Cognitive side effects of anti-epileptic drugs The relevance in childhood epilepsy

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1 Seizure (2006) 15, REVIEW Cognitive side effects of anti-epileptic drugs The relevance in childhood epilepsy Lieven Lagae * University Hospitals KULeuven, Department Paediatric Neurology, Herestraat 49, 3000 Leuven, Belgium Received 14 December 2005; accepted 15 February 2006 KEYWORDS Cognition; Anti-epileptic drugs; Childhood epilepsy; Neuropsychology; IQ; Development Summary In recent years several new anti-epileptic drugs have been introduced, also for the treatment of childhood epilepsy. A major concern is their effect on learning and cognitive development. Testing the genuine effects on cognition of the anti-epileptic drugs is methodologically not easy. At this moment there are very few controlled trials that systematically examine the cognitive side effects of antiepileptic drugs in childhood epilepsy. The available data indicate that the newer anti-epileptic drugs have a safe cognitive profile when prescribed correctly at the right dose and in monotherapy. Possible negative effects are mainly found for speed of processing and attention processes. As these processes are important instruments in every day learning and cognition, it is necessary to test these newer anti-epileptic drugs in well designed studies and in specific childhood epilepsy syndromes. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. Introduction In clinical practice, it is well known that many children with epilepsy have cognitive problems, ranging from mild learning and school problems to mental retardation or even mental decline. Although these problems are also encountered in adults with epilepsy, the impact of epilepsy on developing cognitive processes is likely to be more prominent. The proportion of children with cognitive problems is higher in refractory epilepsy than in well controlled epilepsy. This already points to the possible deleterious effect of the epileptic process itself on cognitive development. In a recent paper, it was shown that only in 16% of the children * Tel.: ; fax: address: Lieven.Lagae@uz.kuleuven.ac.be. with refractory epilepsy, a normal IQ was found. 1 This is in contrast with the data of a pivotal and rather reassuring study by Ellenberg et al. in a group of normal children with easier to treat epilepsy. At the age of 7 years, there was no IQ difference between epileptic children and their siblings, but only if there was no pre-existing mental retardation before the start of the epilepsy. 2 Several non-independent factors and each to a variable extent contribute to the possible cognitive problems in epilepsy but are very difficult to study separately. 3 Probably the most important determinants are the epileptic process itself and the underlying brain dysfunction/pathology. Symptomatic epilepsy has a worse outcome than idiopathic epilepsy. 4 Theuniquecontributionsofthe epilepsy-related factors, such as the age of onset, 5 type of seizures and epilepsy syndrome, frequency /$ see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 236 L. Lagae of seizures and epileptic abnormalities on the EEG are more difficult to disentangle. 6 It is the combination of the underlying brain dysfunction with an epileptic syndrome at a certain age that explains the cognitive profile. For example, tuberous sclerosis is highly associated with infantile spasms in infancy and if these seizures are not well controlled, many of these children become mentally retarded and autistic. 7 Children with TS but without infantile spasms at the critical age have a better prognosis, as well as children with idiopathic infantile spasms. Another nice example illustrating these complex interactions is shown in the paper of Helmstaedter et al. They showed (in adults) that long lasting (and especially left) temporal lobe epilepsy is clearly associated with memory decline, and that this decline could be stopped after resection of the dysfunctional hippocampal structures, but only if there was complete seizure control after the resection. 8 Another factor to consider is the psychosocial environment and educational/school system. It should be realized that even in 2006, in some countries, epilepsy is a reason not to send the children to school, of course increasing the risk for cognitive problems. This short review deals with the effects of the newer anti-epileptic drugs on cognitive functioning. It is actually surprising that only recently this problem has been fully recognized and perhaps already over-emphasized. A major historical step in this respect was the setting-the-scene papers of phenobarbital and its effect on IQ in febrile seizures. 9,10 Long term use of phenobarbital as preventive medication for febrile seizures was shown to decrease the IQ-levels, even after discontinuation of the drug. This paper was also influential because it introduced the measurement of IQ as a major determinant in cognitive studies. Although IQ remains an interesting and global measure, it does not allow precise studies of specific cognitive processes; it only gives a rough estimate of academic potential. With the introduction of several new anti-epileptic drugs, with more or less similar efficacy, the side effect profile and especially the cognitive and behavioural safety are becoming discriminating factors when prescribing these drugs. Unfortunately, cognitive safety is not yet a major issue in the classic randomized controlled trials. In addition, and this will also be illustrated in this review, it is very difficult to design a powerful study that unambiguously will show the negative or positive cognitive effects of anti-epileptic drugs. Here again, the non-independency of AEDs, epilepsy syndrome and brain dysfunction are at play. Methodological issues Already in 1995, Vermeulen and Aldenkamp systematically reviewed the potential methodological problems when studying cognitive processes in epileptic patients. These principles are still valid and can now be focused more on childhood epilepsy. 