Cognitive effects of antiepileptic drugs

Factors which may contribute to cognitive impairments in epilepsy are briefly reviewed. In particular, memory deficits, attentional problems, psychomotor slowing and reading and writing difficulties are highlighted, and the impact of the seizures, brain damage, and anticonvulsant drugs on cognitive function noted. With regards to the latter, the impairments associated with Phenytoin and Phenobarbitone are contrasted with the minimal effects of newer anticonvulsant drugs such as Sodium Valproate and Carbamazepine.     

Cognitive side effects of antiepileptic drugs

Antiepileptic drugs produce global changes in the excitation levels in the central nervous system and often lead to cognitive and behavioral deficits. These deficits vary and must be considered independently in every patient. A number of consistent risk factors have been established. Polypharmacy and high blood levels of an antiepileptic drug (AED) increase the risk of cognitive side effects. Different effects have been demonstrated for some AEDs, but comparative data are incomplete across all of them. Other factors such as patient age and type/frequency of seizures may also be important contributors to the patient's cognitive state. AEDs can have positive or negative effects on mood, providing another consideration in choosing the course of treatment.     

Cognitive and behavioral effects of antiepileptic drugs

In managing epilepsy, drugs that offer the best seizure control to the patient should be used, but their influence on quality of life must also be considered. This must include any effects on mood and mental state, which should be minimal in order that these patients may achieve their full potential. Subtle behavioral and cognitive disadvantages may occur with anticonvulsant drug use. Behavioral changes with phenobarbital are both idiosyncratic and dose related. Carbamazepine and valproic acid can have adverse effects on mood and cognition, but do so less frequently than the other medications or combinations (Table 1). Cognitive dysfunction may relate to antiepileptic drug blood levels, but impairment of skills can occur in the nonintoxicated patient. Thus, office neurologic examinations are insufficient to detect these subtle mental impairments. Practical methods need to be developed to identify and monitor these problems so that in the future cognitive and behavioral dysfunction in epileptic patients can be minimized.     

Cognitive and neurodevelopmental effects of antiepileptic drugs

This article primarily represents the contributions of two young investigators to the understanding of the neuropsychological consequences of epilepsy and its treatment. The authors have reviewed two key areas of importance: the complex relationship between cognitive dysfunction and epilepsy and the risks of cognitive dysfunction in children as a consequence of in utero exposure to antiepileptic drug treatment. The work of two young investigators is presented and future research needs are outlined.     

Cognitive side effects of antiepileptic drugs in children

Cognitive impairment associated with antiepileptic drug (AED) therapy in children is an important concern given the potential negative effects of treatment on school learning and performance. Unfortunately, there have been few studies examining the cognitive effects of AEDs in this population and no adequate studies of newer AEDs. This article will discuss the effects of the traditional and newer AEDs on neuropsychological function in children. Because of various limitations in the designs of these studies, however, many of the studies report inconclusive findings. Although it will be necessary to overcome many programmatic and procedural hurdles, well-designed randomized prospective studies that are of adequate length to determine how AEDs ultimately relate to school performance and social adjustment are needed to firmly establish the cognitive and behavioral effects of AEDs in children.     

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain.     

