Although the cause of myasthenia gravis is still unknown, its pathogenesis appears clear: immunologic attack on synaptic receptors in muscle causes receptor deficiency, decreased miniature endplate potentials, and decrements in the compound action potentials evoked from muscles on repetitive stimulation of peripheral nerves. In addition to the involvement of skeletal muscle, some MG patients may manifest subtle alterations of the function of heart, lung, smooth muscle, and CNS, indicating that this is truly a systemic disorder. Modern therapy involves adjusting treatment to the needs of individual patients. Anticholinesterases, calcium, ephedrine, potassium, and germine partially correct the defect in neuromuscular transmission; prednisone, ACTH. cytotoxic drugs, antilymphocyte serums, gamma globulin, thoracic duct drainage, plasmapheresis,and thymectomy partially modify the abnormalities of the immune system. MUSCLE a NERVE

1:190-205

1978

DlAGNOSlS AND MANAGEMENT BERNARD M. PATTEN, MD, FACP

I n the last five years, significant research advances have taken place which have promoted our understanding of myasthenia gravis (MG). As a consequence, M G has been identified not only as a disorder of skeletal muscle but also as one of the foremost examples of autoimmune disease in man. In addition, subtle alterations of heart, lung, smooth muscle, and central nervous system have been described that indicate that M G is truly a systemic disorder. O u r new understanding of methods to modify this condition has permitted, in most cases, a dramatic improvement in the prognosis of M G and has given us a number of effective tools for management. This article presents the current concepts of M G in a review of the clinical characteristics and the current methods of diagnosis and management of this disease. CLINICAL FEATURES

T h e single most important clinical feature of M G is weakness of skeletal muscle worsened by exercise and relieved by rest. Without this feature there can be no diagnosis. This weakness with easy fatigability is the From the Department of Neurology, Baylor College of Medicine. Houston. TX Acknowledgments Dr Yadollah Harati read, criticized. and corrected the manuscript Terry Tomkins organized the tables and typed the drafts This work was supported by a grant from the South Texas Chapter of the Myasthenia Gravis Foundation. a grant Irom the Muscular Dystrophy Associations of America, Inc , a gift from Rosalie and Joe Eisenberg of San Antonio, T X , and a gift from Dorothy and Leon Williams of Brownwood, TX Address reprint requests to Dr Patten at the Department of Neurology, Baylor College of Medicine, Houston. TX 77030 Received for publication March 3, 1978

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only constant in the disease-and all other features are variable. For instance, the weakness is usually worse in the afternoon and evening, though some patients are weaker in the mornings when they first awake. Usually the muscles supplied by the cranial nerves are the first and the most severely affected, with resultant diplopia, ophthalmoplegia, dysphagia, dysphonia, dyspnea, and dysmimia. Then the disease may involve proximal lower- a n d upper-extremity muscles. In rare instances, however, proximal muscles weaken first. T h e involvement of individual muscles may be symmetric but often is asymmetric, with the dominant leg and arm usually weaker than their nondominant counterparts. M G can also present as weakness in a single muscle, for example, the external rectus or superior oblique in one eye; .or as a single complaint, for example, jaw ptosis from inability to close the mouth. Rarely, it presents as a symptom seemingly unrelated to the neuromuscular system, for example, burning eyes from exposure keratitis (from incomplete eye closure during sleep) or sore throat on waking (from mouth-breathing during sleep). T h e disease may affect people a t any age and of either sex. It varies in severity from mild nonprogressive disease involving eyes only (ocular form), to severe cases that may be rapidly fatal, such as the acute fulminant form usually afflicting older men. PHYSICAL SIGNS

No two myasthenic patients look alike or have the same signs or symptoms. T h e classic appearance of the patient with moderately severe disease is unmistakablc (fig. 1). However, the more subtle early presentations

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Figure 1 . Typical facial appearance of myasthenia. Note that the corners of the mouth do not rise despite the patient's best effort to smile. Left ptos~sIS almost complete, and the forehead is wrinkled and the eyebrows elevated to try to compensate for this.

are just as important and should not be missed (fig. 2). Detailed examination of individual muscles often shows excessive fatigue and weakness, which should alert the physician to the presence of neuromuscular disease. In uncomplicated MG, aside from weakness and fatigability of the involved muscles, there are few physical signs. Trigrooved tongue, though common, is not specific for MG since it can be found in amyotrophic lateral sclerosis. However, the appearance and disappearance of trigrooved tongue with treatment is a way of distinguishing M G from other neuromuscular conditions associated with this sign. Deep tendon reflexes are usually hyperactive, sometimes with clonus. If a reflex is repeatedly elicited, the jerk may decrease progressively until it disappears. There is increasing interest in those clinical observations that suggest the disorder involves much more of the body than just skeletal muscle dysfunction. Evidence is slowly accumulating that points to involve-

Diagnosis and Management of MG

Figure 2. This woman might look normal even to the experienced physician. Note, however, the failure of the corners of the mouth to rise when she smiles and the slight droop of the left eyelid with the attempt to compensate by elevation of the outside margin of the left eyebrow. She complained of easy fatigability of sixmonths duration. The only finding on examination, besides the mild ptosis, was weakness of the deltoids. At operation. the surgeon removed a hyperplastic thymus within which was a golf-ball-sized rnvasive thymoma. This patient illustrates the importance of thymectomy even in those who have mild myasthenia.

ment of the central nervous system in this disorder. In my experience, a small percentage of patients will have transient signs usually considered indicative of CNS dysfunction, such as Hoffrnann sign, cross adductor reflexes, and unilateral or bilateral Babinski signs. These usually disappear as the disease comes under therapeutic control. The presence of abnormal reflexes in myasthenia gmvis should not cause undue concern. Angiograms and myelograms are not needed to evaluate these findings. We already know that MG is associated with normal contrast studies. Of course, persistent signs of central nervous dysfunction, especially when associated with cerebellar signs or optic neuritis, should point to the possibiIity that the patient

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has the overlap syndrome-in which clinical and laboratory features of myasthenia gravis and multiple sclerosis coexist in the same patient a t the same time.77 I have been impressed that some patients with myasthenia complain of decreased intellectual ability, emotional lability, and insomnia, all of which improve with treatment. Abnormal sleep with decreased rapid eye movement time has been reported recently. 75 MG patients have a higher than normal frequency of seizures. Transitory trigeminal anesthesia,? anosmia,j ageusia,% as well as muscle stiffness are found in myasthenia.gOThese findings suggest another group of abnormalities (little understood and as yet not investigated) which involve central cholinergic transmission. The presence in human MG5? and in experimental autoimmune MG in rabbits?* of cholinergic receptor antibodies, which are produced locally in the central nervous system and circulate in the cerebrospinal fluid, may help to explain the observations that suggest a concomitant disorder in the central nervous system. EVIDENCE FOR SYSTEMIC INWLVEMENT

