IMMUNOSUPRESSION WITH CORTICOSTEROIDS
AND THYMECTOMY IN MYASTENIA GRAVIS
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
A N E V A L U A T I O N O F I M M E D I A T E A N D S H O R T
T E R M R E S U L T S I N 20 P A T I E N T S
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
J. LAMARTINE DE A88I8 * PAULO E. MARCHIORI **
ANTONIO A. ZAMBON ** NAGIB CURI ***
LUIZ TARCISIO BRITO FILOMENO ** MILBERTO S C A F F ****
Management of the severe form of myasthenia gravis ( M G ) , by
immuno-suppression with oral corticosteroids gained impetus during the seventies, with the
research carried out in most medical centers that treat this disease
1-13,15,16.Because with rare exceptions 9, controlled trials are few, controversies abound i*.
In preparation for thymectomy, immunosuppression with corticosteroids has
re-cently been u s e d
1 2»
1 3, even though there is no certainty that this improves the
results
1 3.
W e report the immediate and short-term effects of this management before,
during and after thymectomy.
M A T E R I A L . A N D M E T H O D S
F o r t y p a t i e n t s o f b o t h s e x e s w e r e s u b m i t t e d t o t h y m e c t o m y , b u t 20 o f t h e m r e c e i v e d p r e d n i s o n e p r e o p e r a t i v e l y . C h a r a c t e r i s t i c s o f t h e d i s e a s e a n d o t h e r f a c t o r s w e r e k e p t a s s i m i l a r a s p o s s i b l e i n b o t h g r o u p s . T h e i m m e d i a t e a n d s h o r t t e r m r e s u l t s o f b o t h g r o u p s w e r e c o m p a r e d . B y s h o r t t e r m i s m e a n t t h e i m m e d i a t e p o s t -o p e r a t i v e p e r i -o d a n d t h e f -o l l -o w i n g t w -o -o r t h r e e w e e k s . T h e l -o n g t e r m r e s u l t i s u p t o 6 m o n t h s a f t e r s u r g e r y . T h e a g e o f t h e g r o u p r e c e i v i n g p r e d n i s o n e t h e r a p y v a r i e d f r o m 9 t o 35 y e a r s . A n a v e r a g e o f 22.7 y e a r s a n d s t a n d a r d d e v i a t i o n ( s d ) o f 6.97. D u r a t i o n o f t h e d i s e a s e w a s f r o m 3 m o n t h s t o 13 y e a r s w i t h a m e a n o f 3.05 a n d a s d o f 3.69 y e a r s . T h e g r o u p w i t h o u t p r e v i o u s p r e d n i s o n e t h e r a p y v a r i e d i n a g e f r o m 16 t o 37 y e a r s , w i t h a n a v e r a g e o f 25.25 a n d s d o f 5.12 y e a r s . T h e l e n g t h o f i l l n e s s w a s f r o m 6 m o n t h s t o 13 y e a r s w i t h a n a v e r a g e o f 3.52 a n d s d o f 3.16 y e a r s .
B o t h g r o u p s h a d t h e g e n e r a l i z e d f o r m o f M G a n d r e s p o n d e d l i t t l e t o m e d i c a l m a n a g e m e n t . T h e i m m u n o s u p p r e s s i v e r e g i m e n w a s b e g u n w i t h 80 m g d a i l y a n d p r o g r e s s i v e r e d u c t i o n a f t e r t h e 10th o r 15th d a y . T h r e e p a t i e n t s b e g a n t h e t r e a t m e n t w i t h 100 a n d t h r e e w i t h 60 m g . T h e m e a n p r e o p e r a t i v e d o s e o f p r e d n i s o n e w a s 45.5 m g w i t h a s d o f 22.05 m g . A l l p a t i e n t s n e e d e d t o b e k e p t o n a n t i c h o l i n e s t e r a s e u p t o t h e t i m e o f s u r g e r y . P y r i d o s t i g m i n e b r o m i d e w a s u s e d r o u t i n e l y i n o r a l d a i l y d o s e s v a r y i n g f r o m 60 t o 1,560 m g , w i t h m o s t p a t i e n t s r e c e i v i n g 60 t o 180 m g . T h e m e a n
d o s e o f p r e o p e r a t i v e p y r i d o s t i g m i n e w a s 402 m g w i t h a s d o f 416.64 m g a n d o f 184
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.2S m g w i t h s d o f 104.53 m g a t s u r g e r y . T h e d o s e s w e r e a l w a y s r e d u c e d t o a m i n i m u m .T h y m e c t o m y w a s a l w a y s d o n e v i a a m e d i a n s t e r n o t o m y a n d t h e c e r v i c a l r e g i o n e x a m i n e d f o r p o s s i b l e e c t o p i c t h y m u s t i s s u e .
