Myasthenia Gravis



Myasthenia graves is an autoimmune condition that causes muscle weakness that gets progressively worse with activity and improves with rest.

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.

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.

Pathophysiology

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.

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.

 

Presentation

The severity of symptoms can vary dramatically between patients. They can be mild and subtle or life threateningly severe. 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

Examination

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).

Diagnosis

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.

 

Edrophonium Test

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.

 

Treatment options

  • 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

  • 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.

 

Myasthenic Crisis

Myasthenic crisis is a severe complication of myasthenia gravis. It can be life threatening. It causes an acute worsening of symptoms, often 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. Patients may require non-invasive ventilation with BiPAP or full intubation and ventilation.

Medical treatment of myasthenic crisis is with immunomodulatory therapies such as IV immunoglobulins and plasma exchange.

Last updated April 2019
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