Myocardial abnormalities exist in myasthenia. In one recent series, over 40% of myasthenic patients had prolonged Q-T intervals on electrocardiogram (ECG) and about 20% had sinus tachycardia or bundlebranch block. l 2 Kinetocardiograms may show paradoxical systolic outward movements indicative of myocardial dyskinesis,6' and one autopsied patient had myocardial necrosis. I Smooth-muscle involvement has been documented less commonly. Intestinocolonic measurements in 84 patients confirm gut involvement in MG; interestingly, these smooth-muscle defects improve after thymectomy.9s Direct pupillary responses to light and the derivative curves (velocity and acceleration) of pupillary reactions can be recorded by infrared video pupillography. Analysis of the pupillary responses showed a reduction in amplitude, maximal velocity, and maximal acceleration of pupillary constriction in the myasthenic patients compared with normals.'"' O n the other hand, changes in pupillary dilation were minimal. Abnormal values returned toward normal within 5 min after intravenous injection of 5 mg of edrophonium hydrochloride.lo1 These results suggest that the iris sphincter is commonly involved in myasthenia. Some myasthenia have cold hands and feet and red shiny skin around the nail beds and over the elbows and knees-changes reminiscent of those of dermatomyositis but less severe. Lung abnormalities are also present in some. Severe bronchial asthma was present in 4% of my own patients. Other patients may

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have alterations of length-tension characteristics of the alveoli and episodic large (e.g., 2-liter) changes in functional residual capacity.69Alternate-day prednisone may be associated with a small reduction in respiratory function during the off day.68 There appears to be an increased risk of cancer, especially in patients who have not had thymectomy. In a recent series, 126 neoplasms were found among 1,556 myasthenic patients (8%).74The period of highest risk followed the onset of disease in those who had not undergone thymectomy. Of all neoplasms, one-half occurred within the first 5 years of disease-more than two-thirds within the first 10 years. Colorectal cancer was the most common primary finding in myasthenic men. Breast cancer was the most common primary neoplasm in myasthenic women, with 20% of the breast cancers present bilaterally. Risk of cancer increases with the severity of the myasthenia and decreases 2 years following thymectomy. A relationship between decreased peripheral lymphocyte counts, increased severity of myasthenia, and increased incidence of neoplasm was also observed in this series.74 IgA levels are low in some myasthenic patients who have not had thymectomy, but may rise after the procedure. Since IgA deficiency has been shown to be correlated with predisposition to cancer,8 thymectomyinduced increases in IgA levels may be one mechanism accounting for cancer risk decreases after These subtle abnormalities of central nervous system, heart, smooth muscle, and lung, as well as this significant increase in the incidence of malignant neoplasms, suggests that myasthenia is a more complex disorder than one that simply involves skeletal muscle. CLINICAL CLASSIFICATION

Table 1 lists the modified Osserman classification of MG currently in use worldwide by myasthenia specialists. Table 2 lists another classification of MG. Each type in the table-2 list can be modified by describing the severity (mild, moderate, severe), the time course (acute, subacute, chronic), and any associated disease that might have a significant effect on the prognosis. Thus, a 22-year-old woman with generalized myasthenia of two-years duration would be classified as subacute, moderate adult type I MG. A 65-year-old man with sudden onset and rapid progression of MG to respiratory impairment would be classified as having acute, severe adult type I1 MG. This classification (table 2), though more complex, is more exact and has important clinical implications. For instance, the young woman described above would be likely to have HL-A8 tissue antigen and a hyperplastic thymus, and would probably respond well to thymectomy and anticholinesterase therapy. The middle-aged man

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would be likely not to have HL-A8, but he might have HL-A2, and he has a high chance (approximately 60%) of having a thymoma. In his case, response to anticholinesterases would probably be disappointing, but prednisone treatment might result in dramatic improvement. EVIDENCE FOR IMMUNE SYSTEM DYSFUNCTION

This material was reviewed in this journal in a recent two-part article by S i m p ~ o n . ~ ’ . ~ ~ LABORATORY CONFIRMATIOM OF CLINICAL MG Eloctmphyriol~y. The clinical diagnosis of MG is often confirmed by observing the electrical responses of a muscle to repetitive supramaximal stimulation of its the motor nerve.72 At a frequency of 3 Hz,1R*19,71,7b voltages of motor action potentials are fairly consistent in normal adults. The fifth response may be slightly smaller than the first, at 3-Hz stimulation, but the decrement is less than 8%.Although the muscle voltage response to a single-nerve stimulus is usually normal in a myasthenic person, even in severely affected muscle, the response to repetitive nerve stimulation at low rates

Table 1. Clinical classification of myasthenia gravis

a

GROUP /-Ocular Myasthenia Involvement of ucular muscles only, with ptosis and diplopia Very mild, no mortality GROUP //-Generalized Myasthenia A Mild Generalized Slow onset, frequently ocular, gradually spreading to skele tal and bulbar muscles Respiratory system not involved Response to drug therapy good Low mortality rate 0. Moderate Generalized Gradual onset with frequent ocular presentation, progressing to more severe generalized involvement of the skeletal and bulbar muscles. Dysarthria, dysphagia, and poor mastication more prevalent than in mild generalized MG. Respiratory muscles not involved. Response to drug therapy less satisfactory and the patient’s activities restricted, but mortality rate low. ~~

C. Severe Generalized Acute Fulminating: Rapid onset of severe bulbar and skeletal muscle weakness with early involvement of respiratory muscles. Progression of disease usually complete within six months. Percentage of thymomas highest in this group. Response to drug therapy less satisfactory and the patient’s activities restricted, but mortality rate low. Late Severe: Severe myasthenia gravis develops at least two years after onset of Group I or Group I1 symptoms. Progression of MG may be either gradual or sudden. Second highest percentage of thymomas. Response to drug therapy and prognosis poor. aModffied from Osserman KE Myasthenia G r a m New York, Grune 8 Stratton, I958

Diagnosis and Management of MG

(two to five per second) usually is distinctly abnormal (greater than 8% decrement). There is a progressive decrease in voltage beginning with the second response, almost always reaching a minimal level at the fifth response, after which voltages may increase slightly (fig. 3). The short-term decrement at two to three stimuli per second is thought to be related to the kinetics of acetylcholine release from the motor-nerve ending,’l but that type of EMG abnormality is not exclusive to MG. It also occurs in partially curarized normal muscle and has been identified in a few patients with amyotrophic lateral sclerosis.6zThis decrement simply indicates that the neuromuscular safety margin has been reduced by one of several possible r n e c h a n i ~ m s .In ~ ~ some MG patients, low rates of stimulation (2-5 Hz) may cause a n early abnormal increment or “facilitation” (40% or more), with or without preceding initial decrements, as is typical of and greater in patients with the facilitating myasthenic syndrome described by Lambert and E a t ~ n . ~ ’ The characteristic feature of the myasthenic state, postactivation exhaustion, is not found in partially curarized normal muscle. It is disclosed by eliciting a brief intense activity of the neuromuscular apparatus either by nerve faradization, 30-100 Hz for 2-10 sec, or by maximum voluntary contraction for 15 sec. Immediately thereafter, a 3-Hz nerve stimulation (given intermittently as bursts of three stimuli every 30 sec) shows a transient facilitation of neuromuscular transmission that is followed by a neuromuscular block that increases to maximum 2 to 4 min after exercise and recovers slowly and more or less completely. In mildly Or in patients presenting a diagnostic problem, the decrement with 3-Hz nerve stimulation may be slight or absent in the rested muscle, but the postactivation exhaustion phenomenon can be seen clearly. A test has been devised by Desmedt and Borenstein to permit a more sensitive delineation of subclinical myasthenic involvement. I9 It combines forearm ischemia (cuff around the upper arm) with stimulation of the ulnar nerve below the cuff at 3 Hz continuously for 4 min. A myasthenic patient may develop distinct decrement during 4 min, with the circulation still occluded, whereas normal subjects maintain amplitude. This phenomenon, occasionally helpful in increasing the percentage of positive diagnoses,72is characteristic of MG but is not found in all muscles nor in all myasthenic patients. For practical purposes, the ischemic test can be used in the ulnar-supplied muscles of women patients with the criterion that decrements exceeding 10% are diagnostic of myasthenia. In men, decrements of as much as 23% in the ulnar muscles of normal subjects occasionally appear. Thus, decrements