Mood effects of antiepileptic drugs

This article reviews our knowledge about a specific subgroup of chronic CNS-related side effects of antiepileptic drugs (AED) treatment, i.e., the effects of AEDs on mood. In line with a recent hypothesis, using the experience of AED treatment in psychiatry, we examined whether mood effects are related to the known anticonvulsant mechanisms of action of the AEDs. Specifically we examined whether AEDs, acting through potentiation of GABAergic neurotransmitter release, have "sedating" effects on mood, whereas AEDs that act through the reduction of excitatory glutamate neurotransmitter release have "activating" effects on mood. The results of this review yield evidence that there are relationships between the known anticonvulsant mechanisms of action of the AEDs and mood effects. Mood effects occur especially when the drugs have a sustained effect on neuronal mechanisms, in particular when the inhibitory or excitatory neurotransmitter release is altered. Drugs with "use-dependent" impact on sodium or calcium channels probably have a more transient impact and do not lead to interictal stable mood effects. Drugs with multiple mechanisms of action seem to combine a favorable efficacy profile with an increased risk of severe mood problems. The quality of the evidence, however, is not conclusive and there are many paradoxical results. One reason for this lack of "fit" may be the use in this review of a simplified classification, based only on the predominant mechanism of action to classify a drug. Only a limited number of AEDs (ethosuximide, tiagabine) are characterized by a single anticonvulsant mechanism of action. Probably more detailed coupling of mechanisms of action (e.g., inspecting the type and route of impact on GABA release) and mood effects may give less confusing results. The use of magnetic resonance imaging techniques such as spectroscopy may provide interesting results.     

Adverse effects of antiepileptic drugs

Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.     

Adverse effects of antiepileptic drugs

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects.     

Adverse effects of antiepileptic drugs

Adverse effects of antiepileptic drugs (AEDs) are considered by patients to be at least as important as repetitive seizures in terms of quality of life. AED toxicity is frequent and contributes to a high proportion of treatment failures. Despite its high prevalence and clinical relevance, screening for adverse reactions to AEDs is not systematically included in everyday clinical practice; therefore it is very likely that it remains underestimated. Because there is little difference among AEDs in terms of efficacy, drug selection is often based on the adverse effects profile. AED toxicity is classified according to different parameters, such as severity, time of occurrence, organ system involvement, and mechanisms of action. Although most toxic reactions to drugs can be predicted from cumulative experience, prevention is not always possible, since multiple mechanisms and individual susceptibility to each drug participate in the final outcome. However, adverse effects can be reduced and appropriate action can be taken in time by means of a high degree of suspicion, knowledge of risk factors, and close follow-up. This article highlights factors to consider for detecting and managing AED adverse effects.     

Neurodevelopmental effects of antiepileptic drugs

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.     

Teratogenic effects of antiepileptic drugs

Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed.     

The spectrum of the new antiepileptic drugs

Over the last decade, many new drugs have been added to the therapeutic armamentarium for epilepsy. These drugs differ considerably in their mechanisms of action and, consequently, in their spectrum of efficacy against various seizure types. Oxcarbazepine, gabapentin, tiagabine and vigabatrin are especially useful in the management of partial seizures (with or without secondary generalization) and, probably, also primarily generalized tonic-clonic seizures, with vigabatrin being of particular value also in the treatment of infantile spasms. The spectrum of efficacy of lamotrigine and topiramate is broader than that of the other drugs and includes, in addition to partial and tonic-clonic seizures, also drop attacks associated with the Lennox-Gastaut syndrome. Lamotrigine is also effective against absence seizures, while the activity of topiramate as a potential anti-absence drug has not been adequately explored. Oxcarbazepine, vigabatrin and tiagabine may aggravate myoclonic and absence seizures and, likewise, gabapentin may aggravate myoclonic seizures. Therefore, the latter drugs should not be used (or used with great caution) in patients with syndromes associated with these seizure types. Apart from differences in spectrum of efficacy, side effect profiles also differ considerably from one drug to another, with the risk of serious adverse effects limiting considerably the use of felbamate and vigabatrin. When added to preexisting therapy in patients with refractory epilepsies, the new drugs improve seizure frequency in 15% to 40% of cases, but only rarely freedom from seizures is achieved. In newly diagnosed patients, the efficacy of the new drugs is similar to that of older agents, but further studies are required to confirm the claim that the tolerability of some of these agents is superior to that of established drugs such as carbamazepine or valproate. The new antiepileptic drugs represent a useful addition to the therapeutic armamentarium, but because of limited clinical experience and cost considerations their firstline use cannot be recommended in most situations.