Motor neurone disease
Description
- Progressive degeneration of upper AND lower motor neurones
- UMN + LMN signs in the same territory, no sensory loss, no sphincter involvement, eye movements spared
- Those four negatives are what make the diagnosis
- Painless, asymmetric, focal onset that spreads to contiguous regions
Phenotypes
| % | Features | Survival | |
|---|---|---|---|
| ALS (classic) | ~70% limb onset | Mixed UMN + LMN, asymmetric; often proximal arm or asymmetric foot drop | Median 2-3 yr |
| Bulbar onset | ~25% | Dysarthria, dysphagia, tongue wasting + fasciculation | Worst - ~2 yr |
| Progressive muscular atrophy (PMA) | ~10% | LMN only, generalised or patchy onset | Longer |
| Primary lateral sclerosis (PLS) | ~10% | UMN only for >4 years, bulbar then limbs | Best - decades |
| Flail arm / flail leg | LMN-predominant, restricted for long periods | Longer | |
| Respiratory onset | 3-5% | Orthopnoea, dyspnoea, morning headache | Poor |
Bulbar vs pseudobulbar palsy - a standard exam pair
| Bulbar (LMN) | Pseudobulbar (UMN) | |
|---|---|---|
| Tongue | Wasted, fasciculating, flaccid | Small, spastic, slow ("stiff"), cannot protrude |
| Speech | Nasal, flaccid dysarthria | Strained, "Donald Duck", spastic |
| Jaw jerk | Normal or absent | Brisk |
| Gag | Absent | Brisk |
| Emotion | Normal | Emotional lability / pseudobulbar affect |
| Causes | MND, GBS, polio, brainstem infarct, myasthenia, syringobulbia | Bilateral capsular infarcts, MS, MND |
- *MND is the classic cause of a combined bulbar and pseudobulbar palsy*
Epidemiology
- Incidence ~2-3/100,000/yr; prevalence 6-9/100,000; lifetime risk ~1 in 300
- Peak onset 58-63 (sporadic), 47-52 (familial); M>F ~1.5:1, converging with age
- ~10% familial, but a pathogenic variant is found in ~10-15% of apparently sporadic cases too
- Risk factors (weak, inconsistent): smoking, military service, heavy physical activity, head injury, heavy metals
Aetiopathogenesis
- Degeneration of Betz cells and corticospinal tracts (UMN) + anterior horn cells and brainstem motor nuclei (LMN)
- TDP-43 cytoplasmic mislocalisation and aggregation in ~97% - the shared molecular substrate with FTD
- Exceptions: SOD1 and FUS cases, which do not have TDP-43 pathology
- Mechanisms: RNA processing failure, protein misfolding, impaired autophagy, glutamate excitotoxicity (the rationale for riluzole), oxidative stress, axonal transport failure, neuroinflammation
Genetics
- C9orf72 GGGGCC hexanucleotide repeat expansion - the commonest genetic cause of both ALS and FTD
- Normal up to ~30 repeats; hundreds to thousands in disease
- ~40% of familial ALS, ~5-10% of sporadic; autosomal dominant, incomplete penetrance
- Predicts the ALS-FTD overlap phenotype and psychiatric presentations
- SOD1 ~12-20% of familial - the one with a targeted therapy (tofersen)
- TARDBP, FUS (young onset), and >30 others
- Offer genetic testing to everyone with ALS now - it changes treatment eligibility and family counselling
Selective vulnerability - why the negatives hold
- Oculomotor nuclei and Onuf's nucleus (sphincters) are spared -> eye movements and continence preserved until very late
- Sensory pathways are not primarily involved
Diagnosis
- Diagnosis is clinical, supported by EMG, with mimics excluded
Gold Coast criteria (2019) - now standard, superseding revised El Escorial
- 1. Progressive motor impairment documented by history or repeated examination, preceded by normal motor function; AND
- 2. UMN and LMN dysfunction in at least one body region (both in the same region if only one is involved), OR LMN dysfunction in at least two body regions; AND
- 3. Investigations exclude other disease processes
- EMG evidence of denervation counts as LMN dysfunction - it substitutes for clinical signs
- Effect: a single "possible ALS" category is gone, diagnosis is made earlier, and more patients qualify for trials and therapy
