COGNITIVE FUNCTIONS, EPILEPTIC SYNDROMES
AND ANTIEPILEPTIC DRUGS
PAULO R. M. BITTENCOURT * — MARIA JOANA MADER ** MONICA M. BIGARELLA ** — MARIBEL P. DÓRO ** — ANA M. GORZ *
TANIA M. MARC OUR AKIS *** — ZULMA 8. FERREIRA ***
S U M M A R Y — C o g n i t i v e f u n c t i o n o f p a t i e n t s o n m o n o t h e r a p y s p e c i f i c f o r t h e i r e p i l e p t i c s y n d r o m e h a s b e e n s t u d i e d i n f r e q u e n t l y . W e e v a l u a t e d 7 p a t i e n t s w i t h s y m p t o m a t i c l o c a l i s e d e p i l e p s i e s ( S E L ) o n p h e n y t o i n a g e d 3 0 ± 1 2 ( m e a n ± s t a n d a r d d e v i a t i o n ) y e a r s , 8 w i t h i d i o p a t h i c g e n e r a l i s e d e p i l e p s i e s o n s o d i u m v a l p r o a t e a g e d 1 8 ± 4 y e a r s , 1 6 w i t h S E L o n c a r b a m a z e -p i n e a g e d 2 8 ± 1 1 y e a r s , a n d 3 5 h e a l t h y c o n t r o l s a g e d 2 7 ± 1 1 y e a r s . A l l s u b j e c t s w e r e o f n o r m a l i n t e l l i g e n c e , e d u c a t e d a p p r o p r i a t e l y t o a g e , a n d l e d p r o d u c t i v e l i v e s i n t h e c o m m u n i t y . T w o o f t h e p a t i e n t s o n c a r b a m a z e p i n e a n d o n e o n v a l p r o a t e h a d l e s s t h a n f i v e p a r t i a l , a b s e n c e o r m y o c l o n i c s e i z u r e s m o n t h l y , t h e r e m a i n i n g w e r e c o n t r o l l e d . C a r b a m a z e p i n e s e r u m c o n c e n t r a t i o n s w e r e 1 2 ± 5 u g / m l , p h e n y t o i n w e r e 2 3 ± 7 , a n d v a l p r o a t e w e r e 6 2 ± 2 3 ( m e a n ± s d ) . T e s t s i n c l u d e d i m m e d i a t e r e c a l l a n d r e c o g n i t i o n f o r p i c t u r e s , S t r o o p t e s t , d e l a y e d r e c a l l a n d r e c o g n i t i o n o f p i c t u r e s . P a t i e n t s o n p h e n y t o i n a n d v a l p r o a t e p e r f o r m e d s i g n i f i c a n t l y w o r s e t h a n c o n t r o l s o n i m m e d i a t e r e c a l l , a n d p a t i e n t s o n c a r b a m a z e p i n e p e r f o r m e d s i g n i f i -c a n t l y w o r s e t h a n -c o n t r o l s i n S t r o o p t e s t ( p < 0 , 0 1 ) . T h e r e s u l t s i n d i -c a t e r e l a t i v e l y m i n o r e f f e c t s o f t h e e p i l e p t i c s y n d r o m e s a n d o f p h e n y t o i n , c a r b a m a z e p i n e a n d v a l p r o a t e o n c o g n i t i o n o f p a t i e n t s w i t h c o n t r o l l e d e p i l e p s y l e a d i n g p r o d u c t i v e l i v e s i n t h e c o m m u n i t y . W e c o n c l u d e t h a t t h e c o g n i t i v e d e f i c i t f o u n d i n c h r o n i c e p i l e p t i c p a t i e n t s o n p o l y t h e r a p e u t i c d r u g r e g i m e n m u s t b e m u l t i f a c t o r i a l , a n d t h a t f u t u r e s t u d i e s n e e d t o c o n t r o l f o r a l l p o s s i b l e v a r i a b l e s i n o r d e r t o a c h i e v e m e a n i n g u l r e s u l t s .
