Myaesthenia Gravis

Question 1

Pathophysiology

Answer 1

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.

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).

Question 2

Clinical Features

Answer 2

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) particularly on sustained upgaze
• Weakness in facial movements
• Difficulty with swallowing
• Fatigue in the jaw when chewing
• Slurred speech
• Progressive weakness with repetitive movements

Question 3

Who tends to be affected with myasthenia gravis?

What other condition is associated with myasthenia?

Answer 3

Typical patients are either a woman under the age of 40 or a man over the age of 60.

There is a strong link between thymoma (tumours of the thymus gland) and myasthenia gravis

Question 4

What to examine in a patient with myasthenia gravis?

What else should you keep in mind?

Answer 4

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 5

Diagnosis

Answer 5

Diagnosis can be made testing directly for the relevant antibodies:

• Acetylcholine receptor (ACh-R) antibodies (85% of patients)
• Muscle-specific kinase (MuSK) antibodies (10% of patients)
• LRP4 (low-density lipoprotein receptor-related protein 4) antibodies (less than 5%)

A CT or MRI of the thymus gland is used to look for a thymoma.

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

Question 6

What is the edrophonium test?

Answer 6

Patients are given an IV dose of edrophonium chloride (or neostigmine).

Edrophonium block acetylcholinesterase 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 7

Management

Answer 7

• 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
• Thymectomy can improve symptoms even in patients without a thymoma
• Monoclonal antibodies:
  i) 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.
  ii) Eculizumab is a monoclonal antibody that targets complement protein C5. This could potentially prevent the complement activation and destruction of acetylcholine receptors.

Question 8

Myaesthenic Crisis

What is it?

What triggers it?

Management

Answer 8

Myasthenic crisis is a severe complication of myasthenia gravis. It can be life threatening. It causes an acute worsening of symptoms.

Triggered by another illness such as a respiratory tract infection. This can lead to respiratory failure as a result of weakness in the muscle of respiration.

MANAGEMENT

• Patients may require NIV with BiPAP or full intubation and ventilation.
• Medical treatment is with immunomodulatory therapies such as IV immunoglobulins and plasma exchange.