Included under this title is a group of diseases affecting the neuromuscular junction, the most important of which is myasthenia gravis. Most of these disorders exhibit the characteristic and striking features of fluctuating weakness and fatigability of muscle. Some degree of weakness is usually present at all times but it is made worse by activity. The weakness and fatigability reflect physiologic abnormalities of the neuromuscular junction that are demonstrated by clinical signs and by special electrophysiologic testing. As an aid to understanding the diseases discussed in this chapter, the reader should consult the discussion of the structure and function of the neuromuscular synapse given in Chap. 45.

The cardinal feature of myasthenia gravis, usually referred to simply as myasthenia, is fluctuating weakness of voluntary (skeletal) muscles, particularly those innervated by motor nuclei of the brainstem, i.e., ocular, masticatory, facial, deglutitional, and lingual. Manifest weakening during continued activity, quick restoration of power with rest, and dramatic improvement in strength following the administration of anticholinesterase drugs such as neostigmine are the other notable characteristics. Myasthenia is an immune disease in which circulating antibodies against components of the motor postsynaptic membrane and subsequent structural changes in that membrane explain virtually all the features of the disease.

Historical Note

Several students of medical history affirm that Willis, in 1672, gave an account of a disease that could be none other than myasthenia gravis. Others give credit to Wilks (1877) for the first description and for having noted that the medulla was free of disease, in distinction to other types of bulbar paralyses. The first reasonably complete accounts were those of Erb (1878), who characterized the disease as a bulbar palsy without an anatomic lesion, and of Goldflam (1893); for many years thereafter, the disorder was referred to as the Erb-Goldflam syndrome. Jolly (1895) was the first to use the name myasthenia gravis, to which he added the term pseudoparalytica to indicate the lack of structural changes at autopsy. Also it was Jolly who demonstrated that myasthenic weakness could be reproduced in affected patients by repeated faradic stimulation of the motor nerve and that the “fatigued” muscle would still respond to direct galvanic stimulation of its membrane. Interestingly, he suggested the use of physostigmine as a form of treatment but there the matter rested until Reman, in 1932, and Walker, in 1934, demonstrated the therapeutic value of the drug. The relationship between myasthenia gravis and tumors of the thymus gland was first noted by Laquer and Weigert in 1901, and in 1949, Castleman and Norris gave the first detailed account of the pathologic changes in the gland.

In 1905, Buzzard published a careful clinicopathologic analysis of the disease, commenting on both the thymic abnormalities and the infiltrations of lymphocytes (called lymphorrhages) in muscle. In 1973 and subsequently, the autoimmune nature of myasthenia gravis was established through a series of investigations by Patrick and Lindstrom, Fambrough, Lennon, and A.G. Engel (1977) and their colleagues (see further on). These and other references to the historical features of the disease can be found in the reviews by Viets and by Kakulas and Adams; A.G. Engel’s monograph (1999) is an excellent comprehensive reference.

Clinical Manifestations

Myasthenia gravis, as the name implies, is a muscular weakness formerly with a grave prognosis. As mentioned, repeated or persistent activity of a muscle group exhausts contractile power, leading to a progressive paresis, and rest restores strength, at least partially. These are the identifying attributes of the disease and their demonstration, assuming that the patient cooperates fully, is usually enough to establish the diagnosis.

The special vulnerability of the neuromuscular junctions in certain muscles gives myasthenia a highly characteristic clinical appearance. Usually the eyelids and the muscles of eye movement, and somewhat less often, of the face, jaws, throat, and neck, are the first to be affected. Infrequently the initial complaint is referable to the limbs or to breathing. Specifically, weakness of the levator palpebrae or extraocular muscles is the initial manifestation of the disease in about half the cases, and these muscles are involved eventually in more than 90 percent of cases. Ocular palsies and ptosis are usually accompanied by weakness of eye closure, a combination that is virtually always indicative of the disease although it may be observed in certain muscular dystrophies. Diplopia is common in myasthenia, but it does not correspond to the innervatory pattern of a nerve; instead, it is the result of asymmetrical weakness of several muscles in both eyes. As the disease advances, it spreads insidiously from the cranial to the limb and axial muscles, but there are instances of fairly rapid development, sometimes initiated by an infection, usually respiratory. In rare cases, the distal extremity muscles may be involved, such as the “myasthenic hand” described by Janssen and colleagues. Symptoms may first appear during pregnancy or, more commonly, during puerperium or in response to drugs used during anesthesia.

