Pediatric Annals

Myasthenia Gravis

Gerald M Fenichel, MD

Abstract

Myasthenia gravis comprises a group of disorders characterized clinically by easy fatigability or fixed weakness of muscles in a child or adult. The pathophysiology of the condition relates to a disturbance in neuromuscular transmission at the myoneural junction (motor endplate) of skeletal muscle (Figure). A classification of myasthénie syndromes in children has been recently described,1 which categorizes the disorders into genetic and acquired forms (Table 1). The onset of symptoms in genetic myasthenia typically occurs in the newborn period or during infancy, whereas acquired myasthenia usually has an onset in childhood.

ACQUIRED MYASTHENIA GRAVIS

Acquired myasthenia gravis is divided into those types in which circulating antibodies directed against the acetylcholine receptor (AChR) of the motor endplate are detectable and those forms in which circulating antibodies are not present. Antibodies, when present, bind to the receptor protein and prevent acetylcholine (ACh) from properly depolarizing the motor endplate oí muscle. As a rule, increased concentrations of AChR antibody are associated with generalized myasthenia, while low or nondetectable concentrations are associated with ocular myasthenia.

Juvenile Myasthenia Gravis

Juvenile myasthenia denotes myasthenia gravis in children, but since the acquired form of myasthenia in children is not different from myasthenia gravis in adults, the term should not suggest a separate disease. Among children with antibody-positive myasthenia, some exhibit generalized symptoms while others have only ocular involvement. Generally, children with high concentrations of antibody have more generalized disease than those with low concentrations, although exceptions do occur.

The onset of symptoms in juvenile myasthenia appears after 6 months of age, and 75% of children first become symptomatic after 10 years. Girls are more often affected than boys. Prominent features of both the ocular and generalized forms include ptosis and diplopia. Pupillary function is always preserved. Oculomotor weakness is not constant initially hut changes trom examination to examination. Both eyes are usually affected but not to the same degree.

Forty percent to 50'>u ot affected patients also demonstrate weakness ot hulbar muscles (dysfunction of chewing and swallowing) as well as weakness, usually symmetrical, ot the neck, trunk, or extremities. As in adults, children tend to be strongest in the morning, with increasing fatigue and weakness in the afternoon and evening hours. Patients with generalized myasthenia will experience diffuse weakness within one year ot the initial ocular symptoms. Dysarthna, dysphagia, difficulty chewing, and limb muscle tarigahility are observed. As many as 40% of patients will ultimately experience respiratory insufficiency (myasthénie crisis) it not adequately treated.

Antibody-positive juvenile mysasthenia gravis is associated with an increased incidence ot other autoimmune disorders, especially thyroiditis and collagen vascular disease.

Diagnostic Studies - Several diagnostic studies are available to confirm or deny the presence of myasthenia gravis (Table 2). Of these procedures, the intravenous injection of edrophonium chloride is the routine first step in diagnosis. Edrophonium chloride is an acetylcholinesterase inhibitor, which prevents the rapid breakdown of ACh at the rnyoneural junction. Its pharmacologie effect of improving muscle strength is dramatic hut transient. Before injecting the drug, it is important to determine the endpoint for the test procedure. The best result is the resolution of ptosis or the restoration of ocular motility. Ptosis generally responds better to edrophonium chloride than does oculomotor paralysis. Improvement in appendicular strength is more difficult to evaluate.2

The usual intravenous dose of edrophonium chloride in children is 0.15 mg/kg body weight, not to exceed 10 mg/dose. A test dose or one tenth the total dose initially is administered to identity the occasional patient who is hypersensitive to the drug with the appearance of muscular fasciculations and respiratory depression. Atropine (O.I to 0.4 mg intravenously) is an effective antedote…

Myasthenia gravis comprises a group of disorders characterized clinically by easy fatigability or fixed weakness of muscles in a child or adult. The pathophysiology of the condition relates to a disturbance in neuromuscular transmission at the myoneural junction (motor endplate) of skeletal muscle (Figure). A classification of myasthénie syndromes in children has been recently described,1 which categorizes the disorders into genetic and acquired forms (Table 1). The onset of symptoms in genetic myasthenia typically occurs in the newborn period or during infancy, whereas acquired myasthenia usually has an onset in childhood.

