199
Epilepsy Res., 11(1!992) 199-203 Elsevier EPIRES 00465
Cognitive effects of oxcarbazepine and phenytoin monotherapy newly diagnosed epilepsy: one year follow-up
in
M. Aikiti”, R. KAvi%nenb, J. Siveniusb, T. Halonenb and P.J. Riekkinenb ‘Department of Neurology, Kuopio Universiv Hospital and bDepamnent of Neurology, University of Kuopio, Kuopio (Finland) (Received 20 September 1991; revision received 17 January 1992; accepted 20 January 1992) Key words: Cognition; Antiepileptic drugs; Oxcarbazepine; Phenytoin
We evaluated the effect of initial oxcarbaxepine (OXC) monotherapy on memory, attention and simple psychomotor speed in 14 patients; 15 patients with initial phenytoin (PHT) monotherapy served as reference patients. Neuropsychological assessments were performed before starting the treatment and after 6 and 12 months follow-up with steady-state drug treatment. Differential cognitive effects of OXC and PHT were not apparent in our study. As the efficacy of present antiepileptic drugs in adult epilepsy is analogous, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in both OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either antiepileptic over the other.
INTRODUCTION As dose-related neurotoxic side effects such as sedation and impaired cognition are common with all antiepileptic drugs (AEDs) available todayr3*16, the need for careful neuropsychological evaluation is emphasized in the development of new AEDs. Oxcarbazepine (OXC) is the lO-keto derivate of the well-known and widely used AED carbamazepine (CBZ). More than 600 patients with epilepsy have been studied in clinical trials with OXC? and controlled studies comparing OXC with CBZ have Correspondence to: Marja Ailtia, Department of Neurology, Kuopio University Hospital, P.O. Box 1777, SF-70211 Kuopio, Finland.
indicated OXC to be as effective as CBZ but with fewer side effects1*5.9. In a 1Zmonth follow-up study of 41 patients comparing OXC and CBZ, no deterioration of memory and attention was observed’, and in a 4-month follow-up study comparing effects of CBZ, OXC and sodium-valproate only minimal effect on cognition was found”. Phenytoin (PHT) is an effective AED, the use of which in healthy volunteers and in epileptic patients has been associated with a decline in cognitive functions, especially memory, concentration and motor speed4*“. Recent studies have, however, suggested subtle differential cognitive effects of AEDs, including PHT3s3’2. This randomized double-blind study compared the effects of OXC monotherapy with PHT on memory, attention and simple psychomotor speed
0920-1211/92/$05.00 @ 1992 Elsevier Science Publishers B.V. All rights reserved
200 during a 1 year follow-up in newly diagnosed patients with epilepsy. METHODS
Subjects
Thirty-seven adult patients with newly diagnosed epilepsy and normal intellectual capacity initially entered the study. All patients had had at least two epileptic seizures during the last 2 years or one seizure and epileptiform EEG. Patients with progressive neurological disorders, severe cognitive defects, alcohol or drug abuse, severe psychiatric problems or other severe medical disorders were excluded. The study followed a double-blind design with the patients randomly allocated to treatment with either OXC (n = 19) or PI-IT (n = 18). At subsequent visits the daily dose was individually increased until serum concentrations were 30-120 pmol/l for lo-hydroxy-OXC and 40-80 pmol/l for PI-IT. PHT levels in serum were determined by enzyme immunoassay (EMIT, Syva, Palo Alto, CA, USA) and the levels of the biologically active metabolite of OXC, IO-hydroxy-OXC, by high performance liquid chromatography’. The titration phase varied from 4 to 8 weeks. After the titration phase, the patients were followed at the maintenance dose for 12 months. In the OXC group nine patients were seizure-free and five had adequate seizure control (1-5 partial or generalized seizures during the 1Zmonth maintenance phase), and in the PHT group 11 patients were seizurefree and four had adequate seizure control. Patients were withdrawn from the study in case of inadequate seizure control or intolerable side effects. The reasons for treatment failure were inadequate seizure control (n = l), non-compliance (n = 3) and allergic skin reaction (n = 1) in the OXC group and non-compliance (n = l), allergic skin reaction (n = 1) and hirsutism (n = 1) in the PI-IT group. Thus 29 patients completed the entire 12month follow-up, 14 patients in the OXC group and 15 patients in the PI-IT group. Neuropsychological