In addition to certain circulating autoantibodies, inflammatory thymic abnormalities of several types are closely connected with the disease, as elaborated further on, and weakness may begin months or years before or after removal of a thymoma.

Particular ocular signs are highly characteristic of myasthenia. For example, sustained upgaze for 30 or more seconds will usually induce or exaggerate ptosis and may uncover myasthenic ocular motor weakness. Cogan described a twitching of the upper eyelid that appears a moment after the patient moves the eyes from a downward to the primary position (“lid-twitch” sign). Or, after sustained upward gaze, one or more twitches may be observed upon closure of the eyelids or during horizontal movements of the eyes. Repeated ocular versions when tracking a target or by an optokinetic stimulus may disclose progressive paresis of the muscles that carry out these movements. Unilateral painless ptosis without either ophthalmoplegia or pupillary abnormality in an adult will most often prove to be a result of myasthenia. Usually, there is subtle ptosis of the other eye that can be revealed by manually elevating the more affected eyelid. Attempts by the patient to overcome ptosis may impart a staring expression of the opposite eye. Bright sunlight is said to aggravate the ocular signs and cold to improve them. The application of an ice pack over the eye often relieves the ptosis for a brief period.

Muscles of facial expression, mastication, swallowing, and speech are affected in 80 percent of patients at some time in the illness, and in 5 to 10 percent, these are the first or only muscles to be involved. Less frequent is early involvement of the flexors and extensors of the neck, muscles of the shoulder girdle, and flexors of the hips. (This pattern may be associated with a special autoantibody as discussed later.) Of the trunk muscles, the erector spinae are the most frequently affected. In the most advanced cases, all muscles are weakened, including the diaphragmatic, abdominal, and intercostal, and even the external (skeletal muscle) sphincters of the bladder and bowel. As the disease progresses, the involvement of any group of muscles closely parallels their degree of weakness early in the disease. The clinical rule also holds that the proximal muscles are far more vulnerable than distal ones, as they are in most other forms of myopathy.

Another characteristic and understandable feature of myasthenic weakness is its tendency to increase as the day wears on or with repeated use of an affected muscle group but curiously, patients seldom volunteer this information. A few patients report paradoxical worsening on awakening, especially if they have not taken medication during the night. In general terms, therefore, myasthenia gravis may be conceived as a fluctuating and fatigable oculofaciobulbar palsy.

Other features conform to the topography and fatigability of the disease. The natural smile becomes transformed into a snarl; the jaw may sag, so that it must be propped up by the patient’s hand; chewing tough food may be difficult and the patient may have to terminate a meal because of inability to masticate and swallow. It may be more difficult to eat after talking, and the voice fades and becomes nasal after sustained conversation. Women may complain of inability to fix their hair or makeup because of fatigue of the shoulders, or of difficulty in applying lipstick because they are unable to purse and roll their lips. Weakness of the neck muscles causes fatigue in holding up the head. In cases with generalized weakness, there is difficulty in retaining flatus because of weakness of the external rectal sphincter.

A peculiarity of myasthenic muscle contraction that may be observed occasionally is a sudden lapse of sustained posture or interruption of movement resulting in a kind of irregular tremor, similar to that of normal muscle nearing the point of exhaustion. A dynamometer demonstrates the rapidly waning power of contraction of a series of hand grips, and repetitive stimulation of a motor nerve at slow rates while recording muscle action potentials shows the same decremental strength in a quantitative fashion (see Fig. 45-4A and further on).

Weakened muscles in myasthenia gravis undergo atrophy to only a minimal degree or not at all. Tendon reflexes are seldom altered. Even repeated tapping of a tendon does not usually tax muscles to the point where contraction fails. Smooth and cardiac muscles are not involved and other neural functions are preserved. Weakened muscles, especially those of the eyes and back of the neck, may ache, but pain is seldom an important complaint. Paresthesias of the face, hands, and thighs are reported infrequently but are not accompanied by demonstrable sensory loss. The tongue may display one central and two lateral longitudinal furrows (trident tongue), as pointed out originally by Buzzard; the tongue may be atrophic in the MuSK (muscle-specific tyrosine kinase) form of disease (see further on).

