Myasthenia Gravis

Pathophysiology

Myasthenia Gravis is an autoimmune disorder of the neuromuscular junction. It is caused by the production of autoantibodies against components of the neuromuscular junction.

Epidemiology

Prevalence: 1 / 10,000

Age of onset: bimodal – 20s (F > M), 50s – 70s (M > F)

Associations: other autoimmune disease (Grave’s, RA, SLE), thymoma / thymic hyperplasia (85%)

Classic presenting complaint

People present with fatigable weakness – i.e. weakness that gets worse with exertion or as the day goes on – most commonly affecting the extraocular muscles, the neck, and the upper limbs.

Symptoms

The hallmark of Myasthenia is fatigable weakness of one or several muscle groups. The most common presentation is due to weakness of the head and neck muscles, particular those controlling eye movements and eyelid opening. The presentation depends on the muscle group/s affected:

  • Ocular weakness: diplopia, ptosis
  • Bulbar: dysphagia, dysphonia, dysarthria
  • Facial: abnormal facial expression
  • Limbs: proximal myopathy (arms > legs)
  • Neck extensors: head drop
  • Respiratory muscles: type 2 respiratory failure

If not treated, the symptoms of Myasthenia generally become progressively worse in terms of severity and frequency.

Acute flares of the disease may be precipitated by a number of medications, including:

  • Neuromuscular blockers: e.g. suxamethonium
  • Antibiotics: aminoglycosides and fluoroquinolones
  • Beta-blockers

On examination

On inspection:

  • Evidence of walking aids (MG can affect the lower limbs)
  • Facial expression: loss of normal expression, ‘myasthenic snarl’
  • Thymoma/thymectomy scar
  • Ptosis
  • Head drop

Face

  • Eye movements: the classic finding is a fatigable complex external ophthalmoplegia, i.e. weakness of multiple extraocular muscles worse on repeated testing / sustained gaze
  • Ptosis: fatigable ptosis
  • Speech: dysarthria, dysphonia
  • Bulbar weakness

Limbs

  • Fatigable proximal myopathy
  • Normal tone, reflexes, sensation, co-ordination

Diagnosis

Simple tests:

  • Ice pack test:
    • Principle: cold temperatures inhibit the activity of the enzyme acetylcholinesterase, which degrades ACh at the NMJ. This therefore potentiates neuromuscular transmission.
    • Method: an ice pack is placed over the eyelids for 2 minutes and the degree of ptosis is assessed after
  • Edrophonium / Tensilon test:
    • Principle: Edrophonium is a fast-acting inhibitor of the enzyme acetylcholinesterase (AChE). AChE degrades acetylcholine at the NMJ. Inhibition of AChE therefore enhances neuromuscular transmission.
    • Method: Edrophonium is given IV in boluses up to a max of 10mg. The degree of ptosis / extra-ocular weakness is assessed after.
    • Cautions: AChE inhibition also potentiates the effects of ACh at muscarinic synapses. Therefore serious side effects include bradycardia, heart block, bronchospasm. The test should be performed with adequate monitoring and a muscarinic antagonist – atropine – available.

Antibody testing:

  • Definitive confirmation of the diagnosis requires demonstration of a pathogenic antibody. The 2 most common antibody targets are the nicotinic ACh receptor (nAChR) and muscle-specific kinase (MUSK).
  • Around 10% of people with a clinical diagnosis of MG are seronegative for anti-nAChR and anti-MUSK antibodies.

Neurophysiology

  • Repetitive nerve stimulation:
    • Principle: repetitive stimulation of a motor nerve leads to a slight decrement in the number of ACh-containing vesicles released with each stimulus. The normal postsynaptic membrane has a very high concentration of nAChRs, and so has a ‘buffer’ – i.e. postsynaptic action potentials can be generated even in the face of rapid neuromuscular transmission. A reduction in the number of functional nAChRs at the postsynaptic membrane reduces this buffer and thus renders the postsynaptic membrane less effective at responding to high-frequency stimulation.
    • Method: a motor nerve is stimulated with several trains of 2 – 3 Hz stimuli. Recording electrodes placed on the innervated muscle record the compound muscle action potential. The patient is then asked to exercise the muscle, and the test is repeated.
    • A decrement of >10% in the CMAP is diagnostic. This is exaggerated after exercising the muscle.
  • Single-fibre EMG:
    • Principle: a reduction in the fidelity of neuromuscular transmission increases the probability that for any incoming presynaptic action potential, there will be a failure of postysynaptic action potential generation. The time lag between presynaptic action potential and postsynaptic action potential is therefore more ‘random’.
    • Method: a stimulating electrode is place on a single motor axon. Recording electrodes are placed in two separate muscle fibres innervated by that axon. The time lag (“jitter”) between the two postsynaptic action potentials is measured. The jitter reflects the degree of impairment of NMJ transmission.
  • CT/MRI thorax: required to exclude thymoma

Treatments

The management of Myasthenia involves symptomatic relief, long-term immunosuppression, and treatment of severe acute episodes.

Symptomatic relief: Acetylcholinesterase inhibitors

Mechanism: inhibition of AChE prevents degradation of ACh at the NMJ, potentiating neuromuscular transmission.

Examples: pyridostigmine, neostigmine

Adverse effects: these are largely due to increased activation of muscarinic acetylcholine receptors and include:

  • Cardiac: bradycardia, arrhythmia,
  • Resp: bronchospasm
  • GI: diarrhoea, cramp, hypersalivation

Immunomodulation

For people with disease refractory to symptomatic relief with an AChE inhibitor, long-term immunomodulating agents can be considered. These include steroids (as a short course to induce remission), azathioprine, mycophenolate, and cyclosporine.

Management of Myasthenic crisis

There are some people for whom rapid control of myasthenic symptoms is required. These include people who present in neuromuscular respiratory failure, and with rapidly progressive symptoms, and pre-operative patients with uncontrolled disease. The two options available for controlling symptoms over days are plasma exchange and IVIG.

Plasma exchange

  • Method:
    • whole blood is removed from the patient
    • this is centrifuged and the plasma is removed
    • the remainder of the blood is replaced
    • the plasma is replaced with albumin solution
  • Principle:
    • plasma contains the pathogenic antibodies in MG. Removal of these antibodies leads to rapid restoration of normal neuromuscular transmission in the short term.
  • Adverse effects
    • Hypotension: the procedure involves large fluid shifts
    • ‘Rebound’: symptoms can worsen in the weeks following plasma exchange

IVIG

  • Mechanism: IV immunoglobulin is a mixture of polyclonal immunoglobulins from large cohorts of donors. It is a useful immunosuppressant but its mechanism is controversial.
  • Adverse effects
    • Infusion reactions
    • Anaphylaxis
    • Acute kidney injury
    • Volume overload
    • Arterial thrombosis: CVA, MI, PE

Thymectomy

Surgical thymectomy is indicated in all MG patients under 60 with anti-AChR antibodies who do not have contra-indications to surgery. Even in the absence of an identified thymoma, thymectomy improved outcomes at 3 years.