262
SOME ASPECTS OF MYASTHENIA GRAVIS ON MERSEYSIDE.
*GEORGE W. PENNINGTON, 'M.D., M.R.C.S., L.R.C.P., Department of Pharmacology and Therapeutics, University of Dublin. URING the course of an investigation into the incidence of myasthenia gravis in the Merseyside conurbation (Pennington and Wilson") the salient features of the disease have been noted and an analysis made of the occurrence of these as they have been found in 65 patients admitted to hospitals in the Merseyside region.
D
Signs and Symptoms: The essential clinical feature of myasthenia gravis is the weakness and excessive fatiguability of the voluntary musculature, coupled with periodic exacerbations and remissions in the intensity of the signs and symptoms. This weakness of voluntary muscles may be conveniently divided into two main groups, viz., bulbar, when the weakness is confined to those structures innervated by the somatic and branchial branches of the cranial nerves, and peripheral, when the voluntary muscles in other parts of the body are involved. The initial signs and symptoms in 52 eases and their subsequent progression during a period of 3 years are shown in Table I. It can be seen that 42% of the patients presented with bulbar T A B L E I, ~i~as and Symptoms of Myasthenia Oravis at onset and after thre~ years. Signs a n d S y m p t o m s after three years Initial Signs a n d Symptoms
;ulbar . . . . ;ulbar and peripheral 'eripheral
.. ..
No. of patients
Pop cent
22
42.4
27
51-9 5.7
3
Bulbar
5
B u l b s r !Peripheral and [p e r i p h e r s l II 20 1
1
None
Dead
2
4
4 --
3 1
52
symptoms alone, 52% with bulbar and peripheral symptoms, and only 5.7% with entirely peripheral symptoms. The subsequent progression of signs and symptoms in these patients is interesting. Of those presenting with bulbar symptoms 23% remained bnlbar while 50% became more generalised. In the majority (74%) of those with bulbar and peripheral symptoms the distribution remained unchanged, while only 15% had no evidence of the disease at the end of the three year period. Remission of symptoms figures prominently in most descriptions of the disease (Brain, ~ Dana, ~ Keschner and Strauss, ~ Nevin, "2 Price," Simon"). For example, of the 70 eases reported by Viets and Schwab3s only 7 had complete remissions which lasted from I to 20 years. Although the criteria for remissions varies from observer to observer the patients with remissions in this study are those who at the time of the survey *Present Address : Department of Pharmacology, Trinity College, Dublin.
263
SOME A S P E C T S O F M Y A S T H E N I A G R A V I S ON M E R S E Y S I D E
had complete absence of signs and symptoms of the disease. Six patients have had periods of complete remission. One became symptom-free for 22 years, and after a return of mild symptoms lasting 8 years again had complete remission which so far has lasted for 8 years. The other 5 patients have had remissions which have lasted 3 months, 2 years, 3 years, 6 years and 10 years respectively.. It is noteworthy that the highest mortality rate occurred in those with bulbar symptoms.
Age of Onset and Sex Distribution: Viets and Schwab reported that myasthenia grads may occur any time between the ages of 10 and 70 years with peaks of incidence in the second and fifth decades, while Kennedy and Moersch '' considered the age of onset to lie more commonly in the third and fourth decades. Pennington and Wilson have shown that in the Merseyside conurbation the disease occurs most frequently in females between the ages of 14 and 25 years, and between 44 and 55 years. In the male population no corresponding increase in incidence in these age groups was evident. The age at which the disease was first diagnosed in the 65 patients with myasthenia gravis admitted to hospitals within the Merseyside region is shown in Table FL It will be noted that the largest overall TABLE
II.
Number of patient~ with Myasthenia Gravis in each age group at the time of diagnosis. Total n u m b e r o f patients
Age Group 0 - - - 5
6---10 11--15 16---20 21--25 26--30 31--35 36--40 41--45 46---50 51~55 56--60 61--65 66--70 71--75 76-~
~ 9
. . . . . . . . . . . . . . .
.