Certain epidemiologic features of the disease are of clinical interest. Its prevalence is variously estimated to be from 43 to 84 per million persons and the annual incidence rate is approximately 1 per 300,000. The disease may begin at any age, but onset in the first decade is relatively rare (only 10 percent of cases begin in children younger than 10 years of age). The peak age of first symptoms is between 20 and 30 years in women and between 50 and 60 years in men. Under the age of 40, females are affected two to three times as often as males whereas in later life, the incidence in males is higher (3:2). Of patients with thymomas, the majority is older (50 to 60 years) and males predominate.

Familial occurrence of myasthenia is known, but it is rare. Many such cases prove to have one of the genetically determined myasthenic syndromes and not the acquired autoimmune form of disease (see further on). More common is a family history of one of the autoimmune diseases enumerated earlier. For example, in the series reported by Kerzin-Storrar and associates 30 percent had a maternal relative with a connective tissue disease, suggesting that myasthenia gravis patients inherit a susceptibility to autoimmune disease. Two of our patients have sisters with lupus. There have also been reports of the concurrence of myasthenia and multiple sclerosis, but this association is less certain. There is an increased representation of HLA-B8 and -DR3 haplotypes, as occurs in other autoimmune diseases, which is discussed further on.

Clinical Grading

To facilitate clinical staging of therapy and prognosis, the classification introduced by Osserman remains useful; it can be found in his monograph cited in the references and in previous editions of this book. This system has been replaced by a scheme suggested by a task force of the Myasthenia Gravis foundation (see Jaretzki et al) as reproduced here.

• Class I Any ocular muscle weakness
  
  
  
  • May have weakness of eye closure
    
  • All other muscle strength is normal
  
  
• Class II Mild weakness affecting other than ocular muscles
  
  
  
  • May also have ocular muscle weakness of any severity
  
  
• IIa Predominantly affecting limb, axial muscles, or both
  
  
  
  • May also have lesser involvement of oropharyngeal muscles
  
  
• IIb Predominantly affecting oropharyngeal muscles, respiratory muscles, or both
  
  
  
  • May also have lesser or equal involvement of limb, axial muscles, or both
  
  
• Class III Moderate weakness affecting other than ocular muscles
  
  
  
  • May also have ocular muscle weakness of any severity
  
  
• IIIa Predominantly affecting limb, axial muscles, or both
  
  
  
  • May also have lesser involvement of oropharyngeal muscles
  
  
• IIIb Predominantly affecting oropharyngeal muscles, respiratory muscles, or both
  
  
  
  • May also have lesser or equal involvement of limb, axial muscles, or both
  
  
• Class IV Severe weakness affecting other than ocular muscles
  
  
  
  • May also have ocular muscle weakness of any severity
  
  
• IVa Predominantly affecting limb and/or axial muscles
  
  
  
  • May also have lesser involvement of oropharyngeal muscles
  
  
• IVb Predominantly affecting oropharyngeal muscles, respiratory muscles, or both
  
  
  
  • May also have lesser or equal involvement of limb, axial muscles, or both
  
  
• Class V Intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

Others, for example, Compston and colleagues, have proposed a classification based on a constellation of the age of onset, presence or absence of thymoma, antibody level against acetylcholine receptor (AChR), and association with human leukocyte antigen (HLA) haplotypes. Their system is as follows: (1) myasthenia gravis with thymoma—no sex or HLA association, high AChR antibody titer; (2) onset before age 40, no thymoma—female preponderance and an increased association with HLA A1, B8, and DRW3 antigens; (3) onset after age 40, no thymoma—male preponderance, increased association with HLA A3, B7, and DRW2 antigens, low AChR antibody titer. The last group includes a proportion of older men with purely ocular symptoms (formerly Osserman type I). Classifications such as these are meant to capture certain types and contexts of myasthenia more than to convey the severity of illness.

