ALTERATIONS OF CELL-MEDIATED IMMUNE RESPONSE
IN CHILDREN WITH FEBRILE SEIZURES
TEREZINHA C.B. MONTELLI*, ANGELA M.V.C. SOARES**, MARIA R. PARISE-FORTES**,
MARIA T. REZKALLAH-IWASSO**, NIURA M.R. PADULA*, MARIA TEREZINHA S. PERAÇOLI**
ABSTRACT - The aim of the present investigation was to study the distribution of T-cell subsets in peripheral blood defined by monoclonal antibodies and by the lymphocyte proliferative response to phytohemagglutinin (PH A) in 30 children with febrile seizures and in 14 age-matched control subjects. Frequent respiratory, urinary and dermatologic infections were observed in 22 patients. The immunologic parameters showed that 6 4 % of the patients presented an increased number of CD8+ cells and a low helper/suppressor ratio was observed in 60% of the patients. In addition, the proliferative response of lymphocytes to PHA was impaired in the patients. It was observed the presence of inhibitory activity on lymphocyte function in the plasma of 3 3 % of children with febrile seizures. These results suggest that patients with febrile seizures have an impairment of cellular immunity that may be connected with this epileptic syndrome and explain the infections observed.
KEY W O R D S : febrile seizures, infections, T cell subsets, lymphocyte proliferative response.
Alterações da resposta imune celular em crianças portadoras de convulsão febril
R E S U M O - O objetivo da presente investigação foi estudar a distribuição das subpopulações de células T por meio de anticorpos monoclonais e a resposta proliferativa de linfócitos em resposta a fito-hemaglutinina (PHA) em 30 crianças portadoras de convulsão febril e em 14 crianças saudáveis de mesma faixa etária dos pacientes. Infecções respiratórias, urinárias e dermatológicas frequentes foram observadas em 22 pacientes. Os parâmetros imunológicos demonstraram que 6 4 % dos pacientes apresentaram valores elevados de células CD8+. Diminuição da relação de células CD4/CD8 foi observada em 6 0 % dos pacientes. Além disso, a resposta proliferativa de linfócitos frente a PHA apresentou-se deprimida nos pacientes. Foi observada a presença de atividade inibidora da função de linfócitos no plasma de 3 3 % das crianças com convulsão febril. Esses resultados sugerem que pacientes com convulsão febril apresentam depressão da resposta imune celular que poderia implicar em associação patogênica com esta síndrome epiléptica e explicar as infeções observadas.
PALAVRAS-CHAVE: convulsão febril, infecções, subpopulações de linfócitos T, resposta proliferativa de linfócitos.
A f e b r i l e s e i z u r e is t h e m o s t c o m m o n c o n v u l s i v e d i s o r d e r of e a r l y c h i l d h o o d . It m a y o c c u r
b e t w e e n 3 m o n t h s a n d 6 y e a r s of a g e , a s s o c i a t e d w i t h f e v e r b u t w i t h o u t e v i d e n c e of i n t r a c r a n i a l
i n f e c t i o n o r d e f i n e d c a u s es
. F e b r i l e s e i z u r e s a r e to b e d i s t i n g u i s h e d f r o m e p i l e p s y w h i c h is
c h a r a c t e r i z e d b y r e c u r r e n t n o n f e b r i l e s e i z u r e s3
. F e b r i l e s e i z u r e s u s u a l l y o c c u r in c h i l d r e n w h o a r e
d e v e l o p m e n t a l l y n o r m a l b u t m a y b e a l s o p r e s e n t in c h i l d r e n w i t h p r e e x i s t i n g n e u r o l o g i c o r
d e v e l o p m e n t a l a b n o r m a l i t i e s7
. T h e m o s t f r e q u e n t c a u s e of i l l n e s s e s in c h i l d r e n p r e s e n t i n g the first
*Department of Neurology and Psychiatry, School of Medicine and **Department of Microbiology and Immunology, Institute of Biosciences (IB), State University of São Paulo (UNESP), Botucatu, São Paulo, Brazil. Aceite: 27-janeiro-1997.
febrile s e i z u r e is viral i n f e c t i o n " . T h e s e i n f e c t i o n s u s u a l l y affect t h e u p p e r r e s p i r a t o r y a i r w a y s , t h e
m i d d l e ear, a n d t h e g a s t r o i n t e s t i n a l tract. S e i z u r e s t h a t o c c u r after D P T o r m e a s l e s i m m u n i z a t i o n ,
m a y b e r e l a t e d in r e s p o n s e to t e m p e r a t u r e e l e v a t i o n " .