Neuropsychological
evaluation
assessment was performed
at baseline and after 6 and 12 months maintenance treatment. Six subtests of the Wechsler Adult Intelligence Scale (WAIS) were used as a measure of general intelligence at baseline. The tests used in the follow-up were selected to measure cognitive functioning in three major areas: verbal memory, sustained attention and simple psychomotor speed. Verbal learning and memory were assessed with the List Learning test. A list of 10 words was read 5 times and after each presentation, an immediate free recall of words was asked. The delayed recall of words was asked after a l-h delay filled with other tasks. The score was the sum of the immediately recalled words and the number of words recalled after delay. Sustained attention was measured with the Stroop test14 and the Trail Making test”. The Stroop test consisted of two versions, form I requiring naming the color of dots as fast as possible, and form II, in which the patient was asked to name the color of words printed in a color other than the one spelled by the letters. In part A of the Trail Making test the patient was asked to draw a line connecting series of randomly arranged numbers in numerical sequence, and in part B a line connecting numbers and letters in alternating sequence. In these two tests the time to complete the task was recorded. Simple psychomotor speed was assessed by a modified finger tapping test. Tapping rate, using the thumb, was determined over 10 s in three trials for each hand. Total tapping score was summed from the average score of each hand. Tests at baseline and at 12 months were the same, at 6 months parallel forms of the List Learning test and the Trail Making test were used. Statistical analysis
The data for continuous variables are expressed as means +- SD and for categorized variables as frequencies. The differences between the pretreatment group means were analyzed with Student’s two-tailed t-test for independent samples. Fisher’s exact test for independent samples was used for comparison of frequency differences. Neuropsychological follow-up data were aqalyzed by repeated measures multivariate analysis of var-
201
iance (MANOVA) with time as within-subjects factor and the drug as between-subjects factor. Pearson’s correlation test was used for comparison of correlations between neuropsychological scores and the AED serum concentrations. A P-value co.01 was considered statistically significant. RESULTS The number of patients succesfully treated for 12 months was similar in both groups. There were no differences in demographic and clinical characteristics between the patient groups completing the neuropsychological follow-up (Table I). The mean serum concentrations for lo-hydroxy-OXC were 35.8 f 10.2 pmol/l at 6 months and 42.6 f 12.2 pmol/l at 12 months and for PHT 57.1 + 18.3 pmol/l at 6 months and 61.3 f 18.9 pmol/l at 12 months. The baseline neuropsychological scores did not differ between the patient groups. Table II shows the neuropsychological test scores at baseline and after 6 and 12 months of treatment for both drug groups. MANOVA for repeated measures revealed no significant interaction effect of group and time in any neuropsychological measure. The
TABLE I Demographic and clinical characteristics of the patients treated with oxcarbazepine (OXC) and with phenytoin (PHT)
Age, years (*SD) Male/Female Organic etiology Seizure type partial only partial complex with secondary generalization primary generalized unclassified generalized IQ (&SD)
OXC (n=14)
PHT (n=I5)
33.6514.0 519 3
32.7k12.5 6l9 2
3 9 2 3 98.4f12.3
9 2 1 100.3+13.9
neuropsychological test scores did not correlate with AED serum concentrations. DISCUSSION Our study shows no significant differential cognitive effects between OXC and PHT in newly diagnosed epilepsy patients with adequate seizure
TABLE II The mean neuropsychological test scores (+ SD) at baseline and afier 6 and 12 months’ treatment in oxcarbazepine (OXC) and phenytoin (PHT) groups Test
Drug
Baseline
6 months
12 months
Memory Word list Immediate recall Delayed recall
oxc PI-IT oxc PI-IT
39.4 35.7 6.3 4.7
+ f f +
5.7 6.0 2.8 2.5
34.9 + 34.0 f 4.2f 4.5 +
5.8 7.7 3.8 2.5
39.2 37.5 5.9 5.6
+ + + +
4.0 5.0 2.7 2.7
