Myasthenia Gravis

Introduction
• It is a disorder of neuromuscular haratris by :
• Weakness san fatigue of some of all muscle group
• Weakness worsening on sustain or repeated exertion or towards the end of
the day, relive by rest.
• This condition is a consequence of an autoimmune destruction of the
NICOTINIC POSTSYNAPTIC RECEPTORS FOR ACETYLCHOLINE.
• Myasthenia gravis is rare, with a prevalence of 5 per 100 000. The
increased incidence of autoimmune disorders in patients and first degree
relatives and the association of the disease with certain histocompatibility
antigens (HLA)-B, B, and DR, - suggests an IMMUNOLOGICAL BASIS.
AETIOLOGY
• Antibodies bind to the receptor sites resulting in their destruction
(complement mediated).These antibodies are referred to as
ACETYLCHOLINE RECEPTOR ANTIBODIES. (AChR antibodies) and are
demonstrated by radioimmunoassay in the serum of 90% of patients.
• Human purified IgG (containing AChR antibodies) injected into mice
induces myasthenia-like disease in these recipient animals.
• In human myasthenia gravis a reduction of acetylcholine receptor
sites has been demonstrated in the postsynaptic folds. Reduced
receptor synthesis and increased receptor destruction, as well as the
blocking of receptor response to acetylcholine, all seem responsible
for the disorder.
• The role of the thymus: Thymic abnormalities occur in 80% of
patients. The main function of the thymus is to effect the production
of T-cell lymphocytes, which participate in immune responses.
Thymus dysfunction is noted in a large number of disorders which
may be associated with myasthenia gravis, c.g. systemic lupus
erythematosus
Muscle biopsy- may show abnormalities :
• Lymphocytic infiltration associated with small necrotic foci of muscle
fibre damage.
• Muscle fibre atrophy (type I and II or type II alone).
• Diffuse muscle necrosis with inflammatory infiltration (when associated
with thymoma).
Motor point biopsy-
• May show abnormal motor endplates.
• Supravital methylene blue staining reveals abnormally long and
irregular terminal nerve branching.
• Light and electron microscopy show destruction of ACh receptors with
simplification ofthe secondary folds of the postsynaptic surface.
 CLINICAL FEATURES
• Up to 90% of patients present in early adult life (<40 years of age).
Female: male ratio 2:1.The disorder may be selective, involving specific
groups of muscles.
Several clinical subdivisions are recognised:
• Class 1- ocular muscles only - 20%
• Class 2- Mild generalised weakness.
• Class 3 Moderate generalised and mild to moderate ocular-bulbar
weakness.
• Class 4-Severe generalised and ocular-bulbar weakness.
• Class 5- Myasthenic crises
• Approximately 40% of class I will eventually become widespread. The rest
remain purely ocular throughout the illness. Respiratory muscle
involvement accompanies severe illness.
Cranial nerve signs and symptoms-
• Ocular involvement produces ptosis and muscle paresis.
• Weakness of jaw muscles allows the mouth to hang open.
• Weakness of facial muscles results in expressionless appearance.
Bulbar involvement may result in:
• dysarthric dysphonic speech and dysphagia.
• nasal regurgitation of fluids-nasal quality to speech.
• The tongue occasionally shows the characteristic triple grooved appearance
with two lateral and one central furrow.
Limb and trunk signs and symptoms-
• Weakness of neck muscles may result in lolling of the head. Proximal limb
muscles are preferentially affected. Fatigue may be demonstrated by
movement against a constant resistance.
• Muscle wasting occurs in 15% of cases, Stress, infection and pregnancy and
drugs that alter neuromuscular transmission all exacerbate the weakness.
• Limb reflexes are often hyperactive and fatigue on repeated testing.
Natural history: 10% of patients entered a period of remission of long
duration.(Before treatment became available)
• 20% experienced short periods of remission (1 to several months).
• 30% progressed to death. The remainder showed varying degrees of
disability accentuated by exercise.
INVESTIGATION
PHARMACOLOGICAL
• Anticholinesterase drugs are used to confirm diagnosis.Tensilon
(edrophonium) - shortaction, 2-4 minutes, given i.v. 2-10 mg slowly,
with atropine available to counter muscarinic side effects (nausea and
bradycardia). This is positive when noticeable improvement in
weakness occurs on objective testing. A control injection of saline is
useful, especially when assessing limb weakness only. The Tensilon
test may be negative in ocular myasthenia and give a false positive in
the Lambert-Eaton syndrome
SEROLOGICAL
• Acetylcholine receptor antibodies are detected in 90% of patients and
are virtually specific to this disease. In ocular myasthenia, only 60%
show antibodies. Magnitude of titres correlates with disease severity.
• Other antibodies e.g. microsomal, colloid, rheumatoid factor, gastric
parietal cell antibody- are occasionally found. These reflect the
overlap between myasthenia gravis and other autoimmune disorders.
• Anti striated muscle antibodies are found in 30% of all patients and in
90% of those with thymoma.
ELECTROPHYSIOLOGICAL
• Reduction of the amplitude of the compound muscle action potential
evoked by repetitive supramaximal nerve stimulation - 'the
decrementing response'.
• Various rates of stimulation;even as low as 3/second may produce
adecrementing response.
• Single fibre electromyography-measure of "Jitter- the time interval
variability of action potentials from two single muscle fibres of the
same motor unit- is a more sensitive index of neuromuscular function
and is increased (95% of mild cases are abnormal).
ADDITIONAL
• Chest X ray will show a large mediastinal mass but will not exclude a
small thymoma. CT of chest should be performed in all newly
diagnosed cases.
Treatment
EMERGENCY TREATMENT
MYASTHENIC/CHOLINERGIC CRISES
• Identify and treat precipitating cause, e.g. infection, drug interaction or overdose
• Sit patient at 45", clear airway, give nasal O, and if overt respiratory failure-
intubate and ventilate for as long as required.
Myasthenic crisis.
• IV neostigmine 8-12 mg/24 hrs-sc. atropine 0.5 mg tdsPrednisilone 100 mg daily-
Consider plasmapheresis or IVIG.
• Change IV to oral anticholinesterases when able to swallowCholinergic crisis.
• Withdraw all anticholinesterases
• Monitor respiratory function (vital capacity)Wean from ventilation when
appropriate - Re-introduce oral anti-cholinesterases inlow dose and gradually
increase.
NEONATAL form of myasthenia gravis:
• This develops in a number of infants of myasthenic mothers.- Suggested by
poor crying sucking and floppy limbs.
• Presents within 48 hours of birth and may persist until the end of 3rd
month.-Caused by passive transplacental passage of IgG (acetylcholine
receptor antibodies).
• Treatment with anticholinesterases is required until spontaneous recovery
occurs. Remission occurs following exchange transfusion.
• This disorder may occur in infants even when their mother has been in
remission for many years.
• CONGENITAL form of myasthenia gravis
• This usually commences in infancy and persists through adult life. Receptor
antibodies are not found and the disease may result from structural
abnormalities of the receptors themselves. (A number of such disorders
havebeen identified.) Thymectomy is contraindicated in this disorder.