11 If one wants to study the cognitive effects of an anti-epileptic drug, it seems logical that this would be done first in normal non-epileptic subjects. However, only short term exposure is feasible in nonepileptics and this will therefore not reflect the cognitive side effects after prolonged administration of the drug. Long term and preferentially monotherapy trials are ideal. More importantly, a drug should theoretically be tested in well defined epilepsy syndromes with as homogeneous as possible patient populations. An anti-epileptic drug theoretically can induce different cognitive effects in different epilepsy syndromes. For instance, it is known that frontal epilepsy in a child is more prone to attention problems 12 ; if this epilepsy would be treated with a drug with known effects on attention processes, the attention problems in this child could become worse, and will indeed over-emphasize the negative attention side effects of the drug. In addition, children of different ages are susceptible to different effects of the anti-epileptic drugs. A similar dysfunction of the attention system at the age of 4 years can cause other problems in a child of 8 years, even if both children are known with the same epilepsy syndrome. Another major pitfall is the seizure frequency. Studying cognitive effects of an AED after a convulsive seizure will certainly influence the cognitive profile. 13 It has been shown that several days after a seizure, subjects were still not at their cognitive baseline. Seizure-free patients are therefore the best candidates for cognitive studies. Along the same line, and this has received considerable attention in the last few years, is the effect of subclinical epileptic EEG discharges, which can cause substantial performance differences during cognitive testing. 14,15 One can therefore argue that optimal cognitive testing should always be performed under EEG guidance. 16 An underestimated problem is drug dosages and more specifically drug blood levels. Clinicians do realize that for optimal seizure control, a drug blood level is often a bad guide, especially since we do not understand the exact relationship between blood and brain levels of the drug. However, for cognitive issues, drug dosages are perhaps much more important. 17,18 In a way, it seems that two study designs are optimal, but both are difficult to perform at large scale:

3 Cognitive side effects of anti-epileptic drugs Long term monotherapy in seizure-free patients with well defined epilepsy: comparison between pre-treatment and treatment period. In some (benign) epilepsies, double blind cross-over with placebo is possible. - Monotherapy withdrawal study in seizure-free patients. 19 Cognitive testing Several neuropsychological batteries can be used to study cognitive functions and the influence of anti-epileptic drugs. Because testing is time consuming and not every cognitive process can be tested in detail, it is very important to select the most appropriate tests and this should be a hypothesis-driven process. Most batteries therefore are a compromise. However, one should be aware of some basic principles in neuropsychology. One can of course define the most important cognitive processes (Table 1, left column), but here also these categories are not independent. Actually, one can make a distinction between basic cognitive instruments (attention processes, working memory, cognitive speed, etc.) and more specific processes (visuospatial abilities, language, etc.) (Table 1, right column). The underlying idea is that one needs the instruments to perform normally on the more specific tasks. Therefore, it seems logical that a cognitive test battery should at least contain testing of processing speed and attention. Another methodological remark has to do with the scoring of the tests. Normally, scores are compared with ageappropriate norms and expressed as a z-score or percentile. However, in mentally retarded children, it will be difficult to find specific neuropsychological dysfunctions: they will perform badly on most tests Table 1 Sensory processing/ perception Attention/concentration Speed of processing Working memory Psychomotor speed Neuropsychological processes } Visuospatial abilities Problem-solving Non-verbal memory Verbal memory Motor control/ performance Verbal reasoning Imagery General intelligence IQ } Cognitive instruments Specific processes Academic potential Table 2 Leuven cognitive battery Intelligence WPPSI-R, WISC-R Attention and TEA-Ch, Tower executive functions Memory Verbal AVLT; numbers, stories, word pairs (CMS) Non-verbal Pictures, dot location, family scenes, faces (CMS); complex figure (ROCF DSS) Language Boston Naming Test, Token Test, Word Fluency Visual/spatial Developmental Test of Visual Motor Integration (VMI) Motor Purdue Pegboard Test Checklists Child behaviour checklist (parents), youth self report (YSR), everyday memory questionnaire AVLT: Auditory Verbal Learning Test; CMS: Children s Memory Scale; ROCF DSS: Rey Osterrieth Complex Figure Developmental Scoring System. when you compare their results with age-matched controls. To overcome this problem, one can compare the test results of the patient with the mental age instead of the chronological age. Mental age can be deduced from the non-verbal or verbal IQ. For instance, a 10-year-old child with a non-verbal IQ of 75 approximately performs at a mental age of 7.5 years and his test results in the specialized neuropsychological batteries should therefore be compared with 7.5 years controls. 20,21 This methodology allows finding of specific neuropsychological dysfunctions in one or more domains even in globally retarded patients. In Table 2, an example is given of a rather extensive neuropsychological battery that is now being used in our centre for different cognitive studies. To gain time, we ask the Centre of Student Guidance (CLB) which is present in every school to perform an age appropriate IQ test; the more specific tests are done in our centre. Working mechanism of the anti-epileptic drugs and cognitive profile In a recent paper by Sankar and Holmes, animal studies are reviewed that addressed the cognitive side effects of anti-epileptic drugs. 22 Theoretically, knowing the exact working mechanism and the site of action of anti-epileptic drugs, it should indeed be possible to predict the type of cognitive side effects of an anti-epileptic drug. Two problems however arise. First of all, we do not understand the exact