K E Y W O R D S : e p i l e p s y , c o g n i t i v e d i s o r d e r s , n e u r o p s y c h o l o g y , p h e n y t o i n , c a r b a m a z e -p i n e , s o d i u m v a l -p r o a t e .
Funções cognitiva*, síndromes epilépticas e drogas antiepilépticas
R E S U M O — F u n ç ã o c o g n i t i v a d e p l a c i e n t e s e m m o n o t e r a p i a e s p e c í f i c a p a r a s í n d r o m e e p i l é p t i c a t e m s i d o p o u c o a v a l i a d a . E s t u d a m o s : 7 p a c i e n t e s c o m e p i l e p s i a s l o c a l i z a d a s s i n t o m á t i c a s ( S E L ) u t i l i z a n d o f e n i t o í n a , c o m 3 0 ± 1 2 ( m é d i a ± d e s v i o p a d r ã o ) a n o s d e i d a d e ; 8 c o m e p i l e p s i a s g e n e r a l i z a d a s i d i o p á t i c a s u t i l i z a n d o v a l p r o a t o d e s ó d i o , c o m 1 8 ± 4 a n o s ; 1 6 c o m S E L u t i l i z a n d o c a r b a m a z e p i n a , c o m 2 8 ± 1 1 a n o s ; 3 5 c o n t r o l e s s a d i o s , c o m 2 7 ± 1 1 a n o s . T o d o s t i n h a m i n t e l i g ê n c i a n o r m a l , e d u c a ç ã o a p r o p r i a d a p a r a a i d a d e e v i d a s p r o d u t i v a s n a s o c i e -d a -d e . D o i s -d o s p a c i e n t e s u t i l i z a n -d o c a r b a m a z e p i n a e u m v a l p r o a t o -d e s ó -d i o t i n h a m m e n o s d e 5 c r i s e s p a r c i a i s , d e a u s ê n c i a o u m i o c l ô n i c a s a o m ê s . O s o u t r o s p a c i e n t e s t i n h a m c r i s e s c o n t r o l a d a s h á m a i s d e 6 m e s e s . A s c o n c e n t r a ç õ e s s é r i c a s d e c a r b a m a z e p i n a , f e n i t o í n a e v a l p r o a t o d e s ó d i o f o r a m 1 2 ± 5 , 2 3 ± 7 e 6 2 ± 2 3 u g / m l . O s t e s t e s i n c l u í r a m m e m ó r i a e r e c o -n h e c i m e -n t o i m e d i a t o e t a r d i o d e f i g u r a s e S t r o o p . P a c i e -n t e s d o g r u p o d e f e -n i t o í -n a e v a l p r o a t o t i v e r a m p e r f o r m a n c e p i o r q u e c o n t r o l e s e m m e m ó r i a i m e d i a t a ; o g r u p o d e c a r b a m a z e p i n a f o i p i o r q u e c o n t r o l e s n o t e s t e d e S t r o o p ( p < 0 . 0 1 ) . O s r e s u l t a d o s i n d i c a m e f e i t o s d i s c r e t o s d a s s í n d r o m e s e p i l é p t i c a s , d e f e n i t o í n a , c a r b a m a z e p i n a e v a l p r o a t o d e s ó d i o n a c o g n i ç ã o d e p a c i e n t e s c o m e p i l e p s i a e m i n e n t e m e n t e c o n t r o l a d a e v i d a p r o d u t i v a n a c o m u n i d a d e . O d é f i c i t d e p a c i e n t e s c o m e p i l e p s i a c r ô n i c a s o b r e g i m e s p o l i t e r a p ê u t i c o s d e v e s e r m u l t i f a t o r i a l . E s t u d o s f u t u r o s d e v e m c o n t r o l a r , e m s e u p l a n e j a m e n t o , f a t o r e s c a u s a i s p o s s í v e i s p a r a q u e s e u s r e s u l t a d o s s e j a m r e l e v a n t e s .