oxc PHT oxc PI-IT oxc PHT oxc PI-IT oxc PI-IT
31.4f 32.3 + 63.6 + 54.3 f 41.0 + 43.5 + 113.3 + 107.7 + 89.0 + 87.0 +
7.1 8.8 25.0 15.6 12.7 10.6 55.6 39.1 10.9 13.2
30.3 + 30.0+ 57.6 f 54.1 + 41.0 + 41.7 + 135.4 f 111.7 f 87.2 + 86.8 f
5.6 8.9 18.2 17.0 17.0 13.4 94.8 50.8 14.1 11.8
28.7f 30.7 + 51.4 + 50.6 + 39.4 + 44.1 f 99.8 + 103.3 + 89.0 f 88.0 f
4.1 10.1 15.9 14.8 20.0 20.4 50.6 45.0 14.2 10.8
Attention Stroop I Stroop II Trail Making A Trail Making B Tapping
202 control during the first year of treatment. The follow-up time of 1 year should be sufficient to reveal the long-term effects of AED treatment. However, the mean neuropsychologi~l scores tended mostly to be the same or slightly better after 1 year of treatment. Recent studies have suggested only subtle differential cognitive effects of AEDs. In the VA cooperative study” no consistent differences between CBZ, PHT, phenobarbital (PB), and primidone were found in cognitive tests, only the total behavioral toxicity battery score revealed differences favoring CBZ. In a cross-over study of Meador et al.’ patients with epilepsy receiving CBZ, PB and PHT had comparable neuropsy~holo~~l performance in most measures. Dodrill and Troupin* compared CBZ with PHT and reported that CBZ had fewer adverse neuropsycholo~c~ effects. Recently they reanalyzed their data and after exciuding subjects with high PHT serum levels the significance of differences between CBZ and PI-IT disappeared3. Our results are in agreement with these studies and also give support to the conclusion that the adverse cognitive effects related to PI-IT do not overweigh those related to other AEDs. Scarce evidence for differential cognitive effects of OXC and PHT does not prove that these AEDs do not affect cognitive functions. The improvement in the test scores was only slight and wi~out a group of normal controls tested at the same time intervals, it is impossible to estimate the amount of improvement that would be gained via normal retest effects (e.g., familiarity with the test situation and practice effect). It is thus possible that the practice effect was not present to a normal extent in the patients of our study. As previously suggested, lack of a practice effect may be the first indicator of an AED effect on cognition”. It is also
REFERENCES 1 Dam, M., Ekberg, R., Loyning, Y., Waltimo, 0. and Jakobsen, K., A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy, Epilepsy Res., 3 (1989) 70-76. 2 Dodrill, C.B. and Troupin, AS., Psychotropic effects of
possible that in adequately controlled, newly diagnosed epilepsy the adverse effects of AEDs are minimized, and also several of the neuropsychological tests may be insensitive to these subtle changes in cognitive functions. Apart from AEDs other variables such as the age at onset of epilepsy, etiology of epilepsy, seizure frequency, seizure type and the epileptic process itself influence cognitive functioning of epileptic patients. In this study drugs were assigned randomly under double-blind conditions to avoid selection bias. Since in newly diagnosed patients epilepsy is still at a stage of unknown evolution, a cross-over study design was not considered to be appropriate. The patient groups did not differ from each other in pretreatment demographic and clinical variables including IQ, and the patients served as their own controls during the follow-up. The patients had adequate seizure control during the treatment indicating that seizure effects could not have influenced the results. Similarly, the AED serum ~n~entrations did not correlate with the neuropsychological scores. In conclusion differential cognitive effects of OXC and PHT were not apparent in this study. As the efficacy of current AEDs in adult epilepsy is similar16, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in the OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either AED over the other. ACKNOWLEDGEMENT The authors would like to thank Ciba-Geigy for providing the medication.
carbamazepine in epilepsy: a double-blind comparison with phenytoin, ~euroiogy, 27 (1977) 1023-1028. 3 Dodrill, C.B. and Troupin, A.S., Neuropsychoiogical effects of carbamazepine and phenytoin: a reanalysis, Neurology, 41 (1991) 141-143. 4 Duncan, J.S., Shorvon, S.D. and Trimbie, M.R., Effects of removal of phenytoin, carbamaxepine and valproate on cognitive function, Epilepsiu, 31 (1990) 584-591.
