Motor Neurone Disease
Motor neurone disease is a progressive neurodegenerative condition affecting motor neurones, causing progressive weakness with upper motor neurone and/or lower motor neurone features.
This updated UKMLA guide to motor neurone disease, including amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, and progressive muscular atrophy, is based on NICE NG42, which covers causes, risk factors, symptoms, diagnosis, and management.
Causes and Risk Factors
Most cases (85-90%) occur sporadically [Ref1][Ref2]
10-15% of cases are familial; 4 main implicated genes are associated with up to 70% of familial ALS cases: [Ref1][Ref2]
- C9ORF72 – most common
- Also associated with frontotemporal dementia
- SOD1
- TARDBP (TDP-43)
- FUS
Risk factors include: [Ref1][Ref2]
- Male sex
- Increasing age
- Sporadic ALS: 58-63 y/o
- Familial ALS: 40-60 y/o
- Cigarette smoking
- Past history of military service
- Cyanotoxins
Pathophysiology
The core mechanism of motor neurone disease is the progressive degeneration of both upper and/or lower motor neurones due to a cascade of interlinked intracellular failures.
This leads to progressive failure of motor signalling to skeletal muscles, causing weakness, wasting and loss of voluntary motor function.
Clinical Features
General Clinical Features
The hallmark of motor neurone disease is progressive degeneration of upper motor neurone and/or lower motor neurones.
Classically, a gradual onset of: [Ref1][Ref2]
- Asymmetrical weakness
- Often affecting first the distal muscles
- May result in difficulty with fine motor tasks (e.g. writing, doing buttons, turning keys), foot drop, abnormal gait, frequent falls
- Upper motor neurone (UMN) signs
- ↑ Tone (hypertonia)
- Spastic weakness
- Brisk reflex / hyperreflexia / exaggerated jaw jerk
- Ankle clonus
- Babinski sign (extensor plantar responses) or Hoffmann’s sign
- Lower motor neurone (LMN) signs
- ↓ Tone (hypotonia)
- Flaccid weakness
- Hyporeflexia / areflexia
- Fasciculations – a core symptom
- Bulbar symptoms (due to weakness in the muscles of the face, mouth and throat):
- Dysarthria (→ slurred speech)
- Dysphagia
- Saliva drooling
- Cognitive and behavioural changes
- Motor neurone disease can overlap with frontotemporal dementia in a subset of patients
- 1/3 patients exhibit executive dysfunction (e.g. inattention, poor planning)
- Others may present with apathy, personality changes, or behavioural disinhibition
Key negative signs (classically spared features): [Ref1][Ref2]
- NO sensory symptoms
- NO extraocular muscle (eye movement) and pelvic floor muscle weakness
Type-Specific Clinical Features
The 4 main subtypes of MND are classified based upon the site of origin (upper vs. lower motor neurones) and the severity of neurological involvement [Ref1][Ref2]
| Motor neurone disease subtype | Key clinical features |
|---|---|
| Amyotrophic lateral sclerosis (ALS) | ALS is the most common type of motor neurone disease
ALS progresses rapidly and is typically fatal within 3-5 years
|
| Progressive muscular atrophy (PMA) |
UMN signs may develop in 20-30% of cases, but usually 5-10 years after onset Associated with a slower rate of progression and a relatively better prognosis than ALS |
| Progressive bulbar palsy | Predominantly causes bulbar palsy from onset
Often accompanied by emotional lability (pseudobulbar affect), such as inappropriate crying The disease may then spread to cause wider motor symptoms Progressive bulbar palsy carries the worst prognosis |
| Primary lateral sclerosis (PLS) | PLS is the least common type of motor neurone disease
PLS carries the best prognosis as it spares lower motor neurones for a long period of time |
Prognostic Factors
Poor prognostic factors:
- Speech and swallowing problems (bulbar presentation)
- Weight loss
- Poor respiratory function
- Older age
- Shorter time from first developing symptoms to time of diagnosis
Investigation and Diagnosis
Diagnosis of motor neurone disease is primarily clinical, after performing the following investigations to rule out mimics. [Ref1][Ref2]
Key investigation findings in motor neurone disease: [Ref1][Ref2]
- Normal neuroimaging
- EMG: evidence of LMN degeneration
- Nerve conduction study: normal sensory nerve conduction +/- reduced motor amplitudes
| Investigation | Main purpose | Typical findings in motor neurone disease |
|---|---|---|
| Standard blood tests (including FBC, ESR, CRP, metabolic panel, TFT) | To rule out metabolic, infectious, inflammatory mimics | Normal |
| Nerve conduction study | To exclude demyelination (e.g. CIDP) and multifocal motor neuropathy | Normal sensory nerve function
Motor nerve:
|
| Electromyography (EMG) | To identify and confirm LMN degeneration | Abnormal
These findings would be found in both clinically affected and unaffected regions |
| Creatine kinase | To rule out primary myopathies (e.g. muscular atrophies, polymyositis, inclusion body myositis) | Normal or mildly elevated |
| Muscle biopsy | Signs of neurogenic damage (denervation and reinnervation with the grouping of atrophic and angular fibres)
No hallmarks of primary myopathies |
|
| MRI spine | To be performed in ALL patients with limb-onset ALS
To rule out spinal cord pathologies and root compression |
Normal |
| MRI head and neck | To rule out structural lesions | |
| Lumbar puncture | To rule out multiple sclerosis | Normal
Can assess specific biomarkers (neurofilament light peptide and phosphorylated neurofilament heavy neuropeptides) for ALS |
| Genetic testing | Rules out genetic mimics (e.g. Kennedy’s disease, spinal muscular atrophy) or confirms a familial mutation (e.g. C9ORF72, SOD1) | Mutations +ve in familial cases but -ve in sporadic disease |
Management
Supportive Management (General Symptom Management)
Symptom-guided management:
| Body system | Symptom / problem | Management |
|---|---|---|
| Musculoskeletal | Muscle cramp |
|
| Muscle stiffness, spasticity, increased tone | Consider any of the following:
|
|
| Joint function and mobility | Tailored exercise programmes to maintain joint range, prevent contractures, and reduce discomfort
Use orthoses if necessary |
|
| GI and nutrition | Dysphagia and malnutrition | Early placement of a gastrostomy tube (PEG / RIG) should be discussed before the patient experiences significant weight loss or severe respiratory decline
Late placement carries higher mortality and complications risk |
| Saliva drooling | 1st line: antimuscarinic (glycopyrronium bromide preferred in those with cognitive impairment)
2nd line: Botulinum toxin A (under specialist guidance) |
|
| Thick, tenacious saliva | Advise on hydration, swallowing, oral care
Treat with humidification, nebulisers, carbocisteine |
|
| Respiratory | Breathlessness |
|
| Ineffective cough |
|
|
| General living | Speech and communication loss | Prompt assessment by a speech and language therapist, with provision of augmentative and alternative communication equipment
Refer to a specialised hub for eye gaze access systems if needed |
| Loss of independence |
|
Disease-Modifying Therapy
The only recommended disease-modifying therapy is riluzole
- MoA: NMDA receptor antagonist → reduce neurotoxic pre-synaptic glutamate release
- Indication: ALS form of motor neurone disease (to be prescribed by a specialist)
- Efficacy: prolongs life by 3-4 months (but does NOT improve muscle strength, and does not prolong the end-of-life phase of the disease)
Life-prolonging interventions:
- Non-invasive ventilation – in those who develop respiratory impairment
- Gastrostomy (PEG / RIG) – before the patient experiences significant weight loss or severe respiratory decline