Studies in myasthenia gravis

512

J O U R N A L OF THE N E U R O L O G I C A L SCIENCES

Studies in Myasthenia Gravis Part 1. A clinical study of 180 patients H. J. G. H. O O S T E R H U I S Neurological University Clinic (Head: Pro]essor A. Biemond) , Wilhelmina Gasthuis, Amsterdam (The Netherlands)

INTRODUCTION

From 1958 to 1963 the author made a study of myasthenia gravis. At first the clinical picture, well known in literature since the descriptions of ERB (1879), GOLDFLAM (1893), and OPPENHEIM (1901), and so extensively studied by OSSERMAN (1958), did not seem to be a promising subject for new investigations. Upon closer scrutiny, however, many questions emerged which could be answered only by a personal examination of the patient. At first, certain facts were found which inspired us to add to the considerable literature of the last 10 years. These are based upon the experience of a series of t80 patients with myasthenia gravis, of which 125 were personally examined. Eighty two patients have been observed in the Neurological University Clinic of Amsterdam during the period 1926-1963. This number was extended so as to include all the myasthenic patients who were under observation since 1945 at various other neurological clinics, which regularly referred to us some of their cases for consultation. N 3 recent information about 11 patients could be obtained; the remaining 44 patients were not examined by the author himself, many of them having died. For a review of the extensive literature the reader is referred to the papers by OSSERMAN (1958, 1961) and also to the Proceedings of the Second Symposium (VIETS 1961). The object of this paper is to report a personal study of 180 patients, in which are emphasized certain features of the disease which we consider to be unfamiliar. Furthermore it is desired to publish the results of the immunological work, done on the same group of patients by VAN OER GELO AND FELTKAMP and their co-workers at the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam (DIRECTOR:PROFESSORDR. J. J. VAN LOGHEM, JR). A correlation with the clinical data will be made. Finally, the question will be discussed whether myasthenia gravis should be looked upon as a disease-entity or a syndrome. THE CLINICAL PICTURE

Onset The age of onset of the disease is represented in Table 1. Females are about twice J. neurol. Sci. (1964) I : 5 1 2 - 5 4 6

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513

TABLE 1 THE AGE AT ONSET OF 180 PATIENTS

Age (years)

Female

Male

Total

New-born 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79

3 3 22 29 (1)* 22 (1) 18 (2) 10 (3) 6 I 114 (7)

2 6 8 5 11 (2) 10 (3) 15 (5) 5 (2) 4 66 (12)

5 9 3O 34 (1) 33 (3) 28 (5) 25 (8) 11 ~2) 5 -180 (19)

* Those with thymomas are placed in brackets. TABLE 2 INITIAL SYMPTOMS IN

Location of symptoms

Female living

175 P A T I E N T S Male

dead*

Total

living

dead

Ocular Bulbar Limbs

51 14 23

10 8 5

31 7 6

9 5 6

101 34 40

Total

88

23

44

20

175

* from myasthenia. as often affected as males. This feature can be seen m a i n l y in the r e p r o d u c t i v e age, whereas the ratio o f m e n to w o m e n is s o m e w h a t greater in the older age-groups. These findings are in a c c o r d a n c e with the literature. Initial "symptoms

T h e l o c a l i s a t i o n o f the initial s y m p t o m s , r o u g h l y divided into three groups, is given in T a b l e 2. I n c o m p a r i s o n with the literature, the disease has been f o u n d to begin with weakness o f the extremities in a relatively large n u m b e r o f patients, in all b u t 4 o f w h o m o c u l a r o r b u l b a r s y m p t o m s followed sooner or later. I n general it can be said t h a t an onset with ocular s y m p t o m s predicts a better prognosis quoad vitam t h a n an onset with weakness o f a limb or b u l b a r musculature. The first s y m p t o m s were o c u l a r in 92 o f the 164 patients where the course o f the disease is k n o w n . A n isolated o c u l a r m y a s t h e n i a was present in o n l y 13 patients. D i s s e m i n a t i o n o f the s y m p t o m s t o o k place within 6 m o n t h s after the onset in 52 patients; within a y e a r in 9; within 2-3 years in 4; a n d after the third year in 10 patients. O u r patients d i d n o t in general seek medical advice on a c c o u n t o f a b n o r m a l fatigue. I n one g r o u p o f patients the disability was due to an obvious paresis o f one or m o r e striated muscle-groups, giving rise to ptosis, diplopia, dysphagia, dysarthria, difficulty in chewing, or to weakness o f the limbs, whereby certain m o v e m e n t s b e c a m e J. neurol. Sci. (1964) 1:512-546

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H. J. (;. 1t. OOSTERHUIS

particularly difficult after exertion if not impossible. The other group of patients made vague complaints of general malaise, pains in the arms, legs, neck or head ; blurred vision; or imperfect recovery after some intercurrent illness. In these patients, subjective complaints by far exceeded the physical signs; these varied in intensity and were frequently absent at the time of examination. This disappearance could sometimes be attributed to the enforced rest in the doctor's waiting room. The patient did not know exactly how to describe what he felt, and was inclined to attribute his complaints to his nervousness, especially if he noticed that emotions aggravated or provoked the symptoms. The physician was often misled, so that the disease had to advance before the diagnosis could be made. The interval between the onset of the disease and its recognition (Table 3) reflects this difficulty.

TABLE 3 INTERVAL BETWEEN ONSET AND DIAGNOSIS IN

Interval (months) 0-6 7-12 13-24 25-48 > 48 not known

Total

Living 42 20 24 11 22 4 123

(3)* (4) (3) (6) (16)

Dead 25 3 5 I 6 (3) 1 41 (3)

164

PATIENTS

Total 67 23 29 12 28 5 164

(3) (4) (3) (9) (19)

* T h o s e in brackets constitute the " a t y p i c a l " cases.

Several patients were diagnosed only after 10 or 20 years. It is obvious that in such cases the disease had taken a mild and fluctuating course. Nevertheless, even a slight degree of myasthenia can cause a considerable loss of health. A mild myasthenic state (TETHER 1961) was present in 20 patients, mainly women. The incidence of this mild form is probably far greater than is indicated by the frequency of 20 out of 175, because this form tends to be overlooked. The diagnosis was at times quite difficult, because of the overlap of "functional" and myasthenic manifestations. In these cases provocative measures, including the use of curare, eventually proved necessary. Ocular symptoms Ptosis usually begins in one eye-lid and becomes manifest in the course of the day; some patients however note a severe ptosis on waking, disappearing after an hour, and reappearing at night. SIMPSON (1960) alone has mentioned this feature. The ptosis may change rather abruptly from one eye to the other; or both eyes may be affected in an even or uneven degree. We have often seen the ptosis changing in degree during the course of an interview or examination. Diplopia may develop acutely, and may, for example, follow a sudden emotion. J. neurol. Sci. (1964) I : 512 546

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I t c a n be due to a paresis of one eye-muscle alone, but often several muscles are affected in a varying degree. In about half of the patients who complained of double vision, no obvious paresis of the eye-muscles could be observed on routine examination. If forced to maintain the eyes deviated in one direction for some time, the patient might develop a paretic nystagmus of one eye and an increase in the diplopia. The obliquus superior was the muscle most often affected. A group of patients without obvious paresis of the ocular muscles, and without any subjective complaint of double vision, had vague difficulties such as blurred vision after reading for a while; lacrimation and burning of the eyes, especially at night or in bright sunlight. Reading glasses in the older patients did not give relief. Possibly the muscles used in convergence are readily exhausted. A sluggish reaction of the pupils to light, as reported by BAPTISTA et al. (1961), was never observed, although 50 consecutive patients were examined especially for this symptom. Sometimes a paresis of the orbicularis oculi is present, preventing the patient from closing his eyes at night. If the paresis of the orbicularis oculi is progressive, a retraction of the eyelids may be seen, which is sometimes accompanied by an actual proptosis. This gives the impression of a thyrotoxicosis, and this diagnosis may seem to be supported by the nervousness and a slight or moderate rise in the basal metabolic rate, but is eventually excluded by the more specific tests for hyperthyroidism. This "pseudo-Basedow" condition was encountered at the onset of the illness in 10 patients. Bulbar s y m p t o m s

A mild paresis of the bulbar muscles may also be quite difficult to explain. The patient may complain of slight discomfort in swallowing: the food seems to "stick" behind the breastbone, the throat appears swollen. Such a complaint, if not accompanied by clearcutsigns, is sometimes interpreted as a globus sensation. Paresis of the soft palate results in regurgitation of fluid through the nose and a nasal voice. An early sign of bulbar paresis is the queer way of smiling, known as the myasthenic snarl (GOWERS) and described by the French as le rire vertical. This phenomenon was present in more than half of the patients who had other bulbar symptoms at the time of examination, and other patients still or their relatives referred to it. The laughter is sometimes accompanied by an immediate increase of the ptosis, which gives rise to a very characteristic appearance (Fig. 1). A slight paresis of the facial musculature may be felt as a stiffness or an "anaesthetized" sensation of the lips; a subjective failure of articulation; or to a "thick tongue". The face may entirely lose its expression after exertion, or even at rest, so that the "myopathic face" has been frequently noted in the case-histories. The facial weakness was rarely asymmetrical. Demonstrable sensory phenomena, as described by ALAJOUANINE et al. (1957) were observed in one male patient only, who had lost his taste 2 years before the onset of the myasthenia, his sense of smell being intact. This symptom did not respond to anticholinesterases. Relationship with the myasthenia is doubtful, but the symptom is unexplained otherwise. J. neurol. Sci. (1964) 1:512-546

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H. J. G. H. OOSTERHUIS

Hoarseness or aphonia was never seen in any of our patients as a true myasthenic symptom. This is also the experience of VW.TS (1960). In one patient it was present as a symptom of conversion hysteria.

F ¸¸ ' '

~~!~~ ~ T ~ '

~T'~.