203
5 Houtkooper, M.A., Lammertsma, A., Meyer, J.W.A., Goedhart, D.M., Meinardi, H., van Oorschot, C.A.E.H., Blom, G.F., Hbppener, R.J.E.A. andHulsman, J.A.R.J., Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine?, Epilepsia, 28 (1987) 693-698. 6 Klosterskov-Jensen, P., Oxcarbazepine, 18th International Epifepsy Congress, New Delhi, 1989 (abstract). 7 Laaksonen, R., Kaimola, K., Grahn-Terlvainen, E. and Waltimo, O., A controlled trial of the effects of carbamazepine and oxcarbazepine on memory and attention, 16th Znternational Epilepsy Congress, Hamburg, 1985 (abstract). 8 Meador, K.J., Loring, D.W., Huh, K., Gallagher, B.B. and King, D. W., Comparative cognitive effects of anticonvulsants, Neurology, 40 (1990) 391-394. 9 Reinikainen, J.K., Kerlnen, T., Halonen, T., Komulainen, H. and Riekkinen, P.J., Comparison of oxcarbazepine and carbamazepine: a double-blind study, Epilepsy Res., 1 (1987) 284-298. 10 Reitan, R.M., Validity of the Trail Making test as an indicator of organic brain damage, Percept. Motor Skills, 8 (1958) 271-276.
11 Sabers, A., The effect of carbamazepine, sodium-valproate and oxcarbazepine on neurological and neuropsychological functions in patients with epilepsy, Acta Neurol. &and., H82 (1990) 80. 12 Smith, D.B., Anticonvulsants, seizures and performance: the Veterans Administration experience. In: M.R. Trimble and E.H. Reynolds (Eds.), Epilepsy, Behaviourand Cognitive Function, John Wiley & Sons, Chichester, 1988, pp. 67-78. 13 Smith, D.B., Cognitive effects of antiepileptic drugs. In: D.B. Smith, D. Treiman and M.R. Trimble (Eds.), Neurobehavioral Problems in Epilepsy, Advances in Neurology, Vol. 55, Raven Press, New York, NY 1991, pp. 197-212. 14 Stroop, J.R., Studies of interference in serial verbal reactions, /. Exp. Psycho/., 18 (1935) 643. 15 Thompson, P., Huppert, F.A. and Trimble, M., Phenytoin and cognitive function: effects on normal volunteers and implications for epilepsy, Br. 1. Clin. Psycho/., 20 (1981) 155-162. 16 Treiman, D.M., Efficacy and safety of antiepileptic drugs: a review of controlled trials, Epilepsia, 28 Suppl. 3 (1987) l-8.
Epilepsy Res., 11(1!992) 199-203 Elsevier EPIRES 00465
Cognitive effects of oxcarbazepine and phenytoin monotherapy newly diagnosed epilepsy: one year follow-up
in
M. Aikiti”, R. KAvi%nenb, J. Siveniusb, T. Halonenb and P.J. Riekkinenb ‘Department of Neurology, Kuopio Universiv Hospital and bDepamnent of Neurology, University of Kuopio, Kuopio (Finland) (Received 20 September 1991; revision received 17 January 1992; accepted 20 January 1992) Key words: Cognition; Antiepileptic drugs; Oxcarbazepine; Phenytoin
We evaluated the effect of initial oxcarbaxepine (OXC) monotherapy on memory, attention and simple psychomotor speed in 14 patients; 15 patients with initial phenytoin (PHT) monotherapy served as reference patients. Neuropsychological assessments were performed before starting the treatment and after 6 and 12 months follow-up with steady-state drug treatment. Differential cognitive effects of OXC and PHT were not apparent in our study. As the efficacy of present antiepileptic drugs in adult epilepsy is analogous, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in both OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either antiepileptic over the other.
INTRODUCTION As dose-related neurotoxic side effects such as sedation and impaired cognition are common with all antiepileptic drugs (AEDs) available todayr3*16, the need for careful neuropsychological evaluation is emphasized in the development of new AEDs. Oxcarbazepine (OXC) is the lO-keto derivate of the well-known and widely used AED carbamazepine (CBZ). More than 600 patients with epilepsy have been studied in clinical trials with OXC? and controlled studies comparing OXC with CBZ have Correspondence to: Marja Ailtia, Department of Neurology, Kuopio University Hospital, P.O. Box 1777, SF-70211 Kuopio, Finland.