D u r i n g t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d , t h e s a m e d o s e s o f p r e d n i s o n e w e r e m a i n t a i n e d i n m o s t , w e r e r e d u c e d i n 5 a n d i n c r e a s e d i n 1 p a t i e n t . T h e a n t i c h o l i n e s t e r a s e d o s e r e m a i n e d u n c h a n g e d i n 6, w a s r e d u c e d i n 4 a n d I n c r e a s e d i n t w o c a s e s . T w o p a t i e n t s w h o w e r e n o t o n a n t i c h o l i n e s t e r a s e p r e o p e r a t i v e l y , w e r e g i v e n s m a l l d o s e s d u r i n g t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d . T h e a n t i c h o l i n e s t e r a s e b a d b e e n s u s p e n d e d p r e o p e r a t i v e l y i n 5 p a t i e n t s a n d t h e y c o n t i n u e d s o d u r i n g t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d . I t w a s a l s o d i s c o n t i n u e d i n t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d i n 1 p a t i e n t . T h e m e a n p o s t o p e r a t i v e d o s e o f p y r i d o s t i g m i n e w a s 94.60 m g w i t h a s d o f 98.79 m g . A l l b u t o n e p a t i e n t i n t h e t h y m e c t o m i z e d g r o u p w h i c h d i d n o t r e c e i v e p r e d n i s o n e p r e o p e r a t i v e l y , r e c e i v e d a n t i c h o l i n e s t e r a s e i n t h e i m m e d i a t e a n d s h o r t t e r m p e r i o d .
R E S U L T S
T h e g r o u p o f p a t i e n t s w i t h p r e o p e r a t i v e p r e d n i s o n e t h e r a p y s h o w e d v e r y f a v o r a b l e i m m e d i a t e p o s t o p e r a t i v e r e c o v e r y . T h i r t e e n o f t h e m ( 6 5 % ) s h o w e d c o m p l e t e r e m i s s i o n o r m a r k e d i m p r o v e m e n t . F o u r p a t i e n t s r e p o r t e d s i g n i f i c a n t i m p r o v e m e n t , w h i l e o n e s h o w e d s l i g h t , s l o w b u t p r o g r e s s i v e r e l i e f . T w o p a t i e n t s g o t w o r s e s o t h a t o n e s u s t a i n e d a c h o l i n e r g i c c r i s i s p o s t o p e r a t i v e l y r e q u i r i n g a r e s p i r a t o r f o r 20 d a y s . U s u a l l y i m p r o v e m e n t w a s q u i c k , e a r l y a n d s i g n i f i c a n t w i t h c o m p l e t e r e m i s s i o n i n 8 p a t i e n t s . T h e l a t t e r w e r e o n p r e d n i s o n e t h e r a p y w h e n s u b m i t t e d t o t h y m e c t o m y a n d d u r i n g t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d (10-80 m g ) . T w o o f t h e m g o t w o r s e o v e r a s h o r t p e r i o d , o n e o f t h e m h a d a n a b r u p t r e l a p s e s i x m o n t h s a f t e r c o m p l e t e r e m i s s i o n . S u p p u r a t i o n o f t h e s u r g i c a l w o u n d d e v e l o p e d i n o n e p a t i e n t a n d t h e i n f e c t i o n l a s t e d f o r a l o n g t i m e e v e n t h o u g h t h e r e w a s a r e m i s s i o n o f t h e m y a s t h e n i c s y m p t o m s . E i g h t m o n t h s p o s t o p e r a t i v e l y t h i s p a t i e n t c o n t i n u e s a s y m p t o m a t i c w i t h 10 m g / d a y o f p r e d n i s o n e a n d 180 m g / d a y o f p y r i d o s t i g m i n e b r o m i d e . T h e p r o g r e s s d u r i n g t h e i m m e d i a t e p o s t o p e r a t i v e p e r i o d i n t h e g r o u p w i t h o u t p r e o p e r a t i v e p r e d n i s o n e t h e r a p y w a s v e r y f a v o r a b l e i n 14 p a t i e n t s ( 7 0 % ) . O n e p a t i e n t s h o w e d s i g n i f i c a n t i m p r o v e m e n t a n d 13 c o m p l e t e r e m i s s i o n . T h e r e w a s o n e d e a t h , o n e p a t i e n t w o r s e n e d a n d 4 s h o w e d s l i g h t i m p r o v e m e n t .
