Clinical Manifestations

Three clinical varieties are distinguished in childhood: juvenile myasthenia gravis in late infancy and childhood, congenital myasthenia, and transient neonatal myasthenia. In the juvenile form, ptosis and some degree of extraocular muscle weakness are the earliest and most constant signs. Older children might complain of diplopia, and young children might hold open their eyes with their fingers or thumbs if the ptosis is severe enough to obstruct vision. The pupillary responses to light are preserved. Dysphagia and facial weakness are also common, and in early infancy, feeding difficulties are often the cardinal sign of myasthenia. Poor head control because of weakness of the neck flexors is also prominent. Involvement may be limited to bulbar-innervated muscles, but the disease is systemic and weakness involves limb-girdle muscles and distal muscles of the hands in most cases. Fasciculations of muscle, myalgias, and sensory symptoms do not occur. Tendon stretch reflexes may be diminished but rarely are lost.

Rapid fatigue of muscles is a characteristic feature of myasthenia gravis that distinguishes it from most other neuromuscular diseases. Ptosis increases progressively as patients are asked to sustain an upward gaze for 30-90 sec. Holding the head up from the surface of the examining table while lying supine is very difficult, and gravity cannot be overcome for more than a few seconds. Repetitive opening and closing of the fists produces rapid fatigue of hand muscles, and patients cannot elevate their arms for more than 1-2 min because of fatigue of the deltoids. Patients are more symptomatic late in the day or when tired. Dysphagia can interfere with eating, and the muscles of the jaw soon tire when an affected child chews.

Left untreated, myasthenia gravis is usually progressive and can become life threatening because of respiratory muscle involvement and the risk of aspiration, particularly at times when the child is otherwise unwell with an upper respiratory tract infection. Familial myasthenia gravis usually is not progressive.

Infants born to myasthenic mothers can have respiratory insufficiency, inability to suck or swallow, and generalized hypotonia and weakness. They might show little spontaneous motor activity for several days to weeks. Some require ventilatory support and feeding by gavage during this period. After the abnormal antibodies disappear from the blood and muscle tissue, these infants regain normal strength and are not at increased risk of developing myasthenia gravis in later childhood.

The syndrome of transient neonatal myasthenia gravis is to be distinguished from a rare and often hereditary congenital myasthenia gravis not related to maternal myasthenia that is nearly always a permanent disorder without spontaneous remission (see Table 604-1). Several distinct genetic forms are recognized, all with onset at birth or in early infancy with hypotonia, ophthalmoplegia, ptosis, dysphagia, weak cry, facial weakness, easy muscle fatigue generally, and sometimes respiratory insufficiency or failure, the last often precipitated by a minor respiratory infection. Cholinesterase inhibitors have a favorable effect in most, but in some forms the symptoms and signs are actually worsened. Most congenital myasthenic syndromes are transmitted as autosomal recessive traits, but the slow channel syndrome is autosomal dominant. Five defective postsynaptic molecules have been identified in the pathogenesis of congenital myasthenia gravis and account for 85% of cases; rapsyn may be the most common. Acetylcholine receptor deficiencies have >60 identified genetic mutations. Anti-AChR and anti-MuSK antibodies are absent in serum, unlike autoimmune forms of myasthenia gravis affecting older children and adults.

Three presynaptic congenital myasthenic syndromes are recognized, all as autosomal recessive traits; some of these have anti-MuSK antibodies. These children exhibit weakness of extraocular, pharyngeal, and respiratory muscles and later show shoulder girdle weakness as well. Episodic apnea is a problem in congenital myasthenia gravis. Another synaptic form is caused by absence or marked deficiency of motor endplate AChE in the synaptic basal lamina, and postsynaptic forms of congenital myasthenia are caused by mutations in ACh receptor subunit genes that alter the synaptic response to ACh. An abnormality of the ACh receptor channels appearing as high conductance and excessively fast closure may be the result of a point mutation in a subunit of the receptor affecting a single amino acid residue. Children with congenital myasthenia gravis do not experience myasthenic crises and rarely exhibit elevations of anti-ACh antibodies in plasma.

Myasthenia gravis is occasionally associated with hypothyroidism, usually due to Hashimoto thyroiditis. Other collagen vascular diseases may also be associated. Thymomas, noted in some adults, rarely coexist with myasthenia gravis in children, nor do carcinomas of the lung occur, which produce a unique form of myasthenia in adults called Eaton-Lambert syndrome. Postinfectious myasthenia gravis in children is transitory and usually follows a varicella-zoster infection by 2-5 wk as an immune response.