R e d u c e d s e r u m I g A l e v e l s h a v e b e e n o b s e r v e d in c h i l d r e n w i t h f e b r i l e s e i z u r e s p r e s e n t i n g
r e c u r r e n t i n f e c t i o n s d u e to an i m m u n o d e f i c i e n t s t a t u s2 " '2 2
. I m m u n o l o g i c a l d i s t u r b a n c e s s u c h a s l o w
levels of i m m u n o g l o b u l i n s in s e r u m a n d a l t e r a t i o n s in T cell s u b s e t s o f p e r i p h e r a l b l o o d s u c h as
d i m i n i s h e d n u m b e r o f C D 4 + c e l l s a n d i n c r e a s e d C D 8 + c e l l s h a s b e e n o b s e r v e d in p a t i e n t s w i t h
c o m p l e x partial s e i z u r e s a n d p r i m a r y g e n e r a l i z e d t o n i c - c l o n i c seizures5
'*. A s s o c i a t i o n w i t h i n t e n s e
i m m u n o l o g i c a l d y s f u n c t i o n h a s b e e n d e s c r i b e d in s e r i o u s e p i l e p t i c e n c e p h a l o p a t i e s o f c h i l d h o o d
s u c h as W e s t a n d L e n n o x - G a s t a u t s y n d r o m e s , w i t h d e f i c i e n c y of c e l l - m e d i a t e d i m m u n e r e s p o n s e
a n d altered levels of s e r u m i m m u n o g l o b u l i n s1 2 , 1 4
. In a d d i t i o n , p a t i e n t s w i t h W e s t s y n d r o m e p r e s e n t e d
d e c r e a s e d C D 3 + , C D 4 + s u b s e t a n d C D 4 / C D 8 r a t i o w h i l e C D 8 + c e l l s w e r e e l e v a t e d1 3 .
T h e s e r e s u l t s s u g g e s t t h a t s o m e a b n o r m a l i t i e s o f t h e i m m u n e r e s p o n s e m a y b e a s s o c i a t e d
with s y n d r o m e s a n d e p i l e p t i c e p i s o d e s . T h u s , t h e o b j e c t i v e of t h e p r e s e n t i n v e s t i g a t i o n w a s to
s t u d y c e l l - m e d i a t e d i m m u n i t y in c h i l d r e n w i t h f e b r i l e s e i z u r e s , c o n s i d e r e d to b e a b e n i g n f o r m of
c h i l d h o o d s p e c i a l e p i l e p t i c s y n d r o m e of u s u a l l y t r a n s i t o r y c o u r s e . A l s o , to i n t r o d u c e t h e q u e s t i o n
a b o u t a p o s s i b l e p h y s i o p a t h o l o g i c l i n k a g e b e t w e e n c e l l u l a r i m m u n i t y w i t h febrile c o n v u l s i o n s .
MATERIAL AND METHODS
Patients and controls. A group of 30 children, 19 male and 11 female, with diagnosis of febrile seizures,
seen at Hospital das Clínicas, UNESP, Botucatu, State University of São Paulo, were included in the study. The criteria for include children with febrile seizures in this study were: 1. to have been attended in the outpatient clinic since the fust convulsion; 2. to have regular follow-up, in order to permit a carefull prospective study; 3. to have good nutrition condition. There was no selective procedure about characteristics of febrile seizures, neither frequency of infections. Age at the first febrile seizure ranged from 3 months to 5 years (median age 1.3 years). The seizure episodes were short in 27 patients, with a duration of less than 10 minutes, and prolonged in three of the children. Generalized crisis were observed in 29 patients and a hemigeneralized crisis was observed in one child. The control group included 14 healthy subjects (8 males and 6 females) whose age range was similar to that of the patients.
Immunity was evaluated out of periods of infections, during the follow-up of the patients, six or more months after convulsive episodes. Informed consent was obtained from the parents of patients and controls. The authors had approval from Hospital Ethics Commission to study immunocompetence in children with convulsive disorders.
Antecedents. Recurrence of febrile seizures was reported by 20 children, and 10 had presented only one
seizure episode before the present immunological evaluation. A family history of febrile seizures was verified in 4 children and was absent in 14 patients. Family history of epilepsy was observed in 9 children, and association of epilepsy plus febrile seizures was present in 3 patients. Seventeen children were submitted to continuous treatment with phenobarbital, and one was treated with valproate. Twelve patients were left untreated.