V

Fig. 1. Generalized myasthenia since the age of 1-9 Laughing produces a "'rire vertical" (myasthenic snarl) in the left half of the face and a sudden increase of the ptosis. Right half of the face is paretic

Weakness of the muscles of the limbs Weakness of the muscles of the limbs and of the trunk was considered to be the initial symptom in 40 out of our 175 patients. I f the ocular or bulbar muscles were not obviously affected, the diagnosis was rarely made in that stage of the disease. Symptoms remained confined to the limbs and trunk in only 4 patients. Frequently the vague symptoms like "pains" or abnormal sensations after exertion, were not interpreted as due to muscle paresis. The weakness would only become evident in such patients after sustained exertion, for instance following repeated bending of the knees. Nevertheless, the first movement following a period of rest may also be subjectively diminished in power, so that a "residual" weakness may be assumed. This clinical impression is confirmed by the electromyographic finding that the first provoked action potential is smaller in a group of myasthenic patients when compared with normal controls (JOHNS et al. (1955). One patient (Case No. 4) underwent repeated orthopaedic operations upon the feet because of vague but persistent complaints of low back-pain and fatigue, without obvious myasthenic symptoms. Following the operation (and the use of curare) she was "as if paralysed". The diagnosis was made only years later. After a small dose of curare she developed ptosis, and became totally paralysed with severe dyspnoea. J. neurol. Sci. (1964) 1 : 512 54~

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517

Paralysis o f the legs m a y sometimes occur suddenly after vigorous exertion or emotion. Usually this was not realized to be an organic phenomenon. In some patients paraesthesiae in the territory of the ulnar nerve, headaches radiating from the neck, or low backache were present; all these complaints reacted to anticholinesterases and were obviously due to the weakness o f the muscles o f posture. OPPENHEIM (1901) already noted this in his m o n o g r a p h . Dyspnoea, from paresis o f the respiratory muscles, was seldom an isolated initial complaint. On the contrary, palpitations, dyspnoea and a sensation o f oppression were often encountered even in y o u n g patients after moderate exertion. As a rule the myasthenic nature o f these complaints had not been recognized. The circumstances present at the onset are tabulated in Table 4.

TABLE 4 CIRCUMSTANCES

A'I~rENDANT UPON TIlE ONSET OF MYASTHENIA IN

164 P A T I E N T S

Female

Male

28 4 10 4

9 l1 1 7

37 15 II 1I

313 59

/ 15 J I 8 t 67 164

Surmenage Acute emotional stress Surgical operations I Infection or intoxication Menstrual cycle menarche menopause Pregnancy d u r i n g following - Unknown

6 9 3 5 362 105

Total

Total

2 patients following thymectomy. 2 2 patients with a thymoma, 1 patient with hyperthyroidism. 4 patients with a thymoma.

It is our impression that these disturbances in the physical and psychical balance, ac! as a trigger-mechanism for the underlying pathological process. A n onset after acute emotions was always impressive. The intoxications encountered in this connection were: quinine as treatment o f malaria (2); r e s o c h i n e - - a quinine-like drug as treatment for chronic rheumatoid arthritis (2); and on one occasion pipadox, an antihelmintic drug also resembling quinine in its essential structure. Relationship to changes in the menstrual cycle is not constant but may play a role. Operations sometimes included the use o f curare. Neonatal myasthenia will be discussed later. Since the onset in a b o u t 50 patients was longer than 10 years before the time o f our inquiry, it is probable that a n u m b e r o f them m a y have forgotten the circumstances which attended the original development o f the disease. Course Classification

KEYNES' (1955) statement that myasthenia gravis "never obeys any rules" might J. neurol. Sei. (1964) 1 : 512-546

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H.J.G.H.

OOSTERHUIS

be modified somewhat, but it is true that the clinical picture is polymorphic and the manifestations of the disease may run an erratic course. OSSERMAN (1958) suggested a classification into several types, which we have adopted with some minor changes. The group called "juvenile myasthenia" cannot be considered as being essentially different from the adult group and therefore we do not consider them separately. OSSERMAN'S G r o u p 2, cases of myasthenia gravis of moderate severity, responding well to drug treatment and running a course with exacerbations and remissions, is divided by us into: Group 2A : patients with mild symptoms, not severely interfering with the patients' health and ability to work, and which tend to disappear in the course of time. Group 2B: patients with moderate symptoms, usually more generalized, running a fluctuating course over many years, and which may handicap the patient to a variable extent. Group 2 B-+A: patients whose disease makes a favourable progression out of group 2 B into 2 A. Groups 3 and 4 are the same as in OSSERMAN'sclassification. They are characterized by respiratory and severe bulbar symptoms which make the prognosis poor. In G r o u p 3 a downhill course is present from the onset; in Group 4 the disastrous change in the clinical picture occurs after an interval of 6 months to two years. The classification of our patients according to these criteria is set out in Table 5. TABLE 5 CLASSIFICATION INTO CLINICAL TYPES OF 180 PATIENTS

Groups (modified after Osserman)

Female

Neonatal

Ocular (1) 2A 2B-+ A 2B 3 4 Total

3

4 27* 18 60 8 12 114

Male 2

9 16** 4 19 8 12 66

Total 5

Thymoma -

13 43

3

79 16 24

7 4 5

180

19

* 7 of them subjectively cured. ** 3 o f them subjectively cured.

Factors influencing the course T h y m o m a s were present in 19 patients, 12 males and 7 females. The mean age at the onset of the myasthenia was 47 years, which is distinctly higher than the mean age of the whole group. The relative incidence of a t h y m o m a is strikingly different in the two sexes: 4-25% of the male myasthenics had a t h y m o m a as opposed to 4-5% of the females (see Table 1). The presence of a t h y m o m a made the prognosis worse, though the series contains several exceptions to this statement. The mean period of observation was 10 years for the living, and 3.75 years for the 39 patients who are believed to have died from myasthenia gravis (Table 6). J. neurol. Sei. (1964) 1:512--546

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519

TABLE 6 39

YEARS OF SURVIVAL OF

PATIENTS

Years ofsurvival Total

male female Total

<½

½-1

1-3

3-5

5-10

> 10

5 (1)* 4 (2) 9 (3)

2 (1) 2 4 (1)

7 (2) 5 12 (2)

2 (1) 3 5 (1)

3 (2) 3 6 (2)

1 2 3

20 (7) 19 (2) 39 (9)

* Case with thymomas in brackets.

TABLE 7 RATE OF REMISSIONS

Duration

Female

> 1 year > 3 months Evident changes In one o f these groups

Male

18" 10 23 47

5** 4 7 15

* 1 patient with 3 remissions. ** 1 patient with 4 remissions, and 1 patient with 3 remissions.

TABLE 8 THE INFLUENCE OF INFECTIONS UPON CASES OF MYASTHENIA GRAVIS

Infections

Aggravating Not present No influence Not known Total

Female

Male

Total

42 48 2 13 105

20 24 3 12 59

62 72 5 25 164

(164

PATIENTS)

TABLE 9 INFLUENCE OF EMOTIONS UPON THE COURSE OF MYASTHENIA

(164

Emotions

Female

Male

Total

Aggravating No influence Not known

73 14 18

35 12 12

108 26 30 164

PATIENTS)

T h e c o u r s e o f t h e disease is reflected irt t h e figures f o r r e m i s s i o n s ( T a b l e 7), as well as t h e influence o f i n f e c t i o n s ( T a b l e 8), o f e m o t i o n s ( T a b l e 9), a n d o f the m e n s t r u a l cycle ( T a b l e 10). J. neurol. Sei. (1964) 1:512-546

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The influence of pregnancy upon the disease is shown in Table II. [n our series amelioration was commoner than in most other series (cited by OSSERMAN 1958} in which pregnancy caused the disease to improve in one third, made it worse in one third, and did not influence the disease in another one third of the cases.

TABLE l0 THE INFLUENCE OF THE MENSTRUAL CYCLE ( [ 0 5 WOMEN)

Worsening during the premenstrual period No influence Not known

38 29 12

Menopause

26

improved uninfluenced onset of myasthenia

5 I1 10

TABLE 11 THE INFLUENCE OF PREGNANCY IN CASES OF MYASTHENIA

Pregnancies (37) Improvement Deterioration No influence Onset during pregnancy Onset after pregnancy

17 7 4 3 7

Women (22) II 3 4 3 5

Remissions were rather frequent at the onset, so that for instance a period of diplopia after an infection or a pregnancy may have occurred a year before the generalized myasthenia began. Two patients had a remission of more than one year on 3 occasions. A man had 4 periods of myasthenia, twice generalized with dyspnoea, twice only with ocular symptoms, from the ages of 42 to 70 years; between whiles he had been able to perform heavy work. In general it can be said that the disease tends to improve spontaneously after having reached a peak 2 to 5 years following the onset. This spontaneous betterment is connected with the beneficial effects of treatment and the adaptation of the patient to his illness. Nevertheless, we consider this spontaneous recovery, which is most evident in the patients of G r o u p 2 A, but to a lesser degree also in Group 2 B, as representing the natural history of myasthenia gravis. Exceptions to this rule are seen in the survey of the myasthenic deaths (Table 6), which in some patients occurred after a remittent course of the disease for 5-10 years. In addition to the influence of intercurrent infections, emotional stress, upsets in the endocrine balance, spontaneous changes and the tendency towards a gradual recovery, the unfavourable influence of muscular exertion was ever present. The J, neurol. Sci. (1964) 1:512-546

