Effects of Antiepileptic Drugs on Cognition

CONFERENCES
TOPIC: EPILEPSY

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Address for correspondence:
Prof. Albert P. Aldenkamp, Ph.D.
Head Department of Behavioral Science & Psychological Services
Professor of Neuropsychology. Epilepsy Centre Kempenhaeghe
P.O. Box: 61. NL-5590 A.B. Heeze
The Netherlands
telephone: + 31 40 22 79 234/233. telefax: + 31 22 60 426
e-mail: aldenkampB@kempenhaeghe.nl, aldenk@educ.uva.nl, aldenk@educ.uva.nl

Abstract

The cognitive effects of the most commonly used antiepileptic drugs (AEDs) are reviewed, discussing both the ´absolute effects´ (the effects compared to no-treatment) and the ´relative effects´ (the comparison of one AED with an other).
The cognitive profile per AED is given, based on a literature database, consisting of 1357 articles in peer-review journals. Available information on the newer AEDs is discussed as an addendum.
 
 

Resumen

Revisamos los efectos que sobre las funciones cognitivas producen los fármacos antiepilépticos (FAE) mas comunes, discutiendo tanto los "efectos absolutos" (efecto comparado sin tratamiento) y los "efectos relativos" (comparación de un FAE con otro). El perfil cognitivo descrito para cada FAE se basa en los datos acumulados en un base de datos de la literatura que consiste en 1357 artículos publicados previa revisión en revistas científicas. Además discutimos la información disponible acerca de los nuevos FAE.
 

Antiepileptic drug (AED) treatment may be accompanied by side-effects, the most important being the side-effects that develop and persist during long-term treatment (i.e. 'chronic side-effects'). A multitude of such chronic side-effects have been documented (Reynolds, 1975), but the most frequently reported are effects on the central nervous system. This paper reviews our knowledge about a specific subgroup of such CNS-related chronic side-effects of AED-treatment i.e. cognitive side-effects.

Although the severity of cognitive side-effects is considered to be mild to moderate for most of the AEDs, their impact may be substantial in some patients when critical functions are involved such as learning in children (Aldenkamp, 1995) or driving capacities in adults (often requiring milliseconds precision); or when functions are impaired that are already vulnerable, such as memory function in elderly. Moreover, as the cognitive side-effects represent the long-term outcome of AEDs, the effects may increase with prolonged therapy, which contributes to the impact on daily life functioning in refractory epilepsies (Committee on Drugs, 1985).
 

The interest in the cognitive side-effects of AED-treatment is of recent origin and the first studies are from the early 1970's (Ideström et al., 1972; Dodrill & Troupin, 1977), probably stimulated by the widening range of possibilities for drug treatment during that period.

In the period January 1970 through December 1998, 1357 articles on cognitive effects of AEDs were published in peer-reviewed journals. This database (Vermeulen & Aldenkamp, 1995) is used to give an overview of the effects per drug. We decided, however, to disregard some of the studies in this database, using the following criteria:

Studies that failed to reach acceptable levels of power (.80 according to the conventions proposed by Cohen, 1977), may lead to false negatives (i.e. unjustified rejecting the possibility of cognitive side-effects) and were not included in the overview. This is important in studies on cognitive effects of drugs, becuase of the complications, associated with conclusions drawn from 'negative findings' ('no significant differences'). In general, such 'non-significant' results tend to be regarded as disappointing, but research on cognitive side-effects is a case where actually non-significance is appreciated, for then the results might be interpreted as demonstrating the absence of harmful cognitive effects. This follows from the tendency to test cognitive effects in equivalence studies; hence, in evaluating whether a new drug is equivalent to an established drug with a suggested favourable cognitive profile. An important point to consider here, in drawing conclusions from no-effect results is, however, the statistical power of the study. That is, such conclusions only make sense if the study has a reasonable a priori chance (80% or better) of detecting a cognitive side-effect, when such a side-effect is actually there.

In some studies the description of methods and results arguably fell below currently accepted standards of scientific communication. We therefore only included studies that met the criteria of describing the design, number of subjects, outcome measures, and provided sufficient statistical detail to evaluate the power of the study and the validity of the results.