P A L A V R A S C H A V E : e p i l e p s i a , d e s o r d e n s c o g n i t i v a s , n e u r o p s i c o l o g i a , f e n i t o í n a , c a r b a -m a z e p i n a , v a l p r o a t o d e s ó d i o .
C l i n i c a l N e u r o l o g y ( * ) a n d C l i n i c a l P s y c h o l o g y ( * * ) U n i t s , H o s p i t a l N . S r a . d a s G r a ç a s , C u r i t i b a ; a n d N e u r o l o g y I n v e s t i g a t i o n C e n t e r ( * * * ) , U n i v e r s i t y o f S ã o P a u l o , S ã o P a u l o .
Dr. Paulo R. M. Bittencourt — Hospital Nossa Senhora das Graças Rua Alcides Munhoz 433 -80510 Curitiba PR - Brasil,
Funções cognitiva*, síndromes epilépticas e drogas antiepUépticas
R E S U M O — F u n ç ã o c o g n i t i v a d e p a c i e n t e s e m m o n o t e r a p i a e s p e c í f i c a p a r a s í n d r o m e e p i l é p t i c a t e m s i d o p o u c o a v a l i a d a . E s t u d a m o s : 7 p a c i e n t e s c o m e p i l e p s i a s l o c a l i z a d a s s i n t o m á t i c a s ( S E L ) u t i l i z a n d o f e n i t o í n a , c o m 3 0 ± 1 2 ( m é d i a ± d e s v i o p a d r ã o ) a n o s d e i d a d e ; 8 c o m e p i l e p s i a s g e n e r a l i z a d a s i d i o p á t i c a s u t i l i z a n d o v a l p r o a t o d e s ó d i o , c o m 1 8 ± 4 a n o s ; 1 6 c o m
S E L i u t i l i z a n d o c a r b a m a z e p i n a , c o m 2 8 ± 1 1 a n o s ; 3 5 c o n t r o l e s s a d i o s , c o m 2 7 ± 1 1 a n o s . T o d o s
t i n h a m i n t e l i g ê n c i a n o r m a l , e d u c a ç ã o a p r o p r i a d a p a r a a i d a d e e v i d a s p r o d u t i v a s n a s o c i e -d a -d e . D o i s -d o s p a c i e n t e s u t i l i z a n -d o c a r b a m a z e p i n a e u m v a l p r o a t o -d e s ó -d i o t i n h a m m e n o s d e 5 c r i s e s p a r c i a i s , d e a u s ê n c i a o u m i o c l ô n i c a s a o m ê s . O s o u t r o s p a c i e n t e s t i n h a m c r i s e s c o n t r o l a d a s h á m a i s d e 6 m e s e s . A s c o n c e n t r a ç õ e s s é r i c a s d e c a r b a m a z e p i n a , f e n i t o í n a e v a l p r o a t o d e s ó d i o f o r a m 1 2 ± 5 , 2 3 ± 7 e 6 2 ± 2 3 u g / m l . O s t e s t e ® i n c l u í r a m m e m ó r i a e r e c o -n h e c i m e -n t o i m e d i a t o e t a r d i o d e f i g u r a s e S t r o o p . P a c i e -n t e s d o g r u p o d e f e -n i t o í -n a e v a l p r o a t o t i v e r a m p e r f o r m a n c e p i o r q u e c o n t r o l e s e m m e m ó r i a i m e d i a t a ; o g r u p o d e c a r b a m a z e p i n a f o i p i o r q u e c o n t r o l e s n o t e s t e d e S t r o o p ( p < 0 . 0 1 ) . O s r e s u l t a d o s i n d i c a m e f e i t o s d i s c r e t o s d a s s í n d r o m e s e p i l é p t i c a s , d e f e n i t o í n a , c a r b a m a z e p i n a e v a l p r o a t o d e s ó d i o n a c o g n i ç ã o d e p a c i e n t e s c o m e p i l e p s i a e m i n e n t e m e n t e c o n t r o l a d a e v i d a p r o d u t i v a n a c o m u n i d a d e . O d é f i c i t d e p a c i e n t e s c o m e p i l e p s i a c r ô n i c a s o b r e g i m e s p o l i t e r a p ê u t i c o s d e v e s e r m u l t i f a t o r i a l . E s t u d o s f u t u r o s d e v e m c o n t r o l a r , e m s e u p l a n e j a m e n t o , f a t o r e s c a u s a i s p o s s í v e i s p a r a q u e s e u s r e s u l t a d o s s e j a m r e l e v a n t e s .