Laboratory Findings and Diagnosis

Myasthenia gravis is one of the few neuromuscular diseases in which electromyography (EMG) is more specifically diagnostic than a muscle biopsy. A decremental response is seen to repetitive nerve stimulation; the muscle potentials diminish rapidly in amplitude until the muscle becomes refractory to further stimulation. Motor nerve conduction velocity remains normal. This unique EMG pattern is the electrophysiologic correlate of the fatigable weakness observed clinically and is reversed after a cholinesterase inhibitor is administered. A myasthenic decrement may be absent or difficult to demonstrate in muscles that are not involved clinically. This feature may be confusing in early cases or in patients showing only weakness of extraocular muscles. Microelectrode studies of endplate potentials and currents reveal whether the transmission defect is presynaptic or postsynaptic. Special electrophysiologic studies are required in the classification of congenital myasthenic syndromes and involve estimating the number of ACh receptors per endplate and in vitro study of endplate function. These special studies and patch-clamp recordings of kinetic properties of channels are performed on special biopsy samples of intercostal muscle strips that include both origin and insertion of the muscle but are only performed in specialized centers. If myasthenia is limited to the extraocular muscles, levator palpebrae, and pharyngeal muscles, evoked-potential EMG of the muscles of the extremities and spine, diagnostic in the generalized disease, usually is normal.

Anti-ACh antibodies should be assayed in the plasma but are inconsistently demonstrated. About 30% of affected adolescents show elevations, but anti-ACh receptor antibodies are only occasionally demonstrated in the plasma of prepubertal children. Many juvenile myasthenics who show no anti-ACh antibodies in serum have antibodies against the receptor tyrosine kinase (MuSK), which also is localized at the neuromuscular junction and appears essential to fetal development of this junction. Many cases of congenital myasthenia gravis do not result from a refractory postsynaptic membrane at the neuromuscular junction as in juvenile and adult myasthenia but rather result from failure to synthesize or release ACh at the presynaptic membrane. In some cases, the gene that mediates the enzyme choline acetyltransferase for the synthesis of ACh is mutated. In others, there is a defect in the quantal release of vesicles containing ACh. The treatment of such patients with cholinesterase inhibitors is futile. Assay of anti-rapsyn antibody will become commercially available in the near future.

Other serologic tests of autoimmune disease, such as antinuclear antibodies and abnormal immune complexes, should also be sought. If these are positive, more extensive autoimmune disease involving vasculitis or tissues other than muscle is likely. A thyroid profile should always be examined. The serum creatine kinase (CK) level is normal in myasthenia gravis.

The heart is not involved, and electrocardiographic findings remain normal. Radiographs of the chest often reveal an enlarged thymus, but the hypertrophy is not a thymoma. It may be further defined by tomography or by CT scanning of the anterior mediastinum.

The role of conventional muscle biopsy in myasthenia gravis is limited. It is not required in most cases, but about 17% of patients show inflammatory changes, sometimes called lymphorrhages, that are interpreted by some physicians as a mixed myasthenia-polymyositis immune disorder. Muscle biopsy tissue in myasthenia gravis shows nonspecific type II muscle fiber atrophy, similar to that seen with disuse atrophy, steroid effects on muscle, polymyalgia rheumatica, and many other conditions. The ultrastructure of motor endplates shows simplification of the membrane folds; the ACh receptors are located in these postsynaptic folds, as shown by bungarotoxin (snake venom), which binds specifically to the ACh receptors.

A clinical test for myasthenia gravis is administration of a short-acting cholinesterase inhibitor, usually edrophonium chloride. Ptosis and ophthalmoplegia improve within a few seconds, and fatigability of other muscles decreases.

Treatment

Some patients with mild myasthenia gravis require no treatment. Cholinesterase-inhibiting drugs are the primary therapeutic agents. Neostigmine methylsulfate (0.04 mg/kg) may be given IM every 4-6 hr, but most patients tolerate oral neostigmine bromide, 0.4 mg/kg every 4-6 hr. If dysphagia is a major problem, the drug should be given about 30 min before meals to improve swallowing. Pyridostigmine is an alternative; the dose required is about 4 times greater than that of neostigmine, but it may be slightly longer acting. Overdoses of cholinesterase inhibitors produce cholinergic crises; atropine blocks the muscarinic effects but does not block the nicotinic effects that produce additional skeletal muscle weakness. In the rare familial myasthenia gravis caused by absence of endplate AChE, cholinesterase inhibitors are not helpful and often cause increased weakness; these patients can be treated with ephedrine or diaminopyridine, both of which increase ACh release from terminal axons.