4 238 L. Lagae working mechanism of all anti-epileptic drugs. It is not because we know that a drug is working on a sodium channel, that we automatically understand why this drug is working in a particular epilepsy syndrome. Regional and temporal differences of the expression of this sodium channel in specific excitatory and inhibitory neurons, for instance, are a possible reason for the discrepancies we see in clinical practice. Second, testing cognitive processes in rodents, although valuable, remains at a more rudimentary level with difficult extrapolations to human cognitive processing. Nevertheless, some interesting general conclusions can be drawn from this sort of studies. It appears that sodium channel acting drugs are associated with the least amount of cognitive side effects, while the risk is greatest in drugs with gabergic action. Gabergic drugs especially influence vigilance and attentional processes. Anti-glutamatergic drugs are more associated with effects on learning and memory, especially those drugs that work on the NMDA receptor. Recently, a totally new type of working mechanism was found in levetiracetam. This drug binds to a synaptic vesicle SV2A and influences the release of several neurotransmittors. 23 At this moment, we do not know which cognitive processes are possibly influenced by this synaptic modulator, but it underlines the complexity and the inherent risk for too fast and too simple conclusions in this field. Comparing older and newer anti-epileptic drugs Several excellent reviews are available that describe the cognitive side effects of the older and newer anti-epileptic drugs. 3,18, Although several methodological problems were not dealt with in the studies on the older anti-epileptic drugs, some robust findings were reproduced in most studies, so that some general conclusions are valid. Also, they provide the background against which the effects of the newer anti-epileptic drugs should be compared. It is clear that all the older drugs can induce psychomotor slowing, a basic cognitive instrument (see Table 1), and this to a variable extent. This was, for instance, nicely illustrated in the Holmfrid withdrawal study. 19 Psychomotor slowing is generally measured in reaction time studies and anti-epileptic drugs typically induce a ms increase of reaction time. Although most authors stress that these effects are minimal, this reaction time increase can be very critical in some natural situations and especially during learning situations. Typically, phenobarbital, phenytoin, carbamazepine and valproate are considered as older antiepileptic drugs. As already mentioned in the Introduction, long term use of phenobarbital in children is associated with a decrease in IQ. 9,10,28 Although the decrease is usually lower than 10 IQ points, for some children on the edge, this decrease might be substantial. Subsequent use of phenobarbital has therefore dramatically decreased in recent years, no studies have examined the neuropsychological nature of this IQ decrease. In adults too, phenobarbital has been shown to induce more cognitive side effects than carbamazepine and phenytoin. 29,30 In general, phenobarbital is worse than valproic acid and carbamazepine. 31,32 However, it should also be mentioned that in an open label study in children with well controlled seizures, no IQ differences were found between the phenobarbital, carbamazepine and valproate group. 33 In another study comparing phenytoin, carbamazepine and valproate in childhood epilepsy, it was shown that only minimal changes were seen in the phenytoin group. In this study, carbamazepine treated children performed worse than valproate treated children, especially on memory tasks. 34 Although the methodology was certainly not always comparable, different studies have shown that carbamazepine was better than or equal to phenobarbital and phenytoin. Comparison of phenobarbital and phenytoin with valproate yielded variable results Actually, for all these older drugs some adverse cognitive side effects have been described in childhood epilepsy and phenobarbital seems to be the worst drug in this respect. In the following paragraphs, the most commonly used newer anti-epileptic drugs are discussed in more detail: topiramate, lamotrigine, oxcarbazepine and levetiracetam. Topiramate Topiramate is an effective broad spectrum antiepileptic drug that is being used frequently in several childhood epilepsy syndromes, including some of the more catastrophic epilepsies, such as the Lennox Gastaut syndrome. Studies in healthy adult volunteers have shown that topiramate induces general mental slowing, psychomotor speed reduction and concentration problems, illustrating a general effect on the cognitive instruments. 36 These effects were also dosage dependent. 37 It should be noted that dosage for topiramate in the first registration studies was substantially higher than that

