Myasthenia Gravis

Question 1

What is myasthenia gravis (MG)?

Answer 1

Myasthenia gravis (MG) is a chronic autoimmune disorder of the post-synaptic membrane at the neuromuscular junction in skeletal muscle.

Circulating antibodies against the nicotinic acetylcholine receptor (AChR) or associated proteins impair neuromuscular transmission

Question 2

Briefly describe the characteristics of MG

Answer 2

MG is characterised by muscle weakness that increases with exercise (fatigue) and improves on rest. It commonly presents with drooping eyelids, double vision, oropharyngeal and/or appendicular weakness, and shortness of breath.

Question 3

At what age does MG affect women and men?

Answer 3

Interestingly myasthenia gravis affects men and women at different ages. Typical patients are either a woman under the age of 40 or a man over the age of 60.

Question 4

Briefly describe post-synaptic membranes

Answer 4

Motor nerves communicate with muscles at neuromuscular junctions. At the neuromuscular junction, axons of motor nerves are situated across a synapse from the post-synaptic membrane on the muscle cell. The axons release a neurotransmitter from the pre-synaptic membrane. The neurotransmitter at these junctions is called acetylcholine. This acetylcholine travels across the synapse and attached to receptors on the post-synaptic membrane. They stimulate the receptors, and this signal leads to muscle contraction.

Question 5

Briefly describe the pathophysiology of MG

Answer 5

In around 85% of patients with myasthenia gravis, acetylcholine receptor antibodies are produced by the immune system. These bind to the postsynaptic neuromuscular junction receptors. This blocks the receptor and prevents the acetylcholine from being able to stimulate the receptor and trigger muscle contraction. As the receptors are used more during muscle activity, more of them become blocked up. This leads to less effective stimulation of the muscle with increased activity. There is more muscle weakness the more the muscles are used. This improves with rest as more receptors are freed up for use again.

These antibodies also activate the complement system within the neuromuscular junction, leading to damage to cells at the postsynaptic membrane. This further worsens the symptoms.

There are two other antibodies that cause the other 15% of cases of myasthenia gravis. These are antibodies against muscle-specific kinase (MuSK) and antibodies against low-density lipoprotein receptor-related protein 4 (LRP4). MuSK and LRP4 and important proteins for the creation and organisation of the acetylcholine receptor. Destruction of these proteins by autoantibodies leads inadequate acetylcholine receptors. This causes the symptoms of myasthenia gravis.

Question 6

What is the most common antibodies causing MG?

Answer 6

About 80% to 90% of MG patients have detectable antibodies against the nicotinic acetylcholine receptor (AChR) on the post-synaptic muscle membrane at the NMJ.

Question 7

Identify the 3 types of antibodies causing MG

Answer 7

1. Antibodies against the nicotinic acetylcholine receptor (AChR)
2. Antibodies directed against muscle-specific tyrosine kinase (MuSK)
3. Antibodies against low-density lipoprotein receptor-related protein 4 (LRP4)

Question 8

What is the function of MuSK and LRP4?

Why do antibodies against these lead to MG?

Answer 8

MuSK and LRP4 and important proteins for the creation and organisation of the acetylcholine receptor. Destruction of these proteins by autoantibodies leads inadequate acetylcholine receptors. This causes the symptoms of myasthenia gravis.

Question 9

How is the thymus linked to MG?

Answer 9

There is a strong link between thymoma (tumours of the thymus gland) and myasthenia gravis. 10-20% of patients with myasthenia gravis have a thymoma. 20-40% of patients with a thymoma develop myasthenia gravis.

Virtually all patients with MG and thymoma have AChR antibodies.

Question 10

How do AChR antibodies lead to the symptoms of MG?

Answer 10

In MG characterised by acetylcholine receptor (AChR) antibodies, an autoimmune attack against AChRs results in destruction of the post-synaptic membrane. The reduced number of available binding sites for acetylcholine leads to inconsistent generation of muscle fibre action potentials, which manifests as skeletal muscle weakness.

Question 11

What are the risk factors for MG?

Answer 11

• Family history of autoimmune disorders
• Genetic markers
• Cancer-targeted therapy

Question 12

What are the clinical features of MG?