The use of volunteers has the advantage that factors such as seizure frequency and severity do not confound the interpretation of the results. Volunteers offer the best opportunity to study absolute cognitive effects of AEDs, i.e. effects as opposed to no treatment, which is rarely possible in patients with epilepsy. However, these studies also suffer from validity problems, the most important being that the period of drug exposure is mostly limited. There is evidence, that in most AEDs 'early' cognitive side-effects may develop, only during a short period, i.e. during the first few days or weeks of drug exposure. After this period habituation develops, possibly due to the development of so-called positive tolerance (Kulig & Meinardi, 1977). Although little is known about how tolerance to the cognitive effects of AEDs develops, a failure to take this factor into account may lead to false positives in the evaluation of cognitive side-effects of AEDs (Dodrill, 1992). This important point has to be taken into account in studies with healthy volunteers who are typically given AEDs during a few weeks at most, long term studies not being feasible. Our examination of the normal-volunteer cognitive studies revealed that the majority of these studies use fairly short periods of drug exposure, often no longer that 1 day. It was decided to ignore all claims from studies that used periods of drug exposure of one day or less.

Although polytherapy is the most common treatment in refractory epilepsies, it introduces critical complications in identifying the exact cause of observed cognitive changes. Interactions between antiepileptic drugs can alter therapeutic efficacy and thus, conceivably, cognitive functioning (Brown, 1994). Moreover polytherapy is typically given to patients suffering from refractory epilepsy, and the threat of a 'seizure confound' is thus always serious. 'Seizure confound' refers to a major validity concern: the failure to separate seizure effects from 'genuine' AED-effects. Typically, cognitive AED effects are studied in add-on studies, where a new drug is introduced into a polytherapy regime (e.g. McKee et al., 1994). In this type of study, the seizure confound is even stronger and the effects on cognitive tests are a potpourri of positive and negative seizure effects, AED-effects and drug-drug interactions that can never be disentangled. It is therefore impossible to use this type of study for inferences about cognitive side-effects of AEDs. In general it is found that add-on polytherapy studies underestimate the cognitive effects of AEDs as the positive cognitive effects of seizure control often camouflage cognitive side-effects of the drug.

We have first concentrated on the drugs that are commonly used in clinical practice: phenobarbitone, phenytoin, carbamazepine and valproate. With respect to these drugs three types of data are evaluated:

• a). Absolute drug effects, which are the effects of drug treatment against no-treatment (non-drugs) in the same subjects, which represents is the most valuable information.
• b). Relative drug effects, i.e. the comparison of the cognitive side-effects of a drug with the effects of another drug. Although this is relevant clinical information, this comparison does not rule out the possibility that two drugs are not different because they both impair cognitive function to the same extent.
• c). Information on dose-effects: the relationship with dose-increase or dose decrease.
Finally we will inspect the available data on the newer antiepileptic drugs: oxcarbazepine, lamotrigine, gabapentin, vigabatrin, tiagabine, topiramate, levetiracetam and rufinamide.

 
THE COGNITIVE EFFECTS OF COMMONLY USED DRUGS

Table 1. Absolute cognitive side-effects of established antiepileptic drugs
 

Type of AED	Type of impairment	N. subjects(e=epilepsy; nv=volunteers)
- phenobarbitone  MacLeod et al. 1978	short-term memory	19(e)
- phenytoin Smith & Lowrey, 1975 Thompson et al. 1980 Thompson et al. 1981 Meador et al. 1991 Meador et al. 1993	memory/mental speed memory  memory/attention/mental speed attention/mental speed impairment of memory	10(nv) 8(nv) 8(nv) 21(nv) 15(nv)
- carbamazepine Thompson et al. 1980 Meador et al. 1991 Meador et al. 1993 Aldenkamp et al. 1993	no impairment mental speed/attention  impairment of memory no impairment	8(nv) 21(nv) 15(nv) 56(e)
- valproate Thompson & Trimble, 1981 Craig & Tallis, 1994  Prevey et al., 1996 Aldenkamp et al., 1993	mental speed no impairment mild psychomotor slowing psychomotor slowing	10(nv) 12(e) 18(e) 17(e)


 

For phenobarbitone (PHB) only one study (MacLeod et al., 1978) is available (after applying our criteria) allowing the evaluation of absolute effects, i.e. the differences between PHB and a non-drug condition. This study shows serious memory impairment (short-term memory recall) in 19 patients with epilepsy.