Because of the autoimmune basis of the disease, long-term steroid treatment with prednisone may be effective. Thymectomy should be considered and might provide a cure. Thymectomy is most effective in patients who have high titers of anti-ACh receptor antibodies in the plasma and who have been symptomatic for <2 yr. Thymectomy is ineffective in congenital and familial forms of myasthenia gravis. Treatment of hypothyroidism usually abolishes an associated myasthenia without the use of cholinesterase inhibitors or steroids.

Plasmapheresis is effective treatment in some children, particularly those who do not respond to steroids, but plasma exchange therapy provides only temporary remission. IV immunoglobulin (IVIG) is beneficial and should be tried before plasmapheresis because it is less invasive. Plasmapheresis and IVIG appear to be most effective in patients with high circulating levels of anti-ACh receptor antibodies. Refractory patients might respond to rituximab, a monoclonal antibody to the B-cell CD20 antigen.

Neonates with transient maternally transmitted myasthenia gravis require cholinesterase inhibitors for only a few days or occasionally for a few weeks, especially to allow feeding. No other treatment is usually necessary. In non–maternally transmitted congenital myasthenia gravis, identification of the specific molecular defect is important for treatment; specific therapies for each type are summarized in Table 604-2.

Table 604-2 POTENTIAL THERAPIES IN CONGENITAL MYASTHENIC SYNDROMES

Etiology

The cause of SMA is a pathologic continuation of a process of programmed cell death (apoptosis) that is normal in embryonic life. A surplus of motor neuroblasts and other neurons is generated from primitive neuroectoderm, but only about half survive and mature to become neurons; the excess cells have a limited life cycle and degenerate. If the process that arrests physiologic cell death fails to intervene by a certain stage, neuronal death can continue in late fetal life and postnatally. The survivor motor neuron gene (SMN) arrests apoptosis of motor neuroblasts. Unlike most genes that are highly conserved in evolution, SMN is a uniquely mammalian gene. An additional function of SMN, both centrally and peripherally, is to transport RNA binding proteins to the axonal growth cone to ensure an adequate amount of protein-encoding transcripts essential for growth cone mobility both during fetal development and in postnatal synaptic remodeling.

Clinical Manifestations

The cardinal features of SMA type 1 are severe hypotonia (Fig. 604-1); generalized weakness; thin muscle mass; absent tendon stretch reflexes; involvement of the tongue, face, and jaw muscles; and sparing of extraocular muscles and sphincters. Diaphragmatic involvement is late. Infants who are symptomatic at birth can have respiratory distress and are unable to feed. Congenital contractures, ranging from simple clubfoot to generalized arthrogryposis, occur in about 10% of severely involved neonates. Infants lie flaccid with little movement, unable to overcome gravity (see Fig. 599-1). They lack head control. More than 65% of children die by 2 yr of age, and many die early in infancy.

Figure 604-1 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease). Clinical manifestations of weakness of limb and axial musculature in a 6 wk old infant with severe weakness and hypotonia from birth. Note the marked weakness of the limbs and trunk on ventral suspension (A) and of neck on pull to sit (B)

(From Volpe J: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders, p 644).

In type 2 SMA, affected infants are usually able to suck and swallow, and respiration is adequate in early infancy. These children show progressive weakness, but many survive into the school years or beyond, although confined to an electric wheelchair and severely handicapped. Nasal speech and problems with deglutition develop later. Scoliosis becomes a major complication in many patients with long survival.

Kugelberg-Welander disease is the mildest SMA (type 3), and patients can appear normal in infancy. The progressive weakness is proximal in distribution, particularly involving shoulder girdle muscles. Patients are ambulatory. Symptoms of bulbar muscle weakness are rare. About 25% of patients with this form of SMA have muscular hypertrophy rather than atrophy, and it may easily be confused with a muscular dystrophy. Longevity can extend well into middle adult life. Fasciculations are a specific clinical sign of denervation of muscle. In thin children, they may be seen in the deltoid, biceps brachii, and occasionally the quadriceps femoris muscles, but the continuous, involuntary, wormlike movements may be masked by a thick pad of subcutaneous fat. Fasciculations are best observed in the tongue, where almost no subcutaneous connective tissue separates the muscular layer from the epithelium. If the intrinsic lingual muscles are contracted, such as in crying or when the tongue protrudes, fasciculations are more difficult to see than when the tongue is relaxed.

The outstretched fingers of children with SMA often show a characteristic tremor owing to fasciculations and weakness. It should not be confused with a cerebellar tremor. Myalgias are not a feature of SMA.

