NEUROMUSCULAR JUNCTION DISORDERS

Motor impulses from axonal terminals of peripheral nerves are transmitted to the muscles at motor end­plate, i.e. post synaptic muscle membrane, via release of acetylcholine. Acetylcholine activity in synaptic cleft depends on the amount of acetylcholine released from presynaptic terminals or the number of acetylcholine receptors on post-synaptic membrane.

Myasthenia gravis is an uncommon but important chronic disorder of myoneural junction, characterized by deficiency of acetylcholine receptors and presenting with easy fatigability of muscles.

Etiology: Acetylcholine receptor deficiency in myasthenia gravis is almost always acquired (autoimmune), with presence of acetylcholine receptor antibodies. Many cases are associated with thymoma or other autoimmune disorders, e.g. SLE, rheumatoid arthritis, Hashimoto thyroiditis, etc.

Transient neonatal myasthenia may occur in infants of myasthenic mothers due to transplacental transfer of anti-acetylcholine receptor antibodies, which usually resolves spontaneously in next 3-4 months.

Clinically, juvenile myasthenia gravis usually present after 10^th year of life with:

• Ptosis and diplopia due to extraocular muscle weak­ness (earliest manifestation, most prominent in evenings or after exertion),

• Rapid fatigue of muscles after sustained/repetitive activity, e.g. opening and closing of grip.

• Dysphagia, dysarthria and chewing difficulties in more severe cases.

Muscular weakness progresses in severity with increasing age, leading to recurrent aspirations, respi­ratory infections and ultimately, respiratory failure and death in untreated cases.

Some cases may present with intermittent acute exacerbations of muscle weakness, i.e.

Neonatal myasthenia in infants of myasthenic mothers may present at birth with generalized floppiness, decrea­sed spontaneous movements and feeding/respiratory difficulties, which improve gradually over few weeks. Diagnosis is confirmed with:

• Edrophonium (Tensilon) test: Administration of a short­acting cholinesterase inhibitor, e.g. IV edrophonium chloride (0.1-0.2 mg/kg; max 10 mg) leads to rapid improvement in weakness, e.g. ptosis, within few seconds though effect lasts for only 1-2 minutes.

Edrophonium test should not be done in young children due to the risk of arrhythmia and instead, neostigmine response test (IM 0.02-0.04 mg/kg) may be used, with maximum effect in 20-40 minutes.

• Characteristic nerve conduction studies showing decremental response on repetitive nerve stimulation, till the muscle becomes completely refractory; and

• Anti-acetylcholine receptor (AChR) antibodies in-50-60% of children and adolescent cases, (vs. in nearly all adult cases). Anti-muscle specific kinase (anti-MuSK) antibodies are present in ~40% of these sero-negative myasthenic children.

X-ray chest or CT of anterior mediastinum is indicated in all cases to exclude thymoma or thymic hyperplasia. Treatment may be divided into symptomatic treatment and specific immunosuppressive therapy in autoimmune myasthenia.

• Cholinesterase-inhibitors, e.g. pyridostigmine (PO 1-5 mg/kg q4-6hr) is the treatment of choice for symptomatic relief and should be given 30 minutes before feeding to improve swallowing.

• Immunosuppressive therapy is indicated in cases with high acetylcholine antibody titers, preferably with long-term steroids. Prednisolone must be started with lower dose (PO 1.5 mg/kg/dose on alternate day), which needs to be escalated weekly till desired response. Other immunosuppressive agents, e.g. Azathioprine, cyclophosphamide, cyclosporine or mycophenolaate may be used as steroid-sparing agents or in refractory cases.

• Other modalities, e.g. IV immunoglobulins, pulse methylprednisolone, plasmapheresis and thymectomy are usually reserved for refractory patients or those with myasthenic crisis.

• Transient neonatal myasthenia due to maternal disease does not benefit from immunosuppressive therapy and should be treated only with pyridostigmine.

• Avoidance of drugs with myoneural toxicity, e.g. aminoglycosides, #946;-blockers, chloroquine, phenytoin and neuromuscular anesthetics, which may precipitate myasthenic crisis.

Prognosis is good in treated cases and spontaneous remission is common after few months or years.

Other uncommon neuromuscular junction disorders are as follows:

Congenital myasthenic syndromes are very rare and present at birth or at least before 2 years of life as floppy infant with hypotonia, limb weakness, ptosis, feeding and respiratory difficulties. AChR antibodies are absent in these cases with no benefits with steroid or other immunosuppressive therapy

Acute transient myoneural disorders are caused by pre- synaptic blockade of acetylcholine release, usually seen in organophosphorus poisoning, snake-bite, botulism and tick paralysis and discussed elsewhere.

18.18.4