Taos00058 0636

MYASTHENIA GRAVIS AND ITS OCULAR SIGNS: A REVIEW*
FRANK B. WALSH, M.D. Baltimore, Md.
The primary purpose of this paper is to evaluate our present state of knowledge regarding the ocular signs of myasthenia gravis. However, it is quite impossible to appreciate the ocular symptomatology without having a general knowledge of the disease and of its treatment, for this is one disease in which diagnosis and treatment are largely dependent upon the use of a single drug, prostigmine. Part I is made up of a general review of the subject. It includes the usual descriptions of symptomatology, and also makes brief mention of pertinent experimental work and treatment. From time to time reference is made to summarized case reports which are included in Part II. Part II is concerned with the ocular signs of myasthenia gravis. These signs ordinarily follow so definite a pattern that extended descriptions and numerous case reports may seem superfluous. However, since the examinations serve as the basis for certain conclusions, which may not generally be agreed upon, brief mention is made regarding each of the 63 cases which form the principal basis for this review. Almost all these cases have come under the observation of the writer, and in a majority of them examinations of the eyes were reasonably complete. * From the Wilmer Ophthalmological Institute of the Johns Hopkins University and Hospital, Baltimore. Candidate's thesis for membership accepted by the Committee on Theses. 556
WALSH: Myasthenia Gravtis and Its Ocular Signs 557

PART I-GENERAL REVIEW Historic R&sum. -Probably the earliest description of a case of myasthenia gravis has been quoted by Guthrie and by Palmer from an English book published in 1685: "Those, who being troubled with a scarcity of Spirits, will force them as much as they may to local motions, are able at first rising in the morning to walk, move their arms this way or that, or to lift up a weight with strength, but before noon the stores of the Spirits which influenced the muscles being almost spent, they are scarce able to move hand or foot. I have now a prudent and honest woman in cure, who for many years has been obnoxious to this kind of bastard Palsy, not only in her limbs but likewise in her tongue. This person for some time speaks freely and readily enough, but after long, hasty or laborious speaking, presently becomes mute as a fish, and cannot bring forth a word, nay, and does not recover the use of her voice till after an hour or two."
The earliest description in which the affection was represented as probably deserving recognition as a definite clinical entity is that of Wilks, who in 1877 recorded a case of what appeared to be bulbar paralysis, but without discoverable affection of the medulla (Palmer). In 1878 Erb described three cases which were characterized by ptosis, weakness of the muscles of the jaws and neck, weakness of the extremities, and disturbances in speech and deglutition. Following upon these contributions nothing of note appeared until 1887, when Oppenheim published a report of "a case of chronic progressive bulbar paralysis without anatomic findings," and remarked upon the absence of muscular atrophy, the absence of disturbances of electric excitability (later modified by Jolly), and the negative anatomic findings (Keschner and Strauss). In 1891 Goldflam stressed a most important feature of the disease, namely, that the muscles are not paralyzed but are excessively fatigable. The affection has frequently been described as the "Erb-Goldflam disease." In 1895 Jolly published studies regarding the electric excitability of muscles in myasthenics. He found that the faradic current
558 WALSH: Myasthenia Gravis and Its Ocular Signs

rapidly exhausted the contractions of the muscles, but that responses returned to normal after a period of rest. He did not observe such a response after the application of galvanic current, an observation which is mentioned further subsequently. In 1901 Weigert wrote regarding the pathology of myasthenia gravis. He noted that in some cases there was infiltration of the muscles with lymphoid cells. These collections were later described as "lymphorrhages" by Buzzard. Weigert also drew attention to the occasional association of thymus tumor with myasthenia gravis. From 1900 until 1930 little was added to our knowledge of the disease, but several important papers were published elaborating upon the diagnosis; of these papers, mention is made of only a few. In 1900 Campbell and Bramwell wrote a review article based upon 60 cases. In 1904 Hun, Blumer and Streeter amplified the knowledge regarding the pathology, and again drew attention to the inconstancy of the changes, noting that in many cases there were no abnormal findings. In 1908 Palmer published another review paper containing brief summaries and covering 124 cases. In 1912 Starr published a review based on 241 cases largely selected from the literature. In 1927 Keschner and Strauss contributed toward an analysis of the symptoms, and covered the many theories that had been offered on etiology. In 1930 the era of effective but palliative treatment set in after Edgeworth showed that ephedrine was effective in some degree. In 1934 Walker made the greatest single contribution, when she showed that eserine had a beneficial action in the treatment of this affection. After noting a similarity in the paralyses resulting from myasthenia gravis and those of mild curare poisoning, Walker, on the basis of eserine having a decurarizing effect, tested its influence on myasthenia gravis. Walker and Briscoe observed that prostigmine, a substance closely related to eserine, but less complex, was more effective than eserine. For a year or two after prostigmine was introduced many clinicians who appreciated the value
Fig. 1.-Section of muscle showing collection of lymphocytes (Aut. 17768).
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Fig. 2.-Thymus tumor (high power). The section shows cells of twro types: (1) smaller lymphocytes; (2) sheets of large epithelial cells. In general the proportions of these cells vary. The division into lobules separated by fibrous septa is not shown (Aut. 17768).
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Fig. 3.-A metastasis. Metastases are the same as the primary tumor, but often contain large channels filled with blood. Such channels are sometimes present in lesser degree in primary tumor of the thymus. In this case the metastases were present in the visceral and parietal pleura of only one side.
Fig. 4.-Hyperplasia of the thymus. Note the pronounced hyperplasia of, cortex and the presence of many germinal centers.
WALSH: Myasthenia Gravis and Its Ocular Signs 559

of the substance as a diagnostic agent failed to realize its value in routine treatment. After prostigmine was introduced and recognized as having a profound influence in: strengthening the muscles in myasthenia, it seemed that the true and basic cause of the disease might be determined. This fundamental problem is not yet solved, but through observations regarding the transmission of impulses to myasthenic muscles much useful information has been obtained. Such studies will be mentioned subsequently. At the present time it is possible that further knowledge regarding the affection may be contributed by surgical treatment of the disease. Blalock and his associates have published studies regarding thymectomy in myasthenia gravis. Through such studies it has seemingly been established that thymus changes are constant whether or not the gland is enlarged. In a certain proportion of cases there has been a dramatic but not a complete recovery, whereas in other cases the results have not been particularly encouraging. Pathology.-Since Weigert's original description of collections of lymphoid cells in the muscles and changes in the thymus, relatively little has been added to our knowledge of the pathology. Collections of lymphoid cells in the muscles or the absence of such cells does not indicate the severity of the affection. Buzzard termed these cell accumulations "lymphorrhages," and this term has come into general use. We have observed cases in which lymphorrhages were numerous and others in which they occurred in some sections of the muscles but not in others. It seems altogether likely that in any case of myasthenia gravis if a sufficient number of sections are examined, some of these cell nests may be found between the musclefibers and around the blood-vessels. In addition they may be found in the heart, liver, endocrine glands, salivary glands, and lungs (Wilson). According to Rottino and others myocarditis may be part of the pathology of myasthenia gravis.

Their case exhibited areas of necrosis with secondary inflammatory changes in the heart, a finding described as entirely unlike lymphoid cell infiltration. Myasthenic muscles may undergo slight changes in the increase of sarcolemma nuclei, fatty infiltration, hyaloid appearance, or, according to Wilson, the muscles may become small and pale. Whether or not structural changes amounting to complete atrophy occur is a point on which there is not general agreement, but if so pronounced a change does occur, it might well be observed in the ocular muscles. As regards the thymus in myasthenia gravis, it has been known for a long time that thymus tumor may be associated with the disease, or that there may be hypertrophy of the thymus gland. Thus, Bell, in 56 autopsied cases, found that the gland was hypertrophied in 17 and that tumor was present in 10 instances. From such reports it was reasonable to assume that thymus changes were significant only when tumor or hypertrophy of the gland was present. Recent observations by Blackman and by Sloan seem to establish as constant, changes in the thymus even when there is pronounced and normal involution of the gland. These changes consist of an infiltration of the medulla with lymphocytes and an increase in the relative width of the cortex, which becomes packed with lymphoid cells. The differentiation between the cortex and the medulla of the gland is lost. Lymphoid follicles with germinal centers are present in the medulla. Sloan examined the thymus in cases of Addison's disease, acromegaly, and hyperthyroidism. In three of seven cases of Addison's disease, and in two of five cases of acromegaly, the histologic picture was similar to that seen in myasthenia gravis. In 20 thymus glands removed from individuals with hyperthyroidism there was lack of involution in 18 cases, and in the remaining five the changes were similar to those seen in myasthenia gravis. In the central nervous system, in a great majority of cases,
WALSH: Myasthenia Gravtis and Its Ocular Signs 561 there is no involvement. McAlpine has described slight lymphocytosis in the brain stem, with perivascular infiltration and hemorrhages into the gray matter. He suggested that these findings pointed to an occasional relationship between myasthenia gravis and epidemic encephalitis. Occurrence.-That myasthenia gravis is not a rare disease is evidenced by the number of cases which form the basis for this report. Before prostigmine became available, the diagnosis was frequently missed. Thus Viets remarked that in the Massachusetts General Hospital up to 1935 the diagnosis of myasthenia gravis was made about once a year, whereas from 1934 to 1941, 84 cases were so diagnosed. Our experience in the Johns Hopkins Hospital has been similar. The sexes are about equally affected. In the series reported here there were 27 males and 36 females, and of these, 50 were white and 13 were colored. There were 22 white males and 28 white females, 5 colored males and 8 colored females. As regards the age incidence, the earliest age of onset was eleven months and the oldest age at onset of the disease was seventy-five years. The occurrence according to decades was: Zero to ten years, 5 cases; ten to twenty years, 10 cases; twenty to thirty years, 13 cases; thirty to forty years, 19 cases; forty to fifty years, 5 cases; fifty to sixty years, 7 cases; sixty to seventy years, 3 cases; seventy to eighty years, one case. Heredity rarely appears to play a r6le, and no example was recorded among our cases. Noyes has reported the affection in a father and two daughters, Marinesco in two sisters, Hart in two siblings, and Rothbart in four brothers of a family. The occurrence of myasthenia gravis in infancy and early childhood has always been questioned (by Kinnier Wilson among others). Consequently the observation of five cases in children below ten years of age merits particular attention. Four of these five cases were Negro children under six years of age. It is interesting to note that the affection may begin at as early an age as eleven months (Case 5). Booth
J
(1908) recorded a case at twenty-three months, and Kawaichi and Ito (1942) one at twenty-one months. It seems remarkable that it may begin at the age of seventy-five, as in Case 61, where the diagnosis was established when the patient was eighty-two years old. Contributing Factors.-It is impossible completely to evaluate exciting or contributing factors, since we do not know the etiology of the disease. There can be no doubt regarding the frequency with which the affection first manifests itself after a respiratory infection, since exacerbations are commonly observed, as the result of such infections. The onset may be influenced by normal labor (Case 53); its course may be affected by pregnancy, usually favorably (Viets and others), but not always so (Case 54). Myasthenia gravis does not interfere with normal labor (Laurent). We have observed the development of myasthenia after ptomaine poisoning (Case 57), after severe dog bites (Case 58), and in association with urticaria (Case 45). In a great majority of cases there does not seem to be any exciting or contributing factor. Associated Conditions.-Hysteria or emotional outbursts have been mentioned in several cases that have come under our observation (Cases 11 and 55). We have seen it in patients who exhibited signs of hyperthyroidism (Cases 51 and 52), in another patient who exhibited exophthalmos in the absence of signs of hyperthyroidism (Case 48), and in association with diabetes (Case 43). In one case there was evidence of the previous existence of anterior poliomyelitis or of some other disorder responsible for the smallness of one limb (Case 41). Curschmann reviewed particularly the possible role of the ductless glands in the production of myasthenia gravis, and concluded that in all probability endocrine disturbances were incidental rather than causative. He included congenital defects occurring in myasthenics, and observed it in two cases of aplasia of the female genitals. He referred to the
possible relationship of hyperthyroidism to myasthenia gravis, and was unable to obtain a myasthenic reaction in very severe cases of hyperthyroidism. Curschmann remarked that Marinesco had described hyperplasia of the hypophysis, and Tilney reported adenoma of the hypophysis in cases of myasthenia gravis. Etiology. -The nature of the fundamental disturbances responsible for myasthenia gravis is not known. All the available evidence, both clinical and experimental, points to the defect being in the muscles, and to the neuromuscular junction as the site of the disturbance. The evidence is necessarily incomplete and selective, since the literature is enormous and contains conflicting reports and complicated hypotheses. Probably the earliest, and certainly one of the most productive, discoveries was made by Claude Bernard in 1857, when he found that mild curare poisoning will block impulses passing from nerve to muscle when both are capable of functioning. Because Walker recognized a similarity between paralyses of mild curare poisoning and those of myasthenia gravis, eserine was used in the treatment of myasthenia gravis, since it was known to be a decurarizing agent. Recently acquired knowledge which has an important bearing on the problem concerns the chemical transmission of nerve impulses (Dale, Cannon, and Rosenblueth among others). This work requires only brief mention here. It has been established that in the autonomic system there are chemical transmitter substances, acetylcholine and sympathin. It has been assumed that acetylcholine is the transmitter substance responsible for the contraction of skeletal muscle, and this has been substantiated, in part at least, by the finding of acetylcholine in eserinized perfusion fluid from skeletal muscles when the motor nerve has been stimulated (Dale and Feldberg). As Dale has remarked, if acetylcholine is the chemical mediator which acts as a direct excitor of skeletal muscle fibers, it would have to appear with flashlike suddenness when an impulse reaches the motor nerve end-