Course and Prognosis

The course of the illness is extremely variable. Rapid spread from one muscle group to another occurs in some, but in others the disease remains unchanged for years before progressing or there is no progression. Remissions may take place without explanation, usually in the first years of illness, but these happen in less than half the cases and seldom last longer than a month or two. If the disease remits for a year or longer and then recurs, it then tends to be steadily progressive. Relapse may also be occasioned by the same events that in some cases preceded the onset of the illness, especially infections.

In Simpson’s opinion, and this coincides with our observations, the danger of death from generalized myasthenia gravis is greatest in the first year after onset of the disease. A second period of danger in progressive cases is from 4 to 7 years after onset. After this time, the disease tends to stabilize and the risk of severe relapse diminishes. Fatalities relate mainly to the respiratory complications of pneumonia and aspiration. The mortality rate in the first years of illness, formerly in excess of 30 percent, is now less than 5 percent and with appropriate therapy virtually all patients lead productive lives.

An aspect of interest is the timing and frequency of conversion from ocular and restricted oropharyngeal patterns of weakness to more widespread involvement including the diaphragm. Bever and coworkers have confirmed the general impression that an increasing duration of purely ocular myasthenia is associated with a decreasing risk of late generalization of weakness. In a retrospective study of 108 patients, these authors found that only 15 percent of the observed instances of generalization occurred more than 2 years after isolated ocular manifestations.

A later age at onset was also associated with a higher incidence of fatal respiratory crises. In general, patients whose disease begins at a younger age run a more benign course. Grob and colleagues, who recorded the course of an astonishing 1,036 patients for a mean duration of 12 years, found that the clinical manifestations remained confined to the extraocular muscles and orbicularis oculi in 16 percent. Their data further indicated that localized ocular myasthenia present for only a month was associated with a 60 percent likelihood that the disease would generalize, but in those cases that remained restricted for more than a year, only 16 percent became generalized. In contrast, of 37 consecutive cases carefully studied by Weinberg with only ocular signs, 17 had more widespread weakness within a period of 6 years. Also informative in Grob’s series was that in 67 percent the disease attained its maximum severity within a year of onset, and in 83 percent, within 3 years. It has been stated that the progression of symptoms is more rapid in male than in female patients.

It is not widely recognized that isolated muscle groups may occasionally remain permanently weak even when the ocular and generalized weakness has resolved. The muscles most often affected in this way are the anterior tibialis, triceps, and portions of the face.

The long-term outlook for children with myasthenia is better than it is for adults, and their life expectancy is only slightly reduced. Rodriguez and colleagues followed a group of 149 children for an average of 17 years; 85 of them had thymectomies, one of the main treatments for myasthenia as discussed further on. Approximately 30 percent of the nonthymectomized and 40 percent of the thymectomized patients underwent remission and were free of symptoms, usually in the first 3 years of illness. Those children with bulbar symptoms and no ocular or generalized weakness had the most favorable outcome.

Thymic and Systemic Disorders Associated with Myasthenia

A nonneoplastic lymphofollicular hyperplasia of the thymic medulla occurs in 65 percent or more of cases of myasthenia and thymic tumors occur in 10 to 15 percent. Thymomas with malignant characteristics may spread locally in the mediastinum and to regional lymph nodes but they rarely metastasize beyond these structures; when they do, the lungs and liver are usually affected. It should be emphasized that thymic enlargement and tumors may be missed in plain films of the chest and should be sought by CT scanning.

A striking degree of hyperplasia of the medulla of the thymus characterized by lymphoid follicles with active germinal centers is found in the majority of cases. Hyperplasia is even more frequent in younger patients in the third and fourth decades. The cells in the centers of the follicles are histiocytes surrounded by helper T lymphocytes, B lymphocytes, and plasma cells; immunoglobulin G (IgG) is elaborated in the germinal follicles. These resemble the cellular reaction observed in the thyroid tissue of Hashimoto thyroiditis. Because the latter disease has been reproduced in animals by injecting extracts of thyroid with Freund adjuvants, it had long ago been suggested that the so-called thymitis of myasthenia gravis is the result of a similar autoimmune sensitization but the inciting events for this process are entirely unknown. Immunosuppression with steroids causes involution of the thymus.