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~

Table 2. Myasthenic syndromes. Type of MG NEONATAL

OCULAR

ADULT I

ADULT I1

TRUE CONGENITAL

FAMILIAL I

Characteristics Present in about 12% of children born to myasthenic mothers. Starts within 72 hr of birth; may last 3 to 47 days (average 18 days), then disappears.65 Responds to anticholinesterasez7 and exchange transfusion.22 Anti-AChRAb present.64 Only involves eyes; antibody (antiAChRAb) against the acetylcholine receptor, if present, is usually low titer.2.54 Ocular MG may respond to prednisoneao and/or anticholinesterase and in rare instances may be associated with thymoma.70 Usually women under 40 but may start at any age, including childhood. Thymic hyperplasia and HL-A8 often present.70 Anti-AChRAb present. Responds to thymectomy. anticholinesterases, and prednisone. Incidence of thymoma lower than in adult type II. Usually men over 40. HLA-A2 often present.70 Anti-AChRAb present. Aesponds better than type 1 to steroid27 and worse than type I to thymectomy and anticholinesterases. Incidence of thymoma higher than in adult type 1.70 Starts at birth but does not disappear as the neonatal does. May be familial. No anti-AChRAb present. No response to thymectomy but does respond to anticholinesterases. Poor responseto prednisone. Identical to adult I or I1 except family history is positive.

in men should exceed 25% to be indicative of a pathologic synaptic function.21 Temperature is important in neuromuscular transmission. It is now clear that cooling a myasthenic muscle by only a few degrees considerably reduces the amount of decrement and neuromuscular block. Conversely, warming a cool myasthenic muscle to body temperature (37" C ) increases the decrement. In any patient undergoing EMG testing, it is unsafe to assume that the temperature is within normal range, since distal muscles often have temperatures as low as 29'30' C. This effect of temperature is illustrated in figure 4 A and B, in which the electrical and mechanical responses of the adductor pollicis muscle of a moderately severe generalized myasthenia are recorded a t 35" C and 28" C, respectively. T h e decrement is considerable at 35" C and the force output is below normal. At 28' C the same muscle demonstrates much less decrement in the electrical responses and the force output is

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Type of MG

Characteristics

FAMILIAL II

Positive family history. Any age, either sex, mild, no progression, some response to anticholinesterase. No response to thymectomy or prednisone. Anti-AChRAb absent.

DRUG-INDUCED

Type caused by drug working through an antibody-mediated reaction, e.g , Mysoline, penicillamine. 17.56.57

DRUG-AGGRAVATED

Any type where neuromuscular transmission is compromised by drugs, e.g., curare, quinine, quinidine, Mg + +, procainamide, Inderal. aminoglycoside antibiotics, lithium, streptomycin, colistin, linocin, tetracycline.

EATON-LAMBERT

Often adults; often, but not necessarily, associated with cancer. Reflexes tend to be absent and bulbar muscles tend to be spared. AntiAChRAb absent. May respond to guanidine or anticholinesterases.

ENGEL'S DISEASE

First described by Andrew Engel and colleagues. The hallmarks of this new syndrome are repetitive muscle action potentials from a single nerve stimulus, decreased quanta1 content of the endplate due to a decreased store of quanta, very small nerve terminals, small amounts of postsynaptic acetylcholine receptor and absence of endplate acetylcholinesterase. Clinically, the patient looks like a mild nonprogressive congenital myasthenic except there is no response to anticholinesterases.25Anti-AChRAb absent.

more than four times larger, though still not normal. Therefore, even in routine testing for myasthenia, the electromyographic examination should be conducted in a warm room, the patient should be kept covered as much as possible, and distal muscles should be warmed to body tern perat u re.2n These routine tests for the diagnosis of MG are based on thc characteristic neuromuscular blocking that occurs in this disease. Another technique that also measures neurornuscular blocking in a more sensitive way is single fiber electromyography (SFEMG). With this method, recordings can be made either with voluntary activation or with electrical stimulation." In voluntary activation, an electrode is positioned in the muscle to record activity from two individual muscle fibers belonging to the same motor unit. T h e temporal variability in the recorded muscle action potential from the two fibers, termedjilter, is primarily caused by a variation in the neuromuscular transmission time in

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Figure 3. Electromyographic tracings in myasthenia gravis. The median nerve was stimulated via surface electrodes placed at the wrist, and the electrically evoked muscle action potential was recorded from the thenar muscles. Note that at the stimulus rate of 2 impulses per second the amplitudes of the action potentials decline, reaching a nadir at the fiffh potential, and then tend to rise. This finding is diagnostic for myasthenia gravis. Note also that at the stimulus rate of 20 impulses per second there is no decrement and only a steady increase in the amplitude of the evoked muscle action potential, a finding seen in mild myasthenia or in some muscles in some myasthenic patients as they improve with treatment. It had previously been considered that a neurosis was the cause of the patient’s weakness and easy fatigability.

Figure 4. SFEMG jitter recordings from the extensor digitorum communis muscle of a patient with myasthenia gravis. The oscilloscope sweep is triggered by the first action potential, and the interval variability between the single-fiber action potentials (the neuromuscular jitter) fs seen as a variable position of the second potential. In the upper row, 70 action potentials are superimposed. In the lower row, the oscilloscope sweep is moved downwards. In (A) normal jitter, in (€ increased I) jitter but no impulse blockings, and in (C) increased jitter and occasional blockings. (Reprinted with permission from Stilberg €, Trontelj JL( Schwartz MS: Single muscle fiber recordings of the jitter phenomenon in patients with myasthenia gravis and in members of their families. Ann NY Acad Sci 274:789-202. 7976.)

Diagnosis and Management of MG

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figure 5. Effect of local cooling on the myasthenic neuromuscular failure. Woman, age 20 years. with severe generalized myasthenia gravis. In both A and €3. upper trace is the isometric myogram and lower trace is the belly tendon electric response of the adductor pollicis muscle during stimulation of the ulnar nerve at lO/sec. Note better performance at the intramuscular temperature of 28” C compared to 35” C. (Reprinted with permission from Borenstein S. Desmedt JE: Temperature and weather correlates of myasthenic fatigue. Lancet 2:63-66. 1974.)

found a positive test (greater than 8%decrement) in at least one muscle in 76 (95%) of the M G patients. Two patients who had no decrement had pure ocular myasthenia; the other two with negative tests had clearcut moderate generalized myasthenia. When only one muscle was tested, a positive diagnostic test was obtained in 59% of the cases if the recording was made from an intrinsic hand muscle; whereas, if only the deltoid was tested, a positive result was obtained in 82%of the cases. T h e presence of decremental response could not be predicted on the basis of clinical involvement because many clinically normal muscles showed decrements, and some muscles with severe clinical involvement did not show abnormalities. The conclusions reached by these researchers are that several muscles (including the deltoid) should be tested in individual patients, and the presence of a positive finding in any one muscle does confirm the clinical diagnosis. However, they also concluded that failure to demonstrate decrements does not exclude the diagnosis, since even severely involved typical myasthenia may have normal findings on electromyographic examinati~n.’~

the two motor endplates involved. When neuromuscular transmission is disturbed, jitter increases and, with more severe defects in transmission impulse, blocking occurs (fig. 5). Increased jitter and impulse blockings are found in myasthenia and are correctable with anticholinesterase medication. T h e value of this procedure for the routine diagnosis of M G has not been proved. T h e machine required for such testing is more expensive than the routine electromyograph and, as yet, SFEMG is only available in a few centers. Increased jitter is common in amyotrophic lateral sclerosis and other neuromuscular diseases, so that the specificity of the findings needs to be further defined. Despite these difficulties, SFEMG will probably play an increasingly useful role in neuromuscular research and in the evaluation of routine cases as more electmmyographers learn to use this technique. Meanwhile, the most commonly used laboratory test involving activation of muscle by repetitive supramaxima1 stimulation of its motor nerve will remain the test of choice for confirming the clinical diagnosis of myasthenia. Ozdemir and Young, using electromyographic testing in 80 patients with unquestionable myasthenia, 40 patients with other neuromuscular diseases, and 40 normal subjects, have discovered some general principles that govern diagnostic yield in repetitive-stimulaThey tion studies of neuromuscular transmi~sion.”~