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
Males
Females
9
6 7 4 5 10
6 4
8 3 4 4
1 1
2
1 4 4 4 2 3 2 1 2
6 4 1 6 2 2 5
1 3 2
1 1 2
2 65
4
26
39
number of patients with myasthenia gravis, but not necessarily the highest incidence, because the population from which this number arises is unknown, oecurred within the age group 31 to 35 years (10 eases), and 46 to 50 years (8 eases). When these numbers are broken down according to sex the female to male ratio is 3 : 2. Amongst the patients in the ago groups up to 30 years there were approximately twice the number of female to male patients, an observation which agrees with that of Schwab and LeylandY In the older groups however there were equal numbers of either sex.
264
IRISH JOURNAL OF MEDICAL SCIENCE
From an examination of the ease histories it became evident that signs and symptoms of the disease had been present for a varying length of time before the diagnosis was made. This "time l a g " is shown in Table I H where it may be seen that there was often a considerable delay in estabIishing diagnosis. Thus, while about one-third of the eases were diagnosed soon after the first appearance of symptoms, an equal number of patients were not diagnosed until between 1 to 2 years after the onset of symptoms. This has also been the experience of Garland and Clark ~ who, in their survey of patients in Yorkshire, reported a wide variation between the onset of symptoms and the time when diagnosis was established. TABLE III.
T~mei~rval b ~
o r ~ of symp~oma and di~,oais. N u m b e r of case8
Time Lag 0 wffiw e e k s 1~11 months 1--2 years 3--5 years 6--8 years 8 years§ ..
9
4
t
~
23 5 22 9 3 1 63
The explanation for this delay in diagnosis may be that the first symptoms are often not sufficiently disabling for the patient to seek medical advice, or that the early ~signs and symptoms of myasthenia gravis are not sufficiently readily recognised. It has been most noticeable that this " t i m e lag " in diagnosis is considerably reduced when there is an increased awareness in the community of the characteristic features of myasthenia gravis. Associated Clinica~ and Pathological Features. The Thymus Gland: Much attention has been focussed on the thymus gland as an important ~eature of myasthenia gravis. The extensive and well documented observations of Keynes ~" ~,a ~,b and of his associates Ross~ and Simpson ~8 have provided considerable information about the weight of the thymus gland in patients with myasthenia gravis and of the effects of thymectomy. This and other evidence gives little support to the previous belief that the thymus gland in patients with myasthenia gravis is significantly larger than that of patients in the eorrespoiiding age groups, who have not had myasthenia gravis. In the present survey the weight of the thymus glands removed from 16 patients ranged from 12 G. to 40 G. (Table IV) and are within the range recorded by the authors referred to above. The histological structure of the thymus gland has been studied partieularly by Castleman,' who provided evidence that about 65% of
TABLE IV. Comparison of Weight~ of Normal and Myasthenic Thymus Glands.
Age (years) 0--5 6---10 11--15 16---20 21--30 31---40 41--50 51 - - 6 0 61 70
. o
Average Normal Weight of Thymus (G)
Average Weight of Thymus Glands (O) from Patients in Present Investigation
22 28 29 24 19 19 18
30 (4 eases) 16 (2 cases) 6 (2 cases)
~
. ~
. o
o o
~
. ,
~
. o
~
. ~
o .
13
26 (2 cases) 20 (2 cases) 12 (1 case)
12 (1 case)
The ' normal' thymus weights are taken from Spector's Handbook of Biological
Data. (1956). W.B. Saunders Co.