Reagents. Monoclonal antibodies directed against human CD3+ and CD4+ and CD8+ were obtained from
Ortho Diagnostics Systems (Raritan, NJ, USA) and were employed throughout this study. For the indirect immunofluorescence assay, biotinylated horse anti-mouse IgG and fluorescein-labelled avidin-D (Vector Laboratories, Burlingame, PA, USA) were used.
Enumeration of lymphocyte subsets. Peripheral blood mononulear cells were isolated from heparinized
venous blood by Ficoll-Hypaque density centrifugation and resuspended in RPMI1640 medium (Gibco Laboratories, Grand Island, NY, USA) supplemented with 10% (v:v) fetal calf serum. Approximately 2x10^ cells were centrifuged onto a poly-l-Iysine-coated coverslip and staining reactions earned out at 4°C as described previously2 3
. Briefly, after reacting with the monoclonal antibody, the cells were treated with biotinylated horse anti-mouse IgG and fluoresceinated avidin-D and fixed in formaldehyde. At least 500 cells per sample were examined and scored under phase and fluorescence microscopy.
Lymphocyte proliferative response. Lymphocyte cultures were prepared according to Musatti et al."\
cells by Ficoll-Hypaque density centrifugation, the concentration of the cells was adjusted to 5x 1 0s
cells/ml in RPMI medium containing 20% homologous AB or autologous heat-inactivated plasma. Each culture test tube received 2.5 ml of this suspension and triplicates were prepared receiving 40 ug of phytohemagglutinin-P (PHA). Control tubes did not receive any stimulus. Tritiated thymidine, 2uCi specific activity 6.7 Ci/mM (New England Nuclear, Boston, MA, USA), was added to each tube for eight hours before termination of the culture. The cultures were harvested after 72h of incubation. Isotope incorporation by harvested cell cultures was counted in a Beckman liquid scintillation espectrometer. The results are expressed as counts of radiation emission per minute (cpm) and defined as "blastogenic index" (BI) which is the ratio: cpm of stimulated tubes/cpm of control tubes. Based on the response of healthy controls, BI > 20 were considered to be positive.
Statistical analysis. The results from patients and control groups were analysed by Students t test.
Significant values are considered to occur at p < 0.05. Altered results were considered when exceeded ± 2 SD mean values of controls.
RESULTS
F r e q u e n t i n f e c t i o u s e p i s o d e s w e r e d e t e c t e d in 2 2 of t h e 3 0 c h i l d r e n with febrile s e i z u r e s
s t u d i e d . R e c u r r e n t u p p e r r e s p i r a t o r y i n f e c t i o n s w e r e o b s e r v e d in 17 p a t i e n t s , m o r e t h a n t w o e p i s o d e s
of p n e u m o n i a s in 8, u r i n a r y i n f e c t i o n s in 4 a n d m y c o t i c i n f e c t i o n o f t h e skin w a s p r e s e n t in 4
c h i l d r e n . P r i m a r y t u b e r c u l o s i s i n f e c t i o n w a s o b s e r v e d in o n e c h i l d after B C G v a c c i n e ( a t t e n u a t e d
a g e n t ) , r e q u i r i n g t r e a t m e n t with h y d r a z i d e . C l i n i c a l m a n i f e s t a t i o n w a s r e g i o n a l a x i l l a r l y m p h a d e n i t i s
a n d fever. A l s o , o n e c h i l d p r e s e n t e d flaccid p a r a l y s i s of t h e l o w e r e x t r e m i t i e s w i t h n o s e n s o r y loss,
a n d w i t h c o m p l e t e r e c o v e r y . O n l y 8 of 3 0 p a t i e n t s s t u d i e d d i d n o t p r e s e n t f r e q u e n t i n f e c t i o n s .