T h e various types of epileptic seizures, a number of antiepileptic drugs and factors in the previous history of patients with long-standing epilepsy have been associated with the genesis of the mental changes seen in patients with epilepsy 5.
In spite of a great number of studies that recently have attempted to clarify their relative role, it is as yet unclear whether epileptic patients have impairments that can be ascribed directly to one or more causative factors. Binnie et al.4
, have looked at the effect of seizure discharges on verbal and spatial memory tasks, without taking into account the drugs patients were taking. T h i s is just one example of the diffi-culties encountered when the variable to be assessed, in this case measurements of cognitive function, is subjected to the continuous or intermittent effects of a number if disparate pathophysiological mechanisms, such a s length of history of epilepsy, type of seizure, brain damage of various etiologies including the recently described cyto-toxicity related to N M D A and glutamate receptors 16 acute and chronic effects of drugs, among others 7,8.
In a previous s t u d y3
w e have demonstrated that patients with active sympto-matic localization related e p i l e p s i e s1 2
on therapeutic serum concentrations of pheno-barbitone used in monotherapy, had a generalized deficit of cognition when compared to healthy controls. W e concluded that the deficit could be related to phenobarbitone, to the past or present frequency of complex partial and generalized tonic clonic seizures, eventhough there w a s a difference in cultural and social background between patients and controls. In the present study w e have attempted to g o one step further, by evaluating in a prospective controlled manner a group of patients of superior economic and cultural status, with few if any seizures, with various epileptic syn-d r o m e s1 2
, well controlled on high «therapeutic» serum concentrations of phenytoin, carbamazepine and valproate.
M E T H O D S
Psychometric tests — The battery of quantitative measurements of cognitive function used in the study has been published and validated in epileptic and healthy subjects 3. It can b e carried out routinely and repeatedly o n outpatients of a general hospital 6,9, lasts 25 minutes, and consists of s i x different tests based on simple material. In the immediate recall test land in the immediate recognition test the number o f slides the subjects recall or identify correctly is the score. T h e Stroop test measures the difference in time between identifying simple colours land colours with contradictory visual and verbal identification. It is a test o f attention and concentration. After the Stroop test the recall and recognition procedures w e r e repeated.
Subjects — All subjects agreed to participate in the study after being fully informed about procedure and consequences, a s specified in the Declaration of Helsinki and in its ammendments. Patients were recruted personally b y their private neurologists ( P R M B or A M G ) , when the following criteria could be fulfilled: clear diagnosis o f one of the epileptic syndromes (Comission, 1985); clear history of seizure type and frequency for at least the past year (Comission, 1981); normal mental state and satisfactory social adaptation, as j u d g e d b y the clinician; complete or practically complete control of seizures for at least six months, i.e., only patients with seizures that did not disturb their social, educational or professional activities w e r e evaluated; stable nionotherapeutic drug regimens with phenytoin, valproate o r carbamazepine for longer than one year, with therapeutic serum concentrations as j u d g e d b y laboratory determinations and clinical status, i.e., patients could not have complaints suggestive o f antiepileptic drug toxicity. All patients had in their files detailed neurological, medical and psychiatric history, family history, various physical examinations, and complete neurological and medical investigations, including C T scan, routine and sleep BEG, but not M R I . The majority had been initially refered because of refractory epileptic seizures and had undergone major drug changes before becoming seizure-free. The popu-lation of controls consisted o f medical and nursing students o r staff, as well as of members of the patients' families, chosen to match age, sex and social and cultural characteristics of the patients. T h e psychologist in charge o f the cognitive battery was unaware of the nature of the subjects, and o f clinical details such as d r u g therapy, diagnosis, history of seizures.
found the Mann-Whitney U test was employed to test for differences between the groups of patients and controls, but not among the groups of patients.