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paresis due to exertion and the recovery after a period of rest, used in the test situation to confirm the diagnosis, was always considered as the most characteristic symptom of the myasthenia. Three observations can be made: (1) In 5 to 10~o of the patients the paresis was more intense on waking in the morning, or after a midday rest as noted by SIMPSON (1960). (2) In very severe cases it was not possible to worsen the permanent paresis by way of muscular exertion. (3) A most peculiar fact is the influence of the exertion of certain muscle-groups upon the paresis of other muscles which obviously do not take part in the exertion. This phenomenon, which we have termed the "MARY WALKER effect" has been observed in our clinic in 6 patients, and it has been described in the case-history of 20 others. It is exemplified as follows: a woman (Case No. 5) noted that she would develop a nasal voice after she had been silently carrying out some domestic work. We have also found that extending the arms in the horizontal plane for 2 minutes would produce this nasal voice, which would disappear after rest, and also by way of tensilon. A man (Case No. 2) always got ptosis when he had cycled for 20 minutes on his way to work, so that he would have to rest half way in order to get rid of his ptosis. In another man (Case No. 62) we saw the myasthenic smile appear following 20 knee bends. Following MARY WALKER (1938) this phenomenon has been described by WILSON AND STONER (1944) and GROSSE-BROCKHOFF AND WELTE (1950). They all used a tourniquet test applied to the limb in action and witnessed the ptosis following the release of the tourniquet. STRUPPLER(1955) and TSUKIYAMAet al. (1959) observed adecrease of the provoked action-potentials in one arm following ischaemic exertion of the other. Some doubt might be felt as to the physiological character of the tourniquet procedure. Sunlight not infrequently worsened the ocular symptoms. Changes in temperature sometimes played a definite role, the muscular power of some patients being worse during cold weather. Comment

Some aspects of the full-blown clinical picture require comment. (1) I f the muscle strength is carefully tested and if the opinion of the patient is taken into consideration, more muscles appear to be affected than had first been imagined. In other words, the myasthenia is seldom confined to a few isolated muscles, but is essentially generalized. This is confirmed by the abnormal sensitivity to curare which may bring about a total paralysis in doses which are wholly ineffective in normal individuals. A clinical argument for this statement is given in Table 12, where there are indicated the muscle-groups that were affected at any moment in the course of the disease in our patients. Certainly a difference in sensitivity is present in the various muscle-groups but this is simply a matter of degree. Fortunately the respiratory muscles are relatively resistant to the myasthenic process. Some patients who have been totally paralysed so that they could not move a limb, suffered no dyspnea. Other patients were threatened by rather sudden attacks of dyspnea during which they could move their arms and legs vigorously; in such cases bulbar symptoms were usually present. J. neurol. Sci. (1964) 1:512-546

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(2) At ~_hemoment of examination 10 patients proclaimed that they were completely cured. Our examination and history-taking revealed that this was true in only 3 cases; the other patients were much improved but they could not perform the same exertion as before, or appeared to have slight ocular paresis. TABLE 12 MUSCLE GROUPS AFFECTED AT ANY MOMENT IN THE COURSE OF MYASTHENIA

( 164 PATIENTS) Female

Ocular Bulbar Upper limb Lower limb Trunk Respiratory

Male

living (85)

dead (20)

living (39)

dead (20)

85 72 80 75 72 24

18 14 20 20 18 16

38 27 27 22 9 7

20 20 20 19 18 16

(3) Relative incontinence of mine was a complaint of 13 patients with severe generalized myasthenia. This symptom reacted to the anti-myasthenic medication and seemed to be due to the weakness of the external sphincter of the bladder. (4) Neo-natal myasthenia had been present in 5 children of 4 of our patients, and possibly in one other child of a fifth patient. The clinical picture was as described in the literature (OSSERMAN 1958). In our patients no correlation could be detected between the birth of a myasthenic child and the age of the mother, the severity and duration of the mother's disease, the influence of the pregnancy on the disease, or the birth number of the child. One woman (Case No. 97) had two myasthenic children, one before and one following thymectomy which had improved her condition. Both children had feeding difficulties until their sixth month. Her third child was normal; her myasthenia had not changed since her second child. Two of our patients each had given birth to 3 healthy children during their myasthenia, while the fourth child was myasthenic. The duration of the neo-natal myasthenia was 3-6 weeks. Small doses of prostigmine were given to 3 children with good results. None of the 6 children became myasthenic again later; their ages are now 1, 2, 4, 6, 10 and 22 years respectively. (5) Nine patients developed myasthenia gravis in their first decade. The youngest was a homozygote twin of 1 year who manifested a severe bulbar paralysis during chickenpox. The other twin died and at autopsy there was an atopic normal thymus gland without germinal centres. The disease was recognized in his twin brother who had chickenpox and bulbar paralysis 2 days later. He survived; at the age of 10 years he presents only very mild symptoms (ptosis at night following physical exertion that day). A survey of these young patients is given in Table 13. Of the 7 patients who survived, 5 improved considerably, 2 remained constant. We conclude that this juvenile myasthema is not essentially different from the adult form. (6) Muscle atrophy was seen in 6 of 125 personally examined patients (Table 14). In 3 patients (Cases Nos. 14, 61 and 72) an atrophy due to inactwity cannot be exJ. neurol. Sci. (1964) 1:512--546

523

STUDIES IN MYASTHENIA, PART 1 TABLE 13 JUVENILE MYASTHENIA (9 PATIENTS)

Present condition

Onset Case No.*

group

symptoms

10

2A

mild symptoms, predominately ocular; juvenile neurosis normal atopic thymus gland at autopsy

8

2A

6

Oc

gradual improvement; adversely influenced by emotional factors gradual improvement; paresis R. internal rectus muscle; normal thymus gland at autopsy

group

21

M 1

3

chicken pox

115

M 1

3

chicken pox; died from respiratory paralysis

died

36

F

3

tonsillitis; apnoea and loss of consciousness

69

F 2

Oc

severe ocular symptoms

127

F 2

3

severe generalized myasthenia; died at age of 3 moderate generalized

1½

symptoms

age

sex~age

died

76

M 2

2B

16

2A

mild symptoms

32 53

M 5 M 7

Oc Oc

severe ocular symptoms onset after gastroenteritis

15 18

Oc Oc

50

M 9½

2B

generalized, moderate

15

2B

mild symptoms no improvement ptosis alone reacting to drugs; total ophthalmoplegia no real improvement

* The patients Nos. 21, 115 and 127 have already been reported by BIEMONDAND VAN TROTSENBURG (1955).

cluded. In Case No. 160 the laboratory data are contradictory. The last patient (Case No. 173) presented the combination of myasthenia gravis, a thymoma and the clinical picture of a spinal muscular atrophy, the lasl improving after thymectomy. (7) The psychological status and the personality of the patients are, in our opinion, a part of the clinical picture. This aspect has been elaborated elsewhere (OOSTERHUIS AND WILDE 1964). In short we may state that in our series of patients a neurotic disposition was far more common than might be expected. Our clinical impression has been that a psychasthenic character-formation, sometimes with overt obsessional phenomena and depression, sometimes mixed with passive hysterical traits, is a frequent concomitant feature (60°Jo). Certainly it complicates the organic picture and its treatment. This clinical impression was confirmed by the scores of neuroticism and of introversion of the Amsterdam Biographic Questionnaire (WILDE 1962), a personality test. These scores were significantly higher than in the case of the average Dutchman, matched for sex and age. (8) The presence of weakness of the respiratory muscles in the absence of infection is a bad prognostic sign. The patients within Groups 3 and 4 (Table 5) all finally died in a myasthenic crisis or suddenly from cardiac arrest. In 5 patients a myasthenic crisis was provoked by an infective disorder. Their treatment was managed adequately and they survived. The disease took a favourable course as thymectomy was J. neurol. Sei. (1964) 1:512-546

524

H. J. G. H. OOSTERHUIS TABLE 14 MUSCLE ATROPHY (6 OF 125 PATIENTSt

Case No.

Sex

Age at onset o f myasthenia

Age at time o f examination

Muscle

Remarks

9

M

42

73

L tibialis anterior 3 cm atrophy

14

F

29

53

quadriceps R and L deltoid R and L

61

F

41

69

biceps R and L triceps R and L

moderate atrophy

72

F

14

32

deltoid R and L

160

F

13

24

deltoid L > R

173

M

61

66

mild atrophy electro-diagnostics: normal moderate atrophy EMG: myogenic lesion biopsy: neurogenic atrophy some fasciculation EMG: anterior horn disease clinically: spinal muscle-

slight diffuse atrophy of the muscles of a r m and leg moderate atrophy atrophy of the small muscles of the hand

sensibility: n o r m a l electro-diagnostics : normal Jolly: mild atrophy electro-diagnostics : normal Jolly: -!

performed in 3 of them. The others were children (they are included in Group 2 A). About one third of the patients had such vague complaints as slight dyspnoea, sensations of oppression, or palpitation following exertion. These complaints have been interpreted finally as indicating a mild involvement of the respiratory musculature by the myasthenic process, as no other internal disorder could be found responsible for these complaints. Very curious were the spontaneous attacks of dyspnoea. They occurred mostly at night, sometimes associated with brief loss of consciousness. The patients we observed recovered spontaneously. Attacks of dyspnoea were occasionaly described as resembling asthma but they differed in having a prolonged phase of impeded inspiration. Myasthenic death seems to be the result of one or other of two failures: paralysis of the respiratory muscles or cardiac arrest. We do not know of any reports in the literature where these factors and their relative importance have been analysed. Our experience and information taken from 44 patients are set out in Table 15. Fifteen patients died in a myasthenic crisis preceded by infections (8), or by a gradual deterioration in the general condition. The reaction to drugs was insufficient. Five patients died at a period when no drugs or controlled respiration were available; others died at home. In our series a cholinergic crisis was never the cause of death. Sixteen patients died suddenly without any previous signs of a worsening general condition, or with anything more than a slight dyspnoea. In 8 of these patients a respiratory infection was present. They died through a sudden respiratory failure, developing severe dyspnoea, cyanosis and dilated and inactive pupils. The action of J. neurol. Sci. (1964) 1:512-546

STUDIES IN MYASTHENIA, PART 1

525

TABLE 15 CAUSES OF DEATH (44 PATIENTS)

Myasthenic crisis

without infections associated with infections

8 7 (3)*

Acute respiratory failure

without infections associated with infections Cardiac arrest Not known Internal diseases

8 (2) 8 (2) 2 (1) 6 (1) 5 (1)

* Figures in brackets refer to cases in which there was a thymoma present. the heart failed after cessation of the respiration. One observation concerned a patient who, after the visiting hour, suddenly stopped breathing and became cyanotic with dilated pupils. His pulse at first increased, then after one minute became slow and later, impalpable. At that moment mouth to mouth artificial respiration saved his life. Two patients suddenly died without dyspnoea and cyanosis, suggesting a primary cardiac arrest. In the hearts however, no abnormality could be discovered. In most of these patients no precise, minute-to-minute recordings were available, and the above-mentioned conclusions have been drawn from rough observation. It seems unlikely that the heart can suffer from a myasthenic paresis and the cardiac arrest is possibly due to a vagal inhibitory reflex, enhanced by anoxemia. The sudden arrest of respiration, however, remains unexplained, like other myasthenic phenomena. Many patients who suddenly died had been considered as rather well at the time. Some of them were up and about. The fatal outcome in about 25% of the patients is still a fact in contemporary practice. Drugs, and even controlled respiration, scarcely seem to afford protection. Even in up-to-date hospitals, the carefully supervised patient with myasthenia gravis may suffer a sudden, unexplained death.