indicated OXC to be as effective as CBZ but with fewer side effects1*5.9. In a 1Zmonth follow-up study of 41 patients comparing OXC and CBZ, no deterioration of memory and attention was observed’, and in a 4-month follow-up study comparing effects of CBZ, OXC and sodium-valproate only minimal effect on cognition was found”. Phenytoin (PHT) is an effective AED, the use of which in healthy volunteers and in epileptic patients has been associated with a decline in cognitive functions, especially memory, concentration and motor speed4*“. Recent studies have, however, suggested subtle differential cognitive effects of AEDs, including PHT3s3’2. This randomized double-blind study compared the effects of OXC monotherapy with PHT on memory, attention and simple psychomotor speed
0920-1211/92/$05.00 @ 1992 Elsevier Science Publishers B.V. All rights reserved
200 during a 1 year follow-up in newly diagnosed patients with epilepsy. METHODS
Subjects
Thirty-seven adult patients with newly diagnosed epilepsy and normal intellectual capacity initially entered the study. All patients had had at least two epileptic seizures during the last 2 years or one seizure and epileptiform EEG. Patients with progressive neurological disorders, severe cognitive defects, alcohol or drug abuse, severe psychiatric problems or other severe medical disorders were excluded. The study followed a double-blind design with the patients randomly allocated to treatment with either OXC (n = 19) or PI-IT (n = 18). At subsequent visits the daily dose was individually increased until serum concentrations were 30-120 pmol/l for lo-hydroxy-OXC and 40-80 pmol/l for PI-IT. PHT levels in serum were determined by enzyme immunoassay (EMIT, Syva, Palo Alto, CA, USA) and the levels of the biologically active metabolite of OXC, IO-hydroxy-OXC, by high performance liquid chromatography’. The titration phase varied from 4 to 8 weeks. After the titration phase, the patients were followed at the maintenance dose for 12 months. In the OXC group nine patients were seizure-free and five had adequate seizure control (1-5 partial or generalized seizures during the 1Zmonth maintenance phase), and in the PHT group 11 patients were seizurefree and four had adequate seizure control. Patients were withdrawn from the study in case of inadequate seizure control or intolerable side effects. The reasons for treatment failure were inadequate seizure control (n = l), non-compliance (n = 3) and allergic skin reaction (n = 1) in the OXC group and non-compliance (n = l), allergic skin reaction (n = 1) and hirsutism (n = 1) in the PI-IT group. Thus 29 patients completed the entire 12month follow-up, 14 patients in the OXC group and 15 patients in the PI-IT group. Neuropsychological
Neuropsychological
evaluation
assessment was performed
at baseline and after 6 and 12 months maintenance treatment. Six subtests of the Wechsler Adult Intelligence Scale (WAIS) were used as a measure of general intelligence at baseline. The tests used in the follow-up were selected to measure cognitive functioning in three major areas: verbal memory, sustained attention and simple psychomotor speed. Verbal learning and memory were assessed with the List Learning test. A list of 10 words was read 5 times and after each presentation, an immediate free recall of words was asked. The delayed recall of words was asked after a l-h delay filled with other tasks. The score was the sum of the immediately recalled words and the number of words recalled after delay. Sustained attention was measured with the Stroop test14 and the Trail Making test”. The Stroop test consisted of two versions, form I requiring naming the color of dots as fast as possible, and form II, in which the patient was asked to name the color of words printed in a color other than the one spelled by the letters. In part A of the Trail Making test the patient was asked to draw a line connecting series of randomly arranged numbers in numerical sequence, and in part B a line connecting numbers and letters in alternating sequence. In these two tests the time to complete the task was recorded. Simple psychomotor speed was assessed by a modified finger tapping test. Tapping rate, using the thumb, was determined over 10 s in three trials for each hand. Total tapping score was summed from the average score of each hand. Tests at baseline and at 12 months were the same, at 6 months parallel forms of the List Learning test and the Trail Making test were used. Statistical analysis
The data for continuous variables are expressed as means +- SD and for categorized variables as frequencies. The differences between the pretreatment group means were analyzed with Student’s two-tailed t-test for independent samples. Fisher’s exact test for independent samples was used for comparison of frequency differences. Neuropsychological follow-up data were aqalyzed by repeated measures multivariate analysis of var-
201
iance (MANOVA) with time as within-subjects factor and the drug as between-subjects factor. Pearson’s correlation test was used for comparison of correlations between neuropsychological scores and the AED serum concentrations. A P-value co.01 was considered statistically significant. RESULTS The number of patients succesfully treated for 12 months was similar in both groups. There were no differences in demographic and clinical characteristics between the patient groups completing the neuropsychological follow-up (Table I). The mean serum concentrations for lo-hydroxy-OXC were 35.8 f 10.2 pmol/l at 6 months and 42.6 f 12.2 pmol/l at 12 months and for PHT 57.1 + 18.3 pmol/l at 6 months and 61.3 f 18.9 pmol/l at 12 months. The baseline neuropsychological scores did not differ between the patient groups. Table II shows the neuropsychological test scores at baseline and after 6 and 12 months of treatment for both drug groups. MANOVA for repeated measures revealed no significant interaction effect of group and time in any neuropsychological measure. The
