Myasthenia gravis in children

Introduction

Myasthenia gravis (MG) is a disorder of neuromuscular transmission of skeletal muscles. Fatigability and variability of skeletal muscle weakness are hallmarks of MG. MG in children is classified by the three different pathophysiological mechanisms: transient neonatal myasthenia, congenital myasthenic syndromes, and autoimmune juvenile MG. Transient neonatal myasthenia is caused by transplacental transfer of myasthenic maternal antibodies to infants. The congenital myasthenic syndromes are a group of genetic disorders caused by structural or functional protein abnormalities involved in neuromuscular transmission. Juvenile MG is an autoimmune disorder of neuromuscular transmission caused by production of antibodies against the postsynaptic membrane components of the neuromuscular junction in children. Juvenile MG is characterized by fluctuating weakness and fatigue of the ocular, facial, bulbar or limb muscles during childhood or young adulthood.

Diagnosis may be confirmed by repetitive nerve stimulation, single fiber electromyography (EMG), serological test for antibodies of acetylcholine receptor (AChR) or muscle-specific kinase (MuSK), Tensilon test or neostigmine test, rest test, ice test, and the patient’s clinical response to anticholinesterase medication. AChR antibodies are frequently absent in patients with prepubertal onset of MG. Treatments in juvenile MG include anticholinesterases, corticosteroids with or without steroid-sparing agents, and immune-modulating agents. Thymectomy increases remission rates. Plasmapheresis and intravenous immunoglobulin are useful in preparation for thymectomy and in myasthenic crisis of respiratory failure with the need for mechanical ventilation. The prognosis of patients with juvenile MG is usually good. Clinical remission can be achieved in the majority of patients with the current treatment methods.

Epidemiology

The prevalence of autoimmune MG is 4–10 per 100,000 in the general population. Ten to fifteen percent of MG cases have a juvenile onset. The incidence of juvenile MG is estimated at 1.6 per million. Juvenile MG usually develops after 1 year of age and its incidence increases with age. The female : male ratio ranges from 1.3:1 in prepubertal to 1.8:1 in peripubertal and up to 14:1 in postpubertal patients with juvenile MG. The spontaneous remission rate is 22.4 per 1000 person-years in patients with juvenile MG and 13%–24% with ocular MG.

Ethnicity can affect the incidence and clinical manifestations of MG. Juvenile MG is less common in populations of European descent, with an incidence of 1–5 in a million/year. In North America, the median age of onset for ocular MG was 3.5 years, and 10 years for generalized MG. Patients of European descent have a female predominance during and after puberty. Chinese patients have an earlier age of onset, less severe cases, more ocular involvement, lower median AChR antibody titers, and no late onset peak as observed in those of European origin. In Asians, MG occurs frequently in childhood, with an age peak of 5–10 years. Children constitute half of Asian MG patients, with 70% limited to ocular MG. Asian MG patients have higher remission rates, regardless of treatment, than non-Asians. In addition, in Asians there was no gender difference, a higher incidence of ocular MG, and a more benign course. The incidence of ocular MG among patients with juvenile MG ranges from 9% to 93%, with a higher incidence among Asians. African-Americans have a higher incidence of MG, female predominance regardless of age, lower remission rate, and poorer response to thymectomy compared to patients of European origin.

Pathophysiology

Clinical Manifestations

Variability and fatigability of the skeletal muscle weakness are the hallmarks of MG ( Fig. 86.1 ). Ocular signs, such as ptosis or diplopia, have been reported in 33%–90% of patients with juvenile MG. However, facial weakness without ptosis and ophthalmoplegia is also possible.

Younger children generally develop ocular MG, and older children, generalized MG. Prepubertal children younger than 12 years of age have a higher prevalence of ocular MG, a higher rate of remission, and a lower frequency of AChR antibodies, that make the differentiation of juvenile MG from congenital myasthenic syndromes difficult. Generalized MG is more common than ocular MG (65% vs. 35%) with juvenile MG. Generalized MG patients have a slight female predominance, an older age of onset (median age 10 years), and predominantly European descent (59%). Ocular MG patients have a more pronounced female predominance, a younger age of onset (median age 3.5 years), and Asian ethnicity (44%).

Progression of ocular MG to generalized MG occurs in 8%–15% of patients with a prepubertal onset, 23%–43% with a pubertal onset, and 79% with a postpubertal onset. In general, ocular MG may be limited to extraocular muscles in 10%–15% of patients with juvenile MG, particularly in Asian patients. Children with postpubertal onset have more severe MG, but mortality is uncommon. There was no difference in ethnicity in terms of AChR antibodies, maximum severity, or use of immunosuppression.

Limb weakness is usually proximal with difficulty in climbing stairs, raising arms, or combing hair. Facial muscle weakness may cause the characteristic “myasthenic snarl” in which the corners of the mouth are not raised. Neck extensor weakness results in a dropped chin or head. Bulbar symptoms such as swallowing and chewing difficulties or respiratory symptoms can be fatal. Affected patients often have a soft voice with nasal intonation.

Fever, heat, stress, infections, or menstruation may aggravate symptoms. Remissions and relapses over time are common. Isolated ocular involvement may progress to generalized MG, usually within 1 year, but sometimes up to 9 years after its onset.

Signs such as ptosis, strabismus, restricted eye movement, difficulty in sustaining lateral gaze, decreased gag reflex, and weakness of muscles are frequent. All signs can be aggravated by sustained or repetitive activity of the muscles involved ( Fig. 86.2 ). Strabismus is usually incomitant, but can be comitant in 19% of cases. Vertical strabismus is present in more than one-half of patients. Medial rectus muscle is involved most frequently, however, the lateral rectus muscle is also often involved in Asian children. Exotropia combined with vertical heterotropia is the most frequent type of strabismus followed by exotropia in Asian children. Limitations of supraduction or infraduction were the most frequent type of ocular motility dysfunction (18%). Abduction is limited more often than adduction (15% vs. 3%). Variability of ocular motility is found in 82% of patients. Amblyopia can be caused by ptosis and strabismus in children with MG. Amblyopia treatment may be unsuccessful because of delayed treatment or poor compliance with occlusion therapy.

Autoimmune disorders including rheumatoid arthritis, thyroid disease, asthma, or juvenile-onset diabetes mellitus as well as nonimmune disorders such as epilepsy can be associated with juvenile MG. Infections, heat or stress may aggravate symptoms. Thymoma is rare in children, but it can be malignant.

Diagnosis