Phrrnucologlc Thsts. Tensilon test. Edrophonium chloride (Tensilon) as a test for diagnosis is given in an initial intravenous (IV) dose of 2 mg, which is followed by an additional 8 mg if there is no change within 60 sec. Often the injection produces an unequivocal improvement in muscle strength, but sometimes the test is not clearly interpretable-it should always be preceded by a saline control to identify placebo reactions. Because edrophonium has muscarinic side effects, one can premedicate with atropine or use a more sophisticated placebo control, such as 50 mg of intravenous nicotinic acid. Edrophonium is also sometimes used in those patients who respond unsatisfactorily to anticholinesterase medication, to assess the effect of a proposed increase in medication. If after a 2-mg dose IV the patient becomes weaker, then he is overdosed; if he becomes stronger, he is underdosed. T h e danger of this test is that a given patient at some point in time may be underdosed with respect to one muscle group and overdosed with respect to another. It would be a grave error, for instance, to increase the dose of an anticholinesterase in a patient whose arms became stronger after edrophonium but whose respiratory function, measured by vital capacity, declined. This can happen easily if vital capacity is not routinely and repeatedly measured in all patients with M G who have changing medication needs or show a poor response to treatment. There is another danger in the use of the edrophonium test. The time at which this test is

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Diagnosis and Management of MG

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performed in relation to the time of peak action of the anticholinesterase the patient is already taking can present serious problems. T h e peak anticholinesterase time can be estimated from the stated usual action of the drug, but that is not always applicable to all myasthenic patients; for some, drug absorption might be accelerated or delayed. Edrophonium given on either side of the anticholinesterase peak might suggest underdosage, but at the peak the patient could be optimally dosed or even overdosed. Raising the baseline anticholinesterase on the basis of this response would result in overdosing. A different kind of problem with the edrophonium test is the rare “syncopal” reaction, in which the patient suddenly “collapses” immediately after injection but recovers rapidly without treatment or residua. We always have a n AmbuB bag and a mouth airway immediately available when performing the edrophonium test, but as yet we have not had to use these for this reaction. In general, we have found the edrophonium test of little value in the day-to-day regulation of anticholinesterase dosage. If the patient is so precariously positioned in relation to his disease that he needs such careful adjustment of anticholinesterase dosage, probably he is relatively refractory to that therapy so even the most sophisticated adjustment of dose will be of little avail. Under such conditions, a switch to another therapy such as prednisone is needed (see below). When it is necessary to adjust the anticholinesterase dose, instead of edrophonium we use clinical judgment in deciding whether the patient needs more or less drug. Clues as to the patient’s real needs include an increase in strength 20 min after the last dose and a fall in performance just before the next dose is due. In this situation, it is likely that the patient needs more drug. Having made the clinical decision regarding the patient’s needs, we act accordingly and observe the effect of the action over the following two to three days. If the patient worsens, then we revise ourjudgment and do the opposite ofwhat we did originally. If the patient improves, we then decide to hold fast or continue on course, depending on the functional status of the patient. Curare test. Myasthenic patients can be 10 to 100 times more sensitive than normal persons to the neuromuscular blocking action of curare and other drugs such as gallamine, pancuronium, and ether, which bind reversibly to the acetylcholine receptor (AChR). The excessive sensitivity of patients with M G to curare is the basis for the diagnostic use of curare in the two types of curare tests: systemic and regional. The systemic curare test is most often used in our hospital to rule out myasthenia in a patient whose

Diagnosis and Management of MG

clinical presentation is atypical and who has had no decrements on the repetitive-stimulation studies. The patient is told that he will receive several medicines via intravenous infusion-some may worsen myasthenia, some may improve it, and some may have no effect. An intravenous infusion is then installed and kept open with normal saline. Detailed measurements are made of hand grips, ptosis, eye movements, head and leg holding times against gravity, and vital capacity. If the patient is clinically weak, it is also a good idea to follow some task that the patient can barely accomplish and some task that the patient just barely cannot accomplish, so that any changes that occur in these borderline functions will be clearcut. T h e dose of curare is one-tenth that of the curarizing dose; this amounts to 0.1 ml of the standard solution of d-tubocurarine (3 mg/ml) per 40 lbs of body weight. This amount is drawn into a tuberculin syringe, then placed into a larger syringe with enough normal saline added to make a total solution of 4 ml. Thus, each 0.5 ml of the mixture will have 1 /80 ( 1 /10 X 1 /8) of the curarizing dose. Then, three injections of 0.5 ml normal saline are given every 2 min through the intravenous line, and the clinical measurement of muscle strength repeated to obtain baseline information. Then, 0.5 ml of the curare solution is injected every 2 min and the measurements are repeated each time. T h e injections of the curare solution are stopped when the full 8/80 (1110) of the curarizing dose has been given or when the patient has shown unequivocal worsening. Usually sensitivity to curare at doses u p to 5/80 indicates the presence of myasthenia. Sensitivity to curare at doses above 5/80 may be seen in some otherwise normal people and, of course, failure to show sensitivity, although against the diagnosis of MG, does not entirely exclude this disease. In fact, negative tests have been known to occur in purely ocular myasthenia and in generalized myasthenia in remission. Unfortunately, the possibility of severe respiratory complications of systemic curare administration to myasthenic patients (we have seen respiratory arrest after injection of only 1/80 of the curarizing dose) requires that someone in the group performing the test know how to intubate and ventilate the patient with the AmbuB bag. Anesthesiology standby is expensive, so it is better if the neurologist himself is expert at intubation and ventilation. The systemic curare test can be terminated with pyridostigmine (Mestinon), and patients who have had positive tests should be under close nursing observation for at least 10 hr. The indications for the regional curare test are similar to those for the systemic curare test and the same precautions should be followed. The test is done by applying a blood pressure cuff around thc arm to be