ings; then it would have to disappear within the brief span of the refractory period. It seems proved that eserine has a protective influence on acetylcholine through rapidly breaking down cholinesterases which hydrolize acetylcholine. Prostigmine, a substance closely related to eserine, has been found to be more effective than the latter in the treatment of myasthenia gravis. However, as regards the action of eserine, it has not been established that it acts entirely by attacking the cholinesterases, and it has been found that it is capable of stimulating motor nerve endings; it has also been determined that cholinesterases are normal in myasthenia gravis (Jones and Stadie). To continue with the evidence which seems to point to the causal factor of myasthenia gravis being associated with abnormality at the neuromuscular junction, there may now be considered the clinical effects of prostigmine, acetylcholine, and other substances in normal individuals and in those suffering from myasthenia gravis. When injected into the brachial artery of normal individuals in amounts of 0.5-1.5 mg. prostigmine produces-(1) a profound paresis of the muscles in the injected extremity (a band is placed about the arm in order to make the injection); (2) fasciculations (twitchings, fibrillations) of the muscle fibers in the extremity and similar but less pronounced twitchings elsewhere after the tourniquet has been removed. Prostigmine similarly injected into the brachial artery or elsewhere in a person suffering from myasthenia gravis gives precisely opposite results, namely (1) partial or complete return of motor power; (2) no fasciculations. Acetylcholine when injected intra-arterially in amounts of 20-40 mg. in normal individuals produces transient weakness of the extremity. If injected into an individual with myasthenia gravis, it produces a sudden contraction of the injected muscles. Quinine, a curarizing agent, when given to normal individuals, produces no change in muscle response. If given to
an individual suffering from myasthenia gravis, there is a pronounced increase in the weakness of the affected muscles (Harvey and Whitehill). One of the exceptions to this generalization may have been observed in Case 12, where only the ocular muscles were involved. This case has possible significance from the standpoint of myasthenia gravis in some instances affecting only the ocular muscles. It is further considered in Part II. Other substances which are said to have a decurarizing effect are potassium chloride, guanidine, and calcium chloride. The administration of these substances to individuals suffering from myasthenia gravis does not produce detectable changes (Harvey and Whitehill). Much experimental work has been done in recording the effects of stimulation of muscles. The electromyograms of normal individuals have been compared with those of individuals suffering from myasthenia gravis both before and after the administration of various drugs. In normal muscles, Cobb and his collaborators confirmed previous work showing that the frequency of the primary waves during contraction diminished from 40 to 60 per second, but that the amplitude increased; and that in myasthenic muscles the frequency did not diminish, but the amplitude was smaller at the beginning than in normal muscles and rapidly diminished. These investigators observed that myasthenic muscle loses its contractile power before the onset of fatigue. Lindsley found that after intramuscular injection of prostigmine the myographic curves became practically normal. Harvey and Masland noted that the action potential recorded from the muscle of an individual suffering from myasthenia gravis was the same as that obtained from a normal individual when a single stimulus was applied. When responses to paired stimuli were compared, it became apparent that the response to the second stimulation was often smaller than that to the first, whereas in normal individuals there was no such difference. When the nerve was stimulated
566 WALSH: Myasthenia Gravis and Its Ocular Signs at low frequencies (50 per second or less), the muscle action potentials showed a rapid decline in voltage during the first few responses and then continued at lower levels of response. However, in normal individuals the muscle potentials showed little change. From figure 5 it may be seen that following the administration of prostigmine the muscle action potentials became approximately normal. Harvey and Masland found increased abnormalities in myasthenics after the administration of quinine, but discovered that potassium chloride, guanidine, calcium chloride, and vitamin B6 did not influence the electromyograms of individuals suffering from myasthenia gravis. Harvey, Lilienthal, and Talbot studied five patients who had been subjected to thymectomy for the treatment of myasthenia gravis. They observed fasciculations in the muscles of three of these patients after the. intra-arterial injection of prostigmine, and all three developed local paresis just as occurs in normal individuals. In these patients, all of whom had been favorably influenced by the operation, electromyograms showed that a large number of muscle fibers responded and that there was greater efficiency in the transmission of pairs and trains of maximal motor nerve stimuli. Largely on the basis of the observations just mentioned, Harvey, Lilienthal, and Talbot concluded that in myasthenia gravis there is a deficiency of acetylcholine at the neuromuscular junction. This, in their opinion, accounts for the charac.teristic changes which they found in electromyograms. Their arguments were set forth as follows: (1) Prostigmine has a protective influence upon acetylcholine. (2) In normal individuals the injection of prostigmine intra-arterially produces local paralysis, and a similar result occurs from the injection of acetylcholine. Since precisely opposite results are obtained from the same procedures in patients with myasthenia gravis, it seems to follow that there is an insufficient amount of acetylcholine to provide for a depressant action. (Case 3 exemplifies such an unfavorable influence from the
injection of prostigmine in an individual with myasthenia gravis. In this case large doses produced general toxic effects but increased the range of the ocular movements which had not been influenced by average doses.) (3) Finally, Harvey and his collaborators drew upon Cannon's theory of sensitization to a transmitter substance and assumed that if less acetylcholine is available, the threshold of the muscle for this substance is lowered. The conclusions of Harvey and his collaborators seem to fit reasonably the facts so far as we know them, but they are, in part at least, based upon hypotheses which have not been completely verified. Many problems require more convincing proof than that available from the translation of electromyograms. It has previously been stated that there is some proof that acetylcholine is the transmitter substance responsible for the mediation of motor nerve impulses to skeletal muscles. However, other mechanisms may play a part in the transmission of such impulses. It has been observed that the intravenous injection of acetylcholine may produce slow tonic contractions of skeletal muscle (Bard), and it was maintained by Duke-Elder and Duke-Elder that there was likely to be selective involvement of the muscles attached to the eyeballs. This is difficult to understand if the skeletal muscles normally contract as the result of the flashlike appearance of acetylcholine, as suggested by Dale. Furthermore, if the extra-ocular muscles are as sensitive to acetylcholine as Duke-Elder's observations imply, it is difficult to understand why these muscles, with the exception of the levator palpebrae, are particularly resistant to prostigmine in individuals suffering from myasthenia gravis.
GENERAL SYMPTOMATOLOGY Myasthenia gravis is characterized by fatigability and weakness of the muscles. It is difficult, if not impossible, to prove that fatigability precedes weakness, but it seems probable that it does. The diagnosis rests essentially upon the
demonstration of fatigability. Usually this is readily accomplished in individuals suffering from myasthenia gravis by repeated opening and closing of the eyes or mouth, counting aloud, opening and closing the hand, raising the leg, or other similar movements intended to tire the affected muscles. As a rule, the diagnosis is made easily, but in some cases it may be difficult to make. The ocular symptoms and signs are mentioned briefly below, since Part II deals more fully with them. Ocular Symptoms and Signs.-In all cases in this series there were ocular symptoms or signs, and these were usually the earliest manifestations of the affection. Diplopia is frequently the earliest symptom of the disease. It may be present where there is no visible evidence of limitation of ocular movements, or it may be associated with ptosis or with muscle paresis. Ptosis, often bilateral, occurs frequently. Characteristically, it is absent or minimal in the morning, becoming more pronounced as the patient becomes fatigued. Limitation of ocular movements varies within wide limits, and often affects both eyes, but may affect only one eye or even a single muscle. Inability to close the eyelids tightly is frequently present; it may be associated with ptosis and with limitation of ocular movements. The ability to converge the eyes is often lost. In. our experience, the pupils are not affected in myasthenia gravis. The visual acuity and visual fields are not altered. It seems highly questionable whether accommodation deficits can properly be attributed to myasthenia gravis. "Bulbar" Signs.-Early writers referred to myasthenia gravis as asthenic bulbar paralysis (Striimpell) because of the following signs: Facial weakness, usually bilateral, is commonly present and was observed in 23 cases. This weakness lends a flat appearance to the face, and a smile seems more like a snarl, since the retractor muscles at the corners of the mouth are more severely affected than the elevators. Facial weakness is often associated with inability to close the eyelids
tightly and with ptosis and paralyses of the extra-ocular muscles. Weakness of the jaw muscles, which was present in 10 cases, accounts for the inability to chew food properly, and often develops toward the end of a meal. In severe cases the lower jaw sags and can be elevated only by the aid of the hands. We observed a myasthenic who placed a rubber band around his head and jaw to keep the latter in position. Weakness of the soft palate and pharynx produces difficulty or inability to swallow properly. In severe cases regurgitation of fluids through the nose occurs (10 cases). Palatal weakness lends a nasal quality to the voice, which is readily demonstrated by asking the patient to count aloud. Weakness of the tongue and larynx adds to the difficulty in speaking, and if the laryngeal muscles are severely affected there is aphonia. Weakness of the intercostal muscles and diaphragm is responsible for dyspnea and varies according to the amount of rest the myasthenic has had. In severe cases periods of respiratory distress come on, at first after tiring, and later appearing spontaneously and without apparent cause. Occasionally respiratory distress is apoplectic in its onset (Case 4), and respiratory failure is a common cause of death in myasthenia gravis. Other Signs. -Weakness of the muscles of the legs and arms may be the earliest evidence of the disease, and in our experience this weakness of the legs is fairly often an early manifestation of myasthenia gravis (Cases 27 and 63). The hands and arms may become weak or powerless after use; 'such weakness was observed as an early sign in Case 63. There may be complaints of weakness only in one arm, or only of the fingers (Case 35). Women often complain of tiring of the arms when combing their hair (Case 63). The weakness may appear to be bilaterally selective, as shown in Case 33, in which the first symptom was weakness of the ring and little fingers of both hands. Weakness of the muscles of the neck

is a frequent sign. On becoming fatigued the patient is unable to hold the head erect and must support it with the hands. Other body muscles, such as those of the spine and abdomen, may be involved. In such cases the patient is unable to sit in a chair for more than a few minutes, and in the few bedridden individuals whom we have observed there have invariably been many evidences of the disease (Cases 26, 27, 44, 46, 49, and 62). Muscular wasting is not commonly present, and in severe cases, according to our experience, it is not pronounced. Whether profound myasthenia gravis may result in permanent paralysis is open to question, but Collier has maintained that this does occur. Our cases do not contain a single example of permanent and complete paralysis of muscles, unless possibly in the instances of external ophthalmoplegia (Cases 1, 3, 18, and 61). We have not observed fibrillations in the muscles of myasthenics save when there has been an overdosage with prostigmine (Case 3). Wilson has described changes in the tongue: "A triple shallow longitudinal furrow is frequently found on the tongue, one running along the raphe and one on each side, midway between the former and the lateral edge." Subjective sensory changes are described occasionally, but are probably incidental. Pain in the region of the eye (Case 17) led to an erroneous diagnosis of aneurysm. In Case 44, pain in the eye seemed the only indication for performing drainage of the maxillary sinus. In this case there was also pain in the legs and arms. Numbness and a sensation of "pins and needles" in the arm were described in one patient (Case 28). Tendon jerks were found to be normal in the cases reported here. Tiring of the knee-jerk is said to occur in myasthenia gravis, but a brief rest results in its reappearance (Wilson). Course.-Myasthenia gravis is essentially a chronic disease, characterized by remissions, which usually are partial, and by
WALSH: Myasthenia -Gravis and Its Ocular Signs 571
exacerbations. In this series, among 63 patients, there were 9 deaths during an eleven-year period. Since, however, the cases were being collected during this period, these figures have no statistical value. The longest duration of the disease in a non-fatal case was twenty-seven years (Case 36), and it is noteworthy that this patient suffered at first only from weakness of the ocular muscles. The shortest course was three and one-half months (Case 24). Respiratory infections are often associated with exacerbations, and such cases have been observed. Pregnancy frequently has a favorable influence, and remissions commonly occur and persist for several months after delivery (Viets and others). It is of some interest that normal labor appeared to precipitate the disease in Case 53. In Case 54 an abortion was performed during the first trimester of pregnancy. In fatal cases, respiratory paralysis is the usual cause of death. The injection of prostigmine is quite often a lifesaving procedure (Case 4). Grinker mentioned cardiac failure as a cause of death in myasthenia gravis, and in this regard the report of Rottino and his co-workers is of interest. Clinical Tests.-The production of fatigue by repeated voluntary efforts has already been mentioned. Closing and opening the eyes may bring on ptosis, and movement of the eyes in various directions may produce limitation of ocular movements. Counting aloud brings out a nasal quality of the voice. The patient may be unable to drink a glass of water. Apparatus such as the dynamometer may be used to record the strength of the hand-grasp. These tests, when repeated after the injection of prostigmine, point to an increased strength of the muscles. Electric Response Tests. -The myasthenic reaction-Jolly's reaction-is not specific for myasthenia gravis since it occurs in other conditions, such as polyneuritis, extreme debility, in some cases of epidemic encephalitis and in cases of brain tumor (Wilson). Furthermore, absence of the myasthenic
572 WALSH: Myasthenia Gravts and Its Ocular Signs reaction is occasionally observed in undoubted cases of myasthenia gravis. The reaction consists of progressive loss of response to rapid stimuli ("faradic" current), whether constantly or intermittently applied. Usually the apparatus employed has 60 cycles per second (60 C.P.S.). Following such loss of response a rest period of several minutes allows the response to reappear and again follow approximately the same course. When a muscle fails to respond to such stimulation, it may respond to voluntary effort, and, conversely, when it has failed to respond to voluntary effort, it may do so to electric stimulation. Slow stimuli ("galvanic" current) also account for progressive loss of response in the muscles stimulated, but it has been found that complete abolition of response with this type of current is not so readily obtained as with the more rapid type. Mention has been made of electromyograms. Tests with Drug Substances.-Prostigmine methylsulfate, when injected subcutaneously in doses of from 0.5 to 1.5 mg., produces pronounced improvement in the muscle power, usually within five minutes, but occasionally within twenty or thirty minutes. If more than 0.5 mg. is given, 0.5 mg. atropine should be added. Ptosis is invariably improved or abolished, and other weaknesses are diminished. The muscles attached to the globe are particularly resistant to prostigmine, and increase in the range of ocular movements cannot be anticipated, although sometimes it does occur. As a result of prostigmine administration abdominal cramps, diarrhea, and loss of control of the sphincters may occur in individuals who do not suffer from myasthenia gravis. An injection of atropine is sufficient to allay these symptoms. In myasthenics large amounts of prostigmine may produce cramps and diarrhea unless sufficient amounts of atropine are given. It is noteworthy that in all, or almost all, cases in which a diagnostic dose of prostigrnine has demonstrated fatigability
WALSH: Myasthenia Griavis and Its Ocular Signs 573
of the muscles, there is a general sense of well-being and increased motor power after its use. If it is impossible to establish the diagnosis on the basis of the history or by the use of prostigmine, quinine may be useful. In the adult one or two doses of 0.6 gm. will almost always increase the symptoms. Such a test occasionally precipitates acute respiratory embarrassment, and in such case an injection of prostigmine gives immediate and dramatic relief. In Case 12 quinidine was given to a patient who exhibited only ocular signs of myasthenia gravis, and since he did not show any evidence of further weaknesses, the diagnosis was questioned. It would seem that since this patient suffered only from severe ocular muscle involvement, it was impossible to detect an increase in his signs if, indeed, they were increased. Laboratory Tests. -These have little or no value either in establishing the diagnosis or in evaluating the progress of myasthenia gravis. According to Williams and Dyke, creatinuria is a definite symptom of myasthenia gravis. These observers found it in four cases, and in two of these there was a low muscle creatine content. They considered the creatinuria to be associated with carbohydrate metabolism defect. Adams and Power were unable to find any abnormality in blood chemistry; calcium, magnesium, sodium, potassium, phosphorus, sugar, urea, creatinine, amino-acids, and uric acid were all normal. These observers found pronounced creatinuria in six of 28 cases, and the extent of the creatinuria did not seem to bear any relationship to the severity of the disease. In almost all their cases the feeding of glycine increased the output of creatine in the urine. Boothby also found increased creatinuria after feeding glycine. Nevin found that the phosphorusholding compounds of muscles in myasthenia gravis were normal, and he concluded that there is no abnormality of muscle metabolism.

TREATMENT Prostigmine methylsulfate, from 0.5 to 1.5 mg. per hypodermic syringe, is used mainly in diagnosis, but is valuable also in emergencies, such as respiratory failure. The oral administration of prostigmine bromide is now generally accepted as the proper routine treatment. It is available in 15 mg. tablets and is given in different amounts according to the severity of the case. It seems a good working rule to give it often in such small amounts as afford relief. In mild cases 15 mg. given three times daily may be sufficient, but in severe cases 150 to 180 mg. or more may be given in divided doses every three hours. In such cases it may be found advantageous to combine ephedrine, 0.25 gm., twice or oftener during the day. If considerable amounts of prostigmine are being used atropine is usually necessary to control abdominal cramps and diarrhea. Viets has written on this subject on the basis of a wide experience. Mention of thymectomy has already been made. X-ray therapy applied to the thymus is said to have influenced some cases favorably. We have not had experience in the use of synthetic adrenal cortical extract, as described by Moehlig. He has injected this substance and has implanted three pellets (150 mg. each) into the subcutaneous tissue of the abdomen, and has reported a favorable result. Little has observed pronounced improvement in one of his patients so treated.
DIFFERENTIAL DIAGNOSIS In the cases recorded here, mention is made of several conditions which were confused with myasthenia gravis. Since, in a majority of cases, the diagnosis of myasthenia gravis demands a correct analysis of ocular signs, it would necessarily follow that conditions regularly associated with ocular signs may be mistaken for myasthenia gravis or vice versa. Ocular signs occurring as the result of abnormal thy-
roid states may also characterize myasthenia gravis (Cases 11, 48 and 51), and myasthenia gravis and hyperthyroidism may coexist (Case 52). Abnormalities in associated movements of the lids which have been shown to result from misdirection of regenerated fibers in the third nerve may also be observed in myasthenia gravis (Cases 11 and 44) where there is no change in the nerves. A mistaken diagnosis of congenital aneurysm was made in Case 17. It seems that infrequently in myasthenia gravis the involvement of muscles results in a picture almost like that seen when there is paresis of the third nerve, but in myasthenia gravis the pupillary responses remain intact. Since describing the ocular signs of intracranial aneurysm (Walsh and King), we have observed a case of aneurysm in which there was evidence of third nerve involvement but absence of any change in the pupil. Such cases are undoubtedly rare, and consequently it seems sound to state that apparent third nerve paralysis without pupillary change should always suggest the possibility of myasthenia gravis, whereas third nerve paralysis associated with internal ophthalmoplegia is often due to aneurysm. Myasthenia gravis may erroneously be diagnosed in the presence of muscular dystrophy which has involved the facial muscles, and in this regard Case 63 is of interest. An acute episode of respiratory failure as a result of myasthenia gravis may be confused with a similar occurrence in the bulbar type of poliomyelitis or encephalitis (Case 4), in which instance the diagnosis can be established only by an injection of prostigmine. Such an episode in myasthenia gravis could be confused with acute hypoglycemia (Case 43). The occurrence of diplopia as an early symptom of myasthenia gravis suggests that, in differentiating it from disseminated sclerosis confusion can arise. In some such instances the diagnosis must remain in doubt until further symptoms develop, or other features seen in disseminated sclerosis may serve to establish that diagnosis.-

