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DISORDERS OF THE NEUROMUSCULAR JUNCTION
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness
and fatigability of skeletal muscles.
Etiology and pathology:
• The underlying defect is a decrease in the number of available acetylcholine
receptors (AChRs) at neuromuscular junctions due to an antibody-mediated
autoimmune attack.
• The disease is most commonly caused by autoantibodies to acetylcholine
receptors (anti-ACRs) in the post-synaptic membrane of the neuromuscular
junction. These antibodies block neuromuscular transmission and initiate a
complement-mediated inflammatory response.
• A minority of patients have other autoantibodies in particular autoantibodies
to a muscle-specific kinase (MuSK).
• About 15% of patients (mainly those with late onset) have a thymoma, and
the majority of the remainder has thymic follicular hyperplasia.
Muscle-like cells within the thymus (myoid cells), which bear AChRs on
their surface, may serve as a source of autoantigen and trigger the
autoimmune reaction within the thymus gland.
Clinical features:
• The disease usually presents between the ages of 15 and 50 years.
• Women affected more often than men in the younger age groups and the
reverse at older ages.
• The cardinal symptom is abnormal fatigable weakness of the muscles
particularly of the ocular, neck, facial and bulbar muscles.
The weakness
increases during repeated use and may improve following rest or sleep.
• Worsening of symptoms towards the end of the day or following exercise is
characteristic.
• The first symptoms are usually intermittent ptosis or diplopia.
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• Bulbar weakness may develop leading to difficulty in swallowing, nasal
regurgitation or aspiration of liquids or food.
• Weakness in chewing is most noticeable after prolonged effort, as in chewing
meat.
• Patient may be unable to undertake tasks above shoulder level, such as
combing the hair, without frequent rests.
• Respiratory muscles may be involved, and respiratory failure is not
uncommon cause of death.
• If weakness of respiration becomes so severe as to require respiratory
assistance, the patient is said to be in crisis (cholinergic or myasthenic crisis).
• Despite the muscle weakness, deep tendon reflexes are preserved.
There are
no sensory signs or signs of involvement of the central nervous system.
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Diagnosis and Evaluation
The suspected diagnosis should always be confirmed by
1-Pharmacological test
The intravenous injection of the short-acting anticholinesterase, edrophonium
bromide (2mg injected
with a further 8 mg given half a minute later, is a valuable
diagnostic aid (the Tensilon test).
Improvement in muscle power occurs within 30
seconds and usually persists for 2-3 minutes.
2-Electrophysiological test
EMG with repetitive stimulation may show the characteristic decremental
response.
3-Immunological test
Anti-acetylcholine receptor antibody (anti-ACRs) is found in over 80% of cases,
though less frequently in purely ocular myasthenia (50%). Anti-MuSK antibodies
are found especially in AChRA-negative patients.
• In addition to these investigations,
all patients should have a thoracic CT to
exclude thymoma, which may not be visible on plain X-ray examination.
• Screening for other autoimmune disorders, particularly thyroid disease, is
important.
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Management:
a- symptomatic
• The duration of action of acetylcholine at remaining receptors in the
neuromuscular junctions is greatly prolonged by inhibiting its hydrolysing
enzyme, acetylcholinesterase.
• The most commonly used anticholinesterase drug is pyridostigmine, which is
given orally in a dosage of 30-120 mg, usually 6-hourly.
• Muscarinic side-effects, including diarrhoea and colic, may be controlled by
propantheline (15 mg as required) or atropine.
b- Disease modifying therapy
1-Plasma exchange & Intravenous immunoglobulin are normally reserved for
myasthenic crisis or for pre-operative preparation.
2-Corticosteroid treatment can be extremely effective in improving myasthenic
weakness and establishing remission.
• Improvement is commonly preceded by marked exacerbation of myasthenic
symptoms and treatment should be initiated in hospital.
• It is usually necessary to continue treatment for months or years, often
resulting in adverse effects.
3-Other immunosuppressant treatment
• Include azathioprine, cyclosporine, tacrolimus and mycophenolate mofetil,
rituximab.
• Immunosuppressant treatment is of value if reducing the dosage of steroids
necessary and may allow steroids to be withdrawn.
4-surgical:
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• Thymectomy in the early stages of the disease leads to a much better overall
prognosis, whether a thymoma is present or not, in
any antibody-positive
patient under 45 years with symptoms not confined to extraocular muscles.
Prognosis:
• Remissions sometimes occur spontaneously.
• When myasthenia is confined to the eye muscles, the prognosis is excellent
and disability slight.
• Young female patients with generalised disease have high remission rates after
thymectomy.
Lambert-Eaton myasthenic syndrome (LEMS)
• N-M transmition is impaired, often in association with antibodies to pre-
synaptic voltage-gated calcium channels.
• It is characterized by muscle weakness which improves after exercise.
• Patients may have autonomic dysfunction (and a dry mouth).
• The cardinal clinical sign is absence of tendon reflexes, which can return
immediately after sustained contraction of the relevant muscle.
• The condition is associated with underlying malignancy, especially
bronchogenic carcinoma, in a high percentage of cases, and investigation
must be directed towards detecting such a cause.