TABLE I Demographic and clinical characteristics of the patients treated with oxcarbazepine (OXC) and with phenytoin (PHT)
Age, years (*SD) Male/Female Organic etiology Seizure type partial only partial complex with secondary generalization primary generalized unclassified generalized IQ (&SD)
OXC (n=14)
PHT (n=I5)
33.6514.0 519 3
32.7k12.5 6l9 2
3 9 2 3 98.4f12.3
9 2 1 100.3+13.9
neuropsychological test scores did not correlate with AED serum concentrations. DISCUSSION Our study shows no significant differential cognitive effects between OXC and PHT in newly diagnosed epilepsy patients with adequate seizure
TABLE II The mean neuropsychological test scores (+ SD) at baseline and afier 6 and 12 months’ treatment in oxcarbazepine (OXC) and phenytoin (PHT) groups Test
Drug
Baseline
6 months
12 months
Memory Word list Immediate recall Delayed recall
oxc PI-IT oxc PI-IT
39.4 35.7 6.3 4.7
+ f f +
5.7 6.0 2.8 2.5
34.9 + 34.0 f 4.2f 4.5 +
5.8 7.7 3.8 2.5
39.2 37.5 5.9 5.6
+ + + +
4.0 5.0 2.7 2.7
oxc PHT oxc PI-IT oxc PHT oxc PI-IT oxc PI-IT
31.4f 32.3 + 63.6 + 54.3 f 41.0 + 43.5 + 113.3 + 107.7 + 89.0 + 87.0 +
7.1 8.8 25.0 15.6 12.7 10.6 55.6 39.1 10.9 13.2
30.3 + 30.0+ 57.6 f 54.1 + 41.0 + 41.7 + 135.4 f 111.7 f 87.2 + 86.8 f
5.6 8.9 18.2 17.0 17.0 13.4 94.8 50.8 14.1 11.8
28.7f 30.7 + 51.4 + 50.6 + 39.4 + 44.1 f 99.8 + 103.3 + 89.0 f 88.0 f
4.1 10.1 15.9 14.8 20.0 20.4 50.6 45.0 14.2 10.8
Attention Stroop I Stroop II Trail Making A Trail Making B Tapping
202 control during the first year of treatment. The follow-up time of 1 year should be sufficient to reveal the long-term effects of AED treatment. However, the mean neuropsychologi~l scores tended mostly to be the same or slightly better after 1 year of treatment. Recent studies have suggested only subtle differential cognitive effects of AEDs. In the VA cooperative study” no consistent differences between CBZ, PHT, phenobarbital (PB), and primidone were found in cognitive tests, only the total behavioral toxicity battery score revealed differences favoring CBZ. In a cross-over study of Meador et al.’ patients with epilepsy receiving CBZ, PB and PHT had comparable neuropsy~holo~~l performance in most measures. Dodrill and Troupin* compared CBZ with PHT and reported that CBZ had fewer adverse neuropsycholo~c~ effects. Recently they reanalyzed their data and after exciuding subjects with high PHT serum levels the significance of differences between CBZ and PI-IT disappeared3. Our results are in agreement with these studies and also give support to the conclusion that the adverse cognitive effects related to PI-IT do not overweigh those related to other AEDs. Scarce evidence for differential cognitive effects of OXC and PHT does not prove that these AEDs do not affect cognitive functions. The improvement in the test scores was only slight and wi~out a group of normal controls tested at the same time intervals, it is impossible to estimate the amount of improvement that would be gained via normal retest effects (e.g., familiarity with the test situation and practice effect). It is thus possible that the practice effect was not present to a normal extent in the patients of our study. As previously suggested, lack of a practice effect may be the first indicator of an AED effect on cognition”. It is also
REFERENCES 1 Dam, M., Ekberg, R., Loyning, Y., Waltimo, 0. and Jakobsen, K., A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy, Epilepsy Res., 3 (1989) 70-76. 2 Dodrill, C.B. and Troupin, AS., Psychotropic effects of
possible that in adequately controlled, newly diagnosed epilepsy the adverse effects of AEDs are minimized, and also several of the neuropsychological tests may be insensitive to these subtle changes in cognitive functions. Apart from AEDs other variables such as the age at onset of epilepsy, etiology of epilepsy, seizure frequency, seizure type and the epileptic process itself influence cognitive functioning of epileptic patients. In this study drugs were assigned randomly under double-blind conditions to avoid selection bias. Since in newly diagnosed patients epilepsy is still at a stage of unknown evolution, a cross-over study design was not considered to be appropriate. The patient groups did not differ from each other in pretreatment demographic and clinical variables including IQ, and the patients served as their own controls during the follow-up. The patients had adequate seizure control during the treatment indicating that seizure effects could not have influenced the results. Similarly, the AED serum ~n~entrations did not correlate with the neuropsychological scores. In conclusion differential cognitive effects of OXC and PHT were not apparent in this study. As the efficacy of current AEDs in adult epilepsy is similar16, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in the OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either AED over the other. ACKNOWLEDGEMENT The authors would like to thank Ciba-Geigy for providing the medication.