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tested. A scalp-vein needle, pointing distally, is inserted into a superficial forearm vein; the arm is elevated for 1 min; and the cuff is inflated to about 250 mm H g or at least 100 mm Hg above systolic pressure. T h e arm is then lowered and a solution of 0.2 mg d-tubocurarine in 20 ml of 0.9% NaCl is injected rapidly. T h e cuff remains inflated for 6.5 min after the start of the injection, to allow for adsorption of the d-tubocurarine onto the motor endplates. Repetitive nerve stimulations at 3 per second are then done with limb ischemia and after the cuff is released. A decrement of greater than 10% is considered a positive test and, if present, usually appears early and may persist for a n hour or longer. Whether this test can be used, as has been claimed, to measure response to thymectomy or to uncover systemic myasthenia in patients who have ocular involvement only, must await further evaluati~n.~' Pupillometric testing. Infrared video pupillography measures pupillary response to light and velocity as well as acceleration of pupillary reactions before and after intravenous edrophonium. This tool may provide objective measures of myasthenia in the future, but the exact role of this test in present clinical practice has yet to be determined.'"' Audiometric testing. Fatigability of the stapedius is increased in some patients with myasthenia and can be measured objectively. Pure tone audiograms, tympanometry, and acoustic reflex tests can be used to distinguish cholinergic from myasthenic crises. Continuation of these investigations is needed to determine the clinical importance of these observation^.^^'.^^ Oculo,yraphy. Rapid eye movements, having high velocity and low amplitude, are common in myasthenic patients and can be observed clinically. They are called quiuer movements and are probably pathognomonic of MG. These voluntary saccades can be studied by elect roocu lograph y. 4 ~ 1 3 ~ 1 Despite 02 the 1i m ited range of eye movements, maximum velocities of 20" and 40' saccades in myasthenic patients are usual, whereas maximum velocities in patients with other types of ophthalmoplegia are significantly lower. Some myasthenics have hypermetric and high-velocity smallamplitude saccades; these are the clinically observed quiver movements characteristic of myasthenia. l 3 Naturally, modification of these abnormalities with edrophonium a n d quantitative assessment with oculography and computer-assisted plotting of amplitude-velocity relationships improve the sensitivity of this test. Incidentally, in myasthenia, the preservation of saccades with high initial velocities, even in the presence of severe ophthalmoplegia, suggests t h a t muscle fibers generating rapid movements during saccades (fast twitch fibers) can be relatively spared when

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the muscle fibers responsible for maintenance of excentric gaze (tonic fibers) are severely affected. This relative sparing of faster twitch fibers may explain the relative sparing of distal muscles in myasthenia, since distal muscles have a greater percentage of fast twitch fibers than proximal muscles. MANAGEMENT OF MG

A complete understanding of the therapies available for myasthenia and the effective role of each in the management of this disease is the cornerstone of successful treatment of this condition. Naturally, good rapport, a sympathetic ear, and %hour availability are important aids in treating MG, as worry can have such an adverse effect on the patient's condition. But these measures can never substitute adequately for effective control of the disease. Success in management also depends on the patient's full understanding of his condition, of the things to avoid that make myasthenia worse, and of the reasons for and goals of the therapies. Myasthenic Hazards. Atropine. Judicious use of atropine to reduce rnuscarinic side effects when treating with

anticholinesterases can benefit some patients, but masking those side effects removes a signal to the patient of excessive dosage. Atropine should not be used in those newly treated myasthenic patients who are just learning the benefits and side effects of anticholinesterase medications. Antzarrhythmic drugs. Of the antiarrhythmic drugs, quinidine is potentially dangerous in myasthenia. One personally observed myasthenic patient treated for cardiac arrhythmia had a n exacerbation of weakness because of quinidine administration. Diphenylhydantoin (DilantinB), used in the therapy of cardiac arrhythmia to decrease membrane excitability and also used as an anticonvulsant, could conceivably have a similar effect and thus should be used with cautionyet, Schwab and Osserman, two clinicians with very extensive experience with myasthenic patients, never observed any weakness attributable to anticonvulsants (personal communication). Quinine, sometimes used as a muscle relaxant, and also occasionally self-administered in the form of tonic water, can also be deleterious. Because the quinine in tonic water may decompensate a myasthenic patient, that drink is prohibited routinely. (In the past, quinine has been used as a provocative test for latent symptoms of MG.) Theoretically, procainamide, because of its depressive action on membrane excitability, might cause weakness in some myasthenic patients. T h e beta-receptor blocking agent propranolol (Inderal @ ) used for digitalis intoxication, high blood pressure, and some arrhythmias, has been associated with sudden worsening of myasthenia.4"

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Antibiotics. The neuromuscular blockade caused by certain antibiotics is not simply related to dose or route of administration. Some antibiotics that have had adverse neuromuscular effects in humans are neomycin, streptomycin, dihydrostreptomycin, gentamicin, kanamycin, polymyxin, bacitracin, a n d A myasthenic syndrome secondary to colistin.36,58,82,96,1W certain antibiotics has been reported in nonmyasthenic persons. The syndrome usually occurs immediately after surgery and is probably caused by the antibioticinduced presynaptic impairment of acetylcholine “mobilization” within or released from the axonal terminal. However, the clinical event usually is associated with other factors that impair the safety of neuromuscular transmission, such as ether anesthesia, curariform and depolarizing muscle-relaxing agents, hypocalcemia, and chronic or acute renal disease. I5.29.58.IOO Calcium is the most effective agent for partially reversing antibiotic-induced weakness in almost all cases: cholinesterase inhibitors, such as neostigmine and edrophonium, are also effective but to a lesser extent and, again, are not effective in all cases.1o1 Pregnancy. The stress of gestation, labor, and delivery should be avoided. Heat. Sunbathing, hot showers or baths, and work on warm days may suddenly worsen the condition. Unexplained severe weakness in the mornings remitted in one case (personally observed) when the patient was told to take a tepid bath instead of her usual hot one. Another patient became so weak during a hot shower that she was unable to shut off the water, unable to stand, and then developed severe respiratory distress. The adverse effect of heat on neuromuscular transmission, as demonstrated by Desmedt and Borenstein,’O is the probable mechanism for the clinical deterioration in warm environments and for the preference of some of these patients for cold drinks, ice cream, sunglasses, and colder climate^.^ Emotional upsets. MG patients should try to maintain a calm philosophic outlook on life, avoiding stress and paying reasonable attention to the rules of good health, including adequate rest, recreation, diet, and sleep.

Drug Therapy. The pharmacologic approach to treating MG is twofold. One is to enhance function at the neuromuscular junction in order to correct the relative deficiency of acetylcholine action with drugs acting directly on the transmission process. The other is to suppress the abnormal immune basis of the disease in those tissues responsible for the altered immune state. The former is symptomatic thcrapy, whereas the latter

Diagnosis and Management of MG

is an attack on an early step in the pathogenesis of the disease. Drugs directly improving neuromuscular transmission. Of the agents that improve neurornuscular transmission, the anticholinesterase drugs are the most commonly used, especially pyridostigmine or sometimes neostigmine (and occasionally ambenonium) for maintenance therapy. Edrophonium is used as a short-acting diagnostic agent. These drugs have greatly improved the length of survival and the life quality of many myasthenic patients, although a significant number sooner or later do not respond adequately. By temporarily inhibiting acetylcholinesterase at the neuromuscular junction, they enhance the action of acetylcholine at that site. Other agents that can improve neuromuscular transmission in MG, but much less effectively, include guanidine, calcium,5I and ephedrine. They act by increasing the presynpatic release of acetylcholine. The veratrum alkaloids were used successfully in the 1930s in myasthenia but were apparently discarded because of the cardiovascular and emetic side effects. A semisynthetic derivative, germine monoacetate, that is free of hypotensive, bradycardic, and emetic effects has been tested more recently with encouraging results in preliminary trials on some myasthenic patients.” The basic mechanism of action of this agent is the production, especially in the muscle itself but also in motor axons, of repetitive electrical activity after a single normal action potential. In using anticholinesterases, our practice has been to become familiar with one drug and use it in all cases. We use Mestinon because it has fewer cholinergic side effects, a smoother time course of action, and is available in 60-mg tablets, as a syrup with 60 mg in each 5 ml, in an intramuscular form (1 mg IM equals about 30 mg orally), and in 180-mg timespan tablets for sustained release at night. Mestinon is usually initiated at doses of 30-60 mg four times daily; then the dose, rate of administration, and time of administration are adjusted by trial and error to achieve maximum benefit. If the patient is having weakness at night or on awakening in the morning, the 180-mg Mestinon timespan may be added at bedtime. Some patients report the excretion of undissolved timespan tablets in their stool; also, regular Mestinon is sometimes poorly a b ~ 0 r b e d . The l ~ proppr maintenance dose depends on the individual patient’s requirements; we have had s o n x who do well on 30 mg twice daily, and some who require 19 g daily in divided doses. The proper dose of medicine is whatever amount is needed to control th e symptoms. Drugs m o d f i i n g immune mechanisms in myasthtnia grauis. ACTH a n d ad renocort icosteroids- Bot h

