Myasthenia gravis (MG) is a chronic autoimmune disorder that affects neuromuscular transmission through autoantibodies targeting the neuromuscular junction (NMJ). It leads to muscular weakness and easy fatiguability.
It is a rare condition that mostly affects women aged 30-40 years old and men aged 60-70 years old.
Pathophysiology
MG is an autoimmune disorder where autoantibodies target the NMJ. Most commonly these autoantibodies are against the nicotinic acetylcholine receptor (AChR) on the post-synaptic membrane at the NMJ. Other antibodies seen are muscle-specific tyrosine kinase (MuSK) as well as low-density lipoprotein receptor-related protein 4 (LRP4).
These autoantibodies are linked to certain HLA alleles (such as HLA-B8 and HLA-DR3) and genetic mutations. MG is also associated with the thymus as thymic hyperplasia is present in 70% of patients and thymomas in 15% of patients (however, around 30-50% of patients with thymomas have MG). Patients with thymoma and MG almost always have AChR antibodies. This is because thymic myoid cells have AChR and autoantibodies are synthesised against the AChR located on these cells.
Let’s discuss these antibodies more:
- Acetylcholine receptor antibodies - these result in destruction of the post-synaptic membrane. It also blocks ACh binding sites which impairs action potentials and causes muscle weakness. It makes up 85% of cases.
- Muscle specific tyrosine kinase - MuSK is a protein on the muscle membranes that anchors the AChR to the membrane. Antibodies that target MuSK prevent AChR aggregation. It is present in about 10% of cases.
- Low-density lipoprotein receptor-related protein 4 - LRP4 interacts with MuSK and other proteins to aggregate AChR on the muscle cell membrane. It occurs in less than 5% of cases.
15% of patients with MG have thymomas while 30-50% of patients with thymomas have MG, while 70% of patients have thymic hyperplasia.
The thymus is located in the anterior mediastinum and plays a role in development and maturation of T-cells. Thymomas are epithelial neoplasias surrounded by maturing T-cells. These epithelial cells are able to express portions of the antigen recognised by the immune system (epitopes) that are cross reactive the AChR, titin and the ryanodine receptor for example. Therefore if MG occurs with thymoma it is considered a paraneoplastic disease of the thymoma.
⚠️ Risk factors
- HLA-B8 and HLA-DR3
- Family history of autoimmune conditions - such as:
- Hashimoto thyroiditis
- Rheumatoid arthritis
- Sarcoidosis
- Systemic lupus erythematosus
- Pernicious anaemia
- Thymoma and thymic hyperplasia
- Immune checkpoint inhibitors
😷 Presentation
- ⭐️ Muscle fatiguability - muscles become progressively weaker during periods of activity and slowly improve after periods of rest.
It affects skeletal muscles such as the following:
- Small muscles of the head and neck:
- Diplopia (extraocular muscle weakness) & ptosis (levator palpebrae muscle weakness) - ocular involvement is the most common initial symptom.
- Slurred speech
- Dysphagia
- Fatigue in the jaw when chewing
- Difficult facial movements
- Proximal muscles of the limbs:
- Difficulty climbing stairs
- Difficulty standing from a seat
- Difficulty raising hands above
- Respiratory muscles:
- Dyspnoea
- Respiratory failure
Symptoms of myasthenia gravis are exacerbated by:
- Infection
- Surgery and anaesthesia
- Pregnancy
- Medications
- Antibiotics - such as fluoroquinolones, aminoglycosides, macrolides.
- Cardiovascular drugs - such as anti-arrhythmics.
- Psychiatric drugs - such as chlorpromazine, risperidone, lithium.
🔍 Investigations
We can perform some physical examination tests to identify signs and symptoms of MG. Patients then need to have further investigations to confirm the diagnosis:
Physical examination:
- Eliciting fatiguability - there are a few ways to elicit fatiguability in the muscles:
- Repeated blinking - will exacerbate ptosis.
- Prolonged upward gazing - will exacerbate diplopia.
- Repeated abduction of one arm 20 times - will result in unilateral weakness when comparing both sides.
- ⭐️ Normal deep tendon reflexes - such as biceps, triceps, jaw jerk, knee jerk, ankle jerk, etc. This is key to differentiate it from the paraneoplastic LEMS in which tendon reflexes are reduced, but improved after a period of muscle contraction (post-tetanic potentiation).
- ⭐️ Asymmetrical ocular weakness (ptosis)
- Ice-pack test - an ice pack placed on the affected eyelid for 5 minutes improves ptosis by ≥2 mm. It has a specificity of over 90%.
Investigations:
- 🥇 🏆 Antibodies to acetylcholine receptors (AChR-Ab) - positive in around 85-90% of patients.
- Seropositive MG refers to MG cases that have positive assays for antibodies against AChR(AChR-Ab).
- Seronegative MG refers to MG cases that are negative for AChR-Ab, but may have positive assays for MuSK antibodies or LRP4 antibodies.
- CT thorax - to exclude thymoma, in all patients with confirmed MG.
- Single fibre electromyography - if the patient is negative for autoantibodies. Measures the electrical activity from the muscle fibres.
- Tensilon test - Tensilon is a drug also known as edrophonium. IV edrophonium or neostigmine are acetylcholine esterase inhibitors. So, in MG, they reduce muscle weakness temporarily so they can be helpful in aiding diagnosis if still uncertain. Not commonly used any more due to the risk of cardiac arrhythmias.
🚨 In a myasthenic crisis, serial pulmonary function tests (spirometry) are performed. If the FVC is ≤15 mL/kg, the patient should be considered for mechanical ventilation.
🧰 Management
We will discuss the long-term management of myasthenia gravis and then look at the acute management of a myasthenic crisis
- 🥇 Long-acting acetylcholinesterase inhibitors - pyridostigmine is the preferred option for first-line treatment.
- 🥈 Immunosuppression - usually not started at diagnosis, but the majority of patients eventually require it in addition to long-acting acetylcholinesterase inhibitors:
- 🥇 Prednisolone
- 🥈 Azathioprine, cyclosporin, mycophenolate mofetil may also be used
- Thymectomy in patients who have thymic hyperplasia or thymoma
Myasthenic crisis is a potentially life-threatening complication of myasthenia gravis. It causes an acute worsening of symptoms, often triggered by another illness, such as a respiratory tract infection. Respiratory muscle weakness can lead to respiratory failure.
Aspects of management include:
- Early intubation or non-invasive ventilation - if there is risk of respiratory failure.
- High-dose prednisolone
- Plasmapheresis or intravenous immunoglobulins (IVIG)
🚨 Complications
- Acute respiratory failure
- Aspiration pneumonia and impaired swallowing