carbamazepine in epilepsy: a double-blind comparison with phenytoin, ~euroiogy, 27 (1977) 1023-1028. 3 Dodrill, C.B. and Troupin, A.S., Neuropsychoiogical effects of carbamazepine and phenytoin: a reanalysis, Neurology, 41 (1991) 141-143. 4 Duncan, J.S., Shorvon, S.D. and Trimbie, M.R., Effects of removal of phenytoin, carbamaxepine and valproate on cognitive function, Epilepsiu, 31 (1990) 584-591.
203
5 Houtkooper, M.A., Lammertsma, A., Meyer, J.W.A., Goedhart, D.M., Meinardi, H., van Oorschot, C.A.E.H., Blom, G.F., Hbppener, R.J.E.A. andHulsman, J.A.R.J., Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine?, Epilepsia, 28 (1987) 693-698. 6 Klosterskov-Jensen, P., Oxcarbazepine, 18th International Epifepsy Congress, New Delhi, 1989 (abstract). 7 Laaksonen, R., Kaimola, K., Grahn-Terlvainen, E. and Waltimo, O., A controlled trial of the effects of carbamazepine and oxcarbazepine on memory and attention, 16th Znternational Epilepsy Congress, Hamburg, 1985 (abstract). 8 Meador, K.J., Loring, D.W., Huh, K., Gallagher, B.B. and King, D. W., Comparative cognitive effects of anticonvulsants, Neurology, 40 (1990) 391-394. 9 Reinikainen, J.K., Kerlnen, T., Halonen, T., Komulainen, H. and Riekkinen, P.J., Comparison of oxcarbazepine and carbamazepine: a double-blind study, Epilepsy Res., 1 (1987) 284-298. 10 Reitan, R.M., Validity of the Trail Making test as an indicator of organic brain damage, Percept. Motor Skills, 8 (1958) 271-276.
11 Sabers, A., The effect of carbamazepine, sodium-valproate and oxcarbazepine on neurological and neuropsychological functions in patients with epilepsy, Acta Neurol. &and., H82 (1990) 80. 12 Smith, D.B., Anticonvulsants, seizures and performance: the Veterans Administration experience. In: M.R. Trimble and E.H. Reynolds (Eds.), Epilepsy, Behaviourand Cognitive Function, John Wiley & Sons, Chichester, 1988, pp. 67-78. 13 Smith, D.B., Cognitive effects of antiepileptic drugs. In: D.B. Smith, D. Treiman and M.R. Trimble (Eds.), Neurobehavioral Problems in Epilepsy, Advances in Neurology, Vol. 55, Raven Press, New York, NY 1991, pp. 197-212. 14 Stroop, J.R., Studies of interference in serial verbal reactions, /. Exp. Psycho/., 18 (1935) 643. 15 Thompson, P., Huppert, F.A. and Trimble, M., Phenytoin and cognitive function: effects on normal volunteers and implications for epilepsy, Br. 1. Clin. Psycho/., 20 (1981) 155-162. 16 Treiman, D.M., Efficacy and safety of antiepileptic drugs: a review of controlled trials, Epilepsia, 28 Suppl. 3 (1987) l-8.
