanidine
• Cramps: quinine 200-300 mg ON (limited evidence)
• Pseudobulbar affect: amitriptyline 10-50 mg ON
• Pain: paracetamol, NSAIDs, neuropathic agents
• Depression/anxiety: SSRIs, counselling

Palliative Care

• Early referral; advance care planning (ADRT, preferred place of death)
• End-of-life: respiratory failure is usual cause of death; opioids + benzodiazepines for dyspnoea/distress

Referral Criteria

• All suspected MND: urgent neurology referral (within 4 weeks — NICE)
• MND Association key worker involvement from diagnosis

Median survival from symptom onset: 2-5 years. Bulbar-onset: worse prognosis (~2 years). Limb-onset: ~3-5 years. ~10% survive >10 years (especially PLS, younger onset). FVC decline is the strongest prognostic indicator. Respiratory failure is the usual cause of death. Riluzole extends survival by ~2-3 months. NIV extends survival by ~7 months. PEG feeding does not clearly extend survival but improves nutrition and quality of life. C9orf72 associated with concomitant FTD and shorter survival.

MND Subtypes

Revised El Escorial Criteria