With regard to thymic tumors, two forms have been described: one composed of histiocytic cells like the reticulum cells in the center of the follicles, and the other predominantly lymphocytic and considered to be lymphosarcomatous. Some of the tumors have a high proportion of spindle-shaped cells. Overlapping types have been common. Thymic tumors may be unattended by myasthenia, though myasthenia has eventually developed in all of the cases under our observation, sometimes 15 to 20 years after the tumor was removed surgically. According to Bril and colleagues, the severity of myasthenic symptoms is no different in patients with thymoma than it is from that in patients without a tumor, but our impression has been that patients with tumors, particularly children, often have a peculiar clinical course. For example, we have observed unexpected sudden remissions and severe relapses, as well as resistance to medications.

Many contemporary studies, including more than 40 autopsies at our hospitals, have confirmed Erb’s original contention that myasthenia gravis is a disease without a central nervous system lesion. The brain and spinal cord are normal unless damaged by hypoxia and hypotension from cardiorespiratory failure. Furthermore, the muscle fibers are generally intact, although in fatal cases with extensive paralysis, isolated fibers of esophageal, diaphragmatic, and eye muscles may undergo segmental necrosis with variable regeneration (Russell). Scattered aggregates of lymphocytes (lymphorrhages) are also observed, as originally noted by Buzzard, but none of these changes in muscle explains the widespread and severe weakness.

The main ultrastructural alterations occur in the motor endplate. These changes, elegantly demonstrated by A.G. Engel and associates (1976, 1977, 1987), consist of a reduction and simplification in the surface area of the postsynaptic membrane (sparse, shallow, abnormally wide, or absent secondary synaptic clefts) and a widening of the synaptic cleft (Fig. 49-1). The number and size of the presynaptic vesicles and their quanta of acetylcholine (ACh) are normal. The observation of regenerating axons near the junction, the many simplified junctions, and the absence of nerve terminals supplying some postsynaptic regions suggested to Engel and coworkers (1976, 1977, 1987) that there was an active process of degeneration and repair of the neuromuscular junction, particularly of the postsynaptic side.

Although not directly relevant to myasthenia, it is of interest that a number of curious neurologic disorders occur in association with thymoma. Among our own patients were 2 with “limbic encephalitis” with memory loss and confusion that could not be differentiated from the paraneoplastic variety of encephalitis (see Chap. 31), 1 case of midbrain encephalitis, 1 of Morvan’s fibrillary chorea (discussed in Chap. 50), and 1 of aplastic anemia. Some of these neurologic processes are associated with antibodies directed against voltage-gated potassium channels (VGKC). Such cases appear in the literature, and all are considered to have a humoral immune basis.

Of biologic and even greater clinical importance is the coexistence of myasthenia gravis and other autoimmune diseases. Thyrotoxicosis with periodic paralysis (5 percent of myasthenic patients; see further on and Chap. 50), lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, mixed connective tissue disease, anticardiolipin antibody, and (curiously) polymyositis have all been associated with myasthenia more often than can be explained by chance. A proportion of young women with myasthenia have moderately elevated titers of antinuclear antibody without the clinical manifestations of systemic lupus.

Etiology and Pathogenesis

The clear demonstration of an immunologic mechanism operative at the neuromuscular junction was the most significant development in our understanding of myasthenia gravis. Patrick and Lindstrom discovered that repeated immunization of rabbits with AChR protein obtained from the electric eel caused a muscular weakness (contrary to what is stated in some books, their discovery was not accidental). Lennon and colleagues recognized this model as being similar to that of myasthenia gravis. Soon thereafter, Fambrough and coworkers demonstrated that the basic defect in myasthenia gravis was a marked reduction in the number of ACh receptors on the postsynaptic membrane of the neuromuscular junction. These observations were followed by the creation of an experimental model of the disease and the demonstration that experimentally induced myasthenia had clinical, pharmacologic, and electrophysiologic properties identical with those of human myasthenia gravis (Engel et al, 1976). It was also shown that humoral antibodies directed against protein components of AChR could transfer the myasthenic weakness to normal animals, and that the weakness as well as the physiologic abnormalities could be reversed by the administration of anticholinesterase drugs. Thus, the accumulated evidence satisfied the criteria for the diagnosis of an autoantibody-mediated disorder (Drachman, 1990).