The ocular signs of myasthenia gravis require differentiation from those of external nuclear ophthalmoplegia and from recurrent ophthalmoplegia, which is most frequently caused by aneurysm. In these conditions there is no response to prostigmine. In the peripheral types of myasthenia gravis confusion might arise with muscular dystrophies (see Case 63) and atrophies. In myasthenia gravis there is an absence of wasting which distinguished the conditions mentioned, and, further, there is an absence of fibrillations of the muscle fibers which characterize muscular atrophies, and absence of the reaction of degeneration which is seen in spinal muscular atrophy. Finally, myasthenia gravis has been described as being associated with the chronic stage of epidemic encephalitis. I have not seen such cases, but it seems probable that cases described as encephalitis with myasthenia gravis represent true myasthenia gravis.
PART II.-THE OCULAR SIGNS Material.-This study is based on 63 proved cases of myasthenia gravis studied in the Johns Hopkins Hospital between 1932 and 1943. Not all the cases so diagnosed are included, because of the uncertainty in the diagnosis before prostigmine came into use, but since the diagnosis was made infrequently in that era, few cases have been discarded. Approximately 25 per cent. (15 of 63) of these patients first sought advice from an ophthalmologist. In most instances the eyes were examined repeatedly and by various examiners. Most of the examinations were reasonably complete, and included mention of the lids, ocular movements, pupils, and visual acuity. The visual fields were charted in a minority of the cases and accommodation power was accurately measured in relatively few. A majority of these patients were observed by the present writer. Case Summaries. Condensed case histories which are appended serve only to document the statements regarding the
ocular signs and symptoms, and consequently they contain only statements which are pertinent to the subject. Frequency of Ocular Involvement.-According to our material, ocular signs are present at some time during the course of the disease. We did not observe a single patient in whom there was no evidence of ocular involvement. In a great majority of them ocular symptoms and signs were early, but in several cases there was a history of weakness elsewhere during prolonged periods before the ocular muscles were affected (Cases 27, 29, 52, and 55). Purely "Ocular" Myasthenia Gravis. -In some instances myasthenia gravis seemingly affects only the ocular muscles during lengthy periods, but such localization does not preclude spread of the weakness, even after many years. Furthermore, in cases of "ocular" myasthenia gravis the injection of prostigmine invariably gives the patient a sense of well-being, even though the affection seems localized in the eye muscles. Cases 6 to 15 inclusive represent what might be regarded as ocular myasthenia gravis. In one instance (Case 6) there was a history of onset some thirteen years before the patient was examined by us.. During that time there had been remissions and exacerbations which always affected the ocular muscles. Other writers have observed the affection to be restricted to the eye muscles for prolonged periods, and in this regard Gavey's patient is of particular interest, since he suffered from such an ocular affection for twenty-five years. However, in the series here reported upon, Case 20 deserves attention in regard to myasthenia confined to the ocular muscles. This patient, after having suffered from recurrent diplopia and ptosis for sixteen years, developed a spread of muscle weakness. It would seem reasonable to test individuals suffering from what appears to be purely ocular myasthenia gravis with quinine. We do not have useful information on this point, having tested only one such individual (Case 12), in whom
there was no increase in signs. When the affection is generalized, the symptoms are increased. From what has been stated, we may conclude that myasthenia gravis is rarely limited to involvement of the ocular muscles, and that it is doubtful whether such limitation is actually as real as it appears to be. Predominance of Ocular Involvements. -The relative frequency and the early involvement of the ocular muscles do not require statistical confirmation. The predominance of the ocular muscle participation in the syndrome can well be the basis of much speculation, particularly when the following considerations are taken into account. It has been shown that the extra-ocular muscles are finer than other voluntary muscles, and that they contain two types of fibers, one of which is thick and the other thin. These muscles contain a large amount of elastic tissue in the perimysium. Further, the complicated structure of the muscles receives an elaborate nervous supply, which is not simply motor, from the third, fourth, and sixth nerves. There are other fibers which, according to Woollard, originate in the mesencephalic root of the fifth nerve and have a propioceptive function. Also, as mentioned under the head of etiology, acetylcholine has a selective action in producing a slow tonic contraction of the normal extrinsic muscles of the eye (Duke-Elder). For some reason, in many cases paralyses of muscles attached to the eyeball are slightly, if at all, influenced by prostigmine. With these observations in mind, it would seem possible that ultimately the frequency of "ocular" myasthenia gravis may be worked out. Ptosis.-Ptosis on one or on both sides is almost always present at some time during the course of myasthenia gravis. There is rarely retraction of the lids, but in one instance (Case 11) in which we have observed this the retraction was preceded by ptosis. In the series here recorded, when the patients were examined bilateral ptosis was present in 34 instances, and unilateral ptosis, in 20. In two cases it was men-
1-.
:.
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Fig. 5.-Muscle action potentials during repetitive stimulation of the ulnar nerve in a patient with myasthenia gravis. (A) Initial tetanus after rest. (B) Second tetanus ten seconds after the first. (C) Same as (B) thirty minutes after use of prostigmine. All nerve stimuli supramaximal. Time, 0.2 seconds. Initial potential, 6.0 millivolts (Harvey and Masland).
Fig. 6.-Before and after injection of prostigmine (P.S.-Case 2).
Fig. 7.-M. J. F. (Case 11). Note the staring appearance of right eye. There was "lid-lag" when the patient looked down. There is drooping of the left upper lid when the eye is abducted and slight elevation of the left lower lid when that eye is adducted. The lowest figure shows the appearance after a diagnostic injection of prostigmine.
tioned as being absent, and in seven cases it was not mentioned. Characteristically, ptosis is most pronounced after the patient has become tired, and consequently it may be absent or minimal in the mornings. In severe cases the lids may be opened widely only once or twice after the patient awakes from sleep (Case 1). Ptosis on one side may be associated with pronounced weakness of the orbicularis oculi, and with other facial weaknesses, and in such cases the eyelids cannot be opened widely or closed tightly. This combination of weakness both in opening and in closing the eyes was observed frequently in the cases here described, and it has seemed that there is always some weakness of lid-closure when ptosis is present. Ptosis is frequently associated with limitation of extra-ocular movements in one or both eyes. Myasthenia gravis may, of course, occur in an individual with congenital ptosis. Courtis and Sitler described such a case. It has been our experience that the injection of prostigmine methylsulfate, in amounts of from 1 to 3 c.c. of a 1: 2000 solution (ampules containing 0.5 to 1.5 mg. prostigmine) invariably produces improvement or disappearance of the ptosis and occasionally results in retraction of the upper lid (Case 2, Fig. 6). When more than one ampule is injected, there should routinely be included 0.5 mg. (1/100 gr.) atropine. If the ptosis has been more pronounced on one side, the lid on that side may be elevated less than its fellow of the opposite side (Fig. 7). In many cases ptosis is relieved hy prostigmine when the muscular palsies are affected scarcely, if at all. Edema of the Lids.-This symptom has been observed by Klar, who considers local edema and generalized urticaria as prodromal symptoms in myasthenia gravis. We have observed edema of the lids as the earliest involvement in Case 5, in which the ptosis remained when the edema disappeared. In Case 45 there was a widespread maculopapular rash at the onset of the affection, and recurrence of the rash with exacerbation. The significance of these symptoms is not at all clear.
Retraction of the Lids.-Retraction of the upper lids is observed infrequently in individuals who suffer from myasthenia gravis. In this series it was unilaterally present in Case 11 (fig. 7) and in Case 58. In both instances retraction was associated with lid-lag. In Case 11 retraction appeared and persisted after ptosis had previously chronically been present. Such a transformation from ptosis to retraction has been described by Collier. Buzzard and Marcus Gunn observed bilateral retraction of the upper lids as a transitory phenomenon in a patient who suffered from myasthenia gravis. There was retraction, which lasted for only a few minutes when the patient awakened, and then ptosis appeared and persisted. These observers regarded the retraction as evidence that the plain muscle fibers of the lids are not involved in the myasthenic process. The combination of ptosis in one eyelid and retraction of its fellow of the opposite side results in an unusual picture (fig. 7). The fact that retraction developed after there had previously been ptosis points to the abnormality being peripheral in myasthenia gravis. An explanation for retraction of one or of both lids in myasthenia gravis is not readily available, but the phenomenon does stimulate speculation. It is interesting to compare figure 7 (Case 11) with figure 6 (Case 2). It may be observed that in Case 2 the injection of prostigmine was responsible for the retraction of a previously ptosed lid, that is, it produced the same condition that was chronically present in the right eye of Case 11. If it is acceptable that acetylcholine is the transmitter substance responsible for the contraction of skeletal muscle, and if it is further acceptable that the threshold of the muscle for this substance may be lowered, it would seem to follow that in Case 11 the elevator muscle of the right upper lid had become exquisitely sensitive to acetylcholine. The lid-lag in Case 11 and Case 48 suggests activity of the plain muscle in the lids. In unilateral cases, such as Case 11, another explanation
might be offered. If an extra-ocular muscle is paretic and the eyes are turned toward the field of action of that muscle, there is a secondary deviation of the sound eye. The retraction of the upper lid of the right eye in Case 11 might represent a state of secondary deviation. However, if this were a true explanation of the anomaly, unilateral retraction of the lid would commonly be seen in myasthenia gravis. Further, bilateral retraction does occur. Actually, retraction of one or both upper lids occurs under a variety of circumstances in which explanation is difficult. It may be observed in hyperthyroidism, and mention is made further on regarding the possible relationship between ocular signs in hyperthyroidism and in myasthenia gravis. It also is seen in association with lesions of the brain stem and posterior commissure (Collier), and it occasionally occurs as a transitory phenomenon in persons whose health seems excellent. A congenital variety has been described (fig. 6, Cases 2, 7, and 11). Abnormal Associated Movements of the Upper Eyelid.-In two cases of this series an interesting anomaly was observed in an associated movement of the upper eyelid (Cases 11 and 44). In Case 11 (fig. 7), previously mentioned in association with retraction of the upper lid of the right eye, there was abnormal lowering of the upper lid of the left eye when that eye was carried into the abducted position. In Case 44 (fig. 8), when the eyes were carried into the field of the paretic left external rectus muscle, there was anomalous elevation of the right upper lid. Both phenomena are precisely similar to what has been described regarding the upper lid in cases of regeneration of the third nerve with misdirection of fibers (Bender and Ford and Ford, Walsh and King). In cases of misdirection of fibers there is elevation of the upper lid when the affected eye is adducted, that is, when it is moved into the field of the internal rectus muscle, which is also innervated by the third nerve. In the instance of the eye being abducted, the upper
lid is abnormally lowered, presumably because the eye is taken out of the field of action of the internal rectus. This is in conformity with Sherrington's law of reciprocal innervation, which is to the effect that contraction of an ocular muscle is associated with simultaneous relaxation of its opponent muscle. However, the upper lid phenomena observed in cases of myasthenia gravis cannot be due to misdirection of nerve fibers, since, so far as we are aware, there is no change in the nerves in myasthenia gravis. That the law of reciprocal innervation is still in effect when myasthenia gravis is present can scarcely be doubted, and in myasthenia the muscular involvements are such that abnormal lowering of the upper lid when the eye is in abduction is an anticipated result. The retraction of the upper lid in Case 44 probably is dependent upon changed threshold of the ocular muscles for transmitter substance. Weakness of the Orbicularis Oculi and Facial Muscles.-It has previously been stated that facial weakness, almost always bilateral, is frequently present in myasthenics. Wilbrand and Saenger found weakness of the orbicularis oculi in 25 of 45 individuals suffering from myasthenia gravis (Taylor, in Posey and Spiller). In our series, 16 cases showed bilateral facial weakness, and in all of these the orbicularis oculi were weak. As a result of this weakness, there is an inability to close the eyelids tightly. In only two cases in this series (Cases 55 and 62) was there apparent to the examiner only weakness of both orbicularis muscles. As has been said, ptosis in myasthenia gravis is often associated with weakness in closure of the eyelids, which is manifest if looked for. Undoubtedly, in all cases in which there is ptosis there is also some degree of weakness of the orbicularis, a symptom that can be elicited by repeated efforts at tightly closing the eyelids. In one instance (Case 32, fig. 9) we observed exposure keratitis. In bilateral or unilateral incomplete facial nerve paralysis efforts to close the eyelids almost invariably result in the
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Fig. 8.-Paresis of the left external rectus muscle and ptosis of the left upper lid. Note the abnormal widening of the palpebral fissure on the right when the eyes are directed to the left. The right eyebrow is considerably lower than the left.
Fig. 9.-Exposure keratitis in Negro suffering from myasthenia gravis (Case 32).

occurrence of Bell's phenomenon (upturning of the eyes on efforts to close the eyelids against resistance). This was observed in Cases 57 and 62, in which the facial weakness was that of myasthenia gravis and was not due to paralysis of the facial nerves. In cases of true facial nerve paralysis the reaction of degeneration (R.D.) is present in some degree at the proper time for such tests. This reaction is quite different from the myasthenic reaction already described. Limitation of Ocular Movements. Limitation of movement of the eyes due to weakness of the extra-ocular muscles varies within wide limits. In mild cases there may be occasional -diplopia when examination does not reveal limitation in range of movements of either eye. In such cases there is danger of the patient being considered "functional." The muscle balance tests vary from time to time. In this regard Abraham's paper is of interest, especially as it applies to Cases 11 and 44. He concluded, erroneously in the opinion of this writer, that in myasthenia gravis the affected muscles are in a prolonged state of contraction, and as evidence he cited irregularity in duction readings and actual turning of the eye in the direction of the apex of the prism. In other cases characterized by minimal ocular involvement there is diplopia, which appears-reglularly in association with slight degrees of ptosis (Cases 8, 9, and 13). Occasionally there may be limitation of movement, restricted to the field of a single muscle, as in Case 15, in which there was a weakness of abduction in one eye only when the patient was tired. In this case prostigmine invariably accounted for widening of the range of movement. Minimal involvements of the extra-ocular muscles may persist for long periods. When cases of this nature are encountered, repeated efforts to move the eyes into various positions usually bring out a manifest limitation in the range of movements in one or more fields. It has often been stated that inability to move the eyes upward is seen most often, that limitation or loss of convergence is next in frequency, and defect in downward move-
584 WALSH: Myasthenia Gravtis and Its Ocular Signs

