Myasthenia Gravis

Myasthenia Gravis

Definition: an autoimmune disease affecting the neuromuscular junction producing weakness of skeletal muscles

Aetiology/ risk factors:

-Mediated by autoantibodies against the nicotinic acetylcholine receptors (AChR), interfering with the neuromuscular transmission via depletion of working post-synaptic receptor sites.

Image result for neuromuscular junction myasthenia gravis

-Both B and T cells are implicated.

Associations:

< 50 years- women, other autoimmune diseases, thymic hyperplasia

> 50 years- men, thymic atrophy or thymic tumour (thymoma), rheumatoid arthritis, SLE

Breakdown in immune tolerance is thought to occur in the thymus. 75% have thymoma.

Epidemiology:

-Prevalence = 8-9/100,000

If < 50 years, commoner in women and if > 50 years, commoner in men.

Symptoms:

-increasing muscular fatigue, muscle weakness worsens with repetitive use or towards end of day

-muscle groups affected, in order: extra-ocular (diplopia = double vision; drooped eyelid)

                                                              bulbar (swallowing, chewing)- nasal food regurgitation

     face- facial weakness, smiling difficulty

     neck

     limb girdle

     trunk

Weakness worsened by: pregnancy, hypokalaemia, infection, over-treatment, change of climate, emotion, exercise, gentamicin, opiates, tetracycline, quinine, procainamide, beta blockers.

Signs:

-bilateral ptosis (drooping upper eyelid), may be asymmetrical

-diplopia (double vision), complex ophthalmoplegia (weakness of extra-ocular muscles)

-test for ocular fatigability- ask patient to sustain upward gaze for 1 min and watch for progressive ptosis

-Ptosis improves by > 2mm after ice application to the shut, affected lid for > 2min

-myasthenic snarl on smiling

Image result for myasthenic sneer

peek sign: after brief opposition to gentle sustained lid closure, the lids separate (peek) to show white sclerae

Image result for myasthenic peek sign

-On counting to 50, the voice fades, disturbed hypernasal speech (dysphonia- rare presentation)

-Reduced power of limbs after repeated use of muscles

-Tendon reflexes normal (synapses do not have time to be fatigued with such a brief muscle contraction)

Investigations:

Bloods- Creatine Kinase (exclude myopathies), TFT (associated autoimmune condition?)

Antibodies: anti-AChR antibodies raised in 90% (70% in ocular-confined MG).

                       MuSK antibodies (muscle specific tyrosine kinase- F:M ≈ 15:2)

Nerve conduction study: decremental response of the muscle action potential to repetitive nerve stimulation

Image result for nerve conduction study myasthenia gravis

MG = myasthenia gravis/ LES = Lambert-Eaton Syndrome

EMG- single fibre EMG may demonstrate jitter (variability in latency from stimulus to muscle potential) indicating fluctuation in neuromuscular contraction

CT thymus- thymus hyperplasia? thymoma?

-Also look for lung malignancy (Lambert-Eaton Syndrome)

Image result for ct thymus myasthenia gravis

Thymic hyperplasia in 41y women with MG

Other tests:

Tensilon test: short acting anticholinesterase e.g. EDROPHONIUM, causes rapid and transient improvement in clinical features.

 Less used due to dangers (bradycardia) and limited usefulness due to subjectivity.

Management:

Symptom control- anticholinesterase e.g. PYRIDOSTIGMINE (60-120mg PO, up to 6x/d, max 1.2g/d), neostigmine

-Blocking the cholinesterase enzyme that breaks down acetylcholine, increases the level of this neurotransmitter in the synapse so that there is more acetylcholine available to compete for its receptor binding sites with the blocking antibodies.

S/E- increased salivation, lacrimation, sweats, vomiting, miosis, diarrhoea, colic

Immunosuppression-

PREDNISOLONE for relapses, reducing dose on remission and giving osteoporosis prophylaxis. Low starting dose given, as weakness is a side effect.

-AZATHIOPRINE- may combine with steroids (2.5mg/kg/d). Monitor FBC and LFTs.

METHOTREXATE- may combine with steroids (weekly)

Thymectomy- consider removal of thymus if onset before 50 years old and disease not easily controlled by anticholinesterases. Thymomas also need to be removed to prevent local invasion.

-IV immunoglobulin (IV Ig) given daily for 5 days pre-op.

=Remission in 25% and worthwhile benefit in a further 50%.

Complications:

Myasthenic crisis- weakness of the respiratory muscles during a relapse → respiratory failure

-Monitor forced vital capacity

-Ventilatory support may be needed (intubation, ventilation), unlikely if vital capacity > 20mL/kg

-Treat with plasmapheresis (plasma exchange) or IV Ig

-Identify and treat trigger for relapse (e.g. infection, medications)

-Cholinergic crisis caused by excessive anticholinesterase = agitation, sweating, fever, flush, hypersalivation, pupillary miosis (constriction), muscle fasciculations, muscle weakness

-Foetal or neonatal myasthenia- caused by transplacental antibodies transfer

Prognosis:

-Relapsing or slow progression.

-Disease restricted to only ocular muscles has good outcome.

-Maximum extent of involvement in an individual patient usually manifests within the first 5-7 years, although disease may wax and wane in severity.

-If thymoma, 5 year survival is 68%.

Comparison to Lambert-Eaton myasthenic syndrome:

= paraneoplastic syndrome (can be autoimmune)

= caused by auto-antibodies against pre-synaptic calcium ion channels, impairing acetylcholine release

=gait difficulty before eye signs, autonomic involvement

= diplopia and involvement of respiratory muscles is rare

= muscle weakness improves after repeated use

= nerve conduction study shows incremental response of the muscle action potential to repetitive nerve stimulation

=Tensilon test shows less response to edrophonium

=Treatment: 3,4-diaminopyridine or IV Ig

References: Cheese & Onion, Rapid Medicine
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