The present view is that myasthenic weakness and fatigue are a result of the failure of effective neuromuscular transmission on the postsynaptic side. The greatly reduced number of receptors and the competitive activity of anti-AChR antibodies (see later) produce postsynaptic potentials of insufficient amplitude to discharge some muscle fibers. Blocked transmission at many endplates results in a reduction in the contractile power of the muscle. This deficiency is reflected first in the ocular and cranial muscles that are both the most continuously active and have the fewest AChRs per motor unit. Fatigue is understandable as the result of the normal decline in the amount of ACh released with each successive impulse.

Antibodies to AChR protein are present in more than 85 percent of patients with generalized myasthenia and in 60 percent of those with ocular myasthenia (Newsom-Davis). The presence of receptor antibodies has proved to be a reasonably sensitive and reliable test of the disease, as discussed later. The manner in which the antibodies that are directed against proteins in the intracellular compartment (such as anti-MuSK discussed later) causes weakness is not known.

Neuromuscular transmission is therefore impaired in several ways: (1) the antibodies block the binding of ACh to the AChR; (2) serum IgG from myasthenic patients has been shown to induce an increase in the degradation rate of AChR. This may be the result of the capacity of antibodies to cross-link the receptors; (3) antibodies cause a complement-mediated destruction of the postsynaptic folds (Engel and Arahata).

Although the evidence that an autoimmune mechanism is responsible for the functional disorder of muscle in myasthenia gravis is incontrovertible, the source of the autoimmune response has not been established. Because most patients with myasthenia have thymic abnormalities and a salutary response to thymectomy, it is logical to implicate the lymphoid reaction in this gland in the pathogenesis of the disease. Both T and B cells from the myasthenic thymus are particularly responsive to the AChR, more so than analogous cells from peripheral blood. Moreover, the thymus contains “myoid” cells (resembling striated muscle) that bear surface AChR. It is not known with certainty that thymic myoid cells are the source of immunologic stimulation in myasthenia gravis. The most obvious objection is that such cells are even more abundant in the normal than in the myasthenic thymus (according to Schluep et al). Another suggested pathogenesis, yet unconfirmed, is that a virus with a tropism for thymic cells might alter such cells and induce antibody formation. A viral infection might at the same time have a potential for oncogenesis, accounting for thymic tumors, but this is all speculative. Scadding and associates have suggested a different mode of thymic involvement; they have shown that thymic lymphocytes from patients with myasthenia gravis can synthesize anti-AChR antibody, both in culture and spontaneously.

Diagnosis

In patients who present with a changeable, specifically fatigable, diplopia or ptosis and the typical myasthenic facies—unequally drooping eyelids, relatively immobile mouth turned down at the corners, a smile that looks more like a snarl, a hanging jaw supported by the hand—the diagnosis can hardly be overlooked. However, only a few patients display this fully developed syndrome. Ptosis, diplopia, difficulty in speaking or swallowing, or weakness of the limbs is at first mild and inconstant and may be mistaken for a cerebrovascular disease. However, the finding that sustained activity of small cranial muscles results in weakness (e.g., increasing droop of eyelids while looking at the ceiling or diplopia when fixating in lateral or vertical gaze or reading for 2 to 3 min) and that contraction improves after a brief rest is virtually diagnostic, even in the early stages of the disease. Any other affected group of muscles may be tested in similar fashion. The characteristic ocular signs have already been described. For confirmation, the measurement of specific antibody (anti-AChR), electromyography, and certain pharmacologic tests described below are necessary. Several special clinical problems and associated conditions are summarized further on.

Electrophysiologic Testing

Characteristic of myasthenia is a rapid reduction in the amplitude of compound muscle action potentials during a series of repetitive stimulations of a peripheral nerve at a rate of 3 per second (decrementing response as shown in Fig. 45-4A). Reversal of this response by neostigmine or edrophonium has been a reliable confirmatory finding in most cases. A decremental response to stimulation can usually be obtained most often from the proximal limb muscles followed by the facial and, to a lesser extent, the hand muscles, which may or may not be clinically weak. During a progressive phase of the disease or during corticosteroid therapy, a slight initial incrementing response may be obtained, not to be confused with the marked incrementing response after voluntary contraction that characterizes the Lambert-Eaton syndrome (see further on).

