Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Adverse cognitive and behavioural effects of antiepileptic drugs in children

The literature was evaluated for cognitive and more general behavioural effects. We distinguished the older antiepileptic drugs (AEDs), from the newer and newest AEDs. The striking finding was the lack of information on children. From the available evidence it would appear that there may be negative cognitive effects with phenobarbital, phenytoin, topiramate and zonisamide, and adverse behavioural effects with phenobarbital, valproate, gabapentin, topiramate, levetiracetam and zonisamide. There is inconclusive data on ethosuximide, clobazam, vigabatrin, felbamate, pregabalin, stiripentol, rufinamide, lacosamide and retigabine. The following drugs appear to be neutral with regard to cognitive effects: valproate, carbamazepine, gabapentin and oxcarbazepine. Carbamazepine appears to be neutral with regard to behavioural effects. Positive cognitive effects have been reported with lamotrigine and levetiracetam. Positive behavioural effects have been reported with lamotrigine. Recommendations are provided.     

Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats

Patients with epilepsy can have impaired cognitive abilities. Many factors contribute to this impairment, including the adverse effects of antiepileptic drugs (AEDs). However, there are few systematic data on the effects of AEDs on specific cognitive domains, such as working memory. The purpose of the present study was to evaluate the effects of AEDs on working memory as measured by delayed spatial alternation behavior in nonepileptic rats. The GABA-related AEDs triazolam and phenobarbital significantly disrupted performance, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blockers carbamazepine and topiramate produced modest but significant disruption of performance, whereas the effects of lamotrigine were not significant and phenytoin produced a modest but significant improvement in performance but at doses that abolished responding in some animals. Levetiracetam had no effect on working memory. In contrast, ethosuximide significantly disrupted working memory. The disruptions produced by triazolam and phenobarbital were similar in magnitude to the effects of the muscarinic antagonist scopolamine. The present results indicate that AEDs can disrupt working memory, but there are differences among AEDs in the magnitude of the disruption that do not appear to be correlated with mechanism of action.     

Teratogenic effects of antiepileptic drugs.

The use of older generation antiepileptic drugs (AEDs) during pregnancy is known to be associated with a two- to threefold increased risk of birth defects in the offspring and possible also other adverse outcomes in the exposed infant. Much less has been known about newer generation AEDs in this respect. Recent studies based on national registries as well as specific epilepsy and pregnancy registries are beginning to provide information on comparative teratogenic effects of different AEDs. Hence, the prevalence of birth defects appears to be higher with exposure to valproate compared with carbamazepine and possibly also in comparison with lamotrigine. Further studies based on larger cohorts are needed to compare AEDs at different dosages and to analyse the possible impact of confounding factors. Furthermore, data is insufficient to assess the human teratogenic potential of other newer generation AEDs than lamotrigine. Retrospective and a few small prospective studies suggest that exposure to valproate also might be associated with a lower verbal IQ at school age, but further prospective studies are needed to draw firm conclusions.     

Effects of antiepileptic drugs on mRNA levels of BDNF and NT-3 and cell neogenesis in the developing rat brain

Epilepsy is a common neurological disorder that occurs more frequently in childhood than in adulthood. Antiepileptic drugs (AEDs) which are used to treat seizures in pregnant women, infants, and young children may cause cognitive impairment or other uncertain injury. However, the exact mechanisms responsible for adverse effects of AEDs in the developing brain are still not clear. In the present study, we investigate the effects of AEDs on mRNA levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), cell neogenesis and mossy fiber sprouting (MFS) in the developing rat brain. Long-term treatment with Phenobarbital (40 mg/kg), valproate (100 mg/kg) and topiramate (40 mg/kg) reduces BDNF and NT-3 mRNA expression in the developing brain, while lamotrigine reduces mRNA expression only at high dose level (80 mg/kg). Cell neogenesis only increases in the rats treated with valproate and lamotrigine. And no differences are observed between the control group and the AEDs-treated groups in the Timm scores of the CA3 region and supragranular region. Our findings present some possible mechanisms to explain why different AEDs cause different cognitive impairment.     