DIAGNOSIS

The clinical picture may be quite easily interpreted so that the diagnosis is quite possible even without ancillary measures. On the other hand, the onset of the diseaseprocess may be erratic, with vague complaints unaccompanied by objective physical signs. The course of the disease with its remissions and exacerbations, may indeed obscure rather than reveal the clinical diagnosis. Besides the symptoms and signs at the time of observation and examination, the author has experience with the following diagnostic procedures: (1) The clinical story should be taken carefully with regard to the symptoms and circumstances as already described. The important feature is the change in the symptoms; the shorter the period of time for this change to take place, the firmer the diagnosis. J. neurol. Sci. (1964) 1:512-546

526

H. J. (i. H. OOSTERHUIS

(2) The most simple provocative measure is exertion. In the routine neurologica~ examination, the strength of individual muscles or muscle-groups is usually judged without testing the effect of exertion. Obvious paresis may appear only at the end of the day, or after repeated movements of the limbs, chewing an apple, drinking a glass of water, singing a tune. reading aloud, whistling or making changes from the lying into the standing position. Ocular or bulbar paresis may occur after exertion of the limb muscles (MARY WALKER effect). (3) Diagnosis by way of ancillary methods may prove convincing. A number of procedures have been worked out (VIETS AND SCHWAB 1955; T~THER 1961), and some well-known facts have been confirmed from our experience. (i) The response of the symptoms to the test-dose varied considerably. Usually 1.5 mg neostigmine intramuscularly had a good effect, Sometimes this dose, even in combination with atropine, caused unpleasant side-effects, and 0.5 mg proved to be sufficient. Some patients reacted well to halfa tablet of neostigmine. In others, the same symptoms responded only to 2 or 3 tablets. During the course of the illness the sensitivity of the patient might or might not change. Twenty patients did not react at all to the first test-dose, so that the diagnosis became dubious. Nevertheless, we believe that the myasthenic weakness is rarely refractory to anti-cholinesterases at any time during the course of the disease. Refractoriness at a given moment cannot be used as the sole argument for rejecting the diagnosis. (ii) We often found that not every muscle had the same sensitivity to anti-cholinesterases. The diplopia might worsen along with a reduction of the ptosis. One patient in a myasthenic crisis reacted well to tensilon, but in his limb muscles, extensive fasciculation occurred. The unequal sensitivity of the various muscles, may make it impossible to find a dosage after which all symptoms would disappear. (iii) The use of placebos may mislead the physician unless he bears in mind the influence of suggestion upon the patient's emotional state. Some patients with severe myasthenia reacted well to injections of saline, a finding which sometimes lead to the false conclusion that they did not suffer from myasthenia gravis. (4) The Jolly reaction has been considered, according to the literature (OSSERMAN 1958), to be of questionable value. We have investigated the value of this procedure in 54 non-selected cases within our series. Muscles of the arm, leg and face were examined. Rhythmic faradic inpulses were applied to the "motor point" of the muscle. The most simple apparatus for electro-diagnostics was used, for it was desired to estimate the scope of the procedure in daily practice and as a bed-side method. Thirty-two patients had a positive reaction in one or more muscles. A reaction was considered to be positive if a decrease of the force of contraction was obvious within 3 minutes, and if this could be reproduced. We met with the same difficulties as BOURGEOIS(1929), in that a slight shift of the electrode, or a change in the pressure at the point of application might diminish the contraction. Nevertheless, we are convinced of the value of this test-procedure, because various muscles may be studied separately and at any moment. A positive Jolly reaction argues in favour of myasthenia, but a negative reaction does not exlude the diagnosis. In the same patient the reaction may be positive in only one of the muscles. As BOURGEOIS(1929) already pointed out, the absence of the Jolly reaction in severely affected muscles

J. neurol. Sci. (1964) 1: 512. 546

527

STUDIES IN MYASTHENIA, PART 1

may be due to a permanent neuro-muscular block. Sometimes there is only a decrease after the first contractions. If this is overlooked, the reaction seems to be negative. To exclude false positive reactions, we found it useful to delay a moment, if the power of contraction had decreased. Following such a pause, the initial power may become restored. (5) A provoked eleetromyogram (EMG) was carried out in 30 patients. This was done by stimulating the ulnar nerve with supramaximal square waves, with a duration of 1 msec each, applied by a bipolar skin electrode at the elbow. At times trains of 10 stimuli were given within 3 seconds with 6 seconds rest. Sometimes continuous stimulation for 3 minutes was performed with a frequency of 3-10 sec. The action potential (AP) was derived from two skin electrodes placed on the abductor muscle of the little finger. In 16 patients a pathological picture was seen at a stimulation rate of 3/see; in 6 patients the picture was pathological only at a stimulation rate of 10/see; in 6 cases (3 in partial remission, 2 with ocular myasthenia) no abnormalities were seen. In 2 patients with ocular myasthenia the provoked E M G proved to be normal, but the decrease in the voluntary contraction of the orbicularis oculi muscle was seen in the E M G , the picture being partly restored by tensilon (Fig. 2). E M G investigations produced a number of results.

0-2 sec

iii

4 0 sec

7

0

20 lOmg

--nr~

40

90

150sec

t e n s i l o n i.v.

Fig. 2. Man, 17 years. Ocular myasthenia. EMG. Voluntary maximal contraction of the m. orbicularis oculi. Concentric needle electrodes. Effect of tensilon.

(i) Typical for the myasthenic failure is a decrease in amplitude of the AP of the muscle following a number of supramaximal stimulations of the nerve. The velocity of the decrease of the AP is a function of the frequency of the stimulation and of the severity of the lesion. Two features call for a special attention. Thus, in 15 patients the second and third AP of each train were decreased compared with the first and subsequent APs. This " d i p " in the curve sometimes occurred only with a frequency

J. neurol. Sci. (1964) 1:512-546

528

H. J. G. H. OOSTERHUIS

of 10/sec and not with 3/sec. Again, in the prolonged continuous first abnormality might be an alternation of normal and reduced combined with a "dip" in the curve (Fig. 3). This fluctuation in the APs was at first considered to be an artefact, but other investigators

stimulation, the APs, sometimes amplitude of the (DENNY B n o w ~

Fig. 3. Woman, 40 years. Mild generalized myasthenia. Note: the dip in the amplitudes of the action potentials after the first; the fluctuation of the amplitude; the final decrease in amplitude.

1949; THII~BAUTet al. 1953; LUNDERVOLD 1954) appear also to have observed the same phenomenon. Previous medication usually reduced the exhaustibility and the "dip"-phenomenon, although they persisted in a lesser degree. (ii) Although the non-provoked E M G was usually normal, the APs were occasionally interpreted as being short and of low amplitude thus raising the possibility of a myopathy. THIi~BAUTet al. (1953) and LUNDERVOLD(1954) have also described these "myopathic" APs. However, other patterns of activity, considered as typical for myopathy, were never seen. We have interpreted these "myopathic" APs with a normal interference pattern, as being the result of the paucity of motor-units contributing to the AP of the first contraction. Sometimes complex APs were registered, suggesting a neurogenic lesion. In summary it can be said that the anomalies described in the provoked E M G may support the clinical diagnosis. The value of this procedure is limited by the choice of certain muscles which may not be affected enough by the myasthenic process, and by the "impactness" of the method. (6) The use of provoking drugs, such as curare and quinidine, has been of definite value. In 30 patients d-tubocurarine was given in a dosage varying from ½ to 3 mg J. neurol. Sci. (1964) 1:512-546

STUDIES IN MYASTHENIA,PART 1

529

intravenously. The use of curare in 7 of them has already been reported by VERJAAL (1957). Personally we followed the cautious technique of ROWLAND et al. (1961), who recommended one-tenth of the normal total paralysing dose, given in 8 fractions with 2 minutes' rest between each dosage. Patients with definite bulbar or respiratory symptoms were excluded. An anaesthesist was always present. This method was not always used by the physicians in those centres from which the patients were recruited; they sometimes injected 1 mg at once, or 2 mg in 1-2 min, so that some of the patients became totally paralysed. In l0 patients (5 with ocular myasthenia, 5 with the generalized form) the symptoms following injection of curare were limited to the ocular and neck muscles. In 19 patients (1 with ocular symptoms, 2 with limb muscle weakness, 16 with generalized symptoms) curare provoked a total paralysis, sometimes with dyspnoea. In one patient with a mild myasthenia no reaction to 3 mg curare occurred. From these experiences we conclude that the curare-test is an important diagnostic procedure in doubtful cases, for instance, if the case history is suspect, but a reaction to prostigmine is lacking. The curare test should not be performed if bulbar or respiratory symptoms are present. In 7 patients the symptoms increased moderately following a dose of 300-600 mg quinidine sulphate. This drug works more gradually so that it may be used in ambulatory patients without bulbar or respiratory symptoms. ASSOCIATEDPATHOLOGY The occurrence of thymic lesions in myasthenia gravis is well-known, and has led to many speculations. Some of these, in their relation to the immunological aspects, will be discussed in our next paper. A thymoma is the most striking disease-process and is associated with myasthenia in 10-15% of all cases in the literature. Changes in the thyroid gland are next in frequency of occurrence, and are reported in 5-10~o of the cases. Aplastic anaemia has been reported in the literature in 7 cases of myasthenia. Cases of myasthenia associated with lupus erythematosis disseminatus have recently been described (ALARC6N-SEGOVIA et al. 1963; GALBRAITH et al. 1964). It remains to be seen whether this association is more than a matter of chance. In our series, in addition to the thymoma and thyroidal lesions, 5 patients are included with a definite rheumatoid arthritis, and also 2 patients with an aplastic anaemia. A relatively high proportion of allergic manifestations was also observed in our cases. Thymoma