M o s t o f t h e p a t i e n t s i n t h e t h y m e c t o m i z e d g r o u p w i t h p r e o p e r a t i v e p r e d n i s o n e c o n t i n u e d i n r e m i s s i o n o r m a r k e d i m p r o v e m e n t , i n s p i t e o f p r o g r e s s i v e r e d u c t i o n of t h e d o s e s o f p r e d n i s o n e a n d a n t i c h o l i n e s t e r a s e d u r i n g a s h o r t t e r m p e r i o d . S i x p a t i e n t s r e m a i n e d w i t h o u t a n t i c h o l i n e s t e r a s e a f t e r t h y m e c t o m y . H o w e v e r , t w o p a t i e n t s
r e s u m e d u s i n g t h e d r u g a l t h o u g h i n s m a l l d o s e s , o n e t h i r t y
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
day3 a n d t h e o t h e r 3 m o n t h s l a t e r . T h e r e m a i n d e r w e r e m a i n t a i n e d o n a c o m b i n a t i o n o f p r e d n i s o n e-a n t i c h o l i n e s t e r -a s e . S i g n i f i c -a n t i m p r o v e m e n t o r r e m i s s i o n d u r i n g l h e s h o r t t e r m p e r i o d w a s s h o w n b y m o s t o f t h e p a t i e n t s i n t h e t h y m e c t o m i z e d g r o u p w i t h o u t p r e o p e r a t i v e p r e d n i s o n e t h e r a p y . B o t h g r o u p s s h o w e d t h e s a m e p r o p o r t i o n o f s i g n i f i c a n t i m p r o v e m e n t a n d c o m p l e t e r e m i s s i o n d u r i n g t h e s h o r t t e r m p e r i o d .
H i s t o l o g i c e x a m i n a t i o n o f t h e t h y m u s d o n e o n 19 p a t i e n t s r e c e i v i n g p r e d n i s o n e s h o w e d 12 w i t h h y p e r p l a s i a ( 6 3 % ) , 4 n o r m a l ( 2 1 % ) , a n d 3 w i t h a t r o p h y ( 1 5 . 7 % ) .
C O M M E N T S
The results of thymectomy on patients previously submitted to steroid
therapy are reported. As stated in the introduction, there are few such reports
and the value of this management is still controversial. The results were
apparently very good, since 6 5 % of the patients receiving preoperative
immunosuppressive drugs reported complete remission or marked improvement.
This occurred without a significant increase in postoperative complications
caused by intensive and prolonged use of steroids. There were really only 4
complications. Only one was due to myasthenic crisis and two were minimal;
namely, infection of the incision. The infection was prolonged in one of these
two cases but there was remission of the myasthenic symptoms. The fourth
patient, who immediately after thymectomy was receiving a double dose of
anticholinesterase, entered a cholinergic crisis requiring the prolonged use of a
respirator.
Considering the patients with complete remission and marked or significant
improvement, 6 5 % improved with this management over a short period of time.
One improved slowly and slightly but progressively and 4 ( 2 5 % ) showed slight
improvement. A high proportion, 9 0 % sustained remission or improvement over
a short term period in spite of the progressive reduction of prednisone and
anticholinesterase. It is notable, that 6 patients ( 3 0 % ) , discontinued the
anti-cholinesterase postoperatively but after a short time, two of them resumed
using the drug but in very small doses. The combination of
prednisone-anti-cholinesterase medications was maintained for a short and mid-term basis in
70% of the cases. There were no deaths over a short term period, although
2 patients were doing poorly.
