Epilepsy and cognition

Patients with epilepsy are more prone to cognitive and behavioral deficits. Epilepsy per se may induce or exacerbate an underlying cognitive impairment, a variety of factors contribute to such deficits, i.e., underlying neuropathology, seizure type, age of onset, psychosocial problems, and treatment side effects. Epilepsy treatment may offset the cognitive and behavioral impairments by stopping or decreasing the seizures, but it may also induce untoward effects on cognition and behavior. The neurocognitive burden of epilepsy may even start through in utero exposure to medications. Epilepsy surgery can also induce certain cognitive deficits, although in most cases this can be minimized. Clinicians should consider cognitive side effect profiles of antiepileptic medications, particularly in extreme age groups. While no effective treatments are available for cognitive and behavioral impairments in epilepsy, comprehensive pretreatment evaluation and meticulous selection of antiepileptic drugs or surgical approach may minimize such untoward effects.     

Discontinuation of Antiepileptic Drugs in Children Who Have Outgrown Epilepsy: Effects on Cognitive Function

Summary: Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls.     

Effect of Seizures and Epileptiform Discharges on Cognitive Function

Summary: Several relationships have been obtained between cognitive impairment and epilepsy-related or treatment-related factors. One of these factors is treatment-related: the central cognitive side effects of the antiepileptic drugs (AEDs). The second and third factors are disease-related factors, i.e., the effect of the seizures and underlying epileptiform discharges in the brain and the localization of the epileptogenic focus in specific areas of the brain. Although most cognitive problems have a multifactorial origin and often several factors combined are responsible for the "make-up" of a cognitive problem, we have attempted to isolate one factor: the effect of seizures and epileptiform EEG discharges on cognitive function. Several studies show the impact of ictal activity, but special attention is required for the postictal and interictal effects of epilepsy on cognitive functions. This may explain substantial cognitive impairments in children with subclinical epileptiform discharges or with infrequent subtle seizures.     

Dravet syndrome and SCN1A gene mutation related-epilepsies: cognitive impairment and its determinants

Some studies have demonstrated that cognitive decline occurs in Dravet syndrome, starting shortly after the onset of seizures, rapidly progressing and then plateauing within a few years. It is unclear whether children that develop the syndrome had entirely normal cognitive skills before seizure onset, since subtle impairment easily escapes recognition in small infants. It is also difficult to demonstrate whether a recognisable profile of cognitive impairment or a definite behavioural phenotype exists. No clear-cut imaging or neuropathological marker or substrate has been recognised for cognitive impairment in this syndrome. However, there are different potentially causative factors, including the specific effects on the Nav1.1 channels caused by the underlying genic or genomic defect; frequent and prolonged convulsive and non-convulsive seizures or status epilepticus; recurrent subtle ictal phenomena, such as that accompanying pronounced visual sensitivity; the use of antiepileptic drugs with cognitive side effects, especially in heavy multiple-drug therapy; and the restrictions that children with severe epilepsy inevitably undergo.     

Differential cognitive effects of antiepileptic drugs

As a group, children and adolescents with epilepsy have a higher prevalence of cognitive and behavioral disorders, although many fall within the normal distribution. For those affected, several causes have been identified, some of which may be interrelated. It has proven to be methodologically sound to isolate the role of specific antiepileptic drugs as a cause of cognitive impairment. The large body of literature that has accumulated on this topic is characterized by a relatively high proportion of inconclusive or contradictory observations. This may be due in part to the many methodological pitfalls in this area of research. The emerging picture is that cognitive effects caused by antiepileptic drugs are neither the rule nor the exception. Although certain drugs appear more likely to be involved, no single drug causes problems in every patient, and no drug can be assumed never to cause any cognitive impairment. The subgroup of patients that are at higher risk cannot