Disturbances of Neuromuscular Transmission−Myasthenic Syndromes 275

often, a narrow head with a raised, “Gothic” palate and possibly other skeletal deformities;

slow progression, or none;

sometimes, cardiomyopathy and/or dementia.

Table 14.8 contains a list of congenital myopathies classified by the histopathological findings of muscle biopsy.

Table 14.8 Congenital myopathies

Central core myopathy Nemaline (rod) myopathy Centronuclear myopathy Multicore myopathy Fingerprint body myopathy Sarcotubular myopathy

Hyaline body myopathy (= myopathy with disintegration of myofibrils in type I fibers)

Disturbances of Neuromuscular Transmission−Myasthenic Syndromes

The myasthenic syndromes are characterized by abnormal fatigability of muscle. The weakness may affect individual muscle groups in more or less isolated fashion, or, alternatively, all of the muscles of the body. Pathophysiologically speaking, these conditions are due to a disturbance of impulse transmission at the motor end plate, usually because of an underlying autoimmune disorder. For example, the most common myasthenic syndrome, myasthenia gravis, is due to the destruction of acetylcholine receptors on the postsynaptic membrane by cross-reacting autoantibodies.

The cellular processes involved in impulse transmission at the motor end plate are discussed on p. 263 and shown pictorially in Fig. 14.2. Theoretically speaking, these processes were impaired in a number of different ways:

inadequate synthesis of acetylcholine, or defective storage of acetylcholine in axon terminals;

inadequate release of acetylcholine from axon terminals;

impaired transport of acetylcholine in the synaptic cleft;

impaired binding of acetylcholine to its specific receptors on the postsynaptic membrane.

The last-named mechanism is at work in the commonest and clinically most important type of myasthenia, namely, myasthenia gravis. In Lambert−Eaton syndrome (p. 277), on the other hand, the underlying problem is inadequate release of acetylcholine from the presynaptic membrane.

Myasthenia Gravis

Epidemiology. The incidence of this disorder is one to four per 100 000 individuals per year; its prevalence in the general population is 140 per million. Women are more commonly affected, in a female-to-male ratio of 3:2. The onset of the disease is usually in the second through fourth decade of life in women, but in the sixth decade in men. In principle, however, myasthenia gravis can appear at any age.

It is not uncommon for myasthenia gravis to be accompanied by certain other diseases: thymoma occurs

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in about 15 % of patients with the disease, hyperthyroidism in 5 %, hypothyroidism likewise in 5 %, and polyarthritis in 4 %.

Pathophysiology. Three-quarters of all patients with myasthenia gravis have hyperplasia of the thymus and 15 % harbor a thymoma. Antibodies are generated against the myoid cells of the thymus; owing to a misdirection of the immune response, these antibodies also attack the acetylcholine receptors of the motor end plate. Acetylcholine receptor antibodies are present in the serum in elevated concentration in a large majority of patients with generalized myasthenia. If the serum of an affected patient is injected into an experimental animal, the animal develops a myasthenic syndrome. The antibodies can be transmitted across the placenta from a myasthenic mother to her child (see below). They are highly heterogeneous and bind to the acetylcholine receptor at a number of different locations.

Clinical manifestations. The clinical features of myasthenia are summarized in Table 14.9. The most prominent manifestation is abnormal fatigability of muscle. Initially, the muscles most obviously affected are those that carry out very fine movements and that accordingly contain unusually small motor units. These are the muscles that react most strongly to a decline in acetylcholine receptor density, i. e., the extraocular muscles, the levator palpebrae m., and the muscles of mastication and deglutition. Thus, the early manifestations of myasthenia gravis often include diplopia, ptosis, dysphagia with frequent aspiration, and difficulty chewing food. Nevertheless, practically any other muscle group can be involved, even at the onset of the disease. The disease manifestations worsen over the course of the day and are worst in the evening. Repeated activation of an affected muscle group leads to rapidly worsening weakness. This phenomenon forms the basis of a number of clinical diagnostic tests.

Diagnostic evaluation. Myasthenic ptosis worsens visibly over the course of a single minute if the patient rapidly and repeatedly closes and opens the eyes, or looks upward for a prolonged period (the Simpson test, Fig. 14.11).