ACQUIRED MYASTHENIA GRAVIS

Acquired myasthenia gravis is divided into those types in which circulating antibodies directed against the acetylcholine receptor (AChR) of the motor endplate are detectable and those forms in which circulating antibodies are not present. Antibodies, when present, bind to the receptor protein and prevent acetylcholine (ACh) from properly depolarizing the motor endplate oí muscle. As a rule, increased concentrations of AChR antibody are associated with generalized myasthenia, while low or nondetectable concentrations are associated with ocular myasthenia.

Juvenile Myasthenia Gravis

Juvenile myasthenia denotes myasthenia gravis in children, but since the acquired form of myasthenia in children is not different from myasthenia gravis in adults, the term should not suggest a separate disease. Among children with antibody-positive myasthenia, some exhibit generalized symptoms while others have only ocular involvement. Generally, children with high concentrations of antibody have more generalized disease than those with low concentrations, although exceptions do occur.

The onset of symptoms in juvenile myasthenia appears after 6 months of age, and 75% of children first become symptomatic after 10 years. Girls are more often affected than boys. Prominent features of both the ocular and generalized forms include ptosis and diplopia. Pupillary function is always preserved. Oculomotor weakness is not constant initially hut changes trom examination to examination. Both eyes are usually affected but not to the same degree.

Forty percent to 50'>u ot affected patients also demonstrate weakness ot hulbar muscles (dysfunction of chewing and swallowing) as well as weakness, usually symmetrical, ot the neck, trunk, or extremities. As in adults, children tend to be strongest in the morning, with increasing fatigue and weakness in the afternoon and evening hours. Patients with generalized myasthenia will experience diffuse weakness within one year ot the initial ocular symptoms. Dysarthna, dysphagia, difficulty chewing, and limb muscle tarigahility are observed. As many as 40% of patients will ultimately experience respiratory insufficiency (myasthénie crisis) it not adequately treated.

Antibody-positive juvenile mysasthenia gravis is associated with an increased incidence ot other autoimmune disorders, especially thyroiditis and collagen vascular disease.

Diagnostic Studies - Several diagnostic studies are available to confirm or deny the presence of myasthenia gravis (Table 2). Of these procedures, the intravenous injection of edrophonium chloride is the routine first step in diagnosis. Edrophonium chloride is an acetylcholinesterase inhibitor, which prevents the rapid breakdown of ACh at the rnyoneural junction. Its pharmacologie effect of improving muscle strength is dramatic hut transient. Before injecting the drug, it is important to determine the endpoint for the test procedure. The best result is the resolution of ptosis or the restoration of ocular motility. Ptosis generally responds better to edrophonium chloride than does oculomotor paralysis. Improvement in appendicular strength is more difficult to evaluate.2

Figure. The neuromuicular junction. Vesicles containing acetylcholine (ACh) dre released from the nerve terminal and bind to the receptor in the skeletal muscle

Figure. The neuromuicular junction. Vesicles containing acetylcholine (ACh) dre released from the nerve terminal and bind to the receptor in the skeletal muscle

Table

TABLE 1Myasthenie Syndromes in Children

TABLE 1

Myasthenie Syndromes in Children

Table

TABLE 2Diagnostic Procedures in Myasthenie Gravis

TABLE 2

Diagnostic Procedures in Myasthenie Gravis

Table

TABLE 3Management of Myasthenla Gravis

TABLE 3

Management of Myasthenla Gravis

The usual intravenous dose of edrophonium chloride in children is 0.15 mg/kg body weight, not to exceed 10 mg/dose. A test dose or one tenth the total dose initially is administered to identity the occasional patient who is hypersensitive to the drug with the appearance of muscular fasciculations and respiratory depression. Atropine (O.I to 0.4 mg intravenously) is an effective antedote tor the muscurinic side effects of edrophonium chloride, but is of no value in counteracting the nicotinic effect on the motor endplate that might result in secondary partial paralysis of skeletal muscles.

An additional diagnostic procedure for rnyasthenia gravis is the rapid electrical stimulation of a peripheral motor nerve, which produces a décrémentai response in all patients with generalized myasthenia and in 17% of patients with ocular myasthenia. * Typically, the ulnar nerve is stimulated repetitively at frequencies which range from 5 to 50 per second.