ment is the least common defect in myasthenia gravis. This study neither supports nor refutes this generalization. It does show that limitation of movement of the eyes may be unilateral or bilateral and in any direction, and that sometimes there is a close resemblance to supranuclear paralysis of conjugate movement. In quite a number of cases in this series there was pronounced limitation of the extra-ocular movements, and in such cases there invariably was severe bilateral ptosis (Cases 1, 18, and 61). These cases of myasthenic ophthalmoplegia are of particular interest for two reasons: First, the extraocular palsies exhibit a pronounced and characteristic resistance to improvement when prostigmine is used as a diagnostic or therapeutic agent. In our cases the ptosis invariably was lessened or abolished by the administration of a diagnostic injection of prostigmine. The paresis of the extra-ocular muscles invariably was improved slightly, if at all. Secondly, there is the possibility that in such cases of almost complete external ophthalmoplegia there may be a permanent structural change in the muscles which amounts to persistent and total paralysis. This study does not contribute toward this problem, but it does seem likely that if myasthenia gravis is ever attended by permanent paralysis, this would occur in the extra-ocular muscles. As regards myasthenia gravis and involvement of ocular muscles of only one eye, the series contains several cases of interest. Such cases have been reported by Moore. In Case 7, along with bilateral ptosis, there was weakness only of one external rectus muscle, as also was observed in Case 15. In Case 23, as a result of weakness of an external rectus muscle, there was inward deviation of the affected eye. In Case 17 there was what appeared to be paralysis of the left third nerve, without, however, any involvement of the pupil. Because of pain in and about the eye, and further because of the misreading of a roentgenogram, it was at first believed
that the diagnosis was aneurysm situated anteriorly on the circle of Willis. Cases of myasthenia gravis in which there appears to be paralysis of conjugate movements of the eyes are unusual, but we have observed two such cases. Case 26 was that of a myasthenic whose ocular movements were bilaterally restricted for vertical movements, but were essentially normal for lateral movements. Case 48 was that of a patient who exhibited limitations of the ocular movements quite the opposite to those in Case 26: there were relatively normal vertical movements, but the lateral movements were almost completely unobtainable and there was inability to converge. Ford has seen a patient suffering from myasthenia gravis who had been sent to the hospital with a diagnosis of pontine tumor based on paralysis of lateral conjugate movements of the eyes. Pupillary Changes.-It has often been stated that in myasthenia gravis the pupillary response to light may become sluggish (Wilson, Brain, Rea, among others). This has not been our experience, and in the cases which are here reported this part of the examination has been done with care because of an earlier observation of the writer. With Dr. Samuel Talbot the writer tested the pupillary response to light in two individuals who had a severe myasthenia gravis with ocular disabilities. In neither of these individuals was there any difference between their photographic records and those of normal persons whose pupillary responses were examined with the same apparatus. Furthermore, it would seem that there would be a tendency toward pupillary dilatation in individuals with severe myasthenia if the pupillary reaction tended to tire-and there is no such tendency so far as the author is aware. Changes in Accommodation.-Accommodation has been reported as tiring rapidly in cases of myasthenia gravis. Rabinovitch and his co-workers demonstrated a rapid reduction in accommodation power by recession of the near point from
586 WALSH: Myasthenia Gravis and Its Ocular Signs 7 to 40 cm. in the right eye, and from 12 to 40 cm. in the left eye; according to retinoscopic examination, their patient exhibited a spasm of accommodation when the test was begun. The cases which have been used in this study cannot be considered as contributing to our knowledge regarding accommodation in myasthenia gravis. In one instance (Case 19), on one occasion, an injection of prostigmine appeared to influence accommodation favorably. The Visual Fields and Visual Acuity.-There was no instance among the cases here reported of any change in visual acuity or in the visual fields which could be attributed to myasthenia gravis. Ocular Signs Common to Thyroid States and Myasthenia Gravis.-The ocular signs associated with thyroid states are generally well known. The same signs may be present in myasthenia gravis. Such signs, as exemplified in appended case reports, are: progressive exophthalmos, retraction of the upper lid with delay in down-following movement (lid-lag), difficult or absent convergence, and muscle palsies, which are particularly likely to be pronounced in so-called exophthalmic ophthalmoplegia. Case 11 exemplifies retraction of the upper lid with Graefe's sign: in this patient there were no thyroid symptoms. In Cases 48 and 51 thyroidectomy had been performed principally because of progressive exophthalmos, although in Case 48 there had been nervousness, fatigability, and slight increase in the basal metabolic rate (never over +30), but no increase in appetite, diarrhea, or excessive perspiration. Case 52 exemplifies beyond question the co-existence of myasthenia gravis and hyperthyroidism. Examination of the muscles in exophthalmic ophthalmoplegia and in some instances in myasthenia gravis may reveal the presence of lymphoid cells in both. As regards the response of the paretic ocular muscles in exophthalmic ophthalmoplegia to prostigmine, this study is not pertinent. In the few cases which were tested here, no
response was observed. However, in myasthenia gravis associated with paralysis of the extra-ocular muscles the injection of prostigmine rarely does more than improve or abolish the ptosis, and in exophthalmic ophthalmoplegia ptosis usually is not present.
SUMMARY OF OCULAR SIGNS This study has nothing to add to what has already been written regarding the ocular signs of myasthenia gravis. However, the following observations were made: (1) Ocular symptoms and (or) signs were present in all cases. (2) Purely "ocular" myasthenia gravis was observed several times, but in such cases there is always the possibility of spread of the weaknesses. (3) The ocular symptoms and signs usually appear early in the course of the disease, but occasionally they are a late development. (4) Ptosis is the most constant ocular sign. (5) Edema of the lids is a rare prodromal sign. (6) Retraction of the lids is a rare ocular sign which was observed in one case after a chronic ptosis. (7) The similarity of abnormal associated movements of the lids in myasthenia gravis, and as a result of misdirection of regenerated fibers in the third nerve, was noted. An explanation for these lid phenomena in myasthenia gravis was not attempted. (8) Weakness of the orbicularis oculi may occur in the absence of ptosis or with it. Probably weakness in closure of the lids is overlooked more often than any other common ocular sign. (9) Limitation of ocular movements occurs unilaterally or bilaterally and in almost all combinations. (10) When pupillary abnormalities are present, it is doubtful if the case is one of myasthenia gravis. (11) Changes in accommodation were observed in only one case. (12) The visual fields and visual acuity are not altered. (13) The similarity of the ocular signs seen in myasthenia gravis and in thyroid states is noteworthy.*
* The writer is pleased to acknowledge valuable advice from Dr. F. R. Ford, Dr. W. H. Marshall. and Dr. S. A. Talbot.

REPORT OF CASES
Several of these cases have been reported elsewhere. Since many are essentially similar, those which seem particularly important from the standpoint of diagnosis are marked with an asterisk.
PATIENTS UNDER TEN YEARS OF AGE (FIVE CASES)
CASE 1.*-Myasthenia gravis in a Negro child aged three years; diagnosis missed when child was first examined; single observation of momentary wide opening of lids led to diagnosis. Prostigmine therapy discontinued. Ophthalmoplegia persisted. Onset was after acute respiratory infection.
E. E. P. (A-10823), aged three years, colored, was one of four members of a family, all of whom had been well. During an illness characterized by an upper respiratory infection the parents observed partial closure of the eyelids and inability to move the eyes. This necessitated turning the head, which was thrown backward in order to direct the gaze. Examination revealed bilateral ptosis. The eyes could not be moved voluntarily nor could they be moved by caloric stimulation. The pupils were of normal size and reacted normally to light. The spinal fluid was clear, and contained five cells; the Pandy test was negative; Wassermann, blood, and spinal fluid tests were also negative. A week after the first examination the child was brought for further examination. While in the waiting room, she fell asleep. Wide opening of the eyelids occurred once when she was awakened, but within a minute the ptosis was as pronounced as it had been previously. Prostigmine (1 mg.) was given subcutaneously, and the ptosis was relieved temporarily. Before the drug had been given the child could not be induced to speak aloud, but for an hour or two after the injection she spoke clearly, after which her voice became squeaky and had only a fraction of the volume. The inability to move the eyeballs was relieved slightly by the prostigmine, but only to the extent of a few degrees in any direction. X-rays did not show any enlargement of the thymus. Treatment with prostigmine was instituted. She was given 7.5 mg. by mouth three times daily. Potassium chloride, ephedrine, guanidine, and insulin-which are said to enhance the influence of prostigmine-were all tried, but only prostigmine seemed effective. After several weeks in the hospital there was no essential change

in her condition. Other than the ophthalmoplegia, the child seemed reasonably well and was discharged. Because of the economic status of the family routine prostigmine therapy could not well be prescribed. This child has been seen several times during the four years that she has been known to us. The ptosis is persistent, and the external ophthalmoplegia is essentially unchanged. The pupillary reactions continue to be entirely normal.
CASE 2.*-Onset of myasthenia gravis at six years of age;four remissions between the ages of six and fifteen years. Unilateral ptosis was first sign of the disease; later, other facial muscles were affected and there was difficulty in chewing and in swallowing.
P. S. (267894), a white girl, aged six years, developed weakness of the left upper lid so that she had to elevate her head when she looked straight forward. The ptosis cleared in about a month. Two years later she suffered a similar weakness of the same lid, which again disappeared within a month. When she was ten years old, the same lid again became ptosed. In addition there was weakness of the upper right lid, weakness of the facial muscles, difficulty in chewing, so that she had to hold her lower jaw with her hands while chewing her food. She frequently had difficulty in swallowing. Other than as described, physical examination and laboratory tests were entirely negative. An injection of prostigmine (1 mg.) completely relieved the ptosis-in fact, the palpebral fissures became wider than normal (see fig. 6). While in the hospital she improved materially and was discharged without treatment. Following discharge the patient had no trouble until she was fifteen years of age, when another episode of myasthenia similar to that described led to a second hospitalization.
CASE 3.*-Toxic reactions from prostigmine in Negro girl aged three years, who exhibited ptosis and limitation of extra-ocular movements as weU as diffiulty in swallowing. With large doses of prostigmine the range of ocular movements was greatly increased, but with average doses only the ptosis was influenced. Ophthalmoplegia persisted during two years' observation.
E. C. (A-18778), a Negro girl, aged three years, was seen because of bilateral ptosis which had been present for two months. There had been no preceding illness. Examination revealed pronounced bilateral ptosis and almost complete inability to move the eyes. The pupils reacted normally to light. Other examinations were negative.

Hypodermic injection of 0.5 mg. prostigmine produced no appreciable effect. The injection of 1 mg. prostigmine caused an elevation of the lids which seemed to confirm the diagnosis. On another occasion the injection of 2 mg. of prostigmine produced complete opening of the eyes and increased the child's ability to move them in any direction, but it also gave rise to abdominal'cramps and diarrhea, as well as to incontinence and some fasciculations. Atropine 0.3 mg. gave relief. During several admissions to the hospital various forms of therapy were tried. Only prostigmine seemed to benefit. On one occasion she was given 30 mg. prostigmine by mouth every three hours without producing any noticeable change in the ptosis or in the range of the ocular movements. Weakness in swallowing had disappeared, and consequently it seemed that only the ptosis and the limitation of ocular movements required consideration. Since dosage of prostigmine below the toxic level did not improve the condition, it was decided to discontinue treatment. A suggestion to elevate one eyelid surgically was not considered feasible. Two years after the child was first seen the condition of the eyes was unchanged.
CASE 4.*-A type of laryngeal crisis marked the onset of myasthenia gravis in a colored boy, aged five years. This case history is unique.
J. T. W. (A-25735), colored, aged five years, was said to have been quite well until the morning of July 5, 1942. He had been playing outdoors and later asked for a drink of water, which he swallowed without difficulty. He was given a piece of chicken and was unable to swallow. Suddenly his eyes rotated upward and his mother believed that he was dying. He grew drowsy, was unable to answer questions intelligibly, and his speech became thick. His only complaint was of pain in the eyes. During the day he passed several non-bloody stools. He was admitted to the hospital on the following morning. Examination revealed bilateral ptosis, and what appeared to be left abducens palsy. The pupils were large, regular, and reacted to light. The optic fundi appeared normal. There was an absence of gag reflex and difficulty in swallowing. He was unable to speak so as to be understood. The temperature and the pulse rate were normal. The leukocyte count was 20,000. After the preliminary examination, the following diagnoses were considered: encephalitis, pontine tumor, tuberculous meningitis. Later on the day of admission there was increased drowsiness.

The patient became totally unable to swallow and to expectorate. The neck appeared to be slightly stiff, and Kernig's sign seemed to be present bilaterally. The ptosis grew more pronounced. An infusion of saline and glucose was administered. Suddenly the patient jumped up in bed, clutched at his throat, and his shoulders twitched convulsively. Breathing became extremely difficult, and he made crowing sounds. He became extremely cyanotic and a tracheotomy set was ordered. At this time Dr. Lieberman suggested that the attack was similar to one he had observed in an individual who had undergone thymectomy for myasthenia gravis. An injection of 0.5 mg. of prostigmine was given intramuscularly. Within six minutes the ptosis had disappeared, the speech had improved, there was no further distress in breathing, and he was able to swallow. For two days it was necessary to give the patient 0.5 mg. prostigmine subcutaneously every three hours, and at the end of each period he would again exhibit respiratory distress and there was a return of the bilateral ptosis. On the third day he was given 22.5 mg. prostigmine by mouth, every three hours during the day and every four hours during the night. Atropine, 0.2 mg., was given each four hours. When the treatment was discontinued during one night all the signs of the disease reappeared. After about a month the dose of prostigmine was reduced to 7.5 mg. every four hours. Later further reductions in the amount of prostigmine were made, and within ten weeks after admission he was discharged without medication. Up to the time of writing there has been no recurrence of symptoms.
CASE 5.-Myasthenia gravis had onset with swelling of eyelids on the left, followed by left-sided ptosis which was foUowed within a week by ptosis on the right. Patient was seen frequently over a period of fourteen years, but the diagnosis was not established with certainty until after recognition of myasthenia gravis in Case 1 here summarized. Varying degrees of bilateral external ophthalmoplegia over a period of fourteen years during which there was never complete remission nor dangerous exacerbation. On many occasons she exhibited alterations in voice, bilateral weakness of facial muscles and some degree of dysphagia.
D. M. (116578), a colored infant, aged eleven months, was brought for examination because of swelling of the eyelids of the right eye. After a week this swelling gradually subsided. There was pronounced photophobia. After the swelling had subsided residual ptosis appeared. Within a week the left upper lid drooped. The child was seen often during the following fourteen years. During the first year of the disease only ptosis was observed. During

the following year bilateral facial weakness and limitation of all the movements of the eyes appeared. To neurologic examination were added electric examinations, and these responses were said to be normal. At no time was there regurgitation of fluids through the nose. In the time from one examination to another there was pronounced change in the voice. A diagnosis of myasthenia gravis was suggested, along with the possibility of progressive external ophthahnoplegia and postencephalitis. The pupillary reactions to light were normal at all times. After a diagnosis had been established in Case 1, previously recorded, this child was given prostigmine. As a result, the ptosis disappeared but the range of movement of the globes was not materially increased. This was done when the child was eight or nine years old. Various therapeutic measures were instituted, but prostigmine was taken only intermittently because, except during occasional exacerbations, the ptosis and ophthalmoplegia did not trouble the patient.
CASES
WITH
PURELY OCULAR SIGNS (TEN CASES)
CASE 6.-Recurrent diplopia at one time diagnosed as post-encephalitic phenomenon. Many recurrences during a period of thirteen years. Signs purely ocular.
D. T. (229428), a white man, aged fifty-six years, first noticed double vision some thirteen years before the first examination. Attacks of diplopia recurred for many years, each attack lasting from two to three weeks, and followed by an interval of normalcy of from two to three months. At the time of our first examination there was pronounced ptosis on the right and also inability to adduct the right eye. Prostigmine administration influenced the ptosis favorably, but failed to alter the adducting power of the internal rectus muscle. About a month later, during which interval he had been taking 15 mg. prostigmine four times daily, there was little change. Three months later the ptosis had completely disappeared, and the internal rectus muscle functioned more effectively. In another three months the ocular movements appeared to be normal.
CASE 7.-Bilateral ptosis and weakness of the left external rectus the only evidence of myasthenia gravis in a thirty-one-year-old Negro man who had interstitial keratitis.
J. C. (208883), aged thirty-one years, colored, male, was admitted to the hospital with the tentative diagnosis of nuclear

ophthalmoplegia and interstitial keratitis. Double vision was present at all times, and there was drooping of the lids. In addition to bilateral ptosis there was pronounced weakness of the left external rectus muscle. Otherwise the eyes were normal. The ptosis, the patient stated, was much worse after working hard and was always less pronounced in the mornings. After an injection of an ampule of prostigmine the ptosis disappeared completely, but the abduction power of the left eye was not improved. The patient was discharged without receiving prostigmine therapy owing to the cost of the drug.
CASE 8.-Occasional blurring of vision in a woman aged fifty-six years, who developed ptosis late in the day. No other evidence of weakness.
I. B., a white woman, aged fifty-six years, complained of occasional blurring of vision and ptosis, which occurred only during a period of a few weeks. Examination showed that the eyes were normal externally, including pupillary reaction and ocular movements. Vision with correction was 20/20 for each eye. Visual fields were normal. Ptosis could be brought on by opening and closing the eyes. Myasthenic reaction was present, but a diagnostic injection of prostigmine was not given.
CASE 9.-"Ocular" myasthenia gravis in a white woman aged thirty-two years. Diplopia and ptosis (left) appeared only when tired and during the late afternoon and evening. Several remissions over a period of three years.
R. S. (160926), a white woman, aged thirty-two years, was observed over a period of four years. Drooping of the left lid with ptosis occurred when she was tired. At no time was there a manifest squint when she was examined. Injection of prostigmine immediately relieved the ptosis and diplopia. No treatment was given.
CASE 10.-A. R. (143014), a white woman, aged forty-eight years. Onset of myasthenia gravis with paresis of muscles supplied by the right third nerve. Normal pupillary reactions to light. Diagnosis of aneurysm and of neoplasm considered as possibilities until prostigmine test relieved the ptosis. The patient then compjained of diplopia. Further details were not available.