patients with myasthenia gravis had some histological abnormality of the thymus gland. The characteristic features of pale germinal centres were noted in 44% of the 23 specimens examined in the present study. On the other hand, 7 were reported to be histologically normal. In 2 patients there was no evidence of any thymus tissue, the specimens consisting entirely of fat and fibrous tissue. There were 3 specimens with thymic tumours, one of which was malignant. The T h y r o i d Gland:
Attention has been drawn by several authors to the association of myasthenia gravis with thyrotoxicosis. These are featured in reports by Carson," Kowallis, Haines and Pemberton, ~' Thorn and Tierney,~ MacLean and Wilson, 2~ McEachern and Parnell, 1' and Millikan and Haines. 21 Eaton 9 showed that at least 6% of patients with myasthenia gravis attending the Mayo Clinic had hyperthyroidism, or had had symptoms of this before the onset of myasthenia gravis. A careful study of the records in the present investigation showed that 9 patients had an enlargement of the .thyroid gland, but that only 2 had frank evidence of thyrotoxicosis. In each case the thyrotoxicosis had preceded the myasthenia gravis. Pregnancy:
The influence of pregnancy in leading to remissions and relapses has been well reviewed by Viets, Schwab and Brazier, ~3 and several writers have subsequently reported the unpredictable effects on the myasthenic state which may occur during pregnancy. These have served to confirm the opinion advanced by Viets, Schwab and Brazier 3' that the direction of change in symptomatology whether less or more severe, may vary from pregnancy to pregnancy in the same individual. In some instances the first evidence of the disease had been noted during pregnancy, although in the majority of studies the observations have
266
IRISH JOURNAL OF MEDICAL SCIENCE
concerned the changes produced during pregnancy in patients already suffering from myasthenia gravis. In the present study only one patient showed the first signs and symptoms of myasthenia gravis during her first pregnancy. Ptosis, diplopia and dysarthria were observed during the third month, but rapidly and completely disappeared after delivery. She remained symptom-free for about eighteen months until the third month of her second pregnancy, since when moderate but well controlled symptoms have persisted. Three patients relapsed during pregnancy : one of these patients after thymectomy had a remission of 10 years, but three months after she became pregnant, signs and symptoms again appeared and persisted after delivery. Another patient became progressively worse and died in respiratory crisis during the 36th week of pregnancy. The third patient had four pregnancies during which the symptoms became generally more severe. Her first child had 'difficulty in breathing, but responded rapidly to prostigmine therapy. The second baby, although blue and asphyxiated at birth, recovered without antieholinesterase treatment, while the third child was normal. In the last weeks of her fourth pregnancy the patient suddenly collapsed and died in respiratory crisis before the foetus was delivered. Treatment:
All patients studied in this survey have either been treated with anticholinesterase compounds, sometimes with the addition of ephedrine, or they have also been subjected to thymeetomy. ,Many reports on the response to thymectomy have been published in Britain (Keynes, 1" Simpson2s) and in America (Eaton and Clagett 10; Schwab2~) and others, references to which are given by Osserman2 s Vv'itha few exceptions the general consensus of opinion is that after thymeetomy the chances of improvement are greatest in the young female patient without evidence of a thymoma. In the present study, an effort has been made to assess the clinical condition of 60 patients, 29 of whom had been treated only with prostigmine or one of its analogues, while 25 have in addition been subjected to thymectomy. Six patients have been treated by irradiation of the thymus gland. The principal disadvantage in the retrospective assessment of the results of treatment is tt/e lack of a standard method of assessment and one has therefore to depend on the various clinical notes made by a number of different clinicians, as well as the patient's own reeoUection of his elinieal condition. Table V records the sex, age at diagnosis and the duration of the myasthenir symptoms, as well as an assessment of the present clinical condition of each patient. This information has been classified under six main headings, complete remission, marked improvement, improvement, unchanged, worse, and deaths. The most striking feature of this assessment is the high proportion of patients who have been improved as a result of thymectomy. Fifty-six
SOME ASPECTS OF MYASTHENIA GRAVIS ON MERSEYSIDE
267
T A B L E V.
Clinical Assezsment of Myasthenia Gravis
Clinical State at t i m e of survey
-
-
'
l
-
-
t
'
-
-
Sex F
Per cent
8
3.4
Marked improvement
Worse
]Deaths
Totals
F F F M
8 5 1 1
F F F F F F F F F M M M M M M M M
8 2 7 24 4 10 2 11 11 8 1 ) 1 1 6 11 1
F M M
3 1 10
F F F M
1 5 2 1
M= 12 F= 17 29
i I
i M e a n 5.3
i
Per cent
Sex
Duration in years
Pe~ cen~
F F
3 36
33
M F F
4 3 1
50
M
3
3
i
i !
Unchanged
Sex
Duration in years
I
i
Improvement
Medication a n d Radiotherapy
f
Duration in years i
Complete remission
Medication and Thymectomy
Medication Alone
13.8
F F F F F
13 9 12 2 2
F F F M M
2 10 2 1 6
F F F M
2 12 1 6
M
8
~ 20 ]
20
16
4
58.6
10.4
13-8 I
F F M
7 14 18
F F F F F M M
4 1 1 1 1 2 4
M= 7 F= 18 25
Mean 5-6
12
28
F= 4 M= 2 6
Mean 7-8 i
268
IRISH J O U R N A L
OF M E D I C A L S C I E N C E
TABLE
VI.