Single-fiber electromyography (EMG) represents an even more sensitive method of detecting the defect in neuromuscular transmission. This technique demonstrates an inconstancy of the normally invariant interval between the firing of muscle fibers connected to the same motor unit (“jitter”—see “Single-Fiber Electromyography” in Chap. 45) or complete blocking of successive discharges from single muscle fibers belonging to the same motor unit. The test requires a great deal of cooperation from the patient and that contraction of a muscle be sustained at just the right amplitude in order to isolate single muscle fibers from the same unit. It is also possible to detect such pairs of fibers by electrical stimulation of a nerve. Nerve conduction velocities and distal motor latencies are normal unless there is a coincident polyneuropathy.

Neostigmine Test

Almost as valuable as electrophysiologic testing is testing with the anticholinesterase inhibitors neostigmine and in the past, edrophonium a more rapidly acting agent. These drugs prolong and exaggerate the effects of ACh in the synapse and thereby produce an increment in muscle power in the patient with myasthenia. Edrophonium is not easily available in the United States at the time of this writing but neostigmine affords a longer time for observation, as noted in the next paragraph. The tests are performed in the following manner. After the estimation of strength in a cranial (usually the levator palpebrae or an extraocular muscle) or limb muscle (by dynamometry), or vital capacity, neostigmine is injected intramuscularly in a dose of 1.5 mg. Atropine sulfate (0.8 mg) should be given several minutes in advance to counteract the unpleasant muscarinic effects of neostigmine (salivation, sweating bronchorrhea, borborygmi, bowel cramps and, sometimes, diarrhea). Neostigmine may alternatively be given intravenously in a dose of 0.5 mg, but its effect is often too brief to be as useful. After intramuscular injection of neostigmine, objective improvement occurs within 10 to 15 min, reaches its peak at 20 min, and lasts up to 1 h, allowing for careful verification of the neurologic improvement. Many neurologists perform this test twice, once with an injection of saline as a control.

Alternatively, 1 mg (0.1 mL) of edrophonium is given intravenously; if this dose is tolerated and no definite improvement in strength occurs after 45 s, another 4 to 9 mg is injected. A total dose of 10 mg is rarely necessary. Most patients who respond do so after 3 to 5 mg has been administered. The mild muscarinic effects of edrophonium are blocked by pretreatment with atropine 0.8 mg subcutaneously as for neostigmine. The clinical effect of improved ptosis, extraocular movements, oropharyngeal function, arm and shoulder abduction, or vital capacity persists for no more than 5 min with edrophonium and 60 min with neostigmine.

One caution: with either drug, some patients deteriorate immediately, but briefly, as a result of an increase in pulmonary secretions. A positive test consists of visible (objective) improvement in muscle contractility, fusion of diplopia, or resolution of fatigable ptosis. Dynamometry and measurement of forced vital capacity serve as more objective markers of improvement, or lack of effect. The report of subjective improvement alone is not dependable and one must be distrustful of equivocal test results, which may occur with ocular palsies due to tumors, thyroid disease, Guillain-Barré syndrome (GBS), progressive supranuclear palsy, or carotid aneurysms (pseudoocular myasthenia).

A negative test with an anticholinesterase agent does not entirely exclude myasthenia gravis but is a strong point against the diagnosis. In a small number of patients with periodic and purely ocular symptoms who later prove to have myasthenia gravis, the edrophonium and neostigmine tests (and electrophysiologic studies and AChR antibody measurements) may be entirely normal during the first or even after several acute episodes. Only later, for inexplicable reasons, do these tests become positive. Finally, the anticholinesterase-inhibiting drugs carry a small risk of inducing ventricular fibrillation and cardiac arrest so that testing should be carried out where emergency support is accessible.