CASE 11.*-Ptosis and retraction of the opposite upper lid in myasthenia
gravis. Interesting associated movements of the lid. Patient was a white girl, aged nineteen years. Purely ocular signs. M. J. F., white girl, aged nineteen years, saw double for the first
time some six months before examination. At about this time there was pronounced ptosis of the left upper lid, and for about a week there was similar marked ptosis of the right upper lid, but the ptosis disappeared, and when examined the eye was wider open than before. The ptosis of the left eye continued and habitually was more pronounced in the afternoon and evening. There was no other complaint of weakness. The parents stated that the girl's disposition had changed and that she was subject to temper tantrums. The appearance of the eyes is shown in figure 7. The pupils were normal in their reactions to light and on convergence accommodation. Visual acuity was normal with a low-grade myopic correction. Fundi and fields were normal.
CASE 12.*-Ocular myasthenia gravis over a period of seven years in a white man aged fifty-four years. An acute cardiac disorder was treated with quinidine which did not visibly influence the state of the ocular muscles.
W. K. (280327), male, aged fifty-four years, was seen seven years prior to his admission. He complained of drooping of the left upper eyelid, which had been present for eight months and was followed by drooping of the right upper lid for four months. At that examination he had bilateral ptosis, inability to elevate the eyes, and restriction of convergence and lateral motions, but could look down fairly normally. Vision, visual fields, and fundi were normal. A typical myasthenic reaction was obtained. On his last admission he complained of chest pains, and it was found that he suffered from myocardial infarction, due to arteriosclerotic heart disease, and paroxysmal ventricular tachycardia. The condition of the eyes was as follows: there was pronounced bilateral ptosis and almost complete inability to move the eyes in any direction. Pupils were normal in their response to light. Visual acuity and the fundi were normal. In the interval between examinations he had worked during the day as a huckster. He described alternating ptosis of the eyes. Quinidine was prescribed for the cardiac disorder. Prostigmine injected subcutaneously improved the ptosis markedly and also increased the range of ocular movements. The quinidine did not appear to have any very definite influence upon his ocular status.

but the bilateral ptosis was extreme and there was almost complete inability to move the eyes.
CASE 13.-Unilateral ptosis and diplopia which usually became troublesome only late in the day occurred in a white man aged thirty-four years. After a few days there was no further trouble for two years, when diplopia recurred and there was ptosis on the left. Further remission. Pseudopapilledema for a time confused the diagnosis.
G. D. S. (148303), white, aged thirty-four years, showed the characteristic response to prostigmine. The recurrence of his myasthenia lasted only for a few weeks, and while he was in the hospital a remission set in. Except for very slight ptosis on the left, there was no other evidence of the disease after he had been in the hospital for only a week and had received only a few doses of prostigmine by mouth.
CASE 14.-Myasthenia gravis with what appeared to be recurrent oculomotor palsies. Many attacks and remissions during three and one-half years.
R. B. H. (198222), white male, aged twenty-seven years, was seen during 1940. Three and one-half years before the present examination he had had double vision lasting for several months. Several episodes characterized by ptosis, which cleared after a month or more, were not recognized as due to myasthenia gravis. Six months before examination he developed ptosis of the right eyelid, which lasted a month and was associated with diplopia. After a month during which there were no symptoms he developed ptosis of the left upper lid. In all, he estimated that he had had about 12 periods during which diplopia was troublesome. Examination revealed only ptosis on the left, and some limitation in vertical movements of the left eye. After an injection of prostigmnine the ptosis disappeared and seemed to establish the diagnosis. The patient was discharged with directions to take 15 mg. prostigmine every six hours.
CASE 15.-Diplopia occurring only when tired, due to weakness of right external
rectus muscle. Relieved immediately by injection of prostigmine.
M. F. (141509), a white woman, aged forty-eight years, complained only of seeing double, and remarked that this symptom occurred late during the day, when she was tired. General examinations were negative. Examination of the eyes showed nothing abnormal until they were moved actively into various positions during a few moments when there was limitation of the movement of the

right eye in abduction. Prostigmine relieved this within a few minutes. The myasthenic reaction could not be demonstrated, but on several occasions the use of prostigmine, either hypodermically or by the mouth, eliminated the diplopia.
CASES IN WHICH OCULAR SIGNS WERE THE FIRST OR EARLY SYMPTOMS
CASE 16.-Onset of myasthenia gravis fifteen years before examination at the age of twenty-two. Inability to close the eyelids was an earlysymptom. After several
months, enjoyed almost complete remission until a few weeks before examination.
B. S. (U45855), a man, aged thirty-seven years, stated that fifteen years before examination he had noticed tightness and numbness about the lips, inability to whistle or to expectorate, and inability properly to close his eyes, so that he slept with the eyes about half-open. He also developed difficulty in swallowing and talking. After a few months the condition gradually improved, leaving slight residual weakness of the facial muscles and some "thickness of the tongue." Three months before our examination all the symptoms returned in greater severity than before. There was bilateral ptosis and also inability properly to close the eyes. Extra-ocular movements were restricted in all directions. The pupillary reactions to light were normal. Bilateral facial weakness, weakness of the jaw muscles, apparent paralysis of the soft palate, regurgitation of fluids through the nose, inability to protrude the tongue, and weakness of the sternomastoid muscles were present. There was no weakness of any other -muscles. This patient was seen before ephedrine and prostigmine came into use and he was discharged unimproved.
CASE 17.-Transient diplopia for a month and transient ptosis of the left eye during that time. Occsonal pain in the left eye. Inability to elevate left eye or to lower it fully. Rmwoenogram showed what was mistaken for involvement of the sella. Erroneous diagnosis of aneurysm.
B. J. (281600), a white girl, aged sixteen years, had had symptoms and signs mentioned above. Although she described the ptosis as less marked in the morning, the pain in the left eye led to the erroneous belief that she had an aneurysm of the circle of Willis. The vision and fields were normal, as were also the pupillary responses. Irregular nystagmus was present. The fact that the left pupil reacted normally to light suggested the possibility of myasthenia gravis. An injection of prostigmine abolished the ptosis.

The patient was seen only once. For a time she did well on prostigm-iine. She died within a few months as a result of a respiratory crisis.
CASE 18.-Almost complete external ophthalmoplegia in a girl aged sixteen years. Prostigmine favorably affected ptosis, but produced little change in the range of movements of the eyes.
R. G. (204579), a white girl, aged sixteen years, noticed, about nine months before examination, that the right eye turned inward, and that, after two weeks, the right upper lid drooped. A month later there was ptosis on the left. For a month she had had trouble in swallowing, and for about the same length of time her voice tired rapidly. While walking up steps, she would frequently fall. She invariably felt strong in the mornings, but would tire in the afternoons. Examination of the eyes revealed pronounced bilateral ptosis and inability to move either eye in any direction for more than two or three degrees. There was an inability to converge. The pupils were normal in their response to light. Vision was normal, as were the visual fields. Accommodation was normal for her age. A diagnostic injection of 1 mg. prostigminie relieved the ptosis but did not provide appreciable increase in the range of extraocular movements of the eyes. The patient was discharged, and 15 mg. prostigmine was ordered to be taken four times daily.
CASE 19.-Ocular igns in a woman aged thirty-nine years. Accommodative power improved after injection of prostigmine.
E. B. (143371), a woman, aged thirty-nine years, had unilateral ptosis some three months before she was first examined. Later there was regurgitation of fluid through the nose and she was unable to speak clearly. Examination of the eyes revealed slight bilateral ptosis. The extra-ocular movements were normal, and no diplopia was elicited with the red glass. The visual fields and optic fundi were normal. The accommodative power was unstable. Visual acuity was 20/30 for each eye without correction. On one occasion she could read J. 1. at 12 inches with sph. + 1.00. On another occasion, then her distance vision was unchanged, she required +2.50 for reading J. 1. On this examination she was given 1 mg. prostigmine hypodermically. Within twenty minutes she read the same print with sph. + 1.00. Prostigmine, 30 mg. three times daily, was prescribed.

CASE 20.-A long duration of bilateral ptosis (sixteen years), then regurgitation of fluids through nose. Upward and lateral movements of the eyes reduced, but eyes could be lowered normaUy. Slight bilateral facial weakness. Weakness of soft palate.
C. G. (K-52156), a white man, aged forty-one years, was examined in the dispensary clinic before prostigmine was available. It was evident that the ptosis which had been present for sixteen years marked the onset of myasthenia gravis, for the ptosis was better in the morning, grew worse toward night, and was variable from day to day. The patient had complained of regurgitation of fluids through the nose, from time to time for about two years. The diagnosis was established by testing the electric reactions, which showed a characteristic myasthenic response.
CASE 21.-Onset with blurring of vision and diplopia in a man aged sixty-three years. After three months there was bilateral ptosis and soon thereafter difficulty in swallowing developed.
H. S. N. (62955), a man, aged sixty-three years, complained of blurring of vision, weakness of the legs, arms, and neck, all of which were most pronounced late in the day. After three months bilateral ptosis was followed by difficulty in swallowing. Examination of the eyes revealed bilateral ptosis and almost complete external ophthalmoplegia. The pupils were normal and reacted normally to light. The optic fundi were normal. Visual acuity was reduced to 20/70 in the left eye, but there was no scotoma in the visual field of that eye. The patient improved remarkablv after the injection of 1 mg. of prostigrnine. He was discharged improved and was directed to use ephedrine. He was under observation before prostigmine was being prescribed for the treatment of myasthenia gravis.
CASE 22.-Myasthenia gravis in syphilitic Negro woman aged thirty-seven years. Commenced with bilateral ptosis and difficulty in swallowing. Remissions.
M. D. (202520), a colored woman, aged thirty-seven years, appeared in the Neurologic Clinic with bilateral ptosis and difficulty in swallowing which resulted in regurgitation of fluids through the nose. The ptosis was slight or absent in the morning, but became more pronounced in the afternoon. There was diplopia for objects held close to her. The left side of the face was weak. The voice was nasal at times, and the soft palate deviated slightly to the left. An injection of prostigmine relieved the ptosis. A routine serologic test for syphilis was positive for the blood, but negative for the spinal fluid.

The patient was given prostigmine and ordered to take 15 mg. four times daily. After a month the symptoms had disappeared, and a year later, during which time she received no medication, there had been no recurrence of the muscle weaknesses.
CASE 23.-Onset with diplopia, divergence of left eye, and slight weakness of left levator palpebrae.
M. A. (37180) (Aut. 14487), a white girl, aged twenty years, complained of diplopia and exhibited divergence of the left eye, and slight weakness of the levator palpebrae, of three weeks' duration, when she was first seen. Examinations were negative. Two months later there was slight occasional weakness in her voice, and in another month she developed pronounced ptosis on the left. Then she seemed to recover, but the following year she developed ptosis on the right. At this time a myasthenic reaction was obtained. She was seen in the Neurologic Clinic from time to time during four years. She contracted a severe upper respiratory infection and was admitted. At this time there were severe bilateral ptosis, diminished pharyngeal reflex, left internal strabismus, nasal voice, generalized weakness, and difficulty in breathing (acute respiratory distress). Prostigmine, 2 to 4 c.c. every three to four hours, with atropine, 0.2 to 0.4 mg., was prescribed. New injections within two days had to be given more frequently. She died forty-eight hours after admission. Autopsy revealed hypertrophy of the thymus and focal necroses in the cortex of the adrenal.
CASE 24.-Myasthenia gravis in a white man, aged sixty years, resulted in death within three and one-half months. Onset uwth unilateral ptosis. Death due to respiratory paralysis. No autopsy.
G. B. (148488), a white man, aged sixty years, exhibited drooping of the upper right eyelid as a first symptom. Within a few days there was slight difficulty in speaking. Ten days before admission to this hospital he complained of diplopia and difficulty in focusing his eyes and in swallowing, and accentuated exertional dyspnea, as well as pronounced weakness of the muscles of the lower jaw, which necessitated his holding the jaw with his hands. Prior to admission he had been taking 60 mg. prostigmine three times daily and 45 mg. at bedtime, with 25 mg. of ephedrine three times daily, and also ten drops of belladonna with meals. Examination of the eyes revealed bilateral ptosis, more pro-

nounced on the right. There was marked restriction of the range of movement of the right eye and downward movement of the left eye was slightly subnormal. The pupils were equal and reacted normally to light. The patient was in the hospital only twelve days. In spite of increased doses of prostigmine, and of giving the drug every two hours, difficulty in respiration increased. On several occasions an additional hypodermic injection of the drug was required. The patient died during an attack of acute respiratory paralysis. Autopsy was not obtained.
CASE 25.-Onset of the disease with complaint of blurred visiOn, then outspoken diplopia and ptosis, later difficulty in swallowing toward the end of a meal, then generalized weakness.
L. L. (64961), a white man, aged fifty-one years, had had his first symptom of myasthenia gravis seven months before examination. The following were the positive findings: bilateral lower facial weakness; bilateral ptosis and proptosis, more marked on the left; pronounced limitation in the field of conjugate movements of the eyes and weakness of convergence; vision, visual fields, and fundi normal; pupillary reactions normal; weakness of soft palate. Myasthenic reaction was demonstrated. The patient was given various preparations, including ephedrine, glycine, and potassium chloride, without marked benefit. He disappeared from observation without having received prostigmine
therapy.
CASE 26.-Onset at sixty-three years. Ocular type commencing with diplopia. Ptosis foUowed, and within a few weeks external ophthalmoplegia affecting upuward and downward movements of the eyes. Moderate weakness of the extremities developed. Prostigmine gave some relief, but its efficiency graduaUy diminished. Respiratory paralysis caused death. Autopsy.
M. S. (107744) (Autopsy 15444), a man, aged sixty-three years, was admitted to the hospital in May, 1937. Six months before admission he complained of double vision and was given a prismatic correction; within a short time he developed more severe diplopia and bilateral ptosis. For two weeks before admission he complained of tiring rapidly and of some difficulty in swallowing toward the end of his meals. It has become difficult for him to hold his head up; his lower jaw tended to droop.
Examination revealed bilateral ptosis, pronounced external ophthalmoplegia, limiting the movements of his eyes to a few degrees

in the horizontal plane. The pupils were regular, equal, and reacted to light. The face was expressionless, with pronounced weakness of the musculature; the neck muscles also were weak. The abdomen was distended, and on assuming an upright position there was pronounced abdominal ptosis. There was moderate weakness of all four extremities; he walked with a wide base, but there was no ataxia. There were no fasciculations. Otherwise physical examination was negative and laboratory tests were not remarkable. The muscles were not tested electrically. Course in Hospital.-He was given 15 mg. prostigmine four times daily, with at first a pronounced improvement in the myasthenia. The external ophthalmoplegia was improved, but not to the extent that the eyes moved freely. The effects of the prostigmine gradually became less marked, and'the dosage was finally regulated at 222 mg. every four hours during the entire day. In order to enhance the effects of the prostigmine he was given potassium chloride, 6 gm. a day, without toxic effect. On one occasion he was given 0.6 gm. of quinine sulphate, which caused extreme exaggeration of the symptoms, which, however, were quickly alleviated by injections of prostigmine. Although his condition was not satisfactory, he was discharged two weeks after admission,' but was readmitted within forty-eight hours in acute respiratory distress. During the day before readmission he had taken 135 mg. prostigrnine without relief. He was placed'in a Drinker respirator, but died within twenty-four hours. Autopsy.-There were extensive lymphocytic infiltration in the muscles, fibrous adhesions at the upper lobe of the right lung, pulmonary edema, fatty infiltration of the liver, as well as arteriosclerotic changes in the kidneys.
CASES WITH MINIMAL OCULAR SIGNS CASE 27.-Sudden onset of weaknes8 in legs fouowing chicken-pox. Five
months laer extenal ophthalmoplegia with 8light bilateral ptosi. Patient went into remisson when eledric responses became quite normal.
M. C. (124171), a white girl, aged sixteen years, fell while playing volley ball and could not stand for about a half-hour. There was extreme weakness of the legs when she attempted to climb steps afterward. For five months she was unable to take part in games, and then noticed drooping of both upper eyelids. The illness was preceded by an attack of chicken-pox. There was slight ptosis. After repeated movements of the eyes the right external rectus muscle became weak. The pupils reacted

normally and vision was normal. The face was flattened and expressionless. The patient was unable to wrinkle her forehead. There was extreme weakness of the biceps, triceps, abdominal and back muscles, hamstrings, and quadriceps. She was unable to rise from bed with the pelvis or knees flexed. There were no sensory changes, and there was nothing remarkable about the tendon reflexes. Application of the faradic current fatigued the ocular muscles after 20 contractions. After an injection of prostigmine, 1 mg., the ptosis disappeared completely and the ocular movements were full. The myasthenia persisted for several months and then there was a remission. During this period electric reactions of the muscles were entirely normal.
CASE 28.-Weakness of arms and legs first complaint of Negro woman thirty years old. Five months later had several teeth extracted and a few days thereafter developed diplopia and ptosis. One month later, there was trouble in talking and in chewing her food, and there were symptoms of numbness and of "pins and needles" sensatton in the left arm.
E. C. (176201), a colored housewife, aged thirty years, described the symptoms mentioned above. Examination of the eyes showed bilateral ptosis and horizontal nystagmus with, however, full range of ocular movements. There was bilateral facial weakness. Speech was slurred. The injection of 0.5 mg. of prostigmine abolished the ptosis and the strength in her arms immediately increased. She was given quinine (a total of 2.4 gm.). The muscles of the face and arms became so weak that an injection of prostigmine became imperative. The patient was followed for three years. During most of this time she took 15 mg. prostigmine four to six times daily, and maintained her strength reasonably well. Ephedrine, 50 mg. four times daily, did not seem to enhance the result obtained from prostigmine alone, and after a short trial it was discontinued.
CASE 29.-Slowly progressive myasthenia gravis comnmencing in the muscles of the neck, then arms, then legs and finauly in the ocular muscles.
H. B. (107740), a white man, aged twenty-seven years, complained of weakness of the muscles of the neck for two years before examination, followed by weakness in the arms. Both improved after rest. Thereafter the legs became weak. The fatigue gradually grew more pronounced, and at the end of a year, after the weakness had been present for many months, the patient had to give up his