T a b l e 1 s h o w s t h e p e r c e n t a g e of total T c e l l s ( C D 3 + ) , h e l p e r i n d u c e r ( C D 4 + ) , c y t o t o x i c /
s u p p r e s s o r ( C D 8 + ) T-ccll s u b s e t s a n d t h e C D 4 : C D 8 r a t i o d e t e c t e d in p e r i p h e r a l b l o o d of p a t i e n t s
a n d h e a l t h y c o n t r o l s . A l t h o u g h t h e m e a n v a l u e s of t h e p e r c e n t a g e s of C D 3 + a n d C D 4 + c e l l s w e r e
c o m p a r a b l e to t h a t of t h e c o n t r o l s , a d e c r e a s e d p r o p o r t i o n o f t h e s e c e l l s w a s o b s e r v e d in 5 a n d 11
c h i l d r e n , r e s p e c t i v e l y . A s i g n i f i c a n t i n c r e a s e in p r o p o r t i o n of C D 8 + T c e l l s w a s d e t e c t e d in 6 4 % of
t h e p a t i e n t s , a n d a c o n s e q u e n t r e d u c t i o n in C D 4 : C D 8 r a t i o w a s o b s e r v e d in 6 0 % of t h e c h i l d r e n
w i t h f e b r i l e s e i z u r e s .
T h e l y m p h o c y t e p r o l i f e r a t i v e r e s p o n s e to P H A w a s i m p a i r e d in t h e p a t i e n t s w h e n c o m p a r e d
to t h e c o n t r o l g r o u p ( T a b l e 2 ) . T h i s d e p r e s s i o n of c e l l - m e d i a t e d i m m u n e r e s p o n s e w a s o b s e r v e d to
t h e s a m e e x t e n t w h e n t h e c e l l s of t h e p a t i e n t s w e r e c u l t i v a t e d in p r e s e n c e of h u m a n A B p l a s m a
( h o m o l o g o u s p l a s m a ) o r in p a t i e n t s p l a s m a ( a u t o l o g o u s p l a s m a ) . M o r e o v e r it w a s d e t e c t e d a p r e s e n c e
o f an i n h i b i t o r y a c t i v i t y o f t h e p a t i e n t s p l a s m a o n l y m p h o c y t e f u n c t i o n in 6 o u t 18 ( 3 3 % ) of t h e
p a t i e n t s as o b s e r v e d b y t h e a n a l y s i s of b l a s t o g e n i c i n d e x p r e s e n t e d in F i g u r e 1.
T h e i n h i b i t o r y effect of p a t i e n t s p l a s m a
o n l y m p h o c y t e p r o l i f e r a t i v e r e s p o n s e of c e l l s
o b t a i n e d from h e a l t h y c o n t r o l s s t i m u l a t e d with
P H A w a s o b s e r v e d by the i m p a i r e d r e s p o n s e of
t h e s e c e l l s . P o o l e d p l a s m a of 4 p a t i e n t s t h a t
p r e s e n t e d an inhibitory effect of their p l a s m a on
their o w n cells, also i n h i b i t e d the l y m p h o p r o l i
-f e r a t i v e r e s p o n s e o -f 4 h e a l t h y p e o p l e c e l l s
s t i m u l a t e d b y P H A . T h e level of the l y m p h o p r o
-l i f e r a t i v e i n h i b i t i o n w a s a b o u t 7 4 % w h e n the
p a t i e n t s p l a s m a w a s a d d e d to the culture (cpm
with A B p l a s m a = 2 9 , 1 5 9 . 3 7 ± 4 , 5 2 1 . 0 ; c p m with
p o o l e d p a t i e n t s p l a s m a = 7 , 6 7 8 . 2 5 ± 1,673.72).
I n t h e p r e s e n t s t u d y , t h e r e w a s n o
and therapy, a g e at the first febrile s e i z u r e , n u m b e r of s e i z u r e e p i s o d e s , or f r e q u e n c y of i n f e c t i o u s
d i s e a s e s .
DISCUSSION
T h i s s t u d y d e m o n s t r a t e d t h a t c h i l d r e n w i t h f e b r i l e s e i z u r e e p i s o d e s e x h i b i t e d a b n o r m a l i t i e s
in t h e c e l l - m e d i a t e d i m m u n e r e s p o n s e . O n e r e l e v a n t o b s e r v a t i o n is t h a t n o n e of t h e c h i l d r e n p r e s e n t e d
a b n o r m a l i t i e s in all p a r a m e t e r s s t u d i e d , b u t all of t h e m s h o w e d a l t e r e d r e s p o n s e s , t o at least o n e o r
m o r e of t h e tests e m p l o y e d to e v a l u a t e i m m u n o c o m p e t e n c e .