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Diseases of Muscle

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276 14 Diseases of Muscle (Myopathies)

Table 14.9 Clinical features of myasthenia

Progressive weakness of individual muscles

The weakness increases on rapid, repeated contraction of the affected muscles

Recovery within minutes, or a fraction of an hour, at rest

The weakness usually worsens toward evening

The eye muscles are often affected first (ptosis, diplopia), or else the pharyngeal muscles (dysphagia, nasal speech)

Variably severe weakness of muscles belonging to different motor units

Occasionally, crises with sudden deterioration of muscle strength

No atrophy or fasciculations

More or less complete resolution of disease manifestations after the administration of a cholinesterase inhibitor, e. g., test injection of edrophonium chloride I.V. (Tensilon test)

Usually, elevated serum titer of antibodies against the acetylcholine receptor (though this is a rare finding in ocular myasthenia)

Further diagnostic tests serve to confirm the clinical diagnosis. In the Tensilon test, 10 mg of the acetylcholinesterase inhibitor edrophonium chloride are injected intravenously over 10 seconds. This drug inhibits the breakdown of acetylcholine in the synaptic cleft, so that acetylcholine is available to its receptors on the muscle cell membrane for a longer time and the deleterious effect of diminished receptor density is counteracted. An improvement is seen within 30 seconds and lasts for about three minutes. A marked ptosis, for example, can transiently disappear.

When a motor nerve is repeatedly stimulated, the electromyogram recorded from the corresponding muscle through a surface electrode reveals a progressive fall-off (decrement) in the amplitude of the muscle potential (Fig. 14.12).

Antibodies against the acetylcholine receptor are demonstrable in the serum of 85 % of patients with myasthenia gravis. They are not found, however, in 50 % of patients with the purely ocular form, as well as in about

a

b

Fig. 14.11 Myasthenia of the extraocular muscles and a Simpson test in a 23-year-old man. The left ptosis (a), becomes increasingly evident on looking up repeatedly in rapid succession—this is a maneuver that activates the levator palpebrae muscle (b). (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

15 % of patients with generalized myasthenia (see below). A chest CT or MRI must be performed to disclose or rule out a thymoma. Other diseases that can mimic or accompany myasthenia must be sought and excluded as well (see below).

a

b

1.39mV

0.64mV =46%

0.5mV	0.5mV

0.1s	5ms

Fig. 14.12 Electromyogram of a 59-year-old man with ocular myasthenia. Electrical activity is recorded from the nasalis m. on repetitive stimulation of the facial n. in the stylomastoid fossa (frequency of stimulation, 3 Hz). The EMG tracing is shown in a. In b, the same curve is shown on an expanded time scale, and the re-

sponses to successive stimuli are superimposed. The summed muscle potential diminishes from one stimulus to the next; the response to the fifth stimulus is 54 % smaller than the initial response. Normally there should be no more than a 10 % diminution in amplitude.

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Disturbances of Neuromuscular Transmission−Myasthenic Syndromes 277

Classification. Myasthenia can be subdivided into a number of stages depending on the extent and severity of muscle involvement. Ossermann classification has four main stages and is reproduced in Table 14.10.

Spontaneous course. The severity of the disease manifestations fluctuates markedly without treatment, even over longer periods. Spontaneous remissions may be long lasting, but true spontaneous cures are rare. The eyes are initially affected in 50 % of patients and are eventually affected at some point in 90 %. Myasthenic manifestations remain confined to the eyes in 16 % (ocular myasthenia). Generalization of manifestations from the eyes to the rest of the body, if it occurs, usually occurs within three years of onset. Transient neonatal myasthenia, caused by placental transmission of antibodies from a myasthenic mother to her child, rarely lasts longer than two weeks.

Treatment. Cholinesterase inhibitors improve the disease manifestations by delaying the breakdown of acetylcholine and thereby prolonging its effect on the remaining functional acetylcholine receptors of the muscle fiber membrane. Pyridostigmine is given several times a day in individual doses of 10 to 60 mg.

Immune therapies with short-lasting effect are used to treat acute exacerbations of myasthenia gravis with impending respiratory failure (myasthenic crises). These include plasmapheresis and intravenous immunoglobulins. Corticosteroids and other immune suppressants, e. g., azathioprine, are given chronically to influence the disease process in the long term. Most patients with myasthenia gravis need these drugs. Steroid treatment can transiently worsen the manifestations of disease and should therefore be initiated very slowly or during an in-patient hospitalization. It usually takes two to four weeks for the positive effect to appear.

Thymectomy should be considered for every patient with myasthenia: the operation brings cures, or at least substantially improves, of myasthenia in 80 % of operated patients, after a latency period of several months or years. There is little controversy regarding the indication for thymectomy in patients below age 60, except for those with the mild ocular form of the disease. Good results have also been obtained in older patients. A thymoma, if present, must be surgically removed whatever the age of the patient. Adjuvant radiotherapy must be given if the resection is subtotal, because 25 % of these tumors undergo malignant degeneration. The operative approach should be chosen to allow the surgeon to inspect the mediastinum thoroughly, so that the thymus or thymoma can be completely resected.