Answer 12

The characteristic feature is weakness that gets worse with muscle use and improves with rest. Symptoms are typically minimal in the morning and worst at the end of the day.

The symptoms most affect the proximal muscles and small muscles of the head and neck. It leads to:

• Extraocular muscle weakness causing double vision (diplopia)
• Eyelid weakness causing drooping of the eyelids (ptosis)
• Weakness in facial movements
• Difficulty with swallowing
• Fatigue in the jaw when chewing
• Slurred speech
• Progressive weakness with repetitive movements

Question 13

What can be found on examination of a patient with MG?

Answer 13

There are a few ways to elicit fatiguability in the muscles:

• Repeated blinking will exacerbate ptosis
• Prolonged upward gazing will exacerbate diplopia on further eye movement testing
• Repeated abduction of one arm 20 times will result in unilateral weakness when comparing both sides

Check for a thymectomy scar.

Test the forced vital capacity (FVC).

Question 14

What investigations should be ordered for MG?

Answer 14

• ACh-R antibodies
• MuSK antibodies
• LRP4 antibodies
• Serial pulmonary function tests
• CT chest
• Edrophonium test
  
  • If the diagnosis is in doubt

Question 15

Why investigate using serial pulmonary function tests?

Answer 15

Indicated for patients with shortness of breath and suspected myasthenic crisis.

Serial measurements of forced vital capacity (FVC) and negative inspiratory force (NIF) are taken.

Question 16

What happens to serial pulmonary function tests in a myasthenic crisis?

Note: FBV and NIF

Answer 16

Myasthenic crisis: low FVC and low NIF.

Question 17

Why investigate using chest CT?

Answer 17

Should be performed in all newly diagnosed patients with adult onset MG to detect thymoma (which occurs in about 15% of patients with MG) or thymic hyperplasia (which occurs in 75% of MG patients).

Question 18

Briefly describe the edrophonium test

Answer 18

The edrophonium test can be helpful where there is doubt about the diagnosis.

Patients are given an IV dose of edrophonium chloride (or neostigmine). Normally, cholinesterase enzymes in the neuromuscular junction break down acetylcholine. Edrophonium block these enzymes and stop the breakdown of acetylcholine. As a result the level of acetylcholine at the neuromuscular junction increases. It briefly and temporarily relieves the weakness. This establishes a diagnosis of myasthenia gravis.

Question 19

Briefly describe the treatment of MG

Answer 19

Reversible acetylcholinesterase inhibitors (usually pyridostigmine or neostigmine) increases the amount of acetylcholine in the neuromuscular junction and improve symptoms.

Immunosuppression (e.g. prednisolone or azathioprine) suppresses the production of antibodies.

Question 20

What is the role of monoclonal antibodies in treating MG?

Answer 20

Rituximab is a monoclonal antibody that targets B cells and reduces the production of antibodies. It is available on the NHS if standard treatment is not effective and certain criteria are met.

Eculizumab is a monoclonal antibody that targets complement protein C5. This could potentially prevent the complement activation and destruction of acetylcholine receptors. There is ongoing research and debate about whether the evidence is strong enough to offer it on the NHS. It is currently not recommended by NICE.

Question 21

What is the role of thymectomy in treating MG?

Answer 21

Thymectomy has been found to be effective in MG patients without thymoma.

Benefit of thymectomy is rarely seen within 6 months, and follow-up of up to 2 to 5 years is required to establish efficacy.

Question 22

What is the role of plasma exchange and intravenous immunoglobulin in treating MG?

Answer 22

Plasma exchange can be used for short-term management in patients undergoing thymectomy in order to avoid peri-operative corticosteroids or other immunosuppressive drugs.

Plasma exchange or intravenous immunoglubulin (IVIG) may also prove useful to maintain remission in patients where MG is otherwise not well controlled. Each can be done intermittently as an outpatient treatment.

Question 23

What are the complications of MG?

Answer 23

• Pyridostigmine-induced adverse reactions
• Respiratory failure
• Impaired swallowing
• Acute aspiration
• Secondary pneumonia

Question 24

What differentials should be considered for MG?

Answer 24

• Lambert-Eaton myasthenic syndrome (LEMS)
• Botulinism
• Primary myopathies