T h e l o w C D 4 : C D 8 r a t i o o b s e r v e d m a y h a v e b e e n r e l a t e d to t h e i n c r e a s e p r o p o r t i o n of C D 8 +
T c e l l s o b s e r v e d in 6 4 % o f t h e p a t i e n t s . E e g - O l o f s s o n et al.f i
d e s c r i b e d i m m u n o l o g i c a l a l t e r a t i o n s
in 2 4 a d u l t p a t i e n t s w i t h partial s e i z u r e s s u c h a s : l o w l e v e l s of I g A , a n d s m a l l p r o p o r t i o n s of C D 4 +
c e l l s a n d high p r o p o r t i o n s of C D 8 + c e l l s . It is i n t e r e s t i n g to n o t i c e t h a t 7 o u t of 2 4 p a t i e n t s h a d
f e b r i l e s e i z u r e s d u r i n g infancy. T h e s e a u t h o r s5
a l s o s t u d i e d 5 0 p a t i e n t s w i t h partial c o m p l e x a n d
a n d l o w C D 4 : C D 8 r a t i o . T h e y d i d n o t find a s s o c i a t i o n of t h e s e i m m u n e a l t e r a t i o n s w i t h t h e r a p y ,
a n d c o n s i d e r e d t h a t t h e s e t y p e of e p i l e p s y m i g h t b e a s s o c i a t e d w i t h a d e f i c i e n t g e n e t i c r e g u l a t i o n
t h a t a l s o affects t h e i m m u n e s y s t e m . T h u s , t h e v a r i a b l e i n t e n s i t y of t h e a l t e r a t i o n s in c e l l u l a r
i m m u n i t y o b s e r v e d in e p i l e p s y m a y b e a c c o u n t e d for b y h e r e d i t y w i t h t h e s a m e g e n e t i c d e t e r m i n a n t s
i n v o l v e d , b u t p e r h a p s in a m u l t i f a c t o r i a l m a n n e r5 .
T h e i m p o r t a n c e o f t h e g e n e t i c m e c h a n i s m s i n v o l v e d in e p i l e p s y h a s b e e n e m p h a s i z e d . T h e
p r e s e n c e of a family h i s t o r y of n o n f e b r i l e e p i l e p s y is a well k n o w n factor t h a t e n h a n c e s the p r o b a b i l i t y
of f u t u r e p r o g r e s s i o n to e p i l e p s y . In f e b r i l e s e i z u r e s t h e r e is a g e n e t i c p r e d i s p o s i t i o n , b u t t h e e x a c t
p a t t e r n of h e r e d i t y is u n k n o w n . If t h e p a r e n t s h a d a p r e v i o u s c h i l d w h o h a d f e b r i l e c o n v u l s i o n s , the
risk of a n o t h e r c h i l d to b e affected is o n e in f i v e2
. M o r e o v e r , a f a m i l y h i s t o r y of f e b r i l e s e i z u r e s a l s o
p l a y s a r o l e in t h e r i s k of r e c u r r e n c e1 7 .
T h e i m p a i r m e n t in l y m p h o c y t e p r o l i f e r a t i v e r e s p o n s e to P H A o b s e r v e d in t h e c h i l d r e n w i t h
f e b r i l e s e i z u r e s , s u g g e s t s a d e p r e s s i o n o f t h i s c e l l u l a r i m m u n e r e a c t i v i t y . B e s i d e s , t h e p l a s m a
i n h i b i t o r y factors d e t e c t e d in 3 3 % of t h e p a t i e n t s r e d u c e d T - l y m p h o c y t e p r o l i f e r a t i o n o f
patients-l y m p h o c y t e s a n d of patients-l y m p h o c y t e s f r o m h e a patients-l t h y c o n t r o patients-l s c u patients-l t u r e d w i t h t h e p patients-l a s m a of p a t i e n t s with
f e b r i l e s e i z u r e s , s u g g e s t i n g t h a t t h e s e f a c t o r s m i g h t i n h i b i t c e l l u l a r i m m u n i t y . In fact, 2 2 ( 7 3 % ) o f
t h e p a t i e n t s p r e s e n t e d f r e q u e n t i n f e c t i o u s e p i s o d e s , i n d i c a t i n g s u s c e p t i b i l i t y to r e c u r r e n c e a n d
r e s i s t a n c e to t r e a t m e n t , as o b s e r v e d in m y c o t i c s k i n i n f e c t i o n s . T h e s e r e s u l t s s u g g e s t that t h e r e