Measurement of Receptor Antibodies in Blood

The detection of anti-AChR antibodies provides a reasonably sensitive and highly specific test for the diagnosis of myasthenia. The radioimmunoassay method of detection is accurate and widely used. Serum antibodies are found in 80 to 90 percent of patients with generalized myasthenia gravis and in approximately 60 percent of those whose symptoms are restricted to the ocular muscles (Vincent and Newsom-Davis). For the most part, adults with myasthenia whose sera are persistently negative for AChR antibodies do not differ clinically or electromyographically from those with antibodies with the exception noted below. Persistently negative AChR antibody tests are more frequently found in patients with ocular myasthenia than in patients with generalized weakness. Patients with a thymoma and severe generalized myasthenia are practically always seropositive. Interestingly, the antibody titers usually remain elevated during clinical remissions.

Instances of “seronegative” disease are sometimes due to antibody production against unusual muscle epitopes that are located on or near the acetylcholine receptor; their detection requires a special panel of tests. However, the majority of such cases have been ascribed to IgG antibodies directed against an intracellular muscle-specific kinase (MuSK). This enzyme plays a role in supporting the normal structure of the postsynaptic membrane and in the arrangement of AChR but its main function may be in developmental synaptic differentiation. Scuderi and colleagues and others have proposed that patients with MuSK antibody, mostly women, have a special clinical syndrome of prominent oculobulbar weakness, often with severe disease and respiratory crises (see also Evoli et al). Others have reported a different pattern of mainly neck and proximal weakness that simulates a typical myopathy. Many of these patients are inadequately responsive to anticholinesterase treatment. Also of interest, but not currently used in routine diagnosis, is the presence of antibodies directed against striated muscle in almost half of myasthenic patients and an even higher incidence (stated to be 85 percent) in patients who also have a thymoma.

Each of the commonly used diagnostic tests, electrophysiology, edrophonium, and antibodies, proves to be about equally reliable. Kelly and coworkers obtained positive results with single-muscle-fiber recording in 79 percent, with the antireceptor antibody test in 71 percent, and with the edrophonium test in 81 percent. Combined, they confirmed the diagnosis in 95 percent of clinically suspected cases. Presumably, had the anti-MuSK receptor antibody test been available, the sensitivity of serologic diagnosis would have been higher.

In keeping with the observation of some myasthenic patients that their weakness improves in the cold, a test has been devised in which an ice pack is placed over a ptotic eyelid for 2 min or to the limit of the patient’s tolerance. Sethi and colleagues found that ptosis was diminished in 8 of 10 patients. In our patients, this effect has not been as consistently evident, but it may be a useful adjunctive test.

Other diagnostic tests performed routinely in essentially all patients with myasthenia gravis include CT of the chest (for the detection of thymic enlargement or thymoma), tests of thyroid function for reasons discussed further on, and in cases of uncertain diagnosis, magnetic resonance imaging of the cranium and orbits to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.

Special Diagnostic Problems

We have encountered the following clinical problems in myasthenia:

1. 
   

   The concurrence of myasthenia gravis and thyrotoxicosis. Thyrotoxicosis may produce a characteristic ocular myopathy and there is a tentative relation to periodic paralysis as indicated in Chap. 50. There is no certain evidence that thyrotoxicosis aggravates myasthenia gravis; some have even observed an inverse relationship between the severity of the two conditions. Hypothyroidism, however, does worsen the myasthenic symptoms. The ophthalmoplegia of thyrotoxicosis can usually be distinguished by the presence of an associated exophthalmos (early in the disease, exophthalmos may be absent), lack of ptosis, and the lack of definitive response to neostigmine. Polymyositis and inclusion body myopathy are differentiated from myasthenia by lack of involvement of extraocular muscles, but they may affect oropharyngeal muscles, as does myasthenia. Finding the signs of these diseases in combination with those of myasthenia indicates a concurrence of two independent autoimmune diseases.

   
   
2. 
   

   The neurasthenic or depressed patient who complains of weakness when actually referring to fatigability.

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   Disorders of the Special Senses Chapter 20. Delirium and Other Acute Confusional States Chapter 24. Fatigue, Asthenia, Anxiety, and Depression Chapter 28. Normal Development and Deviations in Development of the Nervous System Chapter 50. The Myotonias, Periodic Paralyses, Cramps, Spasms, and States of Persistent Muscle Fiber Activity Chapter 38. Developmental Diseases of the Nervous System
   

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