The heart is not involved in SMA. Intelligence is normal, and children often appear brighter than their normal peers because the effort they cannot put into physical activities is redirected to intellectual development, and they are often exposed to adult speech more than to juvenile language because of the social repercussions of the disease.

Laboratory Findings

The serum CK level may be normal but more commonly is mildly elevated in the hundreds. A CK level of several thousand is rare. Results of motor nerve conduction studies are normal, except for mild slowing in terminal stages of the disease, an important feature distinguishing SMA from peripheral neuropathy. EMG shows fibrillation potentials and other signs of denervation of muscle. A secondary mtDNA depletion is sometimes demonstrated in the muscle biopsy of infants with SMA.

Diagnosis

The simplest, most definitive diagnostic test is a molecular genetic marker in blood for the SMN gene. Muscle biopsy reveals a characteristic pattern of perinatal denervation that is unlike that of mature muscle. Groups of giant type I fibers are mixed with fascicles of severely atrophic fibers of both histochemical types (Fig. 604-2). Scattered immature myofibers resembling myotubes also are demonstrated. In juvenile SMA, the pattern may be more similar to adult muscle that has undergone many cycles of denervation and reinnervation. Neurogenic changes in muscle also may be demonstrated by EMG, but the results are less definitive than by muscle biopsy in infancy. Sural nerve biopsy sometimes shows mild sensory neuropathic changes, and sensory nerve conduction velocity may be slowed; hypertrophy of unmyelinated axons also is seen. At autopsy, mild degenerative changes are seen in sensory neurons of dorsal root ganglia and in somatosensory nuclei of the thalamus, but these alterations are not perceived clinically as sensory loss or paresthesias. The most pronounced neuropathologic lesions are the extensive neuronal degeneration and gliosis in the ventral horns of the spinal cord and brainstem motor nuclei, especially the hypoglossal nucleus.

Figure 604-2 Muscle biopsy of neonate with infantile spinal muscular atrophy. Groups of giant type I (darkly stained) fibers are seen within muscle fascicles of severely atrophic fibers of both histochemical types. This is the characteristic pattern of perinatal denervation of muscle. Myofibrillar ATPase, preincubated at pH 4.6 (×400).

Genetics

Molecular genetic diagnosis by DNA probes in blood samples or in muscle biopsy or chorionic villi tissues is available for diagnosis of suspected cases and for prenatal diagnosis. Most cases are inherited as an autosomal recessive trait. The incidence of SMA is 10-15/100,000 live births, affecting all ethnic groups; it is the 2nd most common neuromuscular disease, following Duchenne muscular dystrophy. The incidence of heterozygosity for autosomal recessive SMA is 1 : 50.

The genetic locus for all 3 of the common forms of SMA is on chromosome 5, a deletion at the 5q11-q13 locus, indicating that they are variants of the same disease rather than different diseases. The affected SMN gene contains 8 exons that span 20 kb, telomeric and centromeric exons that differ only by 5bp and produce a transcript encoding 294 amino acids. Another gene, the neuronal apoptosis inhibitory gene (NAIP), is located next to the SMN gene and in many cases there is an inverted duplication with 2 copies, telomeric and centromeric, of both genes; isolated mutations or deletions of NAIP do not produce clinical SMA and generate a mostly nonfunctional isoform lacking the carboxy-terminus amino acids encoded by exon 7. Milder forms of SMA have more than 2 copies of SMN2, and in late-onset patients with homozygous deletion of the SMN1 gene, there are 4 copies of SMN2. An additional gene mapped to 11q13-q21 in SMA may help explain early respiratory failure in some patients. Nucleotide expansions account for only 5-10% of cases of SMA, and deletions or splicing out of exons 7 and 8 are the genetic mechanism in the great majority of cases. Another pair of genes adjacent to the SMN1 and SMN2 genes, SERF1 and SERF2, also may play a secondary role.

Infrequent families with autosomal dominant inheritance are described, and a rare X-linked recessive form also occurs. Carrier testing by dose analysis is available.

Treatment

No medical treatment is able to delay the progression. Supportive therapy includes orthopedic care with particular attention to scoliosis and joint contractures, mild physiotherapy, and mechanical aids for assisting the child to eat and to be as functionally independent as possible. Most children learn to use a computer keyboard with great skill but cannot use a pencil easily. Valproic acid is sometimes administered because it increases SMN2 protein, and gabapentin and oral phenylbutyrate also may slow the progression, but these treatments do not alter the course in all patients. A benefit of antioxidants is unproved. Gene replacement and protein replacement, including lentiviral, therapies are theoretical and experimental at this time.