Complications. Patients in the midst of a myasthenic crisis may require such high doses of cholinesterase inhibitors that they develop toxic manifestations such as nausea, diaphoresis, abdominal cramps, excessive tracheobronchial secretions, agitation, and anxiety. This syndrome is referred to, somewhat simplistically, as a cholinergic crisis. Long-term immunosuppressive ther-

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Table 14.10 Ossermann classification of myasthenia

IOcular myasthenia, i. e., limited to the eye muscles

IIa	Mild generalized myasthenia
IIb	Moderately severe generalized myasthenia, not involving
	muscles of respiration

IIIAcute, rapidly progressive myasthenia, beginning abruptly and progressing to involve

the muscles of respiration within 6 months of onset

IV Chronic, severe myasthenia; may develop from previous Class I or Class II disease after two years of a relatively stable course

Patients in Classes III and IV are subject to higher mortality and suffer more frequently from thymoma

apy can also cause complications, including leukopenia, increased susceptibility to infections, etc.

Seronegative myasthenia gravis and anti-MuSK antibodies. About 70 % of “seronegative” myasthenia gravis patients have antibodies to muscle-specific receptor typrosine kinase (MuSK). These patients are typically women under age 40 at disease onset in whom the cranial and bulbar muscles are severely affected. They often suffer from respiratory crises. Anticholinesterase drugs often yield no useful benefit and may even worsen the manifestations of disease. Thymectomy is also of no benefit. Immunosuppressive therapy, however, is usually effective, just as it is in seropositive myasthenia gravis.

Lambert−Eaton Syndrome

Etiology and pathogenesis. The clinical manifestations of this disease are caused by antibodies against voltagesensitive calcium channels in the motor nerve terminals at the motor end plate. Inactivation of these channels lessens the calcium influx induced by an incoming action potential and therefore results in the release of inadequate amounts of acetylcholine from the nerve terminal. The impairment of neuromuscular transmission in Lambert−Eaton syndrome is therefore located in the presynaptic cell (unlike myasthenia gravis). The underlying etiology in two-thirds of patients is a small-cell carcinoma of the lung: voltage-sensitive calcium channels on the cell membranes of the carcinoma cells initiate a misdirected autoimmune response. In cases of nonneoplastic origin, Lambert−Eaton syndrome is often seen in combination with other autoimmune conditions, such as pernicious anemia, hypoor hyperthyroidism, myasthenia gravis, Sjögren syndrome, and others. The thymus is not enlarged.

Clinical manifestations. The hallmark of this condition is weakness and, above all, abnormal fatigability of the muscles, predominantly in the pelvic girdle and lower limbs. The extraocular muscles and the levator palpebrae m. are sometimes mildly affected. Muscular strength transiently increases, at first, with exercise. The intrinsic muscle reflexes are often absent and many patients complain of dry mouth or other autonomic manifestations (orthostatic hypotension, impotence).

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Diseases of Muscle

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278 14 Diseases of Muscle (Myopathies)

Diagnostic evaluation. In the electromyogram, the first few muscle action potentials on repeated stimulation are low, and the subsequent ones are larger. This is particularly evident with high-frequency stimulation.

Treatment. The weakness and fatigability of muscle respond to immunoglobulins and plasmapheresis, and, in the long term, to corticosteroids and azathioprine. Cholinesterase inhibitors are not very effective.

Rare Myasthenia-like Syndromes

Hereditary myasthenic syndromes are usually of autosomal recessive inheritance. These genetic diseases may be due to either preor postsynaptic disturbances of neuromuscular transmission. Clinically, they are characterized by ocular manifestations and generalized muscle weakness. Cholinesterase inhibitors are therapeutically effective, as is 3,4-diaminopyridine in rare cases. Congenital myasthenia gravis and familial infantile

myasthenia are hereditary syndromes whose manifestations are present over the patient’s entire lifetime. The last-named disease can cause potentially lethal episodes of respiratory insufficiency in affected children, but its severity tends to lessen in later life.

“Slow channel” syndrome is of autosomal dominant inheritance. It usually becomes clinically evident in young adulthood. The underlying abnormality of neuromuscular transmission is that the cation channels of the acetylcholine receptors open too slowly. In addition to exercise-dependent muscle weakness, patients suffer from muscle atrophy. The usual treatments for myasthenia are ineffective in this disease.

Myasthenic weakness can be produced by a number of different substances, including organophosphates and penicillamine. Other substances can worsen myasthenia that is already present, such as aminoglycosides, quinine, antiarrhythmic drugs, and anticonvulsants.

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