For phenytoin (PHT) five studies are available (Smith & Lowrey, 1975; Thompson et al., 1980; 1981; Meador et al., 1991; 1993) comparing PHT with a non-drug condition. These studies all reveal PHT-induced cognitive impairment in the areas of attention, memory and especially mental speed. The magnitude of the reported effects is moderate to large. A caveat is, however, in order as all these studies were carried out in normal-volunteers, which opens the possibility that these effects represent short-term outcomes of the drug.

For carbamazepine (CBZ) there is no consistent report about absolute cognitive-effects. Two studies, one in normal-volunteers (Thompson et al., 1980) and one in patients with epilepsy (Aldenkamp et al., 1993) report 'no cognitive impairment' compared to a non-drug condition. This is challenged by the group by Meador and coworkers (Meador et al. 1991; 1993) that report mild impairments of memory, attention and mental speed, largely the areas that may also be affected by phenytoin.

For valproate (VPA) four studies (Thompson & Trimble, 1981; Craig & Tallis, 1994; Prevey et al., 1996) allow the interpretation of absolute effects and shows mild to moderate impairment of psychomotor and mental speed.
 
 

Table 2. Relative cognitive side-effects of antiepileptic drugs
 

Type of AED	Type of impairment	N. subjects  (e=epilepsy; nv=volunteers)
- phenobarbitone  Gallassi et al., 1992  Vining et al., 1987  Meador et al., 1990  Callandre et al., 1990	-memory/visual-motor (compared with CBZ & PHT) -impairment of intelligence (compared with VPA) -no differences with PHT/CBZ -impairment of intelligence (compared with VPA)	29(e) 21(e) 15(e) 32(e)
- phenytoin Gallassi et al., 1992 Meador et al., 1990/1991/1993 Forsythe et al., 1991	-intelligence and memory compared with CBZ -no differences with CBZ/PHB -no differences with VPA	29(e) 21(nv) 15(nv) 15(e) 20(e)
- carbamazepine Gallassi et al., 1992 Meador et al., 1990/1991/1993	-more favourable profile compared with PHT&PHB -no differences with PHT&PHB	29(e) 15(nv) 21(nv) 15(e)
- valproate Gallassi et al., 1992 Vining et al., 1987 Calandre et al., 1990 Forsythe et al., 1991	-visuomotor and memory compared with CBZ -higher intelligence compared with PHB -higher intelligence compared with PHB -no differences with PHT	29(e) 21(e) 32(e) 20(e)


 

For phenobarbitone, comparisons with other AEDs are available from four studies (Vining et al., 1987; Callandre et al., 1990; Meador et al., 1990; Gallassi et al., 1992), all with patients with epilepsy. One of these shows more impairment for PHB than for phenytoin (PHT) or carbamazepine (CBZ) on visuomotor and memory tests (Gallassi et al., 1992) and two other studies show convincing and clinically highly relevant impairments of intelligence scores after long-term PHB treatment in comparison with valproate (VPA) (Vining et al., 1987; Callandre et al., 1990). Only the study by Meador et al. (1990) does not show differences between PHB and PHT or CBZ.

For phenytoin the results of head-to-head comparisons are somewhat more confusing. Using a ingenious long-term treatment and withdrawal design Gallassi and coworkers (Gallassi et al., 1992) found more cognitive impairment than CBZ. On the other hand, no difference with CBZ, VPA and even with PHB are reported (Meador et al., 1990; 1991; 1993; Forsythe et al., 1991).

For carbamazepine, again we have to consider conflicting results of the Italian study by Gallassi and coworkers, showing a more favourable profile compared with PHT and PHB (Gallassi et al., 1992) and the USA-based study by Meador and coworkers (Meador et al. 1990; 1991; 1993) that showed no differences than PHT and PHB.