The Aspects and Mechanisms of Cognitive Alterations in Epilepsy: The Role of Antiepileptic Medications

Epilepsy is a major health problem. Several studies suggest a significant influence of epilepsy and its treatment on dynamic and functional properties of brain activity. Epilepsy can adversely affect mental development, cognition, and behavior. Epileptic patients may experience reduced intelligence, attention, and problems in memory, language, and frontal executive functions. Neuropsychological, functional, and quantitative neuroimaging studies revealed that epilepsy affect the brain as a whole. Mechanisms of epilepsy‐related cognitive dysfunction are poorly delineated. Cognitive deficits with epilepsy may be transient, persistent, or progressive. Transient disruption of cognitive encoding processes may occur with paroxysmal focal or generalized epileptic discharges, whereas epileptogenesis‐related neuronal plasticity, reorganization, sprouting, and impairment of cellular metabolism are fundamental determinants for progressive cognitive deterioration. Also antiepileptic drugs (AEDs) have differential, reversible, and sometimes cumulative cognitive adverse consequences. AEDs not only reduce neuronal irritability but also may impair neuronal excitability, neurotransmitter release, enzymes, and factors critical for information processing and memory. The present article serves as an overview of recent studies in adult and childhood epilepsy literatures present in PubMed that highlighted cognitive evaluation in epilepsy field (publications till 2008 were checked). We also checked the reference lists of the retrieved studies for additional reports of relevant studies, in addition to our experience in this field. Our search revealed that although the aspects of cognitive dysfunction, risk factors, and consequences have been explored in many studies; however, the mechanisms of contribution of epilepsy‐related variables, including AEDs, to patients' cognition are largely unexplored. In this review, we discussed the differential effect of AEDs in mature and immature brains and the known mechanisms underlying epilepsy and AEDs adverse effects on cognition. The nature, timing, course, and mechanisms of cognitive alteration with epilepsy and its medications are of considerable clinical and research implications.     

The first line of therapy in a girl with juvenile myoclonic epilepsy: Should it be valproate or a new agent?

Juvenile myoclonic epilepsy is a common idiopathic generalized epileptic syndrome that includes generalized myoclonic seizures and commonly generalized tonic–clonic and generalized absence seizures. Before the emergence of the newer antiepileptic drugs (AEDs) in the 1990s, valproate was the usual first-line treatment in both men and women. However, the frequent adverse effect of weight gain and the risk of teratogenicity have resulted in a search for alternative first-line therapies in women. Four new AEDs— lamotrigine, topiramate, levetiracetam, and zonisamide—have been used as monotherapy or adjunctive therapy for juvenile myoclonic epilepsy in small patient series. Because they are not associated with weight gain and because they may have less risk of teratogenicity than valproate, they have been proposed as alternative first-line agents in women who have childbearing potential. However, the new AEDs may not be effective for all the seizure types of juvenile myoclonic epilepsy, and valproate appeared overall more effective in a large comparative trial in idiopathic generalized epilepsy. In addition, valproate is often effective at lower doses that have less teratogenicity, and an extended-release preparation may be less likely to produce weight gain. The current review presents evidence and arguments supporting the use of a new AED and those supporting the use of valproate as the first-line treatment in a girl with newly diagnosed juvenile myoclonic epilepsy. The review then concludes with a compromise approach.     

Antiepileptic Drugs, Learning, and Behavior in Childhood Epilepsy

Summary: Cognitive and behavioral impairments are found more often among epileptic children than among their peers. The cause of these impairments is multifactorial. Identifying the relative contribution of antiepileptic drugs (AEDs) to these problems has been the object of a large number of clinical investigations. This area of research has been characterized by an unusually high number of methodological challenges and pitfalls. Accordingly, results have often been inconsistent and contradictory, except for the more obvious observations that can be derived from clinical experience. Overall, the effects of AEDs on cognition and behavior in children have been overrated in the past. More recent research has benefited from the methodological lessons of previous studies and it suggests that the majority of children taking AEDs do not experience clinically relevant cognitive of behavioral adverse effects from these medications. In addition, some of the newer AEDs may indeed have a better cognitive profile. Nevertheless, clinical experience must be used to identify the subgroup of children who remain at risk for significant and clinically relevant cognitive and behavioral adverse effects of AEDs.     

Drug selection for the newly diagnosed patient: When is a new generation antiepileptic drug indicated?

Abstract. Treatment options in epilepsy have increased dramatically since the early 1990s with the introduction of nine new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). This makes drug selection much more complicated and challenging. This review discusses drug selection in patients with newly diagnosed epilepsy and in particular the role of new AEDs in this population. The choice of treatment should always be based on a careful comparison of the risk-benefit ratio for the different treatment options and the outcome of such evaluation may be different in patients with new onset compared with chronic epilepsy. Efficacy, tolerability and safety are the main criteria for selection of AEDs and any first line drug for patients with newly diagnosed epilepsy must have demonstrated satisfactory efficacy as monotherapy in that patient population. So far, of the new AEDs only lamotrigine, oxcarbazepine and topiramate have documentation sufficient to be granted licence for use as monotherapy in most European countries. Because the new generation AEDs have failed to demonstrate improved effectiveness as monotherapy, old generation AEDs such as carbamazepine and valproate remain drugs of first choice for partial and generalised seizures, respectively. However, there are special situations and populations where a new AED may be a reasonable first line drug. These include vigabatrin in West syndrome associated with tuberous sclerosis, lamotrigine as alternative to valproate in idiopathic generalised seizures in women of childbearing potential and lamotrigine for the treatment of epilepsy in the elderly population. The role of the new generation AEDs is likely to become more prominent as more experience is gained.     

Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously demonstrated that a number of AEDs can impair working memory and attention. The purpose of the present study was to evaluate the effects of AEDs on learning as measured by a repeated acquisition of response sequences task in nonepileptic rats. The GABA-related AEDs phenobarbital and chlordiazepoxide significantly disrupted performance by shifting the learning curve to the right and increasing errors, whereas tiagabine and valproate did not. The sodium channel blockers carbamazepine and phenytoin suppressed responding at higher doses, whereas lamotrigine shifted the learning curve to the right and increased errors, and topiramate was without significant effect. Levetiracetam also shifted the learning curve to the right and increased errors. The disruptions produced by triazolam, chlordiazepoxide, lamotrigine, and levetiracetam were qualitatively similar to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can impair learning, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function and some that block sodium channels producing the most consistent impairment of learning.     

The choice of antiepileptic drugs in newly diagnosed epilepsy: a national French survey.

The choice of an antiepileptic drug (AED) in patients with epilepsy is mainly based on efficacy and safety of each drug. However, these criteria of drug selection should be further evaluated according to the epileptic syndromes, and adjusted to the sex and age of the patient. Unfortunately, very few studies have been conducted based on these latter criteria. We conducted a survey on the management of epilepsy treatment in adults. This survey was undertaken in France, and led to the establishment of a French consensus on antiepileptic drug treatment in adult patients with newly diagnosed epilepsy. Patients were grouped into 18 categories according to the epileptic syndrome (absence epilepsy, juvenile myoclonic epilepsy, undetermined idiopathic generalized epilepsy, symptomatic or cryptogenic partial epilepsy and unclassified epilepsy), and to the patient's gender and age. Our survey suggests that there is a consensus among French epileptologists for the choice of AEDs, mainly based on the epilepsy syndrome. Gender also plays a crucial role. Sodium valproate and lamotrigine are the two drugs of choice for generalized epilepsies, as well as for undetermined epilepsies. Lamotrigine is often prefered for women of childbearing age. First line AEDs in partial epilepsy are carbamazepine (particularly for men), lamotrigine (particularly for women), and gabapentin (in the elderly). In cases of failure and/or intolerance to one of these AED, the principal alternatives are oxcarbazepine, sodium valproate and topiramate.     

Cognitive and Behavioral Effects of Antiepileptic Drugs

Summary: All antiepileptic drugs (AEDs) have the potential for adverse effects on cognition and behavior. Most of the major AEDs, administered in therapeutic doses, cause little or no cognitive or behavioral impairment in group studies. However, individual variability is considerable, and some patients do not tolerate low serum levels, whereas others tolerate high levels without subjective or objective effects. In the past, carbamazepine (CBZ) and valproate (VPA) have been reported to have the fewest adverse cognitive and behavioral effects in children and adults. However, several recent, well-controlled studies have not found significant differences between the effects of phenytoin (PHT) and those of CBZ or VPA. Greater adverse effects have been found for phenobarbi-tal (PB). However, we must use environmentally relevant measures of cognitive and behavioral functioning to measure effects on daily functioning. Future studies must define cognitive and behavioral toxicity in subpopulations (e.g., post-traumatic epilepsy, mental retardation, depression) and with the new AEds.     

Role of valproate across the ages. Treatment of epilepsy in children

In June 2005 a team of experts participated in a workshop with the objective of reaching agreement on the place of valproate use in the treatment of paediatric epilepsy patients. A general 'consensus of the meeting' was that the initiation of antiepileptic drug (AED) treatment should be based on a seizure-syndromic approach in children. Participants of the meeting also agreed that valproate is currently the AED with the broadest spectrum across all types of seizures and syndromes. Its superiority has been shown over almost 40 years of clinical experience. The best results are seen in idiopathic generalized epilepsy with or without photosensitivity, idiopathic focal and symptomatic generalized tonic–clonic seizures (GTCS). Evidence supports the use of valproate, ethosuximide and lamotrigine in absence epilepsies and the use of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and phenobarbital for primary GTCS. For new AEDs trials have been undertaken to define their therapeutic role but studies comparing their role to 'old' broad-spectrum drugs in specific syndromes are missing. Experts concluded that intravenous (i.v.) valproate is a useful agent in the treatment of non-convulsive status epilepticus (SE). There is an easy transition to oral treatment following i.v. valproate use. The discussion also concluded that, despite the lack of studies, valproate is an interesting, underutilized alternative in convulsive SE but more controlled studies are needed. The side effects of valproate use are well documented. Its effect on cognition and behaviour is more favourable than many of the other AEDs which is an important consideration in children. Overall, the clinical consensus of the meeting was that valproate's well established therapeutic properties far outweigh the negative side effects. Contraindication or withdrawal should be assessed individually.     