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ACTH35.'%6737 and corticosteroidsg.'0.16,26,~3,45.49.55.98 are price to pay for the benefits obtained. When to use beneficial in many patients with MG. The usefulness corticosteroid therapy has also been a moot question. of ACTH is limited by its tendency to produce exacerGenkins thinks that the use of corticosteroids prior to bations of weakness in the early stage of treatment, thymectomy impairs the response to thymectomy (peroften requiring management of the patient in a n sonal communication), while Johns uses these agents intensive-care facility. to prepare the patient for thymectomy? Also, there is Those most experienced with ACTH administracontroversy about the concomitant administration of tion in myasthenia recommend a paired course: 100 anticholinestera~es~~ as well as whether the corticosteroids should be initially given on a daily basis46 units, intramuscularly or intravenously, each day for 10 or on alternate days.26 days, then a 5-day (not longer than 7 to 10 days) rest A reasonable approach to treatment that works for period, and then another 10-day course.34After a single me is as follows. Oral prednisone is used as the agent of or paired course, patients are improved clinically to a choice because it is cheap, effective, and available in variable degree-maximally, about a week after the 50-mg tablets. Prednisone has a short half-life, so that end of the course-and for a variable time, usually six alternate-day therapy does not interfere with the pituiweeks to six months (mean, two to three months).34@ tary-adrenal axis. All patients with generalized autoFrequently, during ACTH administration there is a immune M G with or without thyrnomas are candimarked increase in weakness, variably beginning with dates for prednisone therapy if they have been given an the first 5 days (usually the 2nd and 3rd day), and most adequate trial of anticholinesterases and are still not marked by the 6th or 7th day of therapy, with some recovery toward the end of the 10-day p e r i ~ d .T~h ~ e , ~ leading a life that is satisfactory to them. Patients with ocular myasthenia, in general, are not candidates for patient may become unable to chew, swallow, talk, or therapy unless their ocular symptoms interfere with breathe and thus will require assisted mechanical their work, for example, neurosurgeons or entertainers. ventilation, nasogastric-tube feeding, and round-theBefore prednisone therapy is initiated, the patient clock nursing care to survive this profound weakness. should be admitted to the hospital and the physician Four theoretic explanations for the induced weakness who is managing the patient should be familiar with in patients concomitantly receiving ACTH and antithe following important points. cholinesterase are: (1) the patient has undergone rapid Refractory response-Early investigators of corremission, and thus anticholinesterase is a t a n overdose tisone's effect on M G often noted a worsening of the level; (2) there is a n adverse interaction between patient's condition and development of a refractory ACTH and the anticholinesterase; (3) the ACTH alone response to the anticholinesterase drug during the has a transient adverse effect on neuromuscular transperiod of initial corticosteroid adrninistrati~n.~~~~~~~~ mission; or (4) ACTH releases (from lymphoid, adreThe reason for this worsening is not known, but it has nocortical, or other cells) harmful substances that act been ascribed to an adverse interaction between coradversely, alone or in conjunction with anticholinesticostemids and anticholinesterase drugs at the neuterase, on neuromuscular transmission. But this romuscular junction, similar to that which has been ACTH-induced weakness has occurred even in a pademonstrated in the rat.7RVarious regimens have been tient not concomitantly receiving anticholinesterase designed to avoid this initial worsening, but the one drugsLU] that seems simplest and most effective is to gradually At present we use ACTH only in those patients who increase the dose of prednisone from 25 mg orally every do not respond to thymectomy, oral corticosteroids, or other day to 100 mg every other day over a period of anticholinesterases. Strangely enough, patients unreone month.sRO n this regimen, patients usually do not sponsive to these treatments may respond to ACTH experience weakness; rather they experience a progresand can be maintained on weekly or monthly injections. Although oral corticosteroids are effective in the sive increase in strength on the day they take the therapy of MG, the particular indications for the use of prednisone, with a return toward baseline strength on these agents have not been firmly established. Most the day they do not take the prednisone. When predtypes of MG may be expected to benefit fmm oral nisone is given initially in daily doses, exacerbation of corticosteroids, with older men responding better than myasthenic weakness occurs in about 40% of payounger women. Some advocate corticosteroid use in tients. In one series, exacerbations began between ocular myasthenia, particularly if anticholinesterases the 1st and 21st day of therapy, with a mean of 5 days.'5 have been ineffective and if the ocular myasthenia The duration of increased muscle weakness lasted from one hour to 20 days, with a mean of 6 days. In 80% of significantly impairs the patient's life or Others are skeptical about using corticosteroids in ocular patients exacerbations were mild to moderate in severmyasthenia because the side effects may be too high a ity, while in 20% they were so severe that brief respira'0,46955

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NERVE

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tory support was required. Age, sex, duration of illness, timing, degree, or duration of exacerbation cannot be used to predict the ultimate response to prednisone. Patients who become weak may develop a refractory response to anticholinesterase drugs during the period of increased weakness, a finding also reported in another series in which methylprednisone was used instead of prednisone. l o Initial weakening with the induction of corticosteroid therapy has been demonstrated in rat nervemuscle preparations in which corticosteroid abolished anticholinesterase drug-potentiated single-twitch tension amplitude and caused subsequent refractory response in corticosteroid-treated animals to the potentiating effect that normally results from increasing doses of cholinesterase inhibitor^.'^ Our policy has been to avoid these periods of worsening by enforcing rest and by using an alternate-day regimen with gradual build-up in prednisone dosage. Moderate (and sometimes marked) reduction of requirements for cholinesterase inhibitors often occurs during the initial month of therapy and manifests itself initially as cramps, muscle twitches, and occasional diarrhea on the afternoon of the day the patient takes the prednisone. Consequently, anticholinesterases may have to be reduced as rapidly as can be tolerated in order to avoid cholinergic weakness. Some patients can be withdrawn from the anticholinesterases as they continue to improve. We observe the patient in the hospital until he is steadily improving, and then manage him with frequent outpatient contacts (often by telephone) to adjust the dosage of the medicines. During the next few months, the on-off day difference gradually diminishes until the patient is better on both days. Maintenance prednisone therapy-The aim of therapy is to maintain normal functional status with use of the lowest possible dose (given in the safest possible way). Therefore, when the patient has been functionally normal for two to three months, the prednisone dosage may be decreased by 5 mg each month until the lowest dose that will maintain the patient's health is reached. Prednisone regimens-As in other conditions responding to prednisone, compared with other time schedules alternate-day therapy is the best-tolerated regimen (that is, fewest side effects) and also the least effective in controlling the disease. When myasthenia does not improve with alternate-day therapy, once-aday therapy should be tried with the patient taking the entire day's dose in the morning. Those patients whose condition does not improve with daily therapy should be tried on round-the-clock therapy, in which onequarter of the daily dose is taken every 6 hr. Side effects-Side effects of therapy are numerous