The E.ffecCof Thymectomy on Prosligmine Requirements. A.--MEDIC&TION ALONE. I No. Sex Age
Initially
let Year
2nd Year
3rd Year
4th Year
1
M
31
90 rag. 135 rag. 1 2 0 m g . 150 mg.
2 3
M F
30
4
27 F 14 Means
60rag. 165 nag.. k 45rag. 45rag. 45rag. 45 nag. 45 rag. 0 60 rag. 97-5 rag. 55 nag.
5 6
M M
40 35
7
M
30
8
M
63
9
M
69
10 11 12 13 14 15 16
M 36 F 49 F 46 F 51 F 61 F 13 F 65 Means
120 nag. 135 nag. 180mg. 135mg, 180 nag. 150mg. 180mg. 150 rag. 180mg. 135mg. 135mg. 135mg. 151 rag.
17 18 19
M ] 43 F I 36 F 30 Means
300mg. 300 nag. 270 mg. 290 nag.
20 21
M 58 F 25 Means
1530mg. 830 mg. I180 nag.
#
I
135 rag.
45 nag, 0 65 nag.
45 rag. 0 60 nag.
90 nag. . . . . Dead 210 rag. 210mg. 285 nag. 2 4 0 m g , 165mg. 165 nag. .
.
180 nag .
.
150mg . 180mg. 150mg. 420rag. 630 rag. 150mg . 120mg. 222 rag.
. . . 180mg. 150 rag. 495 rag. 180rag. . . . 120 nag. 214 rag.
450mg. 525mg. 1525mg. 3 7 5 m g . 300mg. 300mg. 300mg. 3 0 0 m g . -375 nag. 412 mg. i 412 nag. 337 rag.
.
. I 180 rag. j 150 nag. 495mg. 180 nag. . 90 nag. 230 nag.
180mg. 150 rag. 495 rag. 90 nag. 231 rag.
...........
180 nag. Dead 180 nag.
(i) initial
l~ostigmine requirement 45--100 reg.[day
(ii) initial prostigmine requirement 101--250mg,/day
(iii) initial pmstigmine requirement 251~5oo rag./day
initial prostigmine requirements 501 rag./day +
per cent. of the patients who had surgical treatment were grouped within the first three categories compared with only 17% of the patients who had been treated only with drugs. Further analysis shows that this good response to thymeetomy occurred in 61% of female patients and 44% of the male patients. The death rate in the thymectomy group was high (28%), but four of the seven patients in this group died postoperatively, two of them having tumours which had not been diagnosed before operation. In the non4hymectomy group the death rate was 13.8%. These results would appear to suggest that there is a good chance of improvement after thymectomy in both male and female patients, but that the female patients are likely to obtain the greatest benefit. It might be expected that when thymeetomy improves the clinical condition the improvement would be mirrored by a decrease in the prostigmine requirements of the patient. 'In order to examine this possibility, two groups of patients maintained on varying dosages of prostigmine have been compared in Table VI. Group A consists of 21 patients who
SOME
A S P E C T S OF M Y A S T H E N I A
TABLE
GRAVIS
ON
269
MERSEYSIDE
VI--Continued,
B .--THYMECTOMY.
No.
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
I
2 years before
1 year before
27 16
90 mg.
22 35
90 mg. --
300 rag. 75 mg. 90 mg.
50
-60 mg. 80 rag.
Sex
Age
F F F F F M Means M M M
45
47 29
14 F 31 F 18 F i 24 F ! 50 F 11 F i 56 Means
M
33
F F F
34 2O 20 F 22 Means i F i 46 M 14
M i 51 Means
--
-240 mg. 240 mg. 225 mg. 180 mg. 180 mg. 213 rag.
rag. rag. rag. rag. rag. rag. mg. rag.
315mg.
325 mg. mg. rag. nag. rag. rag. mg.
720 675 rag. 1410 1050 675 mg. 1060 ..........
rag. rag, rag. rag.