20
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
ARQ. NEURO-PSIQUIATRIA (8ÃO PAULO) VOL. 43, N* 1, MARÇO, 1985one patient reported complete remission without anticholinesterase drugs on a
short and mid-term basis after thymectomy.
No significant difference was found on comparing the results of thymectomy
in both groups, i.e., the group receiving immunosuppressive agents and the
control group. However, the statistical analysis of the postoperative
complicat-ions in both groups revealed a significant difference in favor of the group
receiving preoperative immunosuppressive medication. These results led to the
conclusion that preoperative use of prednisone for patients undergoing thimectomy
is beneficial.
The excised thymus was hyperplasic in the majority of patients in the
group managed by immunosupression. This was mainly true in young females
under 23 and in a 9 year old child. The three cases witli atrophic thymus
were 27, 31 and 35 years old. Their disease had begun respectively three,
eighteen months and 8 years previously. As a matter of fact, they responded
very well to the operation. The 4 with histologically normal thymus, varied
in age from 16 to 32 and their illness from 15 days to 10 years. They responded
very well to treatment and only one worsened. These data suggest that the
histologic condition of the thymus does not influence the result of treatment
and that hyperplasia predominates in younger female patients.
S U M M A R Y
A comparatice study was conducted on two groups of patients with the
generalized severe form of myasthenia gravis. The first group of 20 patients
received oral daily doses of 60-100 mg of prednisone prior to thymectomy. The
control group of 20 were submitted to surgery without prior corticosteroid
treatment. The study included statistical analysis of the clinical results and
surgical complications for both groups. The author concluded that the use
of steroids preoperatively is beneficial.
R E S U M O
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
Imunossupressão com corticosteróides e timectomia na miastenia grave:
avaliação dos resultados em 20 pacientes a curto e médio prazos.
São apresentados os resultados da timectomia em 20 pacientes com miastenia
grave generalizada, a maioria severa, e tratados previamente com prednisona em
doses altas (60-100mg, diariamente) por via oral. Os resultados foram
compa-rados aos de um grupo de 20 pacientes muito semelhantes aos primeiros quanto
à idade, sexo e forma clínica da doença, mas sem preparo prévio com
predniso-na. Os autores concluem que os resultados da timectomia nos pacientes
tra-tados ou não com prednisona são semelhantes. Entretanto, aqueles submetidos
ao preparo prévio com o corticóide tiveram menos complicações no
pós-opera-tório imediato e mediato do que os do grupo controle. As diferenças foram
estatisticamente significantes.
S U M M A R Y
A comparatice study was conducted on two groups of patients with the
generalized severe form of myasthenia gravis. The first group of 20 patients
received oral daily doses of 60-100 mg of prednisone prior to thymectomy. The
control group of 20 were submitted to surgery without prior corticosteroid
treatment. The study included statistical analysis of the clinical results and
surgical complications for both groups. The author concluded that the use
of steroids preoperatively is beneficial.
R E S U M O
Imunossupressão com corticosteróides e timectomia na miastenia grave:
avaliação dos resultados em 20 pacientes a curto e médio prazos.
R E F E R E N C E S
1. A S S I S , J.L
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
. — C o r t i c o s t e r o i d e s n o t r a t a m e n t o d a m i a s t e n i a g r a v e . E s t u d o d e 12 c a s o s c o m r e v i s ã o d a l i t e r a t u r a . A r q . N e u r o - P s i q u i a t . ( S ã o P a u l o ) 33:33, 1975.2. A S S I S , J . L . & C U R I , N . — T i m e c t o m i a n a m i a s t e n i a g r a v e . A v a l i a ç ã o d o s r e s u l t a d o s e m 73 p a c i e n t e s . A r q . N e u r o - P s i q u i a t . ( S ã o P a u l o ) 36:16, 1978.
