Myasthenia Gravis
Myasthenia gravis is an autoimmune neuromuscular junction disorder characterised by fluctuating, fatigable skeletal muscle weakness.
This updated UKMLA guide to myasthenia gravis is based on ABN guidelines, which cover causes, risk factors, symptoms, diagnosis and management.
Causes and Risk Factors
Myasthenia gravis is caused by autoantibodies against components of the postsynaptic neuromuscular junction:
- Anti-acetylcholine receptor (AChR) antibodies – most common
- Anti-muscle-specific tyrosine kinase (MuSK)
- Anti-lipoprotein receptor-related protein 4 (LRP4)
These antibodies impair acetylcholine-mediated neuromuscular transmission, resulting in skeletal muscle weakness.
Risk factors and associations: [Ref]
- Thymoma or thymic hyperplasia (in ~10% of patients)
- More common in females <40 y/o and more common in males >50 y/o
- Other autoimmune conditions (esp. autoimmune thyroid disease like Graves’ disease and Hashimoto’s thyroiditis)
Clinical Features
General Features
| Signs and symptoms | Hallmark features: fluctuating, fatigable skeletal muscle weakness
Clinical manifestation of “fatigability“:
Apart from skeletal muscle weakness, generalised fatigue is a very common symptom affecting up to 80% of patients |
| Clinical provocation / manoeuvres | Ice-pack test:
Simpson test:
Bienfang’s test:
Cogan’s lid twitch sign:
|
| Exacerbating factors |
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| Features absent in myasthenia gravis | The following are NOT typical of myasthenia gravis (as myasthenia gravis is a neuromuscular junction disorder affecting skeletal muscles)
|
Myasthenic Crisis
Myasthenia crisis is a medical emergency – a severe exacerbation of MG causing respiratory muscle weakness, which may lead to respiratory failure.
Features of impending myasthenic crisis:
- Worsening breathlessness
- Other signs of respiratory failure include rapid shallow breathing, use of accessory muscles, orthopnoea
- A progressive drop in FVC
- Significant neck drop
- Bulbar features
- Frequent choking
- Severe dysarthria (difficulty speaking)
Myasthenia Gravis vs Lambert-Eaton Syndrome
| Feature | Myasthenia gravis | Lambert-Eaton syndrome |
|---|---|---|
| Mechanism | Affects the post-synaptic NMJ
Antibodies against acetylcholine receptor |
Affects the pre-synaptic NMJ
Antibodies against voltage-gated calcium channels |
| Cause and association | ~10% cases are associated with thymoma | ~50% cases are paraneoplastic (triggered by cancer, specifically small cell lung cancer) |
| Typical clinical features |
|
|
| EMG with repetitive nerve stimulation | Decremental response | Incremental response |
| Response to treatment | Responds well to cholinesterase inhibitors (e.g. pyridostigmine) | Responds well to amifampridine but poor response to cholinesterase inhibitors |
Investigation and Diagnosis
1st line investigations (ALL patients):
| Investigations | Description / notes |
|---|---|
| Anti-acetylcholine receptor (AChR) antibody testing | Positive anti-acetylcholine receptor antibody PLUS compatible clinical features are sufficient to diagnose myasthenia gravis without further investigations |
| TFT | Purpose: to screen for concurrent thyroid disorders |
| Thymus imaging (CT / MRI) | Purpose: to exclude an underlying thymoma or thymic hyperplasia
A chest X-ray is NOT sufficient |
Further investigations are necessary if there is -ve anti-AChR antibody:
| Investigations | Description / notes |
|---|---|
| Further antibody testing (serology) |
|
| Electromyography (EMG) |
Note that pyridostigmine should be withheld for at least 12 hours before testing and symptomatic muscles must be targeted |
MRI of the brain and orbits is indicated with those with diplopia and ptosis AND -ve serology AND –ve electromyography to exclude structural intracranial or orbital diseases
Investigations in summary:
- 1st line: anti-acetylcholine receptor (AChR) antibody testing
- Definitive: electromyography (EMG) – not always necessary if anti-AChR is +ve
Nerve conduction studies are usually normal in myasthenia gravis because the peripheral nerves are structurally intact.
In myasthenia gravis, the pathology lies at the neuromuscular junction, rather than within the nerve itself.
Management
Long-Term Management
1st line management:
- Pyridostigmine for symptomatic management of ocular and mild-to-moderate generalised symptoms
- If a thymoma is identified → thymectomy
Pyridostigmine:
- MoA: cholinesterase inhibitor (inhibits cholinesterase – the enzyme that breaks down acetylcholine → increases availability of acetylcholine at the NMJ → improves nerve-to-muscle signal transmission and reduces muscle weakness)
- Pyridostigmine is typically dosed TDS or QDS (but is highly individualised)
- Use with caution in those with a history of asthma or cardiac disease (ECG should be performed before starting it)
Step up therapy (if symptoms persist despite maximum tolerated dose of pyridostigmine for 4-6 weeks):
- 1st line: oral prednisolone (initial higher induction dose, followed by lower maintenance dose)
- If steroids are insufficient or inappropriate (e.g. unsafe or due to side effects): steroid-sparing agents (e.g. azathioprine, mycophenolate)
Rituximab is recommended for early use in all symptomatic patients with anti-MuSK myasthenia gravis. This specific antibody type is often refractory to conventional treatment.
Acute Myasthenic Crisis
| Aspect / category | Management |
|---|---|
| Care setting | Patients should be managed in HDU / ITU setting |
| Airway / breathing support and monitoring |
|
| Feeding support |
|
| Rescue therapy | 2 main options (both have similar efficacy, initial choice often depends on what is locally available):
Do NOT routinely give both at the same time. If the patient fails to improve after one course of either plasma exchange or IVIg, seek specialist opinion. If IVIg failed, either switch to plasma exchange (preferred) or attempt a 2nd course of IVIg |
| Adjusting standard / long-term medications | Increase corticosteroid dose
If the patient is intubated, do NOT continue pyridostigmine
Delay starting long-term non-steroidal immunosuppressive therapies until the acute crisis has resolved |
Treat any concurrent infections promptly as they might have triggered the crises. Avoid antibiotics known to exacerbate myasthenia gravis (aminoglycosides, macrolides, fluoroquinolones)