Diagnosis and Management of MG

and include fluid retention, aggravation of diabetes, change in facial and body fat (cushingoid appearance), hypertension, cataracts, demineralization of bone, hypokalemia, gastrointestinal bleeding, and sleep disturbance. The occurrence of some of these side effects can be minimized by a high-protein, low-carbohydrate, and low-sodium diet, potassium chloride supplementation, the use of antacids, and the use of supplements with vitamin D and calcium. Cataracts are removed surgically. Dexamethasone-Dexamethasone (20 mg/day orally for 10 days) has considerable promise as a therapy in MG since it has produced the greatest duration and incidence improvement compared to methylprednisolone and p r e d n i ~ o n eHowever, .~ alternate-day dexamethasone is not recommended because the long half-life of the drug suppresses the pituitary axis and may lead to side effects in those patients who need long-term therapy. Thymoctomy. There are two major problems with the

prednisone therapy of MG: side effects, and the tendency for the symptoms to recur as the prednisone dose is reduced. Because of these problems, and until a more effective therapy is available for MG, thymectomy remains the treatment of choice for all types of autoimmune myasthenia except perhaps for those cases of ocular myasthenia which have been proved to be purely ocular by a systemic or regional curare test. The value of thymectomy has been reaffirmed repeatedly by numerous studieshl 1,24,28,29,05,38,39,42.46-48,50.but, regrettably, a randomized prospectivc study comparing patients treated medically with those subjected to thymectomy has not been done. In the absence of such a study, historic controls using computer-assisted retrospective matches for age, sex, severity, and duration of disease confirm the impression of early investigators that in the surgically treated group improvement is greater and mortality is less than in the medically treated control group. I ' Thymectomy may benefit myasthenic patients of either sex with any severity or duration of disease. There is some evidence, however, that when thymectomy is performed earlier, the symptoms and signs are fewer, the removed thymus is more normal by histologic criteria, and the prognosis is better-although individual exceptions to this abound. Results are poor in patients with thymoma, but these patients will usually benefit from postthymectomy prednisone or cytotoxic therapy. Responses to thymectomy cannot be predicted in individual cases. Some patients may be remarkably improved the day of surgery or one or two days thereafter. In fact, a previous ptosis may be replaced by lid retraction and the myasthenic snarl may be re55,57963-74984,85

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placed by a grimace, with surgery alone (ix., no anticholinesterases). This initial dramatic change in the myasthenia quickly fades and has no relation to ultimate outcome. It is important to recognize this so that anticholinesterase dosage can be appropriately rcduced to prevent cholinergic overdosage. In most patients, the response to thymectomy is delayed, in some cases for as long as seven years after operation. Improvement is so gradual that it is often appreciated only in retrospect that the condition improved after surgery. Possible benefits to be expected from thymectomy include: (1) increased chance for remission, (2) better control of disease, (3) reduced requirement for medication, (4)decreased chance of thymoma, and (5) decreased chance of systemic cancer. When thymectomy is called for, patients previously treated with corticosteroids must receive them just before, during, and after surgery, to prevent relative adrenal insufficiency, shock, and possible death. Our practice has been to give 100 mg of hydrocortisone in each liter of intravenous infusion just before, during, and for two days after surgery. The patient may receive three to five liters of solution during that time (ix., a total corticosteroid dose of 300-500 mg). We also administer 100 mg of intramuscular hydrocortisone just prior to surgery in case of inadvertent omission of corticosteroid in the intravenous infusion. The choice of a transverse cervical or a median sternotomy incision is best judged by the surgeon, and the current controversy concerning which approach is bestMseems unjustified because the mortality (which should be zero or close to zero by either approach) and the results are similar for both operations. Thymus location is variable; the thymus may be found from one hilum of the lung to another and from the base of the skull to the diaphragm. Given this anatomic variation, the occurrence of small implants of thymus in mediastinal and pericardial fat, and the finding that thymic hormone activity recovers toward normal one year after even the most meticulous dissections (personal observation), it appears that complete thymectomy is impossible and is not needed for a good result. Cytotoxlc Therapy. Immunosuppressive treatment of MG is effective and safe if carefully monitored, and offers the possibility of c ~ r e . ~ ’ O upractice r has been to use cyclophosphamide (Cytoxin) in doses of 100 mg daily in those patients who have severe myasthenia unresponsive to other therapy or who have severe side effects from corticosteroids. Usually, there is a response within the first two weeks of therapy even in patients who have invasive thymomas. Concurrently administered anticholinesterases and corticosteroids are gradually reduced as the patient improves.

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Diagnosis and Management of MG

Gamma Globulln. Some patients may benefit from 10-

20 ml human gamma globulin injected IM every three weeks. O n this regimen, patients, particularly those over 55 years old, have had excellent results permitting reduction of maintenance prednisone dosage.37 The mechanism of gamma globulin’s action is unclear, but suppression of endogenous IgG synthesis or competitive binding to the AChR preventing the action of antiAChR antibody (AChRAb) may be important. Thoraclc Duct Drainage. Thoracic duct drainage, effec-

tive in immunosuppression used for renal transplantation patients, also has a use in MG treatment. The operation is minor,5b although it can be technically difficult. T h e lymphatic fluid is drained into a bottle via a plastic tube. Large amounts of immunoglobulins and lymphocytes are removed, and fluid and protein losses have to be replaced. Patients improve within 48 hr but relapse when the procedure is discontinued. Of interest, retransfusion of cell-free lymph from the drainage worsens the m y a ~ t h e n i a and , ~ ~ an IgG antibody, which decreases a-bungarotoxin binding to the AChR, has been isolated from this lymph. This procedure may be useful in severe myasthenics who are refractory to other therapies. Antilymphocyto and Antithymocyte Sera. These sera

prepared in goats have been reported to be effective in some p a t i e n t ~ . ~At J ’present, ~ their use is experimental. Plarmaphererir. Plasma exchange may be followed by

a short-term (three-week) remission,B1 and clinical improvement is associated with a decrease in serum antiAChRAb. This procedure requires considerable patient and professional time and is expensive. In most patients long-term benefit can only be achieved by concurrent use of corticosteroid and/or immunosuppressive (i.e., cyclophosphamide 2-3 mg/kg or azathioprine 1-2 mg/kg) treatment. Summary of Suggorted Managemontof MG. Treatments are tailored to suit the needs of the individual patient, but in general all myasthenic patients are initially treated with anticholinesterase therapy; the dose is adjusted to achieve maximum benefit. Those not responding well to anticholinesterases are treated with prednisone or with whatever other therapy appears needed to bring the disease under sufficient control so that thymectomy can be performed. After thymectomy, doses of medicines are reduced slowly as benefits accrue. In our experience, the sternal-splitting procedure is tolerated well by most patients. The management of ocular myasthenia depends on the patient’s

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situation and desires. Generally, we prefer to patch one eye of the patient with ocular myasthenia who does not respond to anticholinesterases rather than subject him to the long-term side effects of corticosteroids or to the risk of thymectomy. Some patients, however, need effective control of ocular myasthenia for occupational reasons, in which cases we act accordingly. Immu-

nosuppressants are reserved for severe myasthenics (usually with invasive thymoma) who are not responding to cholinesterase inhibitors or prednisone or in whom side effects are intolerable. Therapies, such as thoracic duct drainage and plasmapheresis, are reserved for patients who wish to explore additional, more experimental methods of treatment.