- Revised El Escorial (know it as the older framework): certainty graded by how many of the 4 regions (bulbar, cervical, thoracic, lumbosacral) show UMN + LMN signs - definite = 3 regions, probable = 2, possible = 1
Examination findings
- LMN: wasting (first dorsal interosseous, thenar, tongue), fasciculations, weakness, hypotonia
- Fasciculations alone are benign; fasciculation with wasting and weakness is not
- UMN: spasticity, brisk reflexes, extensor plantars, preserved or brisk reflexes in a wasted, fasciculating limb (the pathognomonic combination)
- Brisk jaw jerk; spastic dysarthria; emotional lability
- Split hand sign - thenar and first dorsal interosseous wasting out of proportion to hypothenar
- Head drop, respiratory muscle weakness, orthopnoea
- Cognitive/behavioural screen (ECAS) - apathy, disinhibition, loss of empathy, language change
Investigation
| Test | Purpose |
|---|---|
| EMG | The key test - active denervation (fibrillations, positive sharp waves) + chronic reinnervation (large polyphasic units, reduced recruitment) + fasciculation potentials, in >=2 regions incl. clinically uninvolved muscle. Include thoracic paraspinals and tongue |
| NCS | Normal sensory studies; crucially, excludes multifocal motor neuropathy with conduction block |
| MRI brain + whole spine | Normal in MND - exclude cervical myeloradiculopathy, cord tumour, MS, syringomyelia |
| Bloods | TSH (thyrotoxicosis mimic), CK (mildly raised), B12, SPEP/free light chains, ANA/ENA, HIV, syphilis, ACE, lead |
| Anti-GM1 antibodies | Multifocal motor neuropathy |
| Respiratory | FVC sitting AND supine, SNIP, overnight oximetry, ABG |
| Swallow | Videofluoroscopy/modified barium swallow |
| Genetic testing | C9orf72 and SOD1 at minimum - determines tofersen eligibility and family counselling |
| CSF | Only if an inflammatory or infective mimic is plausible |
Mimics that must be excluded - some are treatable
- Multifocal motor neuropathy with conduction block - pure LMN, asymmetric, upper limb, anti-GM1, responds to IVIg**. The single most important miss
- Cervical spondylotic myeloradiculopathy - LMN arms + UMN legs, but has sensory signs and a sensory level
- Kennedy disease (spinobulbar muscular atrophy) - X-linked AR CAG expansion; gynaecomastia, perioral and tongue fasciculations, sensory neuropathy, slow, much better prognosis
- Inclusion body myositis - quadriceps + long finger flexors, no UMN signs, raised CK
- Myasthenia gravis (fatigable, ocular), thyrotoxic myopathy, lead toxicity, HIV, post-polio syndrome, benign fasciculation syndrome, hyperparathyroidism, lymphoma-associated motor neuronopathy
Management
A. Disease-modifying therapy - modest, but offer it
- Riluzole 50 mg BD - anti-glutamatergic; prolongs survival ~2-3 months (or ~10%)
- Monitor LFTs monthly for 3 months then periodically; nausea, asthenia, neutropenia
- PBS-listed in Australia; available as tablet, oral suspension and oral film for dysphagia
- Edaravone - free radical scavenger; IV cycles or oral suspension. Small effect in a narrowly defined early, rapidly progressing population; not funded in Australia
- Tofersen - intrathecal antisense oligonucleotide for SOD1-ALS only; lowers neurofilament light and slowed decline in open-label extension
- This is why every patient should be offered SOD1 testing
- *AMX0035 (sodium phenylbutyrate/taurursodiol, Relyvrio/Albrioza) was withdrawn in 2024 after the phase 3 PHOENIX trial failed - it is no longer a treatment option*
- Multidisciplinary MND clinic attendance itself improves survival - the strongest "intervention" available
B. Respiratory - the largest survival gain
- Non-invasive ventilation for symptomatic respiratory insufficiency
- Triggers: orthopnoea, morning headache, daytime sleepiness, FVC <80% predicted, abnormal SNIP, or nocturnal desaturation/hypercapnia