360 mg. ! --
390 rag,
~ ~ ~ ~ ~ O ~ O
3 years after
4 years after
(i) 0 mg. 120 m g . 9 165 rag.
-165 rag.
Dead 420 rag. ~ 0 rag. 165 rag. 71 rag.
60 rag, 86 rag.
60 rag. 75 rag.
120 rag.
480 rag.
300 rag.
240 rag. 90 rag. 220 rag, 360 rag. --
2 4 0 m g , 240 rag. 45 r a g 0 rag. -270 rag. --
150 rag. Dead 270 rag. 120 rag. 330 mg. 165 rag. Dead Dead ~ 30mg. ~ 177 rag. i i 180 mg. 540 rag. 210 rag. 90 nag. 30 rag. 210 mg.
initial prostigmine requirement 45---loo m~./day
0 rag,
150 rag.
90 rag.
90 rag. 360 rag. 167 rag. 180 165 120 630 360 600 315 240
2 years after
Dead 30 rng. 15 m g . 120 mg. i 120 rag.
90 m g .
360 360 375 360 300 351
--
420 m g .
1 year after
Oil initial
prostigmine requirement 101--250 reg./day
--
206 rag. -240 rag. -Dead 15 rag, 127 rag.
258 rag.
180mg.
(iii) initial prostigmine requimment 251--500 reg./day
0 rag. 0 rag.
(iv}
initial prostigmine requirements 501 reg./day %
i 450 rag. 300 rag. !1080 rag. 990 rag. 990 rag. 585 rag. Dead 705 m g . 645 rag. I 990 m g . I
have received only prostigmine or its analogues, while Group B consists of 23 patients who have had thymectomy in addition to medical treatment. From Table VI it will be seen that the daily neostigmine requirements have ranged from 45 mg. to 1530 rag. To simplify comparisons between the two types of treatment the two groups have been divided into four sub-groups according to the initial daffy dose of neostigmine. It will be seen that most patients seem to reach their highest daily dose of neostigmine within the first year of treatment and that thereafter little further increase in neostigmine requirements is necessary. This initial period of adjustment in treatment is well demonstrated in Fig. 1 which is a graphic representation of the figures given in Table VI (ii). In the present study the choice of patient for thymectomy has in most eases been arbitrary. Reference to Fig. 1 will show that the mean daily neostigmine requirements of patients chosen for thymect0my were usually much greater thau those of the corresponding non-operated groups; after operation however the neostigmine requirements were closely similar to those of the non-thymectomy group. This comparison
270
IRISH JOURNAL OF MEDICAL SCIENCE
/
z/
~T~N
lacks precision of analysis on account of the small number of patients involved and, whilst it would be unwise to make any firm conclusions about the effects of thymectomy on neostigmine requirements, it is tentatively suggested that one of the results of thymectomy may be to influence the amount of neostigmine absorbed and utitised.
\
'~
of ~J~Tnm'f. {~aRS)
Summary.
1. Some of the salient features of 65 patients with myasthenia gravis in Che Merseyside region have been reviewed. Rather more than half of the patients had signs and symptoms of bulbar and peripheral origin, which did not change very much during a period of 3 years. The majority of the other patients who at the outset displayed only bulbar symptoms later also showed evidence of peripheral involvement. ~'Io. I. Average daily doses of neostigmine in two groupa of patients with myasthenia gravis. (From Table VI, ii). A , treated only with neostigmine ; B,, treated with neostigraine before and after thymootomy.
2. The age and sex distribution of the patients has shown that myasthenia gravis occurred most commonly in females between 16 and 35 years. There is often a considerable interval between the onset of symptoms and the time when diagnosis is first established; it is .suggested that this time lag is reduced when there is an increased awareness of this disease in a community. 3. Nine of the patients had enlargement of the thyroid gland, but only two had evidence of thyrotoxieosis. 4. The influence of pregnancy on the signs and symptoms of 4 of the patients has been noted and discussed. 5. The influence of thymectomy on the clinical condition and daily neostigmine requirements of 25 patients has been studied and discussed. Aeknowt~. My thanks are due to Professor Audrew Wilson for the encouragement he has given me and also to many of the Consultant Physicians and Surgeons of the United Liverpool Hospitals and Regional Hospitals Boewds for allowing me to see and to consult the records of their patients with myasthenia gravis. I t is a pleasure to acknowledge the helpful cooperation I have received from the nursing and secretarial staffs of the individual hospitals. The work was supported by a grant from the Myasthenia Oravis Foundation Inc., New York, and The Distillers Company Ltd., London.