m a y b e a n a s s o c i a t i o n b e t w e e n c e l l u l a r i m m u n e d y s f u n c t i o n a n d t h e p a t h o p h y s i o l o g y of febrile s e i z u r e s . If this is c o n f i r m e d , t h e t r e a t m e n t of i n f e c t i o n s in c h i l d r e n w i t h febrile s e i z u r e e p i s o d e s
s h o u l d b e r e - e v a l u a t e d . C a r e s h o u l d b e t a k e n to p r e v e n t infection b y s p e c i f i c t h e r a p e u t i c o r p r e v e n t i v e
m e a s u r e s a n d w i t h i m m u n i z a t i o n m a i n l y w i t h a t t e n u a t e d m i c r o o r g a n i s m s s u c h as p o l i o a n d m e a s l e s
v i r u s . T h e o c c u r r e n c e of p a r a l y s i s i n d u c e d b y the v a c c i n a l p o l i o v i r u s in i m m u n o d e f i c i e n t c h i l d r e n
h a s b e e n r e p o r t e d1 " '1 9
'2 4
. W e o b s e r v e d a p r i m a r y t u b e r c u l o s i s i n f e c t i o n after B C G v a c c i n a t i o n in
o n e c h i l d w i t h f e b r i l e s e i z u r e s , p r e s e n t i n g s u p p r e s s i o n o f c e l l - m e d i a t e d i m m u n e f u n c t i o n . T h u s ,
i m m u n o t h e r a p y c o u l d b e e m p l o y e d as an a d j u v a n t m e a s u r e in t r e a t m e n t o f f e b r i l e s e i z u r e s . F u r t h e r
r e s e a r c h e s m a y lead to c o n c l u d e for a t r u e s y n d r o m e of c e l l - m e d i a t e d i m m u n e d y s f u n c t i o n a n d
f e b r i l e s e i z u r e s , o r to an i n c i d e n t a l a n d i n t r i g u i n g f i n d i n g of o u r s t u d y .
S o m e o b s e r v a t i o n s h a v e s u g g e s t e d a c o n t r o l of t h e i m m u n e r e s p o n s e by t h e c e n t r a l n e r v o u s
s y s t e m . T h e i m m u n e s y s t e m r e c e i v e s s i g n a l s f r o m t h e b r a i n a n d n e u r o e n d o c r i n e s y s t e m via t h e
a u t o n o m i c n e r v o u s s y s t e m a n d h o r m o n e s a n d s e n d s i n f o r m a t i o n to t h e b r a i n , via c y t o k i n e s . T h e r e g u l a t o r y r e c i p r o c a l i n f l u e n c e s that e x i s t b e t w e e n t h e b r a i n a n d t h e i m m u n e s y s t e m a p p e a r to b e
n e c e s s a r y for c o o r d i n a t i o n of b e h a v i o r a l a n d p h y s i o l o g i c a l r e s p o n s e s to infection a n d i n f l a m m a t i o n4 .
S p e c i f i c r e c e p t o r s for m a n y n e u r o e n d o c r i n e a n d n e r v o u s s y s t e m m e d i a t i n g factors h a v e b e e n
i d e n t i f i e d in i m m u n o c o m p e t e n t c e l l s1 " '2 1
a n d t h e s e f a c t o r s m a y a l s o m o d u l a t e t h e i m m u n e r e s p o n s e
i n d i r e c t l y by a f f e c t i n g t h e p r o d u c t i o n o r a c t i v i t y of l y m p h o k i n e s a n d cytokines'-'-1 5
. In a d d i t i o n , t h e
effects of c o n d i t i o n i n g p r o c e d u r e s o r stress o n t h e s u p p r e s s i o n of h u m o r a l a n d c e l l - m e d i a t e d i m m u n e
r e s p o n s e h a v e b e e n c o n f i r m e d in r e c e n t s t u d i e s ' .
If t h e r e c i p r o c a l i n f l u e n c e s b e t w e e n c e n t r a l n e r v o u s s y s t e m a n d i m m u n e r e s p o n s e a r c
c o n f i r m e d , t h e r e l a t i o n s h i p b e t w e e n e p i l e p t i c d i s e a s e s a n d i m m u n o l o g i c a l d y s f u n c t i o n s m a y b e
b e t t e r u n d e r s t o o d , l e a d i n g to i m p o r t a n t c h a n g e s in t h e m a n a g e m e n t of e p i l e p s y .
Acknowledgements - The authors are grateful to Mis Maria Antonia M. Palma for technical assistance and to Mrs Sonia Maria Faraldo for typing the manuscript.
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