A thymoma was present in 19 of 164 patients where sufficient data was available. Males were twice as often affected asfemales. Hence 25% of the male myasthenics had a thymoma as compared with 6 % in the females. Nine of them died in a myasthenic crisis, 3 of them shortly after or during the course of operation. The other 10 patients were mildly affected, and belong to the Group 2 A or B. In 6 of the patients J. neurol. Sci. (1964) 1:512-546

530

H. J. G. H. OOSTERHUIS

the thymoma has been removed. They sustained the operation without much ditticulty, although two patients needed a respirator for some days. One patient (Case No. 96) had an inoperable thymoma, but he is still living 3 years alter the operation. Two patients died on account of internal diseases. The course and the prognosis of myasthenia gravis are not invariably poor in the presence of a thymoma. However, in the poor cases a thymoma was present ill almost 25%. No complaints could be ascribed to the thymoma itself in our series. In two patients, a man of 50 years (Case No. 95) and a woman of 40 years (Case No. 86), a mild myasthenia developed 11 years and 3 months respectively after extirpation of thymomas which had been detected by routine X-ray screening, and which had not given rise to symptoms. Twelve similar cases have been found in the hterature (FERSTRAND AND SHAW 1951 ; RINGERTZ 1951; MENDELOW AND GENKINS 1954; FISHER AND CHILD 1955; VERAN et al. 1956; STONE 1957; MADONICK et al. 1957; ROWLAND et al. 1957; EHRENREICHAND ALLEN 1958). In one case (RowLAND et al. 1957) 41 years elapsed before the onset of the myasthenia; in some of the other reported cases several years elapsed. Various types of myasthenia developed in these patients. These patients would probably have developed myasthenia even if the thymoma had not been extirpated previously. In some of our patients it could be observed in earlier X-ray plates that a thymoma has been present even before the myasthenia had developed. As a thymoma seems to be a microscopically benign tumour without signs of active growth, we might suppose that in all cases the thymoma precedes the clinical state of myasthenia. The course of the myasthenia was not obviously influenced favourably by the thymectomy, although there were some partial remissions. The indication for thymectomy consisted in a progressively invasive growth of the thymoma. In 75% of the operations and autopsies the thymoma appeared to be adherent to or infiltrating into the surrounding structures, mainly the pericardium. Only one tumour out of 10 was inoperable. The X-ray findings in our series of 19 thymomas were as follows. (1) Ten patients showed a more or less circular shadow in the anterior mediastinum best seen in the lateral views. Four of these tumours showed calcareous deposits. Some of these turnouts could not be detected upon the antero-posterior views and were described as an enlargement of the cardiac shadow, or an extension of the mediastinal structures. (2) Four thymomas appeared to us at the first examination to be tumours in the hila of the lungs. (3) In one patient (Case No. 64) no tumour was visible upon routine X-ray examination; only with use of tomography combined with mediastinal air-insufflalion could a flat thymoma (weight 100 g) be detected. (4) In 3 patients no thymoma was seen by routine X-rays but the tumour was discovered twice at operation, and once at autopsy. The experiences of (3) and (4) indicate that other silent thymomas might be present in our patients. We agree with BAm~TV et al. (1960) that a thymoma cannot be excluded without pneumo-mediastinography. J. neurol. Sci. (1964) I : 512-546

STUDIES IN MYASTHENIA,PART 1

531

Lesions of the thyroid In 17 out of 164 patients (16 females and 1 male), diseases of the thyroid were present. Hyperthyroidism had been present in 8 females, of whom 7 had undergone a partial thyroidectomy. In 6 other women a non-toxic goitre was found (a merely palpable thyroid was not considered as abnormal). There was no relation between the onset of the myasthenia and the hyperthyroidism. In 3 patients a thyroidectomy had been performed before the outbreak of the myasthenia; they were euthyroidal when the myasthenia developed. In 4 patients thyroid surgery did not alter the course of the myasthenia. The see-saw relation of hyperthyroidism and myasthenia (MAc EACHERN AND PARNELL 1948; MACLEAN AND WILSON 1954) was not observed. In a 50-year-old man a nodular intra-thoracic goitre was extirpated; it had appeared on the X-rays as a thymoma. In a 55-year-old woman, who died with a thymoma, autopsy revealed a struma lymphomatosa with destruction of the follicles. A struma lymphomatosa of moderate degree was found at the post-mortem examination of another female patient. In one of the glands removed at operation because of hyperthyroidism a lymphoid infiltration was seen together with some germinal centres. To establish the diagnosis of hyperthyroidism, a moderate increase in basal metabolism was not considered sufficient. This was found in about l0 further patients without real hyperfunction. The combination of nervousness, ocular paresis, paretic exophthalmos and increased basal metabolic rate sometimes lead to the erroneous diagnosis of morbus Basedow. Among the close relatives (parents, children, sisters and brothers) of l l 0 patients, hyperthyroidism was found in 3 members, and nontoxic goitre in 7.

Rheumatoid arthritis This was diagnosed in 5 female patients among our series; in 2 other women the clinical picture was suspicious (Table 16). Seventy-five women in our series are at the present time under investigation between 15 and 65 years, with a mean age of 42 years. In a recent field investigation, DE GRAAEF (1962)calculated the occurrence of rheumatoid arthritis among the Dutch female population between 15 and 65 years as being 1%. The percentage in our series is significantly higher(P < 0.05). Seven out of 110 patients reported that one parent (6 mothers, 1 father) suffered or had suffered from a malady described as rheumatoid arthritis. In patients with myasthenia gravis and in their mothers, rheumatoid arthritis is therefore more common than in the whole Dutch population. The possible significance of this fact will be discussed later.

Allergic manifestations Toxic exanthemata, asthma, hay fever, urticaria, food idiosyncrasies, acute rheumatism, and acute glomerulo-nephritis, were present in the histories of 43 out of 125 personally examined patients. Details are given in Table 17. The incidence of allergic manifestations in the population varies according to the literature from 5 to 2 0 0 , so that the importance in relation to the myasthenia remains uncertain.

J. neurol. Sci. (1964) 1:512-546

532

tt. J. G. H. OOSTERHUIS FABLE 16 RHEUMATOID

ARTHRITIS ASSOCIATED WITH MYASTHENIA GRAVIS

Myasthenia Case No.

Sex

Age at onset

Rheumatoid Arthritis Group

at

Age onset

Type*

Remarks

7

F

34

2A increased after resochine

27

definite

52

F

17

39

66

F

26

2B remission at age 24 2B gradually improved-+ (2A)

41

definite; spontaneously improved definite

89

F

49

54

definite

99

F

31

39

classical

159

F

24

81

F

49

2B remission at onset; ptosis provoked by resochine 2B improvement following thymectomy at age 33

55

myasthenia in remission; grandmother (MM) had rheumatoid arthritis LE-serology: dubious Rose test: negative transitory butterfly rash of the face; LE-serology: positive Rose test: positive Rose test: positive LE-serology: dubious

Possible cases o f rheumatoid arthritis" 2A 40 mild fluctuating mild fluctuating symptoms course

2A mild fluctuating course

arthritis psoriatica; mother had rheumatoid arthritis Rose test: negative LE** serology: negative Rose test: negative LE-serology: negative

mild complaints of finger joints at age 55. At age 61 : multiple joints affected: shoulder-hand syndrome?

X ray: negative Rose test: negative; mother, grandmother and great grandmother (M, MM and MMM) had rheumatoid arthritis Rose test: positive (1 : 128); hyperthyroidism; multiple allergic manifestations

* The qualifications in this column are according to the official criteria for the diagnosis of rheumatoid arthritis. ** LE: systemic lupus erythematosis. Aplastic anaemia

P u r e r e d cell a n a e m i a was e n c o u n t e r e d in 2 p a t i e n t s ; o n e o f t h e s e p a t i e n t s a}so h a d a t h y m o m a . T h e i r c a s e h i s t o r i e s will be r e p o r t e d in d e t a i l e l s e w h e r e (OoSTERHUS et al. 1965). J. neurol. Sci. (1964) 1 : 512- 546

STUDIES IN MYASTHENIA,PART 1

533

TABLE 17 ALLERGIC MANIFESTATIONS ASSOCIATED WITH MYASTHENIA (125 PATIENTS)

Drug exanthema Hay fever Urticaria Bronchial asthma Foods Strawberries Quincke's oedema Acute rheumatism Acute glomerulo-nephritis

8 9 6 2 5 8 3 2 1

In b ri ef they m a y be described as follows. Case No. 96. A 54-year-old man developed a moderate generalized myasthenia at the age of 42. He was treated for 2 years and then developed an almost complete remission. At the age of 49 years he began to. complain of fatigue, palpitations and loss of weight. A circular tumour of the size of a mandarin was visible in the hilum of the right lung. A firm diagnosis could not be made. Two years later he was admitted to hospital because of recurrent pneumonia and severe anaemia, which remained a pure red cell anaemia until the time of the latest period of observation. With the appearance of the aplastic anaemia, the suggestion was made that the tumour might be a thymoma. This was verified by operation when an inoperable thymoma was found. The patient was kept alive with frequent transfusions of erythrocytes. Onl~r mild symptoms of myasthenia were present, in the way of diplopia. Case No. 36. A woman aged 43 years developed a moderate rnyasthenia following the birth of her second child. A year later the myasthenia partially remitted. At the age of 45 (1949) she was admitted to hospital because of a severe generalized oedema and exanthematous rash for which no cause was found except an upset in the blood protein (albumin 3.6 g/100 ml; globulin 3.1 g/100 ml); at that time a mild hypochromic anaemia was present. Six months later she was re-admitted on account of a severe anaemia (haemoglobin 3 g/100 ml). In the bone-marrow no erythropoiesis could be detected. Later, a leucopenia developed. A thymoma was not seen on routine X-ray examination. Definite myasthenic symptoms were not stated. The patient died at home; no autopsy was performed.