I. Brain, R. (1940). D~seas~s of th~ Nervous Sy*tem. 2nd Ed. Oxford Univ. Press. 2. Burr C. W. and McCarthy, D. ft. (1901). A m . J. Me~'l. 8ei., 121, 46.
271
SOME ASPECTS OF MYASTH~IA GRAVIS ON MERSEYSIDE
Campbell, H . a n d Bramwell, E. (1900). Brain, 23, 277. Carson, J . (1943). Prec. Roy. ~qoc. Med., 36, 140. Castleman, B. a n d Norris, E. H. (1949). Med/eine, 28, 27. Castleman B. (1955). Atlas of Tumour Pathology, Armed Forces Inst., P a t h . , Sect. 5, 19, 15. 7. Collins, D. H . (1948). Cir. B r a t t e n in B.M.A. Proceed. p. 159. London. 8. Dana, C. L. (1922). J . A . M . A . , 78, 261. 9. E a t o n , L. M. (1947). Med. Clin. N. Ame~., 31, 907. 10. E a t o n , L. M. a n d Clagett, O. T. (1955). Araer. J. Med. 19, 703. 11. Garla~ad, H. a n d Clark, A. N. G. {1956). Brit. Med. J., i, 1259. 12. Goni, A. R . a n d Leamxi, A. (1943). Med/c/na, 3, 476. 13. Hall, A. J . (1899). B ~ . Med. J . , ii, 1481. 14. Kennedy, F. S. mad Moersch, F. P. (1937). Canad. M. A.J., 37, 216. 15. K e s c h n e r , M. a n d Strauss, I. (1927). Arch. NeuroL & Psych., 17, 337. 16. Keynes, G. L. (1946). Brit. J. Sury., 33, 201. 16a. Keynes, G. L. (1949}. Brit. Med. J., ii, 611. 16/). Keynes, O. L. (1952). J. Obst. Gyn. Brit. Emp., 59, 173. 16c. Keynes, G. L. (1954). Lancet, i, 1197. 17. Kowaillis, G. K, Haines, S. F. and Pemberton, I. J. (1942). Arch. Int. Med., 69 41. 18. McEachern, D. (1943). Medicine, 22, 1. 19. McEachern, D. a n d Parnell, J. L. (1948). J. Clin. Endo., 8, 842. 20. MacLean, B. a n d Wilson, J . A. C. (1954). Lancet, i, 950. 21. Millikan, C. H. a n d Haines, S. F. (1953). Arch. Int. Med., 92, 5. 22. Nevin, S. (1938). J. 1VeuroL & Psych., 1, 120. 22a. :Nevin, S. (1951). Modern Trends in Neurology. Butterworth, London. 23. Osserman, K. (1958). Myasthenia Gravis. Grune and Stratton, New York. 24. P e n n i n g t o n , G. W. a n d Wilson, A. (1959}. Myasthenia Grav/#. C . C . T h o m a s Springfield, Ill. 25. Price, F. W. (1941). Textbook of the Practice of Medicine. Oxford Med. Publ. 3. 4. 5. 6.
London. 26. 27, 28. 29. 30. 31. 32. 33. 34.
Ross, R. T. (1952). Lancet, i, 785. Schwab, R. S. (1959). Myasthenia Gravis. C. C. Thomas, Springfield, Ill. Simon, H . E. (1935). J . A . M . A . , 104, 2065. Simpson, J. A. (1958). Brain, 81, pt. 1., 112, Sloan, H. E. J n r . (1943). Surgery, 13, 154. Tabachniek, H. (1938). J . A . M . A . , 110, 884. Thorn, G. W. a n d Tierney, N. A. (1941}. Bull. Johns Hopkins Hosp., 69, 409 Viers, H. R. a n d Schwab, R. S.(1939). J.A.M.A. 113. 559. Viers, H. R., Schwab, R. 8. a n d Brazier, M. A. B., (1942). J . A . M . A . , 119, 236.
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III
IIIHI
III
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