Finally, for valproate, the comparison with other drugs shows lower performance of memory and visuomotor function compared to CBZ (Gallassi et al., 1992) and a favourable profile compared to PHB on tests for intelligence (Vining et al., 1987; Calandre et al., 1990). One study does not show a difference with PHT (Forsythe et al., 1991).
 

Table 3. Dose-relation; cognitive side-effects of antiepileptic drugs
 

Type of AED	Type of impairment	N. subjects  (e=epilepsy; nv=volunteers)
- phenobarbitone  no studies	--	--
- phenytoin Stevens et al., 1974	no dose effects	107(nv)
- carbamazepine Aldenkamp et al., 1987     Amman et al., 1990 Aldenkamp et al., 1998	more variability at peak levels with conventional CBZ compared with a controlled-release formulation improvement at higher doses no differences between generic forms of CBZ	11(e)     50(e) 12(nv)
- valproate Amman et al., 1987 Read et al., 1998 Brouwer et al., 1992	no dose effects no dose effects no difference with controlled release formulation	46(e) 12(nv) 12(e)


 

The cognitive side-effects of antiepileptic drugs do not only develop at higher dose: there is indeed no significant correlation between dose and cognitive impairment for phenytoin (in the large cohort study of Stevens et al., 1974) and valproate (Amman et al., 1987; Read et al., 1998). This is in accordance with the finding that, generally, side-effects of VPA are not related to dose or serum level (Herranz et al., 1982). This also concurs with the absence of any differences between conventional and controlled-release formulations for VPA (Brouwer et al., 1992). Only for CBZ some effects of dose are reported, with improvement of cognitive function at higher dose (Amman et al., 1990) and with the use of controlled-release formulations (Aldenkamp et al., 1987). One study (Aldenkamp et al., 1998) evaluates the effects of switches between different generic formulations of CBZ revealing no large effects. No information is available for PHB.

No studies were available -after applying our methodological criteria- for clonazepam and clobazam, two drugs that are still commonly used in clinical practice. Clinical reports suggest the possibility of cognitive impairment for clonazepam, especially increase irritability and attentional disorders, whereas, clobazam seems to have a more favourable cognitive profile.

The relatively short period of introduction of most of the newer AEDs illustrates that we can not expect many cognitive studies with these AEDs that fulfil the aforementioned criteria. Most of the available data for these drugs were obtained in add-on polytherapy designs, the gold standard type of design to test the efficacy of a new drug in early clinical studies. It is remarkable that no normal-volunteer studies are available for any of these drugs. Nonetheless we may summarise the available information. Most of the information presented here is based on the exchange of data during the international workshop 'cognitive effects of the newer antiepileptic drugs', organized during the International Epilepsy Congress in Sydney, 1995 (Aldenkamp & Trimble, 1996).

For vigabatrin (VGB), the absence of cognitive side-effects (compared to the existing first-line drugs) is claimed, but the data come from only one centre: Riekinnen and coworkers in Finland (Riekinnen et al., 1990; Mervaala et al., 1989) and are not based on high powered studies. There are a few additional studies, that did, however, not pass our aforementioned criteria, mostly because they were carried out in polytherapy designs. In clinical practice the drugs does not seem to have a large difference with the cognitive profile of carbamazepine or valproate. Mood effects may occur, however (Aldenkamp et al., 1994), secondarily also affecting cognitive performance.

Anecdotal clinical information suggests no cognitive impairment for lamotrigine (LMT) and in some patients even improvement of performance is reported (Aldenkamp et al. 1997) which may be in line with the claimed psychotropic effect of the drug. There is however no empirical evidence from controlled cognitive studies to support this claim. Marciani et al. (1998) studied the cognitive effects of LMT in 11 patients in an uncontrolled study. There is also some anecdotal information in the report by Meador and Baker (1997). Finally the study by Martin et al. (1999) did not show cognitive effects at short term, but this was a low powered study. None of these studies are conclusive, though.