R E S U L T S
Groups of 35 control and 31 epileptic subjects on monotherapy with phenytoin (7), valproate (8) or carbamazepine (16) were evaluated. Their demographic details and educa-tional level are shown in Table 1. The patients on phenytoin and carbamazepine had symptomatic epilepsies with localization, and the patients on sodium valproate had idiopathic generalised epilepsies (Commission, 1985). T h e differences among the groups with regard to age and educational level are related t o the ages of occurrence of the specific syndromes. All patients were well adapted t o productive life in the community, and the educational level of the patients is similar to that of the controls.
T h e mean monthly seizure frequency for each seizure type in the groups of patients on carbamazepine, phenytoin o r valproate is shown in Table 2. Although seven patients had complex partial and three had simple partial seizures in the group on carbamazepine, the monthly frequency was very l o w . One of the subjects on phenytoin had complex partial seizures, while in the group on valproate one patient had tonic-clonic, absence and myoclonic
T h e serum concentrations of valproate, carbamazepine and phenytoin are shown in Figure 1. T h e mean concentrations in the three groups are high and some subjects had concentrations above the usually accepted therapeutic range 22, in spite of the observation that none of the subjects was complaining of symptoms of acute or chronic toxicity.
COMMENTS
T h e results indicated that patients on sodium valproate because of idiopathic generalised epilepsies have a deficit of retention skills when compared to controls. It is impossible to ascertain whether this effect w a s due to the epileptic syndrome or to the drug itself. T h e finding of similar deficit in patients with symptomatic localised epilepsy on phenytoin appears to be specific for the drug, as it w a s not found in the carbamazepine-treated patients with the same syndrome.
T h e worse performance of the carbamazepine-treated patients on the Stroop test appeared to be related to the epileptic syndrome, in view of the similar perfor-mance of the phenytoin-treated patients, which did not reach statistical significance because of the small number of patients. T h e s e findings may indicate that sympto-matic localised epilepsy leads to a deficit of attention, but the possibility that both phenytoin and carbamazepine lead to this effect cannot be ruled out. T h e results of this study contrast with those obtained with the same experimental design and cognitive battery 3, in which patients with symptomatic localized epilepsy with frequent complex partial and tonic-clonic seizures, treated with therapeutic serum concentra-tions of phenobarbitone, displayed a generalized and severe impairment in all the tests used. T h e present results show minor differences a s compared to that study.
It would appear that patients with idiopathic generalized epilepsies, symptomatic loca-lized epilepsies or indetermined epilepsies, treated with high «therapeutic» serum concentrations of valproate, carbamazepine and phenytoin have very mild impairment of some cognitive skills. T h e pharmacological or syndromic specificity of these changes cannot be ascertained on the basis of the present or other studies p u b l i s h e d2
.
On the one hand patients with active epilepsy on phenobarbitone have severe cognitive deficits, on the other patients with inactive epilepsy have few if any deficits, in spite of high therapeutic concentrations of carbamazepine, valproate and phenytoin. These are individuals that achieve usual g o o d standards of middle class in the deve-loped south of Brasil, from the educational, social, professional and economic points of view. Another group, on phenobarbitone with uncontrolled epilepsy 3 achieved less in professional, educational and social measures. It would appear that frequent tonic-clonic and complex partial seizures, as well as treatment with phenobarbitone, are related to worse cognition and lower achievement . On the other hand, in subjects that had active disease for a period short enough not to lead to a drop in social, educational or professional skills, controlled epilepsy, valproate, carbamazepine or phenytoin had little1
effect on cognition and, apparently, on achievement. T h e s e findings are in contrast to experiments in healthy subjects that found effects of both valproate and phenytoin but not carbamazepine in a similar battery of tests of cogni-tive functions 29,31. T h e findings of Aman et a l .2
are of interest, as they concluded that high valproate levels in the blood stream or greater severity of epilepsy led to cognitive impairment.