job in a coal mine. There was occasional ptosis and diplopia, which always disappeared with rest. Examinations showed fatigability of the muscles of the arms, legs, and neck. Slight ptosis increased on repeated movements of the eyes. The ocular movements were normal, and the pupils reacted immediately to light. Prostigmine relieved the weakness and the ptosis. Quinine rapidly caused the symptoms to become more pronounced. A year later the patient had improved under prostigmine therapy but he was still unable to work in the mine.
CASE 30.*-Prostigmine in large doses failed uniformly to help the patient with severe myasthenia gravis. Onset of disease was characterized by weakness of shoulder; later, weakness of all four extremitie; then tiring while eating and finally slight unilateral ptosis. X-ray evidence of a mass in the mediastinum.
L. W. (240409), a white man, aged thirty-four years, suffered from a severe upper respiratory infection which lasted several weeks fifteen months before examination. This was followed by a stiff or weak neck which caused difficulty in turning to the left. He was given short wave treatments for seven or eight weeks. The weakness of the neck muscles then became pronounced, and he was advised to take prostigmine bromide in 15 mg. doses. (From September, 1940, to the time of our examination he stated that he had taken about 5,000 such tablets, often as many as ten to twelve daily, and he usually took tincture of belladonna with the prostigmine.) After having used prostigmiine for a few months there was marked weakness of both arms and legs. The patient then sought the advice of another physician, who attributed the symptoms to some pituitary disorder, and polyarsan and vitamin E were prescribed. After taking these remedies he again sought advice elsewhere, and was told that he possessed a persistent thymus. He was advised to have radiation to the thymus and to take thiamin chloride. There was no improvement. Still another physician told him that the adrenal gland was at fault. Finally he was told that he suffered from myotonia atrophica. Examination showed a typical myasthenic facies. There was minimal right ptosis, and there was an alternating external squint which had been present all his life. The pupils were equal, regular, and reacted to light. The extra-ocular movements were normal. Except for the facial weakness and the ptosis, there were no symptoms of involvement of the structures innervated by the cranial nerves. There was generalized weakness of all extremities without fasciculation. There were no sensory changes. The reflexes were

normal. Prostigmine methylsulfate, 1.5 mg., was injected into the brachial artery. The facial weakness was immediately relieved, and there was pronounced return of power to the general musculature. There was no sensation of fasciculation, and only five or six were seen on the dorsum of the hand between the fourth and fifth metacarpals, and these vanished when the hand was supported. X-ray revealed a round mass in the anterior mediastinum. The patient declined operative removal of the thymus. About a year later he reported some degree of improvement which was attributed to x-ray treatment of the thymus.
CAsE 31.-Disease characterized by weakness of the legs which, however, had been preceded by some diplopia which he disregarded. Absence of ptosis but limitation of movements of eyes in lateral plane. Electrical finding substantrated Jolly's descriptions. Remission.
D. L. (127339), a colored truck driver, aged thirty-six years, complained of intermittent temporary loss of power in his legs and occasional diplopia. On October 8, 1937, while unloading coal, he had a minor accident and thereafter complained of diplopia which did not greatly inconvenience him. In November of the same year he first noticed weakness in the legs, and remarked that if he failed to rest occasionally his legs became "stiff" and he would fall to the ground. On December 13, 1937, he was admitted to the hospital with slight elevation of temperature, abdominal distention, and shortness of breath which rapidly became more pronounced. An ampule of prostigmine gave immediate relief. Examination of the eyes showed limitation in movements of both eyes only in the lateral plane. There was no evidence of any other involvement that might be attributed to affection of the cranial nerves. There was moderate weakness of the extensors of the arms and hands and flexors of the legs. The rectus abdominis muscles were weak. The deep tendon reflexes were normal and active. The cremasteric and abdominal reflexes were absent. There was no muscular wasting nor fasciculation. Electric stimulations of the muscles showed rapid fatigability. The right sternomastoid muscle ceased to respond to the faradic stimulation after 60 to 80 shocks. The galvanic current produced no fatigue after 100 contractions. This difference in reaction of the muscle to the electric current is characteristic of myasthenia gravis. Treatment with prostigmine, 15 mg. by mouth three times daily, kept him quite comfortable and the dose was gradually reduced as remission set in.

CASE 32.*-Myasthenia gravis in a thirty-four-year-old Negro male. Associated tumor of thymus. Death due to respiratory failure. Onset with weakness of facial and jaw muscles. Exposure keratitis. Exophthalmos. Lcitent syphils.
J. G. (150120), a Negro, aged thirty-four years, gave a history of gradually increasing weakness of the muscles about the face and head, which grew worse later in the day. He had had regurgitation of fluids through the nose and had found it necessary to support his lower jaw in order to chew his food. There was no history of ptosis, but he was unable to close his eyes properly. Examination revealed bilateral exophthalmos, which he said had been present all his life. Exophthalmometer: 23 in each eye. The eyelids could not be closed completely, and the right cornea showed scarring and took a fluorescein stain. There was bilateral facial weakness of the face and jaw muscles and of the trapezii and sternomastoids. On examination in the hospital it was shown conclusively that the patient suffered from myasthenia gravis, and he was discharged with instructions to take prostigmine, which he did irregularly. After several months he was admitted during an acute exacerbation. He could neither eat nor drink, and was very short of breath and cyanotic. He was immediately given 2 mg. prostigmine hypodermically and was placed in a Drinker respirator. Death occurred within an hour. At autopsy it seemed probable that death had been caused by a plug of mucus in the bronchi. In addition there undoubtedly had been paralysis of the diaphragm. The thymus weighed 70 gm. (normal weight, about 23 gm.). It contained a sharply outlined tumor nodule (fig. 2). There were metastases in the pleura.and peritoneum of the left side (fig. 3).
CASE 33.-Generalized weakness, more pronounced of the ring and little fingers of both hands foUowed by weakness of the Iwer jaw, choking, and difficulty in speaking, and finally diplopia and intermitten bilateral ptosis.
E. C. H. (42465), a white woman, aged fifty-eight years, complained of the above mentioned symptoms over a period of seven months. There were partial remissions and exacerbations. Examination of the eyes revealed bilateral ptosis, which increased on repeated movements. The ocular movements appeared quite normal, but diplopia was present. The pupils were normal in their reaction to light. Visual acuity and accommodative power seemed normal.

CASE 34.-Weakness of the skeletal musdles, particularly of the arms, which was inconstant but was always initiated or aggravated by emotional disturbance or by prolonged muscular activity. Bilateral ptosis and weakness of the left external rectus muscle were later developments.
D. K. (K-5918), a white woman, aged twenty-four years, was seen before prostigmine was available for testing. The symptoms mentioned above were present for four months. A typical myasthenic reaction in the right sternomastoid muscle was elicited.
CASE 35.-Weakness of fingers first sign of disease in man fifty-three years. Then foUowed drooping of the eyelids, weakness of the jaw muscles. Prostigmine therapy and ephedrine said to have helped materiaUy. Death from respiratory paralysis four months after examination.
C. B. (K-85328), a white man, aged fifty-three years, was seen only three weeks after weakness of the fingers had developed. He was not admitted to the hospital. The muscle reactions to electric stimulation supported the diagnosis of myasthenia gravis. Four months after he was first seen death occurred, apparently during an exacerbation characterized by involvement of the muscles of respiration.
CASE 36.-Myasthenia gravis present for twenty-seven years, from age of twenty-four in white woman fifty-one years. Onset with diplopia and unilateral ptosis. Later weakness of legs. Many partial remissions.
N. S. (U-61196), a white woman, aged fifty-one years, exhibited left-sided ptosis when she was first examined, also inability to look up with either eye, and the left eye could be moved only a few degrees in any direction. The weakness of the legs was profound and she gave a history of occasionally falling spontaneously. During the period she was under observation-some ten yearsthere were pronounced differences in the ocular signs. Sometimes there was unilateral, sometimes bilateral, ptosis, and the ability voluntarily to move the eyes improved and regressed. The diagnosis until the advent of prostigmine was dependent upon the history and the presence of the myasthenic reaction.
CASE 37.-Unilateral ptosis only ocular sign of myasthenia gravis in Negro woman, thirty years. Onset acute with aphonia and dysphagia. Remissions and
exacerbatioms.
C. S. (U-17351), a colored woman, aged thirty years, awoke one morning to find that she could not talk intelligibly, nor could she swallow solid food. Fluids returned through her nose. The condi-

tion improved rapidly, but did not completely disappear for several months, when there was an exacerbation of symptoms which persisted until about the end of the first year of the disease. During the next year there was extreme weakness of the right arm and right side of the face; the left arm was slightly weak. This attack gradually subsided. She sought advice during the next exacerbation, when, in addition to pronounced dysphagia and dysphonia, there was ptosis on the left side.
CASE 38.-Inability to close eyelids tightly, the only ocular evidence of myasthenia gravis in a boy offifteen who complained successively of difficulty in speaking and inability to whistle. There was bilateral facial weakness. At one time it was suggested the facial weakness was present on a hysterical basis.
J. S. (221400), a white boy, aged fifteen years, was brought to a psychiatrist for examination. He complained of difficulty in speaking. Apparently, on the basis of his having worked with a man who had a harelip, it was suggested that the facial weakness present at that time, as well as the difficulty in speech, was on an hysterical basis. Further examination revealed bilateral facial weakness. The facial muscles gave only minimal response to the electric current. The soft palate was weak and tired rapidly. An injection of prostigmine restored his voice to the normal and he was able to close the eyelids tightly. He was discharged, and guanidine hydrochloride, 0.5 gm., at 6 A. M. and 12 noon, and 0.75 gin. at 6 P. M., also ephedrine sulphate, 25 mg. every three hours between 6 A. M. and 9 P. M., were prescribed. The cost of prostigmine was prohibitive for this patient.
CASE 39.-Male, forty-one years old, exhibited weakness in closing eyelids as only ocular sign. Onset of diffiulty in swallowing, and regurgitation of fluid through nose followed so-called "nervous breakdown" characterized -by -speUs of weakness and occasional diplopia.
E. G. (187670), male, aged forty-one years, suffered from difficulty in swallowing fourteen months before examination. At this time he also complained of regurgitation of fluids through his nose. There were occasional periods of diplopia. Two months after the onset of his illness he was given prostigmine, which he discontinued to use after about two months. Since he claimed that he felt quite well after discontinuing the prostigmine, the condition was not regarded as myasthenia gravis, but the possibility of a remission being present was overlooked.
608 WALSH: Myasthenia Gravti and Its Ocular Signs

Two months before admission symptoms of weakness again appeared, particularly in the arms and shoulders, and there was occasional numbness of the sides of the face. Examination showed bilateral weakness of the orbicularis oculi. Also there was facial weakness, weakness of the soft palate, weakness of the constrictors of the pharynx, and weakness of the arms and of the abdominal muscles. The intra-arterial injection of prostigmine proved the nature of the condition. He was discharged and prostigmine and benzedrine were prescribed.
CASE 40.-Transient diplopia with occasional unilateral ptosis only ocular
signs in patient with 8litght bilateral facial weakness and pronounced difficulty in swullounng and speaking. B. F. (U-71486), a white man, aged twenty-nine years, was said to have suffered from an abscess at the base of the tongue immediately before the onset of difficulty in swallowing. These symptoms were present for three months before he was examined. The electric responses and the results of an injection of prostigmine were such as to justify the diagnosis. There was transient diplopia
and occasional unilateral ptosis. It seemed of interest that the range of ocular movements was full in association with almost complete inability to swallow and to talk.
CASE 41.-Onset with diplopia in patient who had had atrophy of left leg during entire life. Prior to onset of ocular difficulties he experienced no difficulty in walking. Thereafter, there was rapid tiring and complaint of weakness in left leg. Difficulty in regulating dosage of prostigmine. X-ray to thymus seemed to improve.
R. A. (237914), a white man, aged fifty-three years, eleven years before the first examination complained of diplopia which disappeared after a short time and reappeared four years later, at which time he sought advice. There was ptosis on the right without other evidence of oculomotor palsy. There was no ptosis on the left, but there was an inability to adduct the left eye beyond the midline. The pupils were active in their reaction to light stimulation. The fundi were negative, and the visual acuity was normal. The muscles of the left leg and thigh were atrophied and the leg was quite weak. The left arm was weaker than the right arm. Dynamometer records were not remarkable. Repeated opening and closing of the eyelids increased the ptosis on the right, but did not
WALSH: Myasthenia Gravts and Its Ocular Signs 609

influence the apparent palsy of the left internal rectus muscle nor did it produce ptosis on the left. The myasthenic response of Jolly was present when the sternomastoid on the right was subjected to the faradic current. It was believed that the patient suffered from myasthenia gravis superimposed on some other condition responsible for the atrophy of the left leg and thigh. Prostigmine was not available at the time this patient was first seen. He was given ephedrine, and when prostigmIine came into general use he received doses of 1 mg. hypodermically, which increased the power in his left leg and enabled him to open the right eye widely. It did not materially change the weakness of the right internal rectus muscle. When this test was made three years after his first examination, there was an inability to move the left eye upward and it could be moved downward only when it was in abduction. The injection relieved the ptosis on the right. The patient was discharged with instructions to take 135 mg. prostigmine in divided doses by mouth daily. His condition improved, but he still became rapidly fatigued. When he increased the dosage beyond the amount stated, he suffered from abdominal cramps. Ephedrine combined with prostigmine did not help the situation. Finally, the possibility of thymectQmy was considered. The operation was not performed, but he was given repeated x-ray treatments to the thymus. When he was seen, twelve years after the onset of the disease, he was comfortable and able to work. He had reduced the prostigmine to 45 mg. in divided doses daily.
CASE 42.-Diplopia first sign in man twenty-four. FoUowed by weakness of legs. Later ptosis developed. Many types of therapy tried: prostigmine, ephedrine, KCl, X-ray mediastinum although no evidence of thymus tumor. Prostigmine effective.
J. M. B. (119151), male, aged twenty-seven years when first examined. Three years previously he had first noticed diplopia when driving a car and in walking. Shortly thereafter his legs would give out completely when he was playing handball. Fifteen months after the onset. of diplopia he developed ptosis and facial weakness. He had been taking ephedrine for a year, but said that it made him sleepless and nervous. He was given prostigmine, 90 mg. in divided doses daily, and although it helped him greatly, he suffered constantly from diarrhea. Examination revealed bilateral ptosis, but no apparent weakness of the muscles moving the eyeballs, and no nystagmus. The remainder of the examination was essentially negative. Repeated

galvanic shocks completely fatigued one of the sternomastoid muscles. After an injection of prostigmine the ptosis disappeared and the sternomastoid muscle contracted 56 times before there was loss of response, that is, twice as often as on the test before the administration of prostigmine, An effort was made to reduce the prostigmine to 60 mg. daily by adding ephedrine sulphate, 0.25 gm., twice daily. The patient complained that the ephedrine made him restless. He was then given 4 c.c. of a 25 per cent. solution of potassium chloride after each meal, combined with prostigmine 15 mg., four times daily. It seemed that the potassium did not enhance the effect of the prostigmine. There was some discussion as to whether or not to prescribe testosterone, with the object of causing atrophy of the thymus, but this plan was rejected because of several unfavorable conditions that may arise when this substance is given to normal males. A course of x-ray treatments of the mediastinum with the same object in mind was given without any particular change in the disabilities, and without influence upon the amount of prostigmine necessary to keep the muscle weakness within control.
CASE ASSoCIATED WITH DIABETES CASE 43.-Myasthenia in a colored girl fifteen years old. Patient had been treated for diabetes mellitus for ten years. Ptosis noted occsionally; acute exacerbations of myasthenia gravis required differentiation from acute hypoglycemia. M. B. (H. L. H. 77024), a colored girl, aged fifteen years, first attended the Harriett Lane Home when she was four years old. Her mother was a known syphilitic, and the patient's blood gave a positive serologic reaction. She was found to have diabetes mellitus,
and was treated in the diabetic clinic. She developed an alternating internal squint. From time to time it was noticed that there was some slight bilateral ptosis, but this did not impress the examiners. When she was fifteen years old she suddenly developed marked bilateral ptosis, generalized weakness, and inability to chew food. She was admitted to the hospital for study. On two occasions she had extreme difficulty in breathing and seemed to be unconscious. There was some hesitation in deciding immediately whether the collapse was due to hypoglycemia or to an exacerbation of the myasthenia, since she had been receiving insulin for the diabetes and prostigmine for the myasthenia. On the basis of recovery after the injection of prostigmine it was quite apparent that the spells