The claim of absence of cognitive effects in oxcarbazepine, (OXC) a compound related to carbamazepine, is based on two studies (Aikiae et al., 1992; Curran & Java, 1993). The latter study reports cognitive improvement (focused attention and speed) in 12 patients in comparison with a non-drug condition, but did not control for the beneficial cognitive effects of improved seizure control.

For tiagabine (TGB) a favourable cognitive profile is reported. Dodrill et al. (1997) showed no cognitive effects in monotherapy with TGB in low or high dose, but some evidence for mood effects in add-on treatment with TGB at higher dosing, possibly related to titration speed. In the polytherapy study by Kalviainen et al. (1996) no cognitive effects were found.

Gabapentin: (GBP) Leach et al. (1998) studied GBP in 21 patients in an add-on polytherapy study after 4 weeks of adjunctive therapy and found no change in psychomotor and memory tests. Drowsiness was more often found in higher dosing (2400 mg). Mortimore et al. (1998) did not find a difference between continued polytherapy or an add-on with gabapentin in measures of quality of life. Martin et al. (1999) used an acute dose and rapid titration in 6 volunteers and did not find cognitive effects of gabapentin. These studies do not show convincing evidence for cognitive effects of GBP but are not conclusive as they were performed in polytherapy designs that do not allow conclusion about a specific drug.

For topiramate (TPM) recent data are available. In the study by Martin et al. (1999), an acute dose of 200 mg TPM and rapid dose escalation to 400 mg in 4 weeks were used. Interestingly, this was very reminiscent of the dose escalation used in the initial randomized clinical trials of TPM, which was associated with somnolence, psychomotor slowing, speech disorders, and concentration and memory difficulties. Martin et al. showed neuropsychometric changes commensurate with these CNS effects. In a randomized controlled trial using dose escalations of 50 mg weekly Meador (1998) reported a much more limited effect of TPM on cognitive function. Out of a test battery of 23 variables, 4 variables measuring attention, vigilance, and word naming, revealed only mild to moderate changes. The sample size of the Meador study adds to its validity: 155 patients with epilepsy. In a recent study comparing TPM with valproate (Aldenkamp et al., 1998) 25mg increments per week were used. In this study, the preliminary analyses showed no difference between VPA and TPM on the major cognitive variables after 20 weeksí treatment. This demonstrates that TPM entails a risk for cognitive impairment that can be prevented using gradual titration.

For the drugs that are still in the experimental phase, we have information about rufinamide (CGP 33.101) showing improvement of cognitive function in lower dose (improvement on reaction-time tests) and a possibility of impairment of short-term memory at higher dose. The company did not yet release these data, although the study had an impressive sample size (> 200; Aldenkamp, 1996). For (UCB L059) levetiracetam, a nootropic effect is claimed. We only have data from a small pilot study that does not allow definite conclusions (Neijens et al., 1995).

• General conclusions:
 
 
• A systematic review on published empirical studies using the outlined criteria allows only reliable conclusions about established drugs, i.e. AEDs that are introduced for clinical use before the 1970's. Even for these drugs a disappointing number of studies pass criteria of design, methodology and statistical analysis that are in line with common scientific conventions (Cohen, 1977; Cook & Campbell, 1979). From a large database of 1357 papers, a rather small group of studies remained that potentially allow valid inferences about the cognitive effects of established AEDs. The most important complication is the evaluation of the cognitive effects of AEDs in polytherapy. For the newer drugs no reliable conclusions are possible.

 
• All established AEDs have reported absolute cognitive side-effects, i.e. all the investigated drugs have effects when compared to no treatment. These effects are definitely large for PHB and possibly larger for PHT than for CBZ or VPA. But even these last two drugs, that are generally considered to be drugs with a safe cognitive profile, have cognitive effects, mostly resulting in a mild general psychomotor slowing.

 
• The respective differences between the four investigated AEDs can be considered as small, with the exception of the cognitive effects of PHB that has positively a less favourable cognitive profile when compared to PHT, VPA and CBZ.

 
• Clinical anecdotal information thus far does not show large differences between the newer AEDs and the established drugs.