Differential effects of antiepileptic drugs on neonatal outcomes

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.     

Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously evaluated a number of AEDs with respect to their effects on working memory. The purpose of the present study was to evaluate the effects of AEDs on attention as measured by five-choice serial reaction time behavior in nonepileptic rats. The GABA-related AEDs triazolam, phenobarbital, and chlordiazepoxide significantly disrupted performance by increasing errors of omission, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blocker carbamazepine increased errors of omission at relatively high doses, whereas the sodium channel blockers phenytoin, topiramate, and lamotrigine were without significant effect. Levetiracetam had no effect on attention. The disruptions produced by triazolam, phenobarbital, chlordiazepoxide, and carbamazepine were similar in magnitude to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can disrupt attention, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function producing the most consistent disruption of attention.     

Use of antiepileptic drugs in the treatment of epilepsy in people with intellectual disability

The main principles of antiepileptic drug treatment of epilepsy in patients with intellectual disability are basically the same as for other patients with epilepsy. However, some specific issues need to be taken into account These are primarily associated with the diagnostic difficulties of epilepsy in this population. In addition, a number of other relevant issues, including the degree and location of brain lesion, the nature of the underlying disease, the higher frequency of difficult-to-treat epilepsies, the additional intellectual impairment caused by inappropriate antiepileptic medication, or by frequent and prolonged seizures, the appropriate use of monotherapy versus rational polytherapy, and the use of broad-spectrum antiepileptic drugs will be discussed in the present paper. Although the goals of treatment are to keep the patient seizure-free and alert while preventing possible mental deterioration, we have to accept compromises between these primary goals in many cases. Some people with epilepsy and intellectual disability are very vulnerable to insidious neurotoxic effects; for example, sedative effects caused by phenobarbital, or cognitive and/or cerebellar dysfunction caused by long-term phenytoin, especially together with other drugs. Because of the adverse effects of phenobarbital and phenytoin, these drugs are no longer recommended as a first-choice drugs when long-term antiepileptic medication is required. In primary generalized tonic-clonic seizures, valproate, oxcarbazepine/carbamazepine and lamotrigine are recommended in this order of preference. The corresponding recommendations are: in typical absences, valproate, ethosuximide and lamotrigine; in atypical absences, valproate and lamotrigine; in juvenile myoclonic epilepsy, valproate, lamotrigine and clobazam; in infantile spasms vigabatrin, ACTH and valproate; in Lennox-Gastaut syndrome, valproate, lamotrigine and vigabatrin; in atonic seizures, valproate and lamotrigine; in simple and complex partial seizures with or without secondary generalization, oxcarbazepine/carbamazepine, valproate/ vigabatrin and lamotrigine; and in status epilepticus lorazepam, diazepam and clonazepam together with phenytoin or fosphenytoin. In cases of poor response to the monotherapy recommended above, the following combinations may be indicated: in primary generalized tonic-clonic epilepsy, valproate and oxcarbazepine/ carbamazepine, or valproate and lamotrigine; in typical absences, valproate and lamotrigine, or valproate and ethosuximide; in juvenile myolonic epilepsy, valproate and lamotrigine, or valproate and clonazepam; and in partial epilepsies, add to the monotherapy one of the following drugs, vigabatrin, lamotrigine, gabapentin, tiagabine, topiramate, zonisamide or clobazam. So far, the order of preference of these new drugs remains undetermined. More data are needed on the efficacy and adverse effects of the new drugs based on controlled studies on patients with intellectual disability and epilepsy.     

Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously evaluated a number of AEDs with respect to their effects on working memory. The purpose of the present study was to evaluate the effects of AEDs on attention as measured by five-choice serial reaction time behavior in nonepileptic rats. The GABA-related AEDs triazolam, phenobarbital, and chlordiazepoxide significantly disrupted performance by increasing errors of omission, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blocker carbamazepine increased errors of omission at relatively high doses, whereas the sodium channel blockers phenytoin, topiramate, and lamotrigine were without significant effect. Levetiracetam had no effect on attention. The disruptions produced by triazolam, phenobarbital, chlordiazepoxide, and carbamazepine were similar in magnitude to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can disrupt attention, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function producing the most consistent disruption of attention.     

Role of valproate across the ages. Treatment of epilepsy in the elderly

In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug–drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly.     

Aggravation of epilepsy by anti-epileptic drugs

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.