T h e s i m u l t a n e o u s occurrence o f m y a s t h e n i a gravis, aplastic a n a e m i a an d a t h y m o m a has been r e p o r t e d 7 times in the literature (OPSAHL 1939; BAKKER 1954; CHALMERS AND BOHEIMER 1954; WEINBAUM AND THOMPSON 1955; THt~VENARD AND MARQUI~S 1955; CASTAIGNE et aL 1961; RADERMECKER 1964). It is i m p r o b a b l e that the association o f these rare disease-processes co u l d be a m a t t e r o f chance. F u r t h e r a r g u m e n t s in f a v o u r o f the existence o f a c o m m o n d e n o m i n a t o r are f o u n d in the clinical course, which in o u r patients an d also in the cases f r o m the literature had the f o l lo wi n g c o m m o n features. Th e m y a s t h e n i a gravis always precedes the aplastic a n a e m i a and the t h y m o m a ; the interval m ay vary f r o m l to 8 years. F u r t h e r m o r e , the m y a s t h e n i a is in a remission when s y m p t o m s o f t h e o t h er diseases b e c o m e manifest.

A s s o c i a t e d u n c o m m o n diseases

Finally a survey is given (Table 18) o f the relatively rare diseases, which c a m e t o light in the case-histories, or at the e x a m i n a t i o n o f o u r patients. Th e choice is somew h a t arbitrary, as the exact percentages o f the occurrence within the general p o p u l a t i o n were n o t k n o w n to serve as a c o m p a r i s o n . A t times the prospects o f the detection J. neurol. Sci. (1964) 1 : 512-546

534

H.J.G.H.

OOSTERHUIS

TABLE 18 UNCOMMON

DISEASES

ASSOCIATED

WITH

MYASTHENIA .

Case No.

Myasthenia Associated disease

Sex

Group

Age at onset

1

F

2BA

31

retinitis pigmentosa

Age at onset

?

H

btfluence upon the myasthenia

none

4

F

2BA

18

diffuse lymphadenopathy

7-15

none

13

F

2BA

21

serous meningitis

29

none

30

F

2B

16

severe diabetes diabetes of father and mother

39

none

35

F

2B

26

chronic schizophrenia

56

none

48

F

2B

16

secondary amenorrhoea increased gonadotrophins

17

amenorrhoea following therapy

2B

s 30

70

M

71

congenital familial ptosis

75

M

Ocular

50

irido-cyclitis

40

none

89

F

2BA

49

discoid lupus of the face LE-serology positive rheumatoid arthritis

54

remission at onset

91

F

2B

13

severe seborrhoic eczema

18

none

94

F

2BA

18

acute familial porphyrinuria

24

none

aplastic anaemia

51

in remission

96

M

2BA

42

none

97

F

2BA

27

psoriasis

29

none

109

M

2B

57

spondylitis ankylopoetica (Bechterew)

~: 35

none

110

F

2B

25

schizophrenia

28-30

improvement during psychosis

129

F

2B

54

intracranial process? asymmetrical enlargement of cerebral ventricles

54

detected before operation Patient died 3 days following operation

136

F

2BA

43

aplastic anaemia

45

remission patient died, probably from nephrotic syndrome

142

F

2B

20

nephrotic syndrome

25

154

M

4

64

8 recurring vital depressions

25

none

61

pernicious anaemia

61

antecedant increased

158

F

2A

162

F

2B

15

arthritis, anaemia elevated ESR

38

163

M

2BA

48

polyglandular insufficiency

50

remission 9

40

difficulty in coughing infection - myasthenia first diagnosed

166

M

4

31

atrial septal defect; thymoma

167

M

2A

48

familial cerebeltar atrophy

169

M

3

52

orchitis

50

none

173

M

2B

61

recurrent venous thrombophlebitis of the legs pleural exudate spinal muscle-atrophy L.E. serology positive

63

increased

66 66

thymoma operated upon; remission

J. neurol. Sci. (1964) I : 512 •546

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of the second disease seem to be increased by the presence of the myasthenia. In very few cases was the myasthenia detected through the medical investigation of the preceding "second" disease. A control series should be studied in order to evaluate the significance of the association of these somewhat uncommon maladies with myasthenia gravis. LABORATORYINVESTIGATIONS In our series the blood picture was essentially normal except in the 2 cases with aplastic anaemia, and in one patient with a thymoma (Case No. 166) who showed a constant lymphocytosis of 50%. No planned serial investigations into the existence of lymphocytosis (as reported by PERLO 1961) were done. Creatinuria was present in one patient (400 mg/24 h) with a thymoma. Only 20 patients were specifically investigated. SCHRIRE (1957) reported creatinuria up to 200 mg/24 h in 33 of 51 patients after thymectomy. LEVENEAND KRISTELLER(1909) and MILHORATAND WOLFF (1938) have also described this feature in patients with myasthenia gravis. The cerebrospinal fluid was investigated in 54 patients at various stages of their disease. An increase in the total protein was found in 6 patients (40-60 mg/100 ml, 3 times; 60-80 rag/100 ml, 3 times), one patient with a thymoma (Case No. 64) had a total protein ofS0 mg/100 ml, a globulin of 20 mg/100 ml and weakly positive colloidal curves; paper-electrophoresis showed an increase of ~-globulin. Neither the clinical picture nor the autopsy gave any explanation for this abnormality. In the other patients the origin of the increased protein also remained obscure. One patient (Case No. 96) later developed aplastic anaemia and a thymoma. At the time when the protein was raised the CSF also contained 47/3 lymphocytes; serological reactions for syphilis were negative in the blood and the CSF. Two other patients also had a thymoma. In 4 patients the myasthenia ran a steadily downhill course as the patients died within l I years after the onset. SIMPSON (1960) mentioned an increased CSF protein in 6 out of his 440 patients but it is unlikely that a lumbar puncture was done in all of them. Apart from this series there has been only one case with an increased protein in the CSF (100 mg/100 ml) as reported by DE HAENE AND ROUSSEL(1955). An increased ?-globulin in the blood-serum was detected in 3 patients with the use of paper-electrophoresis. They are described in detail elsewhere (OOSTERHUISet al. 1964). This investigation was done as a routine procedure in some 20 patients only. In the literature LOWENTHAL AND VAN SANDE (1956) reported an increase of ~globulin in the sera of 12 out of 16 myasthenic patients. OSSERMAN(1958) mentioned a normal protein spectrum in the sera of 12 patients. SIMPSON (1960) found 4 cases of hyper-~-globulinaemia in his 440 cases. CASTAIGNE et al. (1961) found in their patient hyper y-globulinaemia in addition to a thymoma and aplastic anaemia. As will be described later, immuno-electrophoresis (PEETOOM 1963) of the sera of 100 of our patients showed a diffuse increase of the immuno-globulins in 5no/ v /O" Muscle histology

The histological appearances of the muscle were investigated in 30 patients. In 19 J. neurol. Sci. (1964) 1:512-546

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patients a biopsy was taken, usually of one or more clinically affected skeletal muscles : in 5 of these patients the pectoratis or one of the intercostal muscles was studied~ In addition, at 13 autopsies specimens of muscle were taken ranging from 1 to I~ muscles. In 2 patients the muscles had been investigated by biopsy as well as after the patient's death (Table 19). TABLE 19 HISTOLOGY OF MUSCLE (DATA FROM 30 PATIENTS)

Normal picture Lymphorrhages Mild changes only Myositis Neurogenic atrophy

Autopsy

Biopsy

Total

Male female ratio

6 (1)* 6 (4)

9 (1) 6 (5) 2 (1) 1 (1) I

15 (2) 11 (8)** 2 (1) 1 1

6/10 6/4 2/0 1,,'0 0/1

1

30(11)

15/15

* Number of patients with a thymoma in brackets. ** In 2 patients autopsy and biopsy.