were due to the myasthenia. Within a week the myasthenia symptoms disappeared almost completely and treatment with prostigmine was discontinued.
CASES IN WHICH THYMECTOMY WAS PERFORMED (SEVEN CASES) CASE 44.-Severe myasthenia gravis onset with unilateral ptosis and diplopia.
Thymectomy followed by brilliant result. Peculiar associated movement of eyelids.
R. L. (235345), a white woman, aged twenty-eight years. The onset of the disease was marked by diplopia and paralytic left internal strabismus. She complained of pain in the left eye, and as it was suggested that a maxillary sinusitis might be present, drainage was performed. Two months later there was weakness of the legs and pain in them. The arms soon became weak, and the muscles of the trunk as well. Six months later there was weakness of the mouth and tongue. Still later, difficulty in swallowing and regurgitation of fluids through the nose set in. Myasthenia gravis was diagnosed elsewhere, and the patient tried prostigmine in combination with ephedrine and with guanidine. She believed that prostigmine alone was not so effective as were the combinations. She was taking prostigmine bromide, 30 mg., and guanidine hydrochloride, 250 mg., six or seven times daily. Her general weakness was so pronounced that she could not raise her head from the bed in the mornings, and had to take the prostigmine before she could get up. Examination of the eyes revealed ptosis on the left and paresis of the left external rectus muscle. The pupils were normal. There was pronounced weakness of the muscles of the arms, legs, and trunk. There were no neurologic changes. The injection of 1.5 mg. of prostigmine into the right brachial artery with concurrent occlusion of venous return gave the following results: Within fifteen seconds the right-hand grip improved and was virtually normal within another thirty seconds. The cuff was then released, and within three to four minutes there was rapid return of power over the entire body. The ptosis, diplopia, and difficulty in speaking and swallowing disappeared. There were no fasciculations nor was there bradycardia, cramps, and the like. Thymectomy was performed by Dr. Blalock. The thymus was large and "beefy" and showed pronounced hyperplasia. Following the operation there were periods during which she did not require any prostigmine. She was much stronger, and the left ptosis disappeared, although the internal squint remained. Later the ptosis reappeared. During a period of pronounced improvement injection of prostig-

mine into the right brachial artery was followed by subjective and objective weakness of the right hand, and there were scattered fasciculations of small extent. About a minute after release of the cuff there were fasciculations in the ptosed lid. The patient was discharged about five months after operation. The fact that for several weeks before she was discharged she worked in the history room of the hospital is evidence of her inproved condition. Some observers, however, believed that she was still sufficiently weak and that prostigrnine was indicated, but she refused to take it. The peculiar associated movements of the eyelids are considered elsewhere in this paper (fig. 8).
CASE 45.-Patient exhibited maculopapular rash at onset of myasthenia; enjoyed a remission and again had a maculopapular rash with fresh attack of myasthenia. Improvement after thymectomy.
L. K. (127185), a colored girl, aged seventeen years, was seen in August, 1935, complaining of weakness of her mouth, tongue, and arms, and drooping of both upper eyelids. These disabilities had been present for several weeks, and a generalized rash had been manifest for several days at the onset. Physical examinations revealed weakness of the muscles of the eyelids, face, and mouth. She was treated with prostigmine and ephedrine, and improved greatly in seven or eight weeks. Several months later she was readmitted with an upper respiratory infection and an exacerbation of the myasthenia. In February, 1937, she complained of shortness of breath and generalized weakness. There was a maculopapular rash which covered almost the entire body; this lasted for five or, six days and then disappeared. For twenty-four hours her respiratory difficulties demanded frequent administration of prostigmine. Thereafter she improved rapidly and was discharged within two weeks after her admission. Prostigniine, 30 mg. four times daily, by mouth, was ordered. Later she was subjected to thymectomy. The gland was found enlarged. Her symptoms improved materially.
CASE 46.-Preponderance of peripheral over bulbar signs in patient with onset of myasthenia gravis with diplopia which persisted only for about a week and disappeared. Within two weeks pronounced weakness of legs and arms which persisted. Episode8 of regurgitation offluid through nose.
P. T. C. (225775), a colored male, aged thirty-two years. Symptoms were present over a five-month period. Examination of the patient showed the eyes to be normal

externally. After any exertion there was development of ptosis and some degree of external ophthalmoplegia, which was not present when he lay quiet for a time. There was bilateral facial weakness, inability to speak without changes in the quality of the voice, and rapid tiring of the muscles of the legs and arms. The most striking feature was the preponderance of peripheral over bulbar signs. He was unable to walk, and could not even strike a match to light a cigarette. After study he was discharged, and given prostigmine, 240 mg., in six divided doses, with 150 mg. of ephedrine, but he was asked to return for surgical treatment. After removal of the thymus gland (from the anterior mediastinum) it was possible gradually to reduce the dose of prostigmine until finally he was able to get along without it. An arterial injection of prostigmine produced fasciculation, which it had failed to do before operation. The thymus showed hyperplasia.
CASE 47.-Onset with ptosis and diplopia in woman thirty years old. Later weakness of legs and later inability to chew food properly and change in quality of voice. Inability to raise eyes above horizontal level and weakness of all other extraocular muscles. Thymectomy. Result unsatisfactory.
R. S. (234627), a woman, aged thirty years. When she was first seen she stated that ptosis and diplopia had been present for three months. For two months there had been an inability to walk for any distance. For two weeks there had been difficulty in swallowing and in chewing, and the voice had become nasal. She was emotionally upset. An injection of prostigmine established the diagnosis. After having been discharged, and receiving prostigmine and ephedrine, she returned for thymectomy. X-rays had not shown any evidence of thymus tumor. Following the operation it was necessary to continue prostigmine and ephedrine, and she was discharged apparently unimproved. It was observed that the intra-arterial injection of prostigmine excited a few muscle twitchings, an observation that may have pointed to the operation as having had some
effect.
CASE 48.*-Post-operative hypothyroidism at first confused with myasthenia gravis. Woman, twenty-four, had developed progressive exophthalmos and later diplopia, dysphagia, and respiratory difficulty. Limitation of lateral movements of eyes, difficulty in convergence, and slight limitation of vertical movements. Pupils
normal. Thymectomy performed. Resut indifferent. M. W. (257671), a white woman, aged twenty-four years, gave the following history: Four years prior to our examinations, and

after the birth of her second child, she developed nervousness and fatigability which, however, were not associated with increased appetite, diarrhea, tremor, or excessive perspiration. Basal metabolic rate was said never to have exceeded +30. Thyroidectomy was performed. Following upon this operation the eyelids gradually drooped, and it was at first believed that she suffered from hypothyroidism. Fourteen months before admission to this hospital she complained of weakness, diplopia, dysphagia, and respiratory difficulties. There had been some slight but gradual increase in the amount of proptosis. A diagnosis of myasthenia gravis was made. Examinations other than that of the eyes were not remarkable. There was generalized weakness and some dryness of the skin. Basal metabolic rate was -4. There was a sustained leukocytosis with 30 per cent. mononuclear cells; this was not explained. Pronounced proptosis and bilateral ptosis were present. Hertel exophthalmometer reading: R.E., 21; L.E., 21. There was defective convergence power. Later, movements of the eyes were restricted and vertical movements were slightly decreased. The pupils were normal. Visual acuity and optic fundi were normal. Patient was given 30 mg. of prostigmine every four hours with great benefit. Guanidine and ephedrine did not enhance the value of the prostigmine, and implantation of prostigmine pellets was not successful. Withdrawal of prostigmine resulted in alarming symptoms. It was decided to remove the thymus. The gland was not enlarged. It was believed that improvement followed the operation, but large doses of prostigmine were essential to her well-being on her discharge from the hospital. In this case, as in the preceding one, it was suggested that an estimation of thyrotropic hormone might throw some light on the situation, but unfortunately this was not made.
CASE 49.-Unilateral ptosis and limitation of ocular movements in one eye only but later affecting abduction of other eye in patient who ultimately was subjected to thymecomy and did not get good result. Unfavorable response to quinine pointed to the diagnosis. Intra-arterial injection prostigmine failed to produce muscle
fasciculations.
M. W. (204601), a white woman, aged thirty-seven years, was seen in June, 1930. Ten months before examination she was unable to read aloud for prolonged periods. The right upper lid drooped, and then there was successively diplopia on looking to the left,

dysphagia, and general weakness. The patient was treated for anemia, but the severity of the symptoms increased. Six months later the diagnosis was arrived at and prostigmine therapy was instituted, 15 mg. being given four times daily. However, on this dosage she became progressively weaker. For a month before admission she had repeated falls as her knees would give way. She suffered from dyspnea on any exertion. The patient insisted that she felt worse in the mornings than later in the day. Examination revealed right-sided ptosis and limitation of all movements of the right eye. She was unable to raise her head from the bed. She could count to 50, and then became exhausted. Deep breathing exhausted her. The skeletal muscles were weak. She was given 0.6 gin. quinine sulphate at 4 P. M. Within four hours she developed extreme weakness and, in addition to the routine dose of prostigmine by mouth, further dose hypodermically was necessary. After extensive examination she was discharged, and prostigmine bromide, 15 mg. six times a day, and ephedrine, 25 mg. three times a day, was ordered. This combination therapy usually appeared effective. Thymectomy was performed a few weeks later. The thymus was found to be hyperplastic. Following the operation it was found necessary to continue with prostigmine.
CASE 50.*-Sudden onset ocular myasthenia foUoing upon emotional upset. Later development of other symptoms of the disease. Unfavorable influence of respiratory infections. Favorable results unth prostigmine and ephedrine therapy. Later thymectomy. Death.
H. M. (165640), a white woman, aged thirty-nine years, had always been well up to the onset of the present illness, which began five and one-half years previously under interesting circumstances. On the day before the onset of double vision she had become emotionally upset. She awakened with diplopia and was unable to swallow food or fluids, which returned through her nose. She also had difficulty in speaking. She responded well to prostigmine, and was discharged from the hospital with directions to take ephedrine. After ten months there was a complete remission and no symptoms were present. Another attack occurred, and was fairly well controlled with prostigrnine, 15 mg. every two hours, and ephedrine sulphate, 25 mg., in the morning. The patient noticed that with every cold there was pronounced increase in the myasthenia. On this hospitalization it was found that there was a mediastinal mass, and thymectomy was performed.

The patient died on the second day following the operation. Autopsy findings included atelectasis, emphysema, and lobular pneumonia. Biopsy of thymus gland showed a normal thymus. CASES ASSOCIATED
WITH
HYPERTHYROIDISM (Two CASES)
CASE 51.*-Myasthenia gravis confused with exophthalmic goiter because of the exophthalmos occasionally observed in myasthenics. Onset with weakness of lips. Four years later development of difficulty in speaking, diplopia, weakness of limbs. Remissions.
A. F. (134761), a woman, aged thirty-five years, was seen in March, 1938. She exhibited pronounced bilateral exophthalmos, bilateral ptosis, external ophthalmoplegia, which did not, however, interfere with convergence. There was moderate ability to look downward. The pupils reacted normally to light. There was extreme weakness of the facial muscles; swallowing was difficult; the sternomastoid muscles were weak; there was generalized weakness of all four extremities. The sensory system and the deep reflexes were normal. About twelve years before examination she had difficulty playing a saxophone, which was her profession. Her lips became tired rapidly. Four years later she developed difficulty in speaking, diplopia, weakness of the limbs, and at about this time she noticed gradual increasing protrusion of the eyes. Although there were no symptoms, such as general nervousness, tachycardia, etc., thyroidectomy was performed. Following the operation the symptoms of myasthenia increased for a few months. Then there was a remission. Several further remissions occurred before we saw her during a recurrence. It seemed entirely probable that she had never had evidences of hyperthyroidism. After it had been shown that there was a typical response to prostigMine, prostigmine therapy was instituted.
CASE 52.*-Myasthenia gravis and hyperthyroidism in Negro female. Onset of myasthenia with bilateral ptosis and diplopia. Observed over period of eleven years.
N. G. (143931), a colored female, about 1920 had difficulty in carrying on her work as a teacher because of fatigability and nervousness. In 1929 she suddenly developed bilateral ptosis and diplopia, and there was an almost complete inability to move the eyes. The pupils were normal. She exhibited tachyeardia, tremor, goiter, basal metabolic rate, + 18. In 1930 the last was +25.

In 1937 the ocular symptoms remained unchanged, except that the ptosis varied from time to time and was lessasevere early in the morning. Prostigmine was prescribed. In 1938 severe nervousness and tachyeardia appeared. The metabolic rate was +51. The thyroid was radiated, and later in the year a thyroidectomy was performed. In 1941 her general condition was favorable while she continued to take prostigmine. She was taking prostigmine, 15 mg. on arising in the morning, and 7.5 mg. thrice daily thereafter, ephedrine 10 mg. with each dose of prostigmine, and atropine 0.5 mg. by mouth only if she had abdominal cramps or diarrhea.
CASES ASSOCIATED WITH LABOR AND PREGNANCY (Two CASES) CASE 53.-Myasthenia gravi seemingly precipitated by normal labor in thirtyfe-year-old uwoman. Weakness of the facial muscles was an early sign and could
have been attributed to bilateral facial nerve palsy. The orbicularis oculi were relatively weaker than the levator palpebrae for a short time but later there was development of pronounced bilateral ptosis. Prostigmine relieved.
R. C. (B.C.H. 56613), a white woman, aged thirty-five years, a few days after the birth of her second child, complained of difficulty in swallowing and occasional regurgitation of fluids through the nose. Difficulty in talking developed within a day or two. At this time closure of the eyelids was incomplete, giving the appearance of bilateral facial nerve palsy. Her voice became nasal. After a few days pronounced bilateral ptosis and occasional diplopia developed. Injection of prostigmine relieved the ptosis and the difficulty in swallowing and restored her voice to normal. She was discharged from the hospital with directions regarding the taking of prostigmine by mouth.
CASE 54.-Myasthenia gravis unfavorably influenced on two occasions by pregnancy. Patient subjected to therapeutic abortions. Onset with bilateral ptosis, later dysphagia and then fatigue of extremities and trunk muscle8.
M. F. (155152), a married housewife, aged thirty years, when first examined, had suffered from myasthenia gravis for six years. The first symptom was bilateral ptosis. This was followed by difficulty in swallowing, weakness of speech, and rapid tiring of the arms and legs. After having used glycine and ephedrine for two years, she was given prostigmine, 15 mg., six times daily, and after a few months this was reduced to five doses daily. Two years after the onset of myasthenia gravis she became preg-

nant and noticed an increase in the severity of her symptoms; at this time she was not taking prostigmine. A therapeutic abortion was performed. For some reason a lumbar puncture was done, which was followed by a severe exacerbation of the myasthenia. On the occasion of the visit first referred to, she had again become pregnant, and for the first few weeks got along quite well. Later, even with extra doses of prostigmine, she could not eat because of weakness of the muscles. A therapeutic abortion was again performed. Thereafter prostigmine therapy was continued with favorable results. The patient has not been heard from for several years.
MISCELLANEOUS CASES
CASE 55.-Spells of myasthenia gravis associated with situational hysteria in two instances and with ordinary cold in another. Several periods of complete freedom from symptoms. Ocular involvements consisted only of weakness of the orbicularis oculi muscles.
D. P. (182604), a woman, aged thirty-eight years, a stenographer, was seen in 1939. In 1935 she suffered a "nervous breakdown." For several days she complained of severe generalized weakness. A rest in the country for six weeks effected a complete recovery. Two years later (1937) she had a recurrence of symptoms. At this time she was told she had myasthenia gravis and was given glycocol. After a rest of eight weeks she resumed her work and had no further trouble until 1938. Following a cold she complained of generalized weakness, but remained at work. Finally, after a six weeks' rest, she again recovered strength. In 1939 she noticed difficulty in speaking, and spells during which it became impossible for her to type because of weakness of her fingers. These symptoms usually cleared up on week-ends. Next she developed occasional pronounced difficulty in swallowing and in breathing. Examination revealed weakness of the facial muscles, including the orbicularis oculi. An injection of prostigmnine relieved the nasal quality of her voice and increased the strength of her muscles as shown on the dynamometer and by leg-raising tests. Patient died suddenly in 1942, after a respiratory infection.
CASE 56.-Myasthenia gravis in hypochondriacal patient who exhibited weakness of left extrnal rectus muscle and of elevators of right eye. Diagnosis established by use of prostigmine. History of treated syphilis.
G. J. G. (207802), a white male, aged thirty-three years, came for examination because of diplopia of two months' duration. He

had complained of extreme weakness over a period of five years, but examination failed to support his contentions regarding general weakness. Examination of the eyes revealed an absence of ptosis, but there was weakness of the external rectus muscle of the left eye and of the superior rectus and inferior oblique of the right eye. The injection of prostigmine increased the amplitude of movement of the left eye in abduction, and of the right eye in elevation. Dynamometric tests showed pronounced increase in the strength of the hand grasp, which previously had not been regarded as deficient. The patient was given prostigmine methylsulfate, 15 mg., five times daily, and ephedrine, 25 mg. at 2 P. M. daily. Two months after having been examined he was discharged greatly improved, although the limitation of the ocular movements was but little changed.
CASE 57.-Severe myasthenia gravis in white woman fifty-fiwe years old. Onset with diplopia foUlowing what seemed to be ptomaine poionin. Ptosis, weakness of lids, BeU's phenomenon present when attempts made to close eyes. Diffiulty in swallowing, etc.
H. W. (187915), a white woman, aged fifty-five years, after having had an acute gastro-intestinal upset, within a few days developed diplopia, which persisted for about a month and then gradually cleared, but was followed by left-sided ptosis. Two months later she had difficulty in speaking and in swallowing. At the time of admission, about six months after the onset of the condition, there were frequent spells of respiratory embarrassment, which were incompletely controlled by the administration of prostigmine, 15 mg., three times daily. Examination of the eyes showed, in addition to the left-sided ptosis, weakness of the levator of the right eye, which became ptotic after opening and closing the eyelids a few times. There was also bilateral facial weakness, with inability to close the lids tightly. Whenever this was attempted the eyes rolled upward. There was no limitation of ocular movements. The pupils were normal in their response to light and convergence-accommodation. After the injection of prostigmine, 1 mg., speech became quite normal. Serologic tests for syphilis were positive in the blood, but it was decided that treatment for her latent syphilis was contraindicated. The patient was discharged improved, and prostigmine, five times a day, was ordered as follows: 6 A. M. and 11 A. M., 22 mg.;