 
• Cognitive side-effect profile per antiepileptic drug:
 
 
• Phenobarbitone is the only AED with absolute effects that concern specific higher-order cognitive function: when compared with no treatment memory functions are affected. In long-term treatment even impairment or delay of psychological development is reported, leading to intellectual deterioration. No information is available on dose-effects.

 
• Phenytoin has a much milder impact on cognitive function than had hitherto suspected. When compared with no-treatment PHT induces attentional deficit and mental slowing but these are not marked different from the obtained effects in CBZ and VPA. No correlation with dose is found.

 
• Carbamazepine has similar absolute effects as reported for PHT and in most reports no differences have been found with the cognitive effects of VPA and PHT. There is some evidence that dose-effects may occur and that controlled-release formulations have a more favourable cognitive profile than conventional forms. No differences were found between different generic forms of CBZ.

 
• Valproate has mild psychomotor slowing as absolute effect and has a similar cognitive profile when compared with CBZ and PHT. In contrast with CBZ, dose-relationships have not been obtained and there is no effect when switched from conventional to controlled-release formulations.

 
• From the newer antiepileptic drugs recent information showed titration effects with TPM (that could be controlled using gradual titration), mood effects in higher doses with TGB (possibly also titration-related) and inconclusive data for LMT en GBP due to the lack of powered studies. There is evidence of equivalence with CBZ and VPA for OXC and VGB.

 
• For the remaining drugs: rufinamide and levetiracetam further research has to be encouraged.

• Aikiae M, Kaelviaeinen R, Sivenius J, et al. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow up. Epilepsy Research 1992;11(3):199 203.

 
• Aldenkamp AP, Alpherts WCJ, Moerland MC, et al. Controlled Release Carbamazepine: Cognitive Side effects in patients with Epilepsy. Epilepsia, 1987; 28: 507-514.

 
• Aldenkamp AP, Alpherts WCJ, Blennow G, et al. Withdrawal of antiepileptic medication - effects on cognitive function in children - the results of the multicentre 'Holmfrid' study. Neurology, 1993; 43(1): 41-51

 
• Aldenkamp, A.P., Vermeulen, J. Mulder, O.G., Overweg, J., Van Parys, J.A.P., Beun, A.M. & Van 't Slot, B. Gamma-Vinyl GABA (Vigabatrin) and mood disturbances. Epilepsia, 1994, 35(5),999-1004.

 
• Aldenkamp, A.P. Cognitive side-effects of antiepileptic drugs. In: A.P. Aldenkamp, F.E. Dreifuss, & W.O. Renier (Eds). Epilepsy in Children and Adolescents. CRC-Press Publishers, Boca Raton, New York, 1995, 161-183.

 
• Aldenkamp, A.P. The cognitive profile of the experimental antiepileptic drug CGP 33.101. Basel, Presentation at the final Investigators Meeting; March 14, 1996.

 
• Aldenkamp, A.P & Trimble, M.R. Cognitive side-effects of antiepileptic drugs: Fact or Fiction? Abstract Epilepsia, 1996, 37(4), 82

 
• Aldenkamp, A.P., Mulder, O.G., Overweg, J. Cognitive effects of Lamotrigine as first line add-on in patients with localized related (partial) epilepsy. Journal of Epilepsy, 1997, 10, 117-121.

 
• Aldenkamp, A.P., Rentmeester, Th., Hulsman, J., Majoie, M., Doelman, J., Diepman, L., Schellekens, A., Franken, M., Olling, M. Pharmacokinetics and cognitive effects of carbamazepine formulations with different dissolution rates. European Journal of Clinical Pharmacology, 1998, 54, 185-192.

 
• Aldenkamp AP, Baker G, Mulder, O.G, et al. A randomized observer-blind clinical study comparing the cognitive effects of topiramate versus valproate in a first-line add-on design. Epilepsia 1998;39(Suppl 6):188-189.

 
• Amman MG, Werry JS, Paxton JW, et al. Effect of sodium valproate on psychomotor performance in children as a function of dose, fluctuations in concentration and diagnosis. Epilepsia, 1987; 28: 115-124.