Antibody titers against AChR and striated muscle should be determined in all patients with suspected myasthenia gravis. Individuals, usually adults, who harbor a thy moma typically exhibit exceptionally high concentrations of antibody against both the receptor and muscle. As mentioned previously, concentrations of the antibodies are higher generally in individuals with generalized myasthenia than in those with the ocular form.

Management - Management of a child with juvenile myasthenia is medical, surgical, or a combination of the two strategies (Table 3). Children with generalized myasthenia and concentrations of AChR antibody greater than 10 nniol should be considered tor thymectomy upon diagnosis of the disease, with rationale for this surgical procedure relating to the presumed origin of antibodies from t hymns-derived lymphocytes. The majority of children (61%) undergoing thymectomy will experience remission of their symptoms within three years of surgery if performed early in the course of the disease.4 Glucocorricosteroids are routinely begun during surgery in a dose equivalent toprednisone 2 mg/ kg administered daily either parenterally or orally. Thereafter, the dose of prednisone is tapered slowly until a maintenance dose is reached which maintains the patient symptom-free. High dose glucocorticosteroids may cause temporary weakness. For this reason treatment is initiated while the patient is in the intensive care unit with ventilator support, it required. Improvement in muscle strength usually begins within one week posts artery, with continued improvement in the months that follow.

Plasmapheresis is useful as an acute intervention in a patient who is experiencing respiratory insufficiency (myasthénie crisis), or is so weak that muscular strength must he improved prior to thymectomy.

Anticholinesterase therapy is also a useful adjunct for the chronic medical management oí myasthenia. Several preparations of cholinesterase inhibitors are available. Of these, neostigmine and pyridostigmine bromide are the most widely used. The initial dose of neostigmine is O. 5 mg/kg body weight every four hours in children younger than 5 years of age and 0. 2 5 mg/kg in older children. The equivalent dose of pyridostigmine bromide is four times greater. After treatment is initiated, the dose is slowly increased as tolerated. Diarrhea and gastrointestinal cramping arc the major side effects. Edrophonium chloride should not be administered to children receiving cholinesterase inhibitors to determine whether the child would benefit from higher oral doses. The procedure is not an accurate guide and may precipitate a cholinergic crisis in children with generalized myasthenia. The clinical response to anticholinesterase therapy can be longlived or transitory. Patients with primary ocular myasthenia are often refractory to therapy even with high doses of medication. The addition of a glucocorticosteroid may provide temporary relief, but it must be emphasized that the assessment of the efficacy of any drug regimen in primary ocular myasthenia is difficult because of its fluctuating course.

It has been reported that the clinical characteristics and response to treatment of children who are seronegative for AChR antibodies do not differ from those who are seropositive. ~> This may not be the case, as most children with acquired myasthenia who are antibody negative exhibit only ocular symptoms and, thus, may be difficult to distinguish from children with genetic forms which begin in early infancy or childhood. Facial weakness and easy fatigability of the limbs may be present, but dysarthria or dysphagia typically do not occur. The course of antibody-negative myasthenia is characterized by relapses and remissions.6 The relapses are of varying severity and last for weeks to years. Remissions for as long as 14 years have been recorded, with at least 20% of children exhibiting permanent remissions.

The diagnosis of antibody-negative myasthenia gravis is identical to that of" the antibody-positive forms. In some patients, a décrémentai response to repetitive electrical stimulation of a peripheral nerve can be recorded at low (2 to 5 per second), but not at high (50 per second) rates of stimulation.

Anticholinesterase therapy is the treatment of choice for antibody-negative ocular myasthenia. The initial and maintenance doses of either neostigmine or pyridostigmine bromide are the same as those for the antibody-positive disease. As mentioned previously, the response to therapy may be transient, and ocular myasthenia is often refractory to medical management.

Transitory Myasthenia Gravis

A transient myasthénie syndrome is observed in 10% to 15% of offspring of mothers suffering from myasthenia gravis. It is of interest that affected and unaffected newborn infants may exhibit the same high concentrations of AChR antibody as their mothers.7 Passive transfer of antibody to fetus occurs in every instance, but those newborn infants who are symptomatic may also synthesize antibody de novo.