5 Cognitive side effects of anti-epileptic drugs 239 obtained nowadays in clinical practice. This might have over-emphasized these negative cognitive side effects. A postmarketing study confirmed that cognitive complaints (especially psychomotor slowing) were the primary reason for discontinuation of the drug but also that, overall, most patients continued the medication because of its efficacy. In this study, no specific dosage escalation or final dosage was associated with a greater risk for cognitive side effects. 38 In epilepsy patients, topiramate also had an effect on memory and on word fluency, verbal processing and verbal IQ. 39,40 Especially, this latter effect is unique and still mis-understood. Verbal memory, verbal fluency and verbal learning were all shown to be influenced by topiramate. This side effect is not seen with other anti-epileptic drugs and could not be predicted directly from animal studies. In one study, it was estimated that up to one third of the patients showed word finding problems. 41 At this point, there is no satisfactory explanation for this effect. As verbal functions involve the fastest circuits in the brain, one could hypothesize that topiramate preferentially affects these circuits. In children, no systematic studies on cognition and topiramate have been performed yet. Moreland et al. showed that about 20% of epileptic children displayed decreased cognition, however without any further explanation. 42 Lamotrigine Also, for this anti-epileptic drug, no systematic studies on cognition in children are available. As this drug is a rather specific sodium channel blocker, animal studies predict few cognitive side effects. 22 Indeed, in adult volunteers, no differences with placebo were found and Aldenkamp et al. 43 and Meador et al. 44 even showed positive effects on some cognitive functions. This was confirmed in adult epilepsy patients. 36,45 47 For instance, Smith et al. showed that add-on lamotrigine was not associated with adverse cognitive effects in 81 patients with refractory epilepsy. 45 In some studies it was shown that lamotrogine was able to improve cognitive functioning in refractory epilepsy in children, sometimes irrespective of seizure control. This was also shown in mentally retarded children and adults, although effects were not always measured quantitatively However, one should be careful with this sort of findings and not be tempted to call this a genuine psychotropic drug too early. An obvious explanation could be that this drug decreases the amount of background EEG epileptic activity and therefore improves basic cognitive possibilities. Overall, there are no studies in adults that show a negative cognitive effect of lamotrigine. Therefore, the conclusion of a recent review by Aldenkamp and Baker was that lamotrigine was a safe drug at the cognitive level. 53 Oxcarbazepine Oxcarbazepine is also a sodium channel blocker but has a narrower spectrum than lamotrigine. It is especially suited for partial epilepsy syndromes and is related to carbamazepine but tolerability and side effect profile are said to be better than carbamazepine. Again, it is surprising that no specific cognitive studies in children have been published. Curran and Java already in 1993 showed that oxcarbazepine induced a positive effect on attention and motor speed in healthy volunteers. 54 In adult epilepsy patients, the drug did not show any specific cognitive side effects Sabers et al. showed a positive effect on learning and psychomotor speed. In children, the study of Serdaroglu et al. 58 showed that only drowsiness was reported as a possible cognitive side effect. Overall, and as expected, oxcarbazepine seems to be similar in its cognitive safety as lamotrigine. Levetiracetam Levetiracetam is the newest anti-epileptic drug in most countries and is already widely used in childhood epilepsy. It has a broad spectrum profile and is unique in its working mechanism: levetiracetam binds to a pre-synaptical SV2A protein and modulates neurotransmitter release. 23 Few studies on the cognitive side effects are available yet. Cramer et al. 59 showed in a large study in adults with epilepsy that levetiracetam did not differ from other AEDs in the reported frequency of anxiety, emotional lability and nervousness. However, no specific cognitive processes were measured. The study of Neyens et al. 60 showed a positive effect in cognitive tests in levetiracetam responders and no difference from placebo in non-responders. Here again, it is difficult to disentangle seizure reduction effects on cognition from drug dependent effects. In this small study, levetiracetam treatment induced improvement in reaction time, tapping rate of the non-dominant hand and memory for simultaneously presented words. In children, acute psychosis has been described in one, 61 but not in other publications on childhood epilepsy. 62

6 240 L. Lagae Conclusion It should be clear from this overview that we need well designed studies in childhood epilepsy that address the potential cognitive side effects of anti-epileptic drugs in children. We should be careful to extrapolate the existing data in adults to children. Minor cognitive side effects in adults could cause significant learning and cognitive effects in children. In addition, the existing studies in adults still suffer from different methodological flaws, and definite conclusions are therefore difficult to draw. In general however, the available data indicate that the newer anti-epileptic drugs are safer at the cognitive level than the older ones, and this could become a discriminating factor in prescription habits. References 1. Boel M. Behavioural and neuropsychological problems in refractory paediatric epilepsies. Eur J Paediatr Neurol 2005;8: Ellenberg JH, Hirtz DG, Nelson KB. Do seizures in children cause intellectual deterioration? 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