 
• Amman MG, Werry JS, Paxton JW, et al. Effects of carbamazepine on psychomotor performance in children as a function of drug concentration, seizure type and time of medication. Epilepsia, 1990; 31: 51-60.

 
• Brouwer OF, Pieters MSM, Bakker AM, et al. Conventional and controlled release valproate in children with epilepsy: a cross-over study comparing plasma levels and cognitive performance. Epilepsy Research 1992, 13, 245-253.

 
• Brown SW. Clinical aspects of antiepileptic treatment. In: A.P. Aldenkamp, F.E. Dreifuss, W.O. Renier, et al, eds. Epilepsy in Children and Adolescents. New York: CRC-Press Publishers, 1994: 98-112.

 
• Calandre EP, Dominguez-Granados R, Gomez-Rubio M, et al. Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children. Acta Neur. Scand. 1990, 81, 504-506.

 
• Cohen J. Statistical Power analysis for the behavioral sciences. New York: Academic Press, 1977.

 
• Committee on Drugs. Behavioral and cognitive effects of anticonvulsant therapy. Pediatrics, 1985; 76: 644-647.

 
• Cook D, Campbell, DT. Quasi-Experimentation; Design & Analysis Issues for Field Settings. Boston: Houghton Mifflin Company, 1979.

 
• Curran HV, Java R. Memory and psychomotor effects of oxcarbazepine in healthy human volunteers. European Journal of Clinical Pharmacology 1993;44(6):529 533.

 
• Craig I., Tallis R. Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study. Epilepsia 1994, 35, 381-390.

 
• Dodrill CB. Problems in the assessment of cognitive effects of antiepileptic drugs. Epilepsia, 1992; 33(S6): 29 32.

 
• Dodrill, C.B. & Troupin, A.S. Psychotropic effects of carbamazepine in epilepsy: a double-blind comparison with phenytoin. Neurology, 1977, 27, 1023-1028.

 
• Dodrill CB, Arnett JL, Sommerville KW, Shu .V. Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy. Neurology 1997;48(4):1025-31

 
• Forsythe I, Butler R, Berg I, et al. Cognitive impairment in new cases of epilepsy randomly assigned to carbamazepine, phenytoin and sodium valproate. Developmental Medicine and Child Neurology 1991;33:524-534.

 
• Gallassi R, Morreale A, Di Sarro R, et al. Cognitive effects of antiepileptic drug discontinuation. Epilepsia, 1992; 33(S6): 41 44.

 
• Herranz, J.L., Arteaga, R., Armijo, J.A. Side effects of Sodium Valproate in Monotherapy, controlled by Plasma Levels. A study in 88 pediatric patients. Epilepsia, 1982, 23, 203-214.

 
• Ideström CM, Schalling D, Carlquist U, et al. Behavioral and psychological studies: acute effects of diphenylhydantoin in relation to plasma levels. Psych. Med. 1972;2:111-120.

 
• Kalviainen R, Aikia M, Mervaala E, Saukkonen AM, Pitkanen A, Riekkinen PJ Sr. Long-term cognitive and EEG effects of tiagabine in drug-resistant partial epilepsy. Epilepsy Res 1996;25(3):291-7

 
• Kulig B, Meinardi H. Effects of antiepileptic drugs on motor activity and learned behavior in the rat. In: Meinardi H, Rowan AJ, editors. Advances in Epileptology. Amsterdam: Swets & Zeitlinger, 1977: 98-104.

 
• Leach, J.P., Girvan, J., Paul, A. Brodie, M.J. Gabapentin and cognition: a double blind, dose-ranging, placebo controlled study in refractory epilepsy. J. Neurol. Neurosurg.Psychiatry, 1997, 62(4), 372-376.

 
• MacLeod CM, Dekaban AS, Hunt E. Memory impairment in epileptic patients: selective effects of phenobarbital concentration. Science, 1978; 202: 1102-1104.

 
• Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321-327.

 
• Marciani M.G., Stanzione, P., Mattia, D. et al. Lamotrigine add-on therapy in focal epilepsy: electroencephalographic and neuropsychological evaluation. Clin Neuroph. 1998, 21 (1), 41-47.