4 P. M., 30 mg.; 8 P. M., 15 mg.; 9 P. M., 15 mg. Ephedrine, 9 A. M., 24 mg. It was recently learned that the patient died of a thymoma, approximately a little over a year after first having been seen here.
CASE 58.-Onset after having been severely bitten by dog. Weakness of jaws followed by weakness offacial muscles, then right-sided ptosis and diplopia. Palpebral fissure on left wider than normal, lid-lag on left.
M. S. (U-73996), a white woman, aged forty-three years, had been severely bitten by a dog three months before the onset of symptoms. The dog bite became infected and the wound did not heal for two months. Her jaws became tired, and in a few months the left side of her face became so weak that it was believed that she had a left Bell's palsy. Then a remission set in, to be followed by a sudden onset of diplopia eight months after the onset of the first attack of myasthenia gravis. There was associated weakness of the muscles of the face and difficulty in chewing and swallowing. Examination records showed right ptosis and a positive myasthenic reaction. She was discharged from the hospital and prostigmine, 30 mg. three times daily, was ordered. Comment.-Two points were of particular interest. The increased wideness of the palpebral fissure on the left was similar to that of the patient illustrated in figure 7. Also of interest was the antecedent injury, but what part it played is, of course, not known. She was highly emotional about her illness and threatened to commit suicide.
CASE 59.-Possibility of myasthenia gravis or myotonic dystrophy in patient with lenticular opacities, which however, were not typical of myotonic dystrophy. The favorable effects of prostigmine and the unfavorable influence of quinine supported the diagnosis of myasthenia gravis.
H. L. (140036), a female, aged twenty years, complained of weakness in the left knee, which was followed shortly by fatigue on talking and weakness of the jaws in eating. Ptosis of the left upper eyelid ensued, and she developed an immobile facies. There was occasional diplopia after repeated movements of the eyes. Examination records are not detailed, other than to state that there were no changes in the deep or superficial reflexes and in sensation. The lenticular changes, while not subcapsular, were difficult to classify. Because of the pronounced improvement in the ptosis and

in other symptoms after the use of prostigmine and an exaggeration of symptoms after quinine there was little doubt that myasthenia was present.
CASE 60.-Onset of unilateral ptosis followed by weakness of jaw muscles and increased fatigability of aU muscles, particularly legs, in sixty-seven-year-old white man. Later development of ptosis on opposite side.
R. C. (235007), a man, aged sixty-seven years, exhibited no definite involvement of the extra-ocular muscles other than ptosis. When he was seen the entire course of the affection had run three months. He obtained great relief by taking 90 mg. prostigmine in six doses each day.
CASE 61.-Myasthenia gravis in man eighty-two years old. Only ocular signs were almost complete inability to move the eyes and bilateral ptosis. Onset at seventy-five years.
J. T. M. (283261), a white man, aged eighty-two years, complained of bilateral drooping of the upper lids and inability to move the eyes. As the result of an automobile accident he suffered a fracture of the pelvis, and while convalescing developed diplopia and bilateral ptosis. Examination revealed bilateral ptosis and inability to move the eyes excepting downward two or three degrees. The pupils were small, equal, and reacted normally to light. He was unable to converge. Visual acuity was approximately normal, and with +3.50 addition he was able to read small print at 10 to 12 inches. A diagnostic injection of prostigmine, 1 c.c. of a 1: 2000 solution, almost completely cured the ptosis on the right and improved it on the left. He was given prostigmine by mouth (dosage not available). Four years after examination the eye condition was reported as unchanged. He had discontinued the use of prostigmine.
CASE 62.-Inability to close the eyes and occasional diplopia in a boy of fourteen who exhibited other evidence of myasthenia gravis.
E. C. (282999), a boy, aged fourteen years, developed slurring of speech about four months before our examination. Three weeks after this symptom appeared there was an inability properly to close the eyelids, and shortly thereafter there was pronounced general weakness. All symptoms were much improved in the morning.

On admission he could not walk and could not raise his head from the pillow. There was an inability to close the eyes, but there was no suggestion of ptosis. There was occasional diplopia and bilateral weakness of the facial muscles. The arms and legs could be moved about, but were weak. Neurologic examination, other than as stated, was negative. A diagnostic injection of prostigmine enabled the patient to walk and to close his eyes tightly.
CASE 63.-Minimal eye sign in a girl of nineteen who exhibited weaknesses like those seen in muscular dystrophy.
A. T. (260341), a female, aged nineteen years, about two years before examination found that at times she could not mount her horse, and at about this time she noticed diplopia, which was inconstant. After a month or two she experienced no further difficulty until five months before examination. At that time she had difficulty in walking up stairs, and could not run or play tennis. Her arms became weak, and she could not hold them up to comb her hair. Ptosis was present when she was tired, but diplopia was present at all times. Examination of the eyes showed weakness of the external rectus muscles and shortened range of movement upward of the left eye. Convergence was poorly performed. There was nystagmoid jerking when the eyes were in extreme lateral deviation. Ptosis was present only after opening and closing the eyes. Pupils were regular and reacted to light. Vision and visual fields were normal. The neurologic examination showed no fasciculations. Strength seemed good except for movements at proximal joints, such as the shoulders, hips, and knees. She could stand on the toes of either foot, but could not step up on a couch or arise from a squatting position without using her arms. She could not lift her arms above the horizontal, but the hand grip and the muscles of the forearm were quite strong. At the elbows, the flexors and extensors were weak. An injection of prostigmine methylsulfate seemed to establish the diagnosis.' The patient improved materially on prostigmine by mouth, and the improvement was still present six months after the first examination. She was taking a moderate amount of prostigmine.
WALSH: Myasthenia Gratis and Its Ocular Signs 623

REFERENCES Abraham, S. V.: Arch. Ophth. 7: 700-719, 1932. Adams, M., and Power, M. H.: Proc. Staff Meet., Mayo Clin. 9: 598-599, 1934. Adams, M., Power, M. H., and Boothby, W. M.: Ann. Int. Med. 9: 823-833 1936; Jan. Correction, ibid. 9: 1170. Bell, E. T.: J. Nerv. & Ment. Dis. 45: 130-143, 1917. Bender, M. B.: Arch. Ophth. 15: 21-30, 1936. Bernard, Claude: Substances toxiques, Paris, p. 344, 1857. Blackman, S. S., Jr.: Personal communication to the author. Blalock, A., Harvey, A. M., Ford, F. R., and Lilienthal, J. L., Jr.: J.A.M.A. 117: 1529-1533, 1941. Booth, J. A.: J. Nerv. & Ment. Dis. 35: 690-694, 1908. Brain, W. R.: Diseases of the Nervous System, London, Oxford University Press, 1933, pp. 686-691. Briscoe, G.: Lancet, 1: 469-472, 1936. Brown, G. L., Dale, H. H., and Feldberg, W.: J. Physiol. 87: 394-424, 1936. Buzzard, T.: Brit. Med. J. 1: 495-496, 1900. Campbell, E., Fradkin, N. F., and Lipetz, B.: Arch. Neurol. & Psychiat. 47: 645-661, 1942. Campbell, H., and Bramwell, E.: Brain, 23: 277-336, 1900. Cannon, W. B.: Am. J. M. Sc. 198: 737-750, 1939. Cannon, W. B., and Rosenblueth, A.: Autonomic Neuro-Effector Systems, New York, The Macmillan Company, 1937. Cannon, W. B., and Rosenblueth, A.: Am. J. Physiol. 130: 219-229, 1940. Cobb, S., and Forbes, A.: Am. J. Physiol. 65: 234-251, 1923. Collier, J. S.: Brain, 50: 488-498, 1927. Courtis, B., and Sitler, R.: Arq. brasil. de oftal. 5: 163-179, 1942. Curschmann, H.: Ergeb. d. inn. Med. u. Kinderh. 21: 467-497, 1922. Dale, H. H.: The Harvey Lectures, 32: 229-245, 1937; also Bull. New York Acad. Med. 13: 379-396, 1937. Dale, H. H., and Feldberg, W.: J. Physiol. 81: 39-40, 1934. Dale, H. H., Feldberg, W., and Vogt, M.: J. Physiol. 86: 353-380, 1936. Duke-Elder, W. S., and Duke-Elder, P. M.: Proc. Roy. Soc., London, s. B, Edgeworth, H.: J.A.M.A. 94:1136, 1930. Erb, W.: Arch. f. Psychiat. 9: 336-350, 1879. Erb, W.: Arch. f. Psychiat. u. Nervenkrank. 9: 172-173, 1879. Evans, C. L., and Hartridge, H.: Starling's Principles of Human Physiology, Philadelphia, Lea and Febiger, pp. 120-179, 1936. Ford, F. R.: Diseases of the Nervous System in Infancy, Childhood, and Adolescence, Springfield, Il., Charles C. Thomas, pp. 889-893. 1937. Ford, F. R.: Bull. Johns Hopkins Hosp. 68: 309-318, 1941. Gavey, C. J.: Proc. Roy. Soc. Med. 35: 14-15, 1941. Goldflam, S.: Neurol. Centralbl. 10: 162-167 and 204-214, 1891. Grinker, R. R.: Neurology, Springfield, Il, Charles C. Thomas, pp. 821-824, 1934. Guthrie, L. G.: Lancet, 1: 330, 1903. Hart, H. H.: Arch. Neurol. & Psychiat. 18: 439 -42, 1927. Harvey, A. M., and Masland, R. L.: Bull. Johns Hopkins Hosp. 69: 1-13, 1941. Harvey, A. M., and Masland, R. L.: J. Pharmacol. & Exper. Therap. 73: 304-311, 1941. Harvey, A. M., and Whitehill, M. R.: J.A.M.A. 108: 1329-1333, 1937. Harvey, A. M., and Whitehill, M. R.: Bull. Johns Hopkins Hosp. 61: 216-217, 1937. Harvey, A. M., Lilienthal, J. L., Jr., and Talbot, S. A.: Bull. Johns Hopkins Hosp. 69: 529-546, 1941.
107: 332-343, 1930-31.

Harvey, A. M., Lilienthal, J. L., Jr., and Talbot, S. A.: Bull. Johns Hopkins Hosp. 69: 547-565, 1941. Harvey, A. M., and Lilienthal, J. L., Jr.: Bull. Johns Hopkins Hosp. 69: 566577, 1941. Hun, H., Blumer, G., and Streeter, G. L.: Albany M. Ann. 25: 28-55, 1904. Jolly, F.: Berl. klin. Wchnschr. 32: 1-7, 1895. Jones, M. S., and Stadie, W. C.: Quart. J. Exper. Physiol. 29: 63-67, 1939. Kawaichi, G. K., and Ito, P. K.: Am. J. Dis. Child. 63: 354-356, 1942. Keschner, M., and Strauss, I.: Arch. Neurol. & Psychiat. 17: 337-376, 1927. Klar, J.: Klin. Monatsbl. f. Augenh. 85: 224-228, 1930. Laurent, L. P. E.: Lancet, 1: 753-754, 1931. Lindsley D. B.: Brain, 58: 470-482, 1935. Little, M. F.: Personal communication. McAlpine, D.: Brain, 52: 6-22, 1929. Marinesco, G.: Semaine m6d. Paris, 28: 421-429, 1908. Moehlig, R. C.: J.A.M.A. 115: 123-125, 1940. Moore, M. T.: Arch. Ophth. 26: 619-625, 1941. Nevin, S.: Brain, 57: 239-254, 1934. Noyes, A. P,: Rhode Island M. J. 13: 52-59, 1930. Oppenheim, H.: Virchow's Arch. f. path. Anat. 108: 522-530, 1887. Palmer, A. S. M.: Guy's Hosp. Rep. London, 62: 55-133, 1908. Posey, W. C., and Spiller, W. G.: The Eye and Nervous System, Philadelphia, J. B. Lippincott Co., pp. 457-462, 1906. Rabinovitch, V., and Vengrjenovsky, G.: Arch. d'Opht. 52: 23-31, 1935. Rea, R. L.: Neuro-Ophthalmology, St. Louis, C. V. Mosby Co., pp. 345-347, 1941. Rothbart, H. B.: J.A.M.A. 108: 715-717, 1937. Rottino, A., Poppiti, R., and Rao, J.: Arch. Path. 34: 557-561, 1942. Schlezinger, N. S.: Arch. Int. Med. 65: 60-77, 1940. Sloan, H. E., Jr.: Surgery, 13: 154-174, 1943. Starr, M. A.: J. Nerv. & Ment. Dis. 39: 721-731, 1912. Spiller, W. G., and Buckman, E. U.: Am. J. Med. S. 129: 593-598, 1905; J. Nerv. & Ment. Dis. 32: 469-471, 1905. Strumpell, A.: Deutsche Ztschr. f. Nervenh. 8: 16-40, 1896. Taylor, J.: Proc. Roy. Soc. Med. 6: 69, 1912-13; Neurological Section. Tilney, F.: Neurographs, 1: 20-46, 1907-1915. Viets, H. R.: Arch. Neurol. & Psychiat. 47: 859-862, 1942. Viets, H. R., Schwab, R. S., and Brazier, M. A. B.: J.A.M.A. 119:236-242, 1942. Walker, M. B.: Lancet, 1: 1200-1201, 1934. Walker, M. B.: Proc. Roy. Soc. Med. 28: 759-761, 1935. Walsh, F. B., and King, A. B.: Arch. Ophth. 27: 1-33, 1942. Weigert, C.: Neurol. Centralbl. 20: 597-601, 1901. Wilbrand, H., and Saenger, A.: Neurologie des Auges, 1: 219-235, 1900. Wilks, S.: Guy's Hosp. Rep. 37: 7-55, 1877. Williams, B. W., and Dyke, S. C.: Quart. J. Med. 15:269-278, 1921-22. Wilson, S. A. K.: Neurology, Baltimore, William Wood & Co. 2: 1595-1607, 1940. Woollard, H. H.: J. Anat. 65: 215-223, 1931.

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MYASTHENIA GRAVIS AND ITS OCULAR SIGNS: A REVIEW*

FRANK B. WALSH, M.D. Baltimore, Md.

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Fig. 1.-Section of muscle showing collection of lymphocytes (Aut. 17768).

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Fig. 6.-Before and after injection of prostigmine (P.S.-Case 2).

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PURELY OCULAR SIGNS (TEN CASES)

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HYPERTHYROIDISM (Two CASES)