3. B O L O O K I , H . & S C H W A R T Z M A N , R . J . — R o l e o f s t e r o i d s i n m a n a g e m e n t o f p a t i e n t s w i t h m y a s t h e n i a g r a v i s u n d e r g o i n g t h y m e c t o m y . J . t h o r a c . S u r g . 75:754, 1978 4. B R U N N E R , N . G . ; N A M B A , T . & G R O B , D . — C o r t i c o s t e r o i d s i n m a n a g e m e n t o f
s e v e r e , g e n e r a l i z e d m y a s t h e n i a g r a v i s . N e u r o l o g y ( M i n n e a p o l i s ) 22:603, 1972.
5. B R U N N E R , N . G . ; B E R G E R , C . L . ; N A M B A , T . & G R O B , D . — C o r t i c o t r o p i n a n d c o r t i c o s t e r o i d s i n g e n e r a l i z e d m y a s t h e n i a g r a v i s . C o m p a r a t i v e s t u d i e s a n d r o l e in m a n a g e m e n t . A n n . N . T . A c a d . S c i . 274:577, 1976.
6. C L A R K , R . E . ; M A R E A R G E R , J . P . ; W E S T , P . N . ; S P R A T T , J . A . ; F L O R E N C E , J . M . ; R O P E R , C . L . ; F E R G U S O N , T . B . & W E L D O N , C.S. — T h y m e c t o m y f o r m y a s t h e n i a g r a v i s i n t h e y o u n g a d u l t . J . t h o r a c . S u r g . 80:696, 1980.
7. E N G E L , W . K . — M y s t h e n i a g r a v i s . A n n . i n t . M e d . 81:225, 1974.
8. E N G E L , W . K . — M y a s t h e n i a g r a v i s , c o r t i c o s t e r o i d s , a n t i c h o l i n e s t e r a s e s . A n n . N . Y . A c a d . S c i . 274:623, 1976.
9. H O W A R D , F . N . ; D U A N E , D . D . ; L A M B E R T , F . H . — A l t e r n a t e d a y p r e d n i s o n e : p r e l i m i n a r y r e p o r t o f a d o u b l e - b l i n d c o n t r o l l e d s t u d y . A n n . N . Y . A c a d . S c i . 274:596, 1976.
10. J O H N S , T . R . ; M A N N , J . D . ; J O S E P H , B . S . & C A M P A , J . F . — L o n g t e r m a d m i n i s -t r a -t i o n o f c o r -t i c o s -t e r o i d s i n m y a s -t h e n i a g r a v i s . N e u r o l o g y ( M i n n e a p o l i s ) 22:400, 1972. 11. K J A E R , M . — M y a s t h e n i a g r a v i s a n d m y a s t h e n i c s y n d r o m e s t r e a t e d w i t h p r e d n i s o n e .
A c t a n e u r o l . s c a n d . 47:464, 1971.
12. M A N N , J . D . ; C A M P A , J . F . ; M U L L E R , W . H . — L o n g - t e r m p r e d n i s o n e f o l l o w e d b y t h y m e c t o m y i n m y a s t h e n i a g r a v i s . A n n . N . Y . A c a d . S c i . 274:608, 1976.
13. M I N T Z , J . ; P E T E R S E N , S . R . ; M a c F A R L A N D , D . ; P E T A J A N , J . ; R I C H A R D S , R . C . — T h e c u r r e n t r o l e o f t h y m e c t o m y f o r m y a s t h e n i a g r a v i s . A m e r . J . S u r g . 140:734, 1980.
14. R O W L A N D , L . P . — C o n t r o v e r s i e s a b o u t t h e t r e a t m e n t o f m y a s t h e n i a g r a v i s . J . N e u r o l . N e u r o s u r g . P s y c h i a t . 43:644, 1980.
15. S E Y B O L D , M . E . ; D R A C H M A N , D . B . — G r a d u a l l y i n c r e a s i n g d o s e s o f p r e d n i s o n e i n m y a s t h e n i a g r a v i s : r e d u c i n g t h e h a z a r d s o f t r e a t m e n t . N . E n g l . J . M e d . 290: 81, 1974.
16. W A R M O L T S , J . R . ; E N G E L , W . K . — B e n e f i t f r o m a l t e r n a t e d a y p r e d n i s o n e in
m y a s t h e n i a g r a v i s . N . E n g l . J . M e d . 286:17, 1972.
