Disorders of Neuromuscular Transmission and of Motor Neurons

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Chapter 604 Disorders of Neuromuscular Transmission and of Motor Neurons

604.1 Myasthenia Gravis

Myasthenia gravis is a chronic disease characterized by rapid fatigability of striated muscle. The most common cause is an immune-mediated neuromuscular blockade. The release of acetylcholine (ACh) into the synaptic cleft by the axonal terminal is normal, but the postsynaptic muscle membrane or motor endplate is less responsive than normal. A decreased number of available ACh receptors is due to circulating receptor-binding antibodies in most cases of acquired myasthenia. The disease is generally not hereditary and is an autoimmune disorder. A rare familial myasthenia gravis is probably an autosomal recessive trait and is not associated with plasma anti-ACh antibodies. One familial form is a deficiency of motor endplate acetylcholinesterase (AChE). Infants born to myasthenic mothers can have a transient neonatal myasthenic syndrome secondary to placentally transferred anti-ACh receptor antibodies, distinct from congenital myasthenia gravis (Table 604-1).

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.

Recommendations on the Use of Cholinesterase Inhibitors as a Diagnostic Test for Myasthenia Gravis in Infants and Children

Children 2 Years and Older