Difficulty feeding and generalized hypotonia are the major clinical features of transitory neonatal myasthenia. Affected infants are eager to feed, but sucking fatigues quickly and prevents adequate nutrition, prompting the need tor nasogastric tube alimentation. Symptoms usually begin within hours of birth, but can be delayed until the third postnatal day. Weakness of crying and facial affect is present in 50% of infants, whereas limitation of extra-ocular movement and ptosis are present in only 15%. Respirarory insufficiency is uncommon. Weakness worsens in the first few days and then slowly improves. The mean duration of symptoms is 18 days with a range of five days to two months. Recovery is complete, and infants with transitory neonatal myasthenia do not develop myasthenia later in life.

The diagnosis of transitory neonatal myasfhenia gravis is accomplished by demonstrating high serum concentrations of AChR antibodies in the newborn infant and the temporary reversal of weakness by the subcutaneous injection of 0.15 mg/kg edrophonium chloride.

Newborn infants with severe generalized weakness and respiratory distress should be treated with exchange transfusion. For those who are less impaired, intermittent intramuscular injections of 0. 05 to 0.1 mg neostigmine prior to feeding may provide sufficient improvement in sucking and swallowing to allow adequate nutrition. The dose is progressively reduced as symptoms remit. Neostigmine can also be administered via a nasogastric tube at a dose 10 times the patenterai dose.

CONCLUSION

Transitory neonatal myasthenia gravis must be distinguished from congenital myasthenia gravis and familial infantile myasthenia, two conditions in which myasthénie symptoms are present at or following birth, and which persist indefinitely. These infants and children are truly myasthénie, the underlying disorder representing a defect either in the synthesis or release of acetylcholine or an anatomic aberration of the endplate receptor (Table I).0'11 Thus, the conditions are not autoimmune in nature, and serum concentrations of AChR antibodies are within the normal range. Both conditions are considered genetic disorders, typically with an autosomal recessive mode of inheritance. Their diagnosis and management are similar to that described for the acquired, seronegative form of myasthenia gravis.

ACKNOWLEDGMENTS

Table 1 is adapted from Misulis and Fenichel.1

REFERENCES

1. Misulis KE, Fenichel GM: Genetic forms of myasthetiia gtavis. Pediatr Neurol (in press).

2. Daroff RB: The office tensilon test lot mvasthenia Etavis. Arch Neuroi 1986; 43:84i-S44.

3. Oh SJ, Eslami N. Nishihira T, et al: ElecrrophysLoloaical and clinical correlation m myastln-nia firavts. Ann Nenml 1982. 12:i48-354.

4. Rodrigue.: M. Gome; MR. Howard FM, et al Myasthenie EMVIS in children. Longterm follow-up. Ann NettnA 1983; 13:504-510.

5. Soliven BC. Lange DJ. [tnn AS. et al: ScionoEaiive myasthénie gravis. Neonitugy 1988; 13:514-517.

6. Rollmson RD. Fi-nichel UM. Relapsing ociiljr myasrhenia. Neurology 1981; 11:525-326.

7. Lefvert AK. Osterrnan Pu: Newborn infants to myasthenie mothers: A clinical study and an investigation HI acervkhnline recepior antibodies in 17 chilthen. NeunAiigy 1983: 33:135-138.

8. Hate ZH, Sahsashi K. Lambert EH. et al: congenital familial mysmasthemic syndrome caused by a piesynapnc detect of transmitter resynihesis or mobilization. NtwaJogv 1979; 29:556-557.

9. Engel Au: Morphologic and immunopathologic (indinas m myasihenia tjravis and m congenital myasthenic syndromes. J NWJ Neumsurg Piythiotr, 1980; 43:577-589.

10. Robert, WC, Chun RWM. Komguth SE: Familial infantile rayarthetiu Rtavis. Arch Neurol, 1980; 26:101-108.

11. Lecky BRF. Motean-HuEhesJA. Murray NMF. et al: Congenital myasthenia: Further evidence ol diseaw heteropeneiTy. Muscle and Nerve [986; 9:233-242.

TABLE 1

Myasthenie Syndromes in Children

TABLE 2

Diagnostic Procedures in Myasthenie Gravis

TABLE 3

Management of Myasthenla Gravis

10.3928/0090-4481-19890701-09

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