- Improves survival by ~7 months and quality of life - benefit is much smaller with severe bulbar involvement
- Cough augmentation (breath stacking, mechanical insufflation-exsufflation) for weak cough
- Discuss tracheostomy ventilation explicitly and in advance - what it does and does not offer
- Vaccination, prompt treatment of chest infection
C. Nutrition and swallow
- Early dietitian and speech pathology; weight is a prognostic marker
- Gastrostomy before FVC falls below ~50% - the procedure is far riskier after that
- Radiologically inserted gastrostomy (RIG) if respiratory function is marginal
- Discuss it early, before it is urgent - not at the point of aspiration
- Texture modification, thickened fluids
D. Symptom control
| Symptom | Treatment |
|---|---|
| Sialorrhoea | Hyoscine (patch/drops), amitriptyline, atropine drops, glycopyrrolate; botulinum toxin to salivary glands; salivary gland radiotherapy |
| Thick secretions | Nebulised saline, carbocisteine, humidification, suction |
| Spasticity | Baclofen, tizanidine, physiotherapy, botulinum toxin |
| Cramps | Stretching, magnesium; mexiletine; quinine is restricted |
| Emotional lability (pseudobulbar affect) | Amitriptyline or an SSRI; dextromethorphan/quinidine where available |
| Dyspnoea/anxiety at end of life | Opioid + benzodiazepine - effective, and does not shorten life when titrated |
| Pain | Simple analgesia, positioning, spasticity control |
| Communication | Speech pathology, voice banking early, AAC devices, eye-gaze technology |
E. Care planning - start it early
- Advance care directive, discussion of ventilation and gastrostomy, substitute decision maker - while communication and cognition are intact
- Early palliative care referral improves symptoms and does not shorten life
- Occupational therapy: wheelchair, home modification, hoists; NDIS/My Aged Care applications take months - start them early
- Carer support and respite; cognitive/behavioural screening (ECAS) affects capacity and carer burden
- Genetic counselling for the family; MND Australia and state associations
- Discuss voluntary assisted dying where the patient raises it, per state legislation
Associations
- Frontotemporal dementia - ALS-FTD, usually behavioural variant (apathy, loss of empathy, disinhibition, stereotyped behaviour)
- Up to 50% have some cognitive or behavioural change; ~15% meet FTD criteria
- C9orf72 is the shared genetic cause - also psychosis and family histories of dementia or schizophrenia
- Progressive non-fluent aphasia
- Frontal executive dysfunction affecting decision-making capacity
- Parkinsonism and supranuclear gaze palsy in some C9orf72 kindreds
- Weight loss and hypermetabolism - independent adverse prognostic factor
- Depression, anxiety, insomnia; carer depression
- No association with sensory loss, sphincter dysfunction or eye movement abnormality - if present, question the diagnosis
Natural history & complications
- Relentlessly progressive, spreading to contiguous regions
- Median survival 2-3 years from symptom onset; ~50% at 30 months, ~10% survive >10 years
- Death from respiratory failure (hypoventilation, aspiration pneumonia)
Prognostic factors
| Better | Worse |
|---|---|
| PLS, flail limb, PMA phenotype | Bulbar or respiratory onset |
| Younger age at onset | Older age at onset |
| Limb onset | Early respiratory involvement, low FVC |
| Slow rate of ALSFRS-R decline | Rapid ALSFRS-R decline |
| Normal cognition | FTD / cognitive impairment |
| Weight maintained | Weight loss, low BMI |
| Long diagnostic delay (paradoxically indicates slow disease) | Short time from onset to diagnosis |
Monitor
- ALSFRS-R, weight, FVC/SNIP at every clinic visit
- Swallow safety, communication needs, mood, carer strain
- Reassess ceiling of care and advance directives as function changes
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