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REFERENCES 1. Aarli JA, Milde EJ, Thunold S: Arthritis in myasthenia gravis. J Ncurul Neurosurg Psychiatry 38:1048-1055, 1975. 2. Aharonov A, Abramsky 0, Tarrab-Hazdai R , Fuchs S: Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lanccf 2:340-343, 1975. 3 . Alajouanine T, Castaigne P, Nick J, Contamin I, Lhermitte F : Sur I’existence d e signes sensitifs et senoriels au cours de la myasthenie. RN Neurol (Paris) 96242-248, 1957. 4. Baloh RW, Kelsey JC: Saccade fatigue and response to edmphonium for the diagnosis of myasthenia gravis. Ann N Y Acad Sci 274:631-641, 1976. 5. Barnes AD: T h e use of antithymocytc globulin in myasthenia gravis. Postgrad M e d 5 5 2 : 110-1 11, 1976. 6. Blalock A, Mason MF, Morgan HJ, Riven SS: Myasthenia gravis and tumors of the thymic region: report of a case in which tumor was removed. Ann .Sur,< 110:544-561, 1939. 7. Borenstein S, Desmedt J: Temperature and weather correlates of myasthenic fatigue. Lancet 253-66, 1974. 8 . Bramis J, Papatestas AE, Sloane C , Genkins G, Aufses AH Jr: Effects of thymectomy in human oncogencsis. J Surg Re.r 22:305-312, 1977. 9. Brunner MG, Berger CL, Namba T, Grob D: Corticotropin and corticosteruids in generalized myasthenia gravis: comparative studics and role in management. Ann N Y AcadScz 274:577595, 1976. 10. Brunner NE, Namba T, G m b D: Corticosteroids in management of severe, generalized myasthcnia gravis: effectiveness and comparison with corticotropin therapy. Neurolrqy (Minneap) 22:603-610, 1972. 11. Buckingham J M , Howard FM Jr, Bernatz P E , Payne WS, Harrison EG Jr, O’Brien PC, Weiland L H : T h e value of thymectomy in myasthenia gravis: a computer-assisted matched study. Ann Surg 184:453-458, 1976. 12. Biiyuyozturk K , Ozdemir C , Kohen D: Electrographic findings in 24 paticnts with myasthenia gravis. A d a Cardzol (Brux) 31:301-305, 1976. 13. Cogan DG, Yee RD, Gittinger J: Rapid eye movements in myasthenia gravis. 1. Clinical observations. Arch Ophthalmol 94:1083-1085, 1976. 14. Cohan SL, Dretchen KI., Neal A: Malabsorption of pyridostigmine in patients with myasthenia gravis. Neuro1o.v (Minneap) 27:299-301, 1977. 15. Corrado AP, Ramos AO, d e Escobar C T Neumnluscular blockade by neomycin, potcntiation by ether anesthesia and dtubocurarine and antagonism by calcium and prostigmine. Arch Inf Pharmacodyri Thcr 121:380-394, 1959. 16. Dalby A, Kjaer M , de Olivarius B: Continuous treatment of myasthenia gravis with prednisone. Lancet 1 :597-598, 1971. 17. Dawkins RI., Zilko PJ, Owen EJ: Pencillamine therapy, antistriational antibody, and myasthenia gravis. Rr M a d J 4:759760, 1975. 18. Desmedt JE: Presynaptic mechanisms in myasthenia. Ann N Y Acad Sci 1353209-246, 1966. 19. Desmedt JE, Borenstein S: ‘The testing of neuromuscular transmission. Handbook Clin Neurol 7:104-115, 1970. 20. Desmedt JE, Borenstcin S: Diagnosis of myasthenia gravis by nerve stimulation. Ann .VY Arad Scz 274:174-188, 1976.

Diagnosis and Management of MG

21. Desmedt JE, Borenstein S: Double-step nerve stimulation test for myasthenic block: sensitization of postactivation exhaustion by ischemia. Ann Neurol 1:55-64, 1977. 22. Dunn JM: Neonatal myasthenia. A m J Obsfet Gynecol 125:265-

266, 1976. 23. Elmqvist D, Josefsson J-0:T h e nature of the neuromuscular block produced by neomycin. Acta Physzol Scand 54:105-1 10, 1962. 24. Emeryk B, Strugalska M H : Evaluation of results of thymectomy in myasthenia gravis. J Ncurol 21 1:155-168, 1976. 25. Engel AG, Lambert E H , Gomez M R : A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, a n d reduced acetylcholine release. Ann Ncurul 1:315-330. 1977. 26. Engel W K : Myasthenia, corticosteroids, anticholinesterases. Ann N Y Acad Sci 274:623-630, 1976. 27. Engel WK, FestofT BW, Patten BM, Swerdlow ML, Newball H H , Thompson MD: Myasthenia gravis. Ann Infcrn M e d 81:225-246, 1974. 28. Farnsworth A, Pories W, Mendelsohn H: Thymectomy for myasthenia gravis. Auvf NZ J Sur,~46:170-173, 1976. 29. Faulkncr SL. Ehyai A, Fisher R D , Fenichel G M , Bender H W Jr: Contemporary management of myasthenia gravis: the clinical mle of thymectomy. Ann Thorac Surg 23:348-352, 1977. 30. Fischer K C , Schwartman R,J: Oral corticostemids in the treatment of ocular myasthenia gravis. Neurolugy (Minneap) 24:795-798, 1974. 31. Flacke W, Blume RP, Scott W R , Foldes FF, Osserman KE: Germinc mono and diacetate in myasthenia gravis. Ann IVY Acad Scz 183:316-333, 1971. 32. Fulpius BW, Fontana A, Cucnoud S: Central nervous systcm involvement in experimental autoimmunc myasthenia gravis. Lancet 2:350-351, 1977. 33. Genkins G, Homwitz SH, Kornfeld P, Papatestas AE: Studies in myasthenia gravis: gamma globulin and refractory myasthenia gravis (abstract). Myasthenia Gravis Foundation Medical Advisory Board Meeting, New York City, December 1975. 34. Genkins G , Kornfeld P, Osserman JE, Namba T, Grob D, Brunner NG: T h e use o f ACTH and corticosteroids in myasthenia gravis. Ann N Y Acad Sci 183369-374, 1971. 35. Genkins G, Papatestas AE, Homwitz SH, Kornfeld P: Studies in myasthenia gravis: early thymectomy. Elcctrophysiologic and pathologic correlations. A m J M c d 58517-524, 1975. 36. Cnld GN, Richardson AP: An unusual case of neuromuscular blockadc seen with thcrapeutic blood levels of colistin methancsulfnnate (Colymycin). A m J M e d 41 :316-321, 1966. 37. Grob D, Harvey A M : Effect of adrenocorticotropic hormone (ACTH) and cortisone administration in patients with myasthenia gravis and report of onset of myasthenia gravis during prolonged cortisone administration. Johns Hopkzns M c d J 91:125-136, 1952. 38. Gschnitzer F: Thymectiimy in myasthenia gravis. Z Erkr A t mungsorxanc 142:284-289, 1975. 39. Harvey A M : Some preliminary observations on the clinical course of myasthenia gravis before and aftcr thyrnectomy. Bull NY Acad M e d 24:505-522, 1948. 40. Herishanu Y, Roseriberg P: blockcrs and myasthcnia gravis.

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