Few of the many studies of cognition in epilepsy can be interpreted in a clear realistic manner. T h e studies McLeod et al.19 and Camfield et al.1
** related deficits in performance to use of phenobarbitone, but could not rule out the possibility that seizure frequency or type could influence their findings. T h e work of Cull, T h o m p s o n and Trimble 13,14,26-31 suffered from the very basic problem of experiments carried out either in healthy subjects with inappropriate serum concentrations of antiepileptic drugs for short periods of time, or in long-term residents of epilepsy centers with multiple handicaps from the physical, social and mental points of view. It is not surprising that even a decade after these experiments were started they have not yet achieved clear results 15,23,32 while clinicians in the front line see their patienets gra-duating from high school and entering university at the same rate as their patients with migraine, for example.
T h e cognitive deficit of people with multiple handicaps is very likely to oscillate enourmously from one period in time to the next, because of the many variables in concomitant operation. Unless all variables are controlled for, the results m a y have very little meaning indeed, or even produce statistical noise. Although elegant studies such as that of Aldenkamp and c o l l e a g u e s1
demonstrated that controlled release carba-mazepine had less cognitive side-effects during repeated measurements in the same day than usual carbamazepine, they did not specify what other drugs patients were on, and how these concentrations oscillated during the period of study. In one of the few studies that considered seizure types and frequencies, other methodological problems hindered definite conclusions 2 4
type and frequency needs to be evaluated more carefully 13.14,21,24,25. A recent double--blind, triple crossover study by Meador et a l .2 0
, using a comprehensive battery of behavioural tests in groups of patients with complex partial seizures on phenobar-bitone, phenytoin and carbamazepine, demonstrated that phenobarbitone produced the worst results, and failed to show differences between the two other drugs. T h e results of the present study and of that of Bigarella et al.s are in agreement with these findings.
Memory and verbal learning ability have been shown to be impaired in patients with complex partial seziures originated in the left but not right temporal lobes 18. Similarly, subclinical epileptiform discharges from the left temporal lobe have been shown to lead to transitory cognitive verbal impairment, while discharges from the right temporal lobe were related to similar but spatial cognitive changes 4. Galassi et a l .1
? reported improvement in a measure obtained form pooling of various neuropsy-chological tests, in patients withdrawn from phenytoin therapy because they had been free of seizures for a few years. Unfortunately, apparently only five subjects finished their very long-term study.
A criticism valid to the present study and to others in the field of cognition and epilepsy is the lack of clearly validated tests from the anatomical point of view. Until this is achieved it will be problematic to prove the specificity of drug or disease effects on the variables measured. Until it is demonstrated that a test corresponds to damage in a specific neuronal circuit, many confirmations of experimental findings, such as those on Stroop test, memory and retention reported here, will be necessary.
In conclusion, the present and other studies indicate that phenobarbitone, fre-quent tonic clonic or complex partial seizures, and perhaps neuronal damage asso-ciated with long-standing epilepsy have definite effects on cognition. Valproate, phe-nytoin and carbamazepine. even when used chronically with serum concentrations at the top of the so-called «therapeutic» range of serum concentrations have mild effects
on few tests.
Acknowledgement — T h e authors wish to thank Ms. M. G. Calderarl and Mrs. M. Simioni for secretarial assistance and helpful comments.
R E F E R E N C E S
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2. Aman MG, W e r r y JS, Paxton J W , T u r b o t t SH. Effects of sodium valproate on psycho-m o t o r perforpsycho-mance in children as a function of dose, fluctuation in concentration and diagnosis, Epilepsia 1987, 28:115-124.
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