The most important abnormality consisted in lymphorrhages, as first described by WEmERT (1901) in a case with a thymoma. They were found in 11 patients, 8 of whom had a thymoma. In one of our patients with a thymoma (Case No. 166) a biopsy revealed the histological picture of a myositis with an infiltration of neutrophils and lymphocytes and a local destruction of the muscle-fibres. At that time the patient had a severe pulmonary infection with a leucocytosis of 30,000/mm 3. Two biopsies, taken from other muscles after the infection had abated, revealed no abnormality. However, at autopsy, multiple lymphorrhages were found in 8 out of the 13 muscles. In the immediate surroundings of these lymphorrhagic infiltrations, atrophied and sometimes destroyed muscle-fibres were visible. The patient died suddenly 18 months after the first series of biopsies. The marked changes found at the first biopsy have been interpreted as the summation of the infection and of the lymphorrhages due to the myasthenia. Two patients presented slight histological abnormalities, such as ring-fibres or increased sarcolemmal nuclei. One patient (Case No. 160) with an obvious wasting of the deltoid muscle showed a mild, diffuse, neurogenic atrophy. The picture was similar to that of the "small group lesion", described by FENICHEL AND SHY (1963) in 11 out of 37 biopsies of myasthenic patients. Various histological lesions have been reported in the literature, but none of them is considered to be pathognomonic for the disease. RUSSELL(1953) and GENKINSet al. (1961) reported striking abnormalities in muscles removed at autopsy of patients who died after prolonged respiratory infections. Patients with a thymoma predominated in these series. The muscles presented the picture of a myositis and a destruction of the muscle-fibres with polymorphonuclear and lymphorrhagic infiltrations. This picture closely resembles that seen in the above described patient. It might be asked J. neurol. Sci. (1964) 1:512-546

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whether the severe local destruction of the muscle fibres is due to the myasthenic process alone, or to the combination of myasthenia with superimposed bacterial infections. In our series, this picture of myositis was seen only twice in single muscles. A relatively high correlation was found in our cases between lymphorrhagic infiltrations and thymomas. This relationship is not evident in the literature. The muscle-pathology in myasthenia gravis has been studied chiefly by means of autopsy specimens (RUSSELL 1953; RINGERTZ 1955; ROWLAND 1956; GENKINS et al. 1961 ; GROB 1961). STORTEBECKER(1955) and recently FEN1CHELAND SHY (1963) have alone studied biopsies. In none of these series is the relation with the presence of a thymoma clear. Muscle-atrophy was found at clinical examination in 6 of 125 patients (Table 14). Autopsies

Autopsies were performed in 18 of the 39 patients dying from myasthenia gravis. Unfortunately the data were not altogether sufficient. In particular, microscopical examination of the organs was incomplete. As a rule, the death could not be put down to the mild abnormalities found, so that a failure of oxygenation or of cardiac function must be supposed. No unexpected pathology was found except for a small Grawitz tumour in one patient, and an undetected thymoma of 45 g in another. The diagnosis of a thymoma was confirmed in 3 patients. The absence of thymic pathology in 12 patients is striking; 6 had atrophic thymic remnants, and in 4 no thymic tissue was found at all. Two children had a thymus of a normal structure, one of which was situated at the bifurcation of the trachea. In the heart-muscles of 2 patients, lymphorrhages were found. One of them had a thymoma. In 11 patients the heart-muscle was histologically normal, except for the slight abnormalities due to age. In two patients the thyroid showed the picture of a struma lymphomatosa; clinically no abnormality of thyroidal function had been detected in these patients. Lymphorrhages were not present in other organs, except in one thyroid, removed by operation, which also contained germinal centres. QUERIOO (1929) described a case with perivascular lymphorrhagic infiltrations, suggesting a primary perivascular disease. ROWLAND (1956), RINGERTZ (1951) and GENKINS et al. (1961) did not find lymphorrhages in other organs. Microscopy o f the thymomas

A thymoma was present in 12 males and 7 females, a sex-incidence also met with in other case-series. The microscopical picture of 15 thymomas was studied, and checked by Dr. TH. FELTKAMP-VROOM. Afterwards a comparison was made between the microscopical features and the clinical data. The microscopical picture varied considerably from one tumour to another, as well within each single tumour. In some growths lymphocytes predominated, in others the epithelial cells, but as a rule both cell-types were equally distributed. The amount of fibrosis also varied. Reactioncentres, as in myasthenic thymus glands, were never seen. Hassall corpuscles were present in 6 of the 15 thymomas. This represents a larger percentage than is usual in non-myasthenic thymomas, where the corpuscles of Hassall are very rare. Large J. neurol. Sci. (1964) 1 : 512-546

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epithelial cells with a clear protoplasm, considered (CASTLEMAN1955: IVERSON 195(~: LATTES 1962) as typical for the myasthenic thymomas, were seen in varying degree in 14 thymomas. No differences were noted between the 6 clinically benign cases and the 9 fatal cases. Neither the degree of fibrosis nor the microscopical features, such as the dominance of lymphocytes or reticular cells, were essentially different between the two types of case. Signs of malignancy were not present, except in one case which had previously been radiated; in this case invasion of the thymoma into the lung had taken place. The patient (Case 96) with an aplastic anaemia had a thymoma of the mixed cell type. In general the findings of the literature were confirmed. In the literature (LATTES 1962; ELLIS AND GREGG 1964) the spindle-cell type of thymoma has been reported frequently in association with aplastic anaemia. In 15 patients the thymus gland was extirpated; furthermore, a thymus gland was found at 7 autopsies. A striking difference existed between both groups of thymus glands. The glands removed at operation showed reactive (germinal) centres and an abnormal lymphoid infiltration of the medulla in 11 cases. At autopsy an atrophic thymus was found in 6 cases. In 2 children the thymus was normal for the age; in 4 cases no thymic tissue could be found. In other words the reaction-centres were never seen in the microscopical picture. A relation between the number of reaction-centres and the severity of the myasthenia could not be traced; the effect of the thymectomy was not related to the number of reaction-centres. The atrophy found at autopsy was interpreted as being due to the stress the patients had undergone before death.

THERAPEUTIC

MEASURES

Drug therapy Little can be added to the reported extensive experiences of OSSERMAN 0958, 1961 a, b). In our series, neostigmine and pyridostigmine were mainly used; a few patients were convinced of the benefit of additional ephedrine. The response to drugs varied considerably from patient to patient, and also in one patient during the course of the disease. The severity of the symptoms at a given moment frequently had no relation with the dosage of anti-cholinesterases by which they were relieved. The ocular muscles were often resistant to therapy or reacted unevenly, so that diplopia was not relieved and sometimes it worsened. Other isolated muscles were also resistant to the therapy, e.g., the extensors of the foot or of one finger. Side-effects also varied from one patient to another; they might obscure the therapeutic effect when given by injection. However, in general, side-effects were very mild or totally absent, even without the use of atropine. This weU-known fact demands further explanation. It might be that the same relative deficit of acetylcholine exists in the autonomic ganglia, but remains subclinical by the lower intensity of the acetylcholine metabolism.

Thymectomy and thymectomy Thirteen patients from our series were submitted to thymectomy; 11 of them had a severe generalized myasthenia, 2 had a moderate type of the disease. Twelve of J. neurol. Sci. ( 1 9 6 4 ) 1 : 5 1 2 - 5 4 6

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them were females; they all fulfilled the criteria given (SIMPSON 1958) as being favourable for operation. Eleven patients improved following the operation: four of them improved considerably immediately after the operation; the others improved gradually, so that the relationship with the operation may be fortuitous. The time between the onset of the myasthenia and the thymectomy varied from 1½ to 9 years. Thymomectomy was done in 10 patients; 2 patients had no myasthenia atthe moment of the operation and developed a moderate disability afterwards. Three patients died during or soon after the operation (Cases Nos. 64, 141, 148), two of the latter in earlier years when the risks were not weU-known. In 3 patients the disease underwent a partial remission; in 2 patients no change in the course was evident. If a conclusion may be drawn from these few experiences, it may be said that extirpation of a thymoma does not seem indicated as a treatment for the myasthenia itself, as the operative risk in severe cases does not outweigh the prospects of improvement. If the myasthenia has a reasonable prognosis quoad vitam, the indication for extirpation of the thymoma lies in the slowly and usually ingrowing tumour itself. Rest

Generalized physical and psychological rest should be considered as an important therapeutic measure, one which tends to be underestimated. Rest in bed with artificial feeding and a prohibition of speech have saved the life of several of our patients in the period before 1935. A warning should be given that a sudden exacerbation with respiratory paresis may occur after unsuccesful efforts to introduce a stomach-tube. We learned this danger, which had been already mentioned by OPPENHE1M (1909), from a patient with bulbar symptoms, who was in a poor condition and did not succeed in swallowing the tube. Hospitalization means not only physical rest but for many patients also a relative freedom from emotional stress which is nearly always (Table 9) a precipitating factor. The beneficial effect of hospitalization and rest sometimes so improved the symptomatology that actual doubt was thrown upon the original diagnosis. Patients at home should be advised to rest in the middle of the day. We noticed a striking objection in many mildly affected patients to follow this advice, since they tended to consider this rest-period as wasted time. We have interpreted this reluctance as a psychasthenic feature. Psycho therapy

The common neurotic character of the patient, and the adverse influence of emotions and of stress upon the course of the disease make it necessary to emphasize the value of special attention to the psychical state of the patient. We have elaborated this theme elsewere (OOSTERHUISAND W1LDE 1964). Otherwise unexplained exacerbations and remissions sometimes become clearly related to a change in the patient's emotional environment. We entirely agree with OSSERMAN'S(1958) remark that "these patients need a tremendous amount of encouragement". Other measures

The treatment and prevention (as by tonsillectomy) of infections and tbe regulaJ. neurol. Sci. (1964) 1:512-546

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tion of endocrine disturbances (hyperthyroidism) have a specific importance in thc care of the myasthenic patient. The striking improvement after X-ray castration because of metrorrhagia that was seen in two women in our series with eviden t preme nstrual exacerbations, suggests that this measure may be taken into consideration in selected patients. We have no experience with the inhibition of the ovulations, but recently (WHELANAND TAYLOR 1963) benefit from this management has been reported. To the drugs which worsen the symptoms of the disease (curare, quinidine, morphine in cases of respiratory distress) we can add from own experience resochin (chloroquine-diphosphate) used as an antirheumatic, and the antihelmintic drug pipadox (piperazine adipate), both of which have a structural relationship with quinidine. Paresis of the ocular muscles did not react adequately if at all to anticholinesterases in about 50°'o of the patients. Such patients may occasionally be helped with special glasses (ptosis hooks, occlusion of one eye).