 
• McKee PJW, Blacklaw J, Forrest G, et al. A double-blind placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J clin Pharmac. 1994;37:27-32.

 
• Meador KJM, Loring DW, Huh K, et al. Comparative cognitive effects of anticonvulsants. Neurology, 1990; 40: 391-394.

 
• Meador KJ, Loring DW. Cognitive effects of antiepileptic drugs. In: Devinski O, Theodore W, eds. Epilepsy and Behavior New York: Wiley-Liss, 1991:151-170.

 
• Meador KJM, Loring DW, Allen, ME, et al. Comparative cognitive effects of carbamazepine and phenytoin in healthy adults. Neurology, 1991; 41: 1537-1540.

 
• Meador KJM, Loring DW, Abney OL, et al. Effects of carbamazepine and phenytoin on EEG and memory in healthy adults. Epilepsia, 1993; 34(1): 153 157.

 
• Meador KJ. Assessing cognitive effects of a new AED without the bias of practice effects. Epilepsia 1997;38(Suppl 3):60.

 
• Meador, K.J., Baker, G.A. Behavioral and cognitive effects of lamotrigine. J. Child Neurol., 1997, 12 (supplement1), supplement pages 44-47.

 
• Mervaala, E., Partanen, J., Nousiainen, U., Sivenius, J & Riekinnen, P. Electrophysiological effects of gamma-vinyl GABA and carbamazepine. Epilepsia, 1989, 30, 189-193.

 
• Mortimore, C., Trimble, M., Emmers, E. Effects of gabapentin on cognition and quality of life in patients with epilepsy. Seizure, 1998, 7(5), 359-364.

 
• Neijens, L.G.J., Alpherts, W.C.J. & Aldenkamp, A.P. Cognitive effects of a new pyrrolidine derivative (Levetiracetam) in patients with epilepsy. Prog. Neuro-Psychopharmacol. & Biological Psychiatry., 1995, 19, 411-419.

 
• Prevey, M.L., Delaney, R.C., Cramer, J.A., Cattanach, L., Collins, J.F., Mattson, R.H. Effect of Valproate on cognitive function. Comparison with carbamazepine. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group. Arch. Neurol., 1996, 53(10), 1008-1016.

 
• Read, C.L., Stephe, L.J., Stolarek, I.H., Paul, A., Sills, G.J., Brodie, M.J. Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled study. Seizure, 1998, 7(2), 159-162.

 
• Reynolds EH. Chronic antiepileptic toxicity: a review. Epilepsia 1975;16:319-352.

 
• Riekkinen, P.J., Kalviasinen, R., Aikia, M., Partanen, J., Saksa, M. & Sivenius, J. Cognitive and electrophysiological effects of vigabatrin and carbamazepine. Epilepsia, 1990, 31, 620.

 
• Smith WL, Lowrey JB. Effects of diphenylhydantoin on mental abilities in the elderly. J. Am. Geriatr. Soc. 1975; 23: 207-211.

 
• Stevens JH, Schaffer JW, Brown CC. A controlled comparison of the effect of diphenylhydantoin and placebo on mood and psychomotor functioning in normal volunteers. Journal of clinical Pharmacol., 1974; 14: 543-551.

 
• Thompson PJ, Trimble MR. Sodium valproate en cognitive functioning in normal volunteers. Br. Journ. Clin. Pharmacol., 1981; 12: 819-824.

 
• Thompson PJ, Huppert F, Trimble MR. Anticonvulsant drugs, cognitive function and memory. Acta Neurol. Scand., 1980; (S80): 75-80.

 
• Thompson PJ, Huppert FA, Trimble MR. Phenytoin and cognitive functions: effects on normal volunteers and implications for epilepsy. British Journ. Clin. Psychol., 1981; 20: 155-162.

 
• Vermeulen, J. & Aldenkamp, A.P. Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Research, 1995, 22, 65-95.

 
• Vining EP, Mellitis ED, Dorsen MM, et al. Psychologic and behavioral effects of antiepileptic drugs in children: a double blind comparison between phenobarbital and valproic acid. Pediatrics, 1987; 80(2): 165 74.