Dr Ira Shah
M.D, DNB, DCH(Gold Medalist), FCPS

A 13-year-old male child had presented to the orthopedic department with frequent falls since 3 months. He was found to have generalized hypotonia for which he underwent iliotibial tightening. He had delayed recovery from general anesthesia (succinyl choline) following surgery and required ventilation for 4 ½ hours for the same. He was referred for the same complaints to us.

On examination, he was found to have bilateral ptosis, which was present since birth. There was no increase in ptosis or diplopia or other muscle weakness in time or space. There was no similar history in the family. His muscle tone was normal and power was 5/5. His deep tendon reflexes were exaggerated with no decrease on repetitive stimulation. He had joint laxity and had Marfanoid features. However, his arm span was 145 cm with height being 143cm. His metacarpal index was 5 and 2 D Echo was normal thus ruling out Marfan’s syndrome. In view of the bilateral ptosis and delayed recovery post anesthesia, myasthenia gravis was suspected. His EMG on repetitive stimulation showed evidence of electrodecremental activities in orbicularis oculi muscles. Other muscles did not show these electrodecremental responses suggestive of myasthenia gravis. A diagnostic test with IM Neostigmine (1.5mg) was done which showed marked improvement in the ptosis confirming the diagnosis of Myasthenia gravis. His Acetylcholine receptor antibodies (AchR) were absent. His X ray chest showed no increase in the size of the thyroid gland. In view of ptosis since birth and absent AchR a diagnosis of Congenital Myasthenia Gravis was made. He was treated symptomatically with oral Neostigmine (0.01mg/kg titrated to patient response).

Myasthenia Gravis is the commonest neuromuscular transmission disorder.

Congenital myasthenia Gravis - It is seen in children with myasthenia born to mothers without the disease. AchR antibodies are undetectable. Clinical symptoms are heterogeneous. Fetal movements are decreased and newborns have feeding difficulties, ptosis, ophthalmoplegia and a weak cry. The disease is usually protracted with mild symptoms that are refractory to both medical and surgical therapy (thymectomy) though few may undergo spontaneous remission. Treatment of congenital myasthenia is solely symptomatic with anticholinesterase agents.

Juvenile Myasthenia Gravis - Juvenile Myasthenia Gravis is usually caused due to acquired immunological abnormality but some cases may be congenital in origin. The age of onset is in the 2nd decade. It is more common in females as compared to males. Ocular motor disturbances, ptosis or diplopia are the initial symptoms in 2/3rd of the patients. Specific muscle weakness is present. Other muscles involved may lead to oropharyngeal muscle weakness, difficulty in chewing, swallowing or talking. Only 10% of the patients present with limb weakness. The muscle weakness is least in the morning and worsens as the day progresses. Despite hypotonia, the tendon jerks are normal or brisk & disappear after repeat elicitation. The disease is usually progressive and only 10 % of cases have disease limited only to the ocular muscles. Spontaneous improvement occurs in 1/3 rd of the patients. Factors that worsen myasthenic symptoms are emotional upset, systemic viral diseases, thyroid disorders, fever and drugs affecting neuromuscular transmission.

Pathogenesis- In myasthenia gravis, the concentration of acetylcholine receptors on the muscle end plate membrane is reduced and antibodies are attached to the membrane. Ach is released normally but its effect on post- synaptic membrane is reduced.

Role of thymus- 10% of patients have thymic tumor and 70% have hyperplastic changes. Thymic abnormalities cause the breakdown in tolerance that causes an immune - mediated attack on Ach receptors. Patients with thymoma usually have more severe disease.

1. Edrophonium Chloride/ Neostigmine test: Intravenous edrophonium chloride (5mg) or intramuscular neostigmine (0.02-0.04 mg/kg) leads to improvement in the weakness. IM neostigmine is useful in infants and children whose response to edrophonium may be too brief for observation.
   
   
2. Antibodies Against Acetyl Choline Receptor (AchR): An elevated concentration of Ach binding antibodies in a patient with compatible clinical features confirms the diagnosis of myasthenia gravis but normal levels do not exclude the diagnosis. When AchR antibodies are absent, it is necessary to consider congenital myasthenic syndrome.
   
   
3. EMG: Repetitive Nerve Stimulation (RNS) - The amplitude of the 4th or 5th response to a train of low frequency nerve stimulation falls at least 10% from initial value in myasthenic patients.
   
   

Treatment of Juvenile MG is life long. Treatment is individualized according to the severity of the disease, the patient’s age and sex and the degree of functional impairment, only ocular myasthenia is treated with anticholinesterase drugs.

1. Cholinesterase Inhibitors: They retard the enzymatic hydrolysis of Ach at the cholinergic synapses so that Ach accumulates at the NM Junction and its effect is prolonged. Pyridostigmine bromide and Neostigmine bromide are the most frequently used agents. No fixed schedule suits all patients. The need for these inhibitors varies from day to day and different muscles respond differently. Certain muscles get stronger, others do not change and still others become weaker.
   Side effects - They result from Ach accumulation at muscarinic receptors on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscles. Loose motions, nausea, vomiting, abdominal cramps, increased bronchial and oral secretions occur. Symptoms of muscarinic over dosage indicate that nicotinic weakness is also occurring. Excessive over dosage results in myasthenic crisis characterized by severe generalized weakness and respiratory failure.
   
   
2. Corticosteroids : Patients with thymoma and AchR antibodies have best response to prednisolone. The most predictable response occurs when treatment is begun with 1.5-2 mg/kg/day. About 1/3rd of patients become weaker temporarily after starting prednisone within first 7-10 days. Improvement occurs in 6-8 weeks. The dose is then decreased according to the clinical response.
   
   
3. Thymectomy : It is indicated if symptoms recur after withdrawal of corticosteroids after 1 year of therapy or failure of steroids. Results are best in patients with high titers of circulating AchR antibodies and who are symptomatic for less than 2 years. Postoperative improvement is seen after weeks or months. Remission rate after thymectomy is 60%.
   
   
4. Immunosuppressive agents : Azathioprine reverses the symptoms in most patients but effect is delayed by 4 to 8 months. Patients who fail to respond to corticosteroids may respond to azathioprine. However symptoms recur 2 to3 months after the drug is discontinued. Cyclosporine and cyclophosphamide are used in steroid resistant MG.
   
   
5. Plasma exchange : It used as short-term therapy for patients with sudden worsening of myasthenic symptoms and as chronic intermittent treatment for patients refractory to all other treatments. Improvement lasts for weeks or months and has to be followed by thymectomy or immunosuppressive therapy.
   
   
6. Intravenous Immunoglobulin (IVIg) : Favorable response is seen with 2gm/kg IVIg infused over 2 to 5 days.
   
   

Last updated on 16-10-03