DISCUSSION

From our studies and observations on 180 patients with myasthenia gravis we would like to emphasize the following points. (1) Myasthenia gravis may be defined as a disease giving rise to a variable weakness of striped muscles. The essential feature in diagnosis and pathophysiology lies in the changes, whether occurring spontaneously for long or short periods of time, or else provoked by infections, emotions, endocrine imbalance (menstrual cycle, pregnancy, menopause), physical strains, and by the effect of drugs which either improve (anticholinesterases) or increase (curare, quinidine) the symptoms. These variations in the clinical picture may be quite puzzling to the doctor as well as the patient. Nevertheless, they are the rule which myasthenia gravis obeys, even in the most desperate and deteriorating cases. It is not yet clear how the defect in the synthesis of acetylcholine, believed to be the underlying pathogenic factor (DESMEDT1961 ; DILLON et aI. 1961), is influenced by or associated with the above-mentioned factors. (2) Next to this changing weakness and the concomitant neuromuscular block, there appears to occur an irreversible lesion as suggested by: (i) the fact that some muscles do not react to anticholinesterases nor do they show the typical fluctuation of the paresis; (ii) that muscular wasting is sometimes present (as in 6 out of 125 personally examined patients); (iii) that some electromyographic features suggest an irreversible neuromuscular block; and that (iv) lymphorrhages and the microscopical picture of neurogenic atrophy may occur in the muscle. (3) The disease becomes generalized as a rule, with the exception of the respiratory muscles which were affected clinically to some extent in 35% of the patients. The disease was confined to the ocular muscles in only 13 of the 180 patients in our series. The abnormal sensitivity to curare, which is also present in the clinically unaffected muscles, confirms the supposition that the disease is always more or less generalized. This is also suggested by the finding that a complete clinical cure is rare. J. neurol. Sci. (1964) l : 512 546

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An absence of myasthenic symptoms and complaints could be determined in only 3 patients. Although the disease is usually generalized, a striking difference exists in the sensitivity of different muscle-groups, even of the single muscles of one group innervated by the same nerve (DESMEDa"AND MONACO 1960). This individual sensitivity might be related to the number of fibres per motor unit, but in addition a certain random distribution of the affection seems to be superimposed. (4) Two phenomena argue in favour of the presence of a circulating substance namely the MARY WALKER effect and the neo-natal myasthenia. The interpretation of these facts will be discussed in the next article. (5) The Jolly reaction has a certain value in demonstrating the pathophysiology of the neuromuscular synapse and thereby in establishing the diagnosis. Its bedside use and the possibility of testing several muscles are advantages over the use of the provoked electromyogram (EMG). The provoked E M G may show the following rather specific phenomena: (i) a decrease in the amplitude of the provoked action potentials (AP) as a function of the stimulation rate of the nerve; (ii) a relative loss of the amplitude o f the second and third AP and (iii) waxing and waning of the amplitude of the APs. (6) Muscle pathology is a rare but definite phenomenon of the disease. In OSSERMAY'S (1958) series it was present in 6%, in our series in 4 % of the personally examined patients. M any cases have been reported in the literature where muscle atrophy was the reason for rejecting the diagnosis of myasthenia gravis. In a subsequent article we will discuss these cases; it is our opinion that the presence of muscle-atrophy in itself is an insufficient basis for this denial. The origin of the muscle-atrophy remains questionable. Although disuse as the cause of the atrophy cannot always be excluded, it seems more likely that its origin is neurogenic. In one of our patients (Case 160) this was proved by the biopsy. [n the series of FENICHEL AND SaY (1963) neurogenic atrophy was found in 11 of 37 biopsies; it is not reported whether clinical atrophy was present. In general it may be stated that a certain degree of muscle-atrophy may not be detectable by clinical examination, so that it might be present in all those muscles which are resistant to the anti-cholinesterases. A defect of the function of the motor nerves never having been demonstrated in this disease, it is probable that the motor nerves are affected within their intramuscular course. The results of electromyography sometimes indicate the presence of a neurogenic lesion (complex action potentials). In some of our patients, short action potentials of low amplitude, produced by voluntary effort, have suggested a myopathy; the restoration of the normal pattern by anti-cholinesterases lead us to conclude that they are a myasthenic rather than a myopathic phenomenon. (7) Attention must be drawn to the fact that myasthenic death is not readily explained in some cases. Apart from the myasthenic crisis with increasing respiratory failure, death may result from sudden respiratory failure without a crisis; or from sudden cardiac arrest. At autopsy no obvious pathology is found. The cardiac muscle does not participate in the myasthenic process, according to our understanding of the pathophysiology. Careful observations of dying myasthenic patients are very rare in the literature. The J. neurol. Sci.

(1964) 1:512 546

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cause of death is sometimes a matter of conjecture. The cardiac arrest is possibl> due to a vagal inhibitory mechanism following anoxia. (8) At least 4 disease-processes are present in our patients in a frequency thai cannot be explained by chance. The occurrence of a thymoma in 10°/~ with a relative predominance in the male, and of thyroid pathology in 10% predominating in the female, is also known from the experience of other series. The association of myasthenia with rheumatoid arthritis in 5 females, and with aplastic anaemia in 2 patients, is probably no coincidence. It may be mentioned that in most of our patients the thyrotoxicoses and the rheumatoid arthritis occurred when the myasthenia gravis had not yet developed, or when it was in remission, The same is true for all the patients with aplastic anaemia reported in literature and also in our own series of cases. This negative relation as to the time of occurrence, is the more remarkable as intercurrent diseases usually increase or provoke the myasthenia. Probably the growth of a thymoma also antedates the myasthenia gravis because it is impossible for a large thymoma to grow in the period of clinically recognizable myasthenia, which is sometimes very short. If this supposition is true, more thymomas will be detected by routine examination of the chest, before the myasthenia develops. A somewhat high number of patients had another rare disease (Table 18). We have not been able to investigate whether or not, this incidence exceeds chance. The specific relation with allergies also remains unproven because it has not yet been studied in a suitable control series. (9) The special relationship with lesions of the thymus not only emerges from the presence of a thymoma, but also from the effect of thymectomy and from the presence of germinal (reaction) centres in the thymus glands removed at operation. Certain remarks may be made on this relationship: (i) Our series of 12 thymectomies is too small for definite or statistical conclusions. Some patients improved strikingly after operation, but in others the improvement was very gradual over the course of months or years. Only one man was operated upon, and with good results. The current opinion, mainly based on SIMPSON'S (1958) investigation, is that thymectomy should be carried out in females only, under certain conditions. However, it is not clear why the operation should not be performed in the male. In S1MPSON'S series, the beneficial effect in the male was not statistically evident, but it might be provable in a larger series. SIMPSON'Scase-material was scattered over a long period: his controls consisted of the patients of the time before operation, in the early period of drug-therapy and of the patients who were rejected for operation. It may be doubted if the controls were treated with the same skill and with the same care as the operated patients. The psychological factors at least that might have contributed to a favourable course, differ widely between the operated and the controt group. This is reflected in the relatively large number of patients in the control group of which no detailed case-records are present. The results of OSSERMAN'S(1958) conservatively treated group, are better than those in SIMPSON'S (1958) control group. Although personally we are impressed by the effect ofthymectomyin certain patients, we suggest further investigation as to the factors J. neurol. Sci. ( 1 9 6 4 ) I : 5 1 2 - 5 4 6

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that might play a role in the effect of the operation in females as well as in males. (ii) The presence of germinal (reaction) centres in the thymus gland is a striking fact. They are mainly described in myasthenia gravis, although SLOAN(1943), who was the first author to report them, has also found them 3 times in the thymus at autopsy of 7 patients with Addison's disease, and in 10 of 150 young adults who died suddenly. Recently a case was described of systemic lupus erythematosis (MACKAY AND DE GAIL 1963) with reaction-centres in the thymus. In our material, reaction-centres appeared in 11 of 15 available thymus glands removed by operation, but in none of the 8 glands found in 12 autopsies. Probably the involution of the thymus glands found at autopsy is due to the influence of infections before death. The significance of these facts has still to be evaluated, as there exists no control series of thymus glands removed at operation in cases of unrelated diseases, or of sudden death at various ages. In the subsequent article we will discuss the possible pathophysiological significance of the germinal (reaction)centres. In that article we shall also report the immunological investigations carried out in our patients; their correlation with certain clinical findings; and their interpretation in the pathophysiology of myasthenia. SUMMARY

A survey is given of the personal findings and para-clinical investigations in a group of 180 patients suffering from myasthenia gravis. The clinical picture is described in detail; emphasis is laid upon some less well-known features of the disease. The procedures which may contribute to the occasional difficulty in diagnosis are described; these include the Jolly reaction, the provoked electromyogram and the curare test. The associated pathology in this series includes a thymoma in 10%, thyroidal lesions in 10%, rheumatoid arthritis in at least 5 women, aplastic anaemia in 2 patients, allergies and some rare diseases in many patients. Laboratory investigations include the muscle-histology in 30 patients, data of 18 autopsies and the microscopy of the thymomas. Hyper ~,-globulinaemia was found in 3 patients. The therapeutic measures used in our series include anti-cholinesterases, thymectomy, rest and supporting psychotherapy. ACKNOWLEDGEMENTS

Prof. A. Biemond and Dr. W. A. den Hartog Jager have greatly assisted this study with their valuable interest and constructive criticism. Dr. J. Bethlem supervised the study of the muscle-biopsies; Th. Feltkamp-Vroom studied the microscopy of the autopsies, W. Hootsmans supervised and assisted in the electromyographic investigations. We also thank Prof. J. Droogleever Fortuijn, Prof. J. F. Folkerts, E. J. E. Frohn, H. Herngreen, E. Jaspers, J. G. Y. de Jong, W. Kramer, W. M. A. M. van der Lugt, J. H. van Luijk, O. Magnus, H. M. van der Maesen de Sombreff, F. G. MSnnich, F. E. Posthumus Meijes, Prof. J. J. G. Prick, J. J. Prick, H. W. Stenvers Jr., J. M. J. Tans, L. van Trotsenburg, and A. Verjaal, who permitted us to examine their patients. This study was partially supported by a grant from Hoffman La Roche, Basle. J. neurol. Sci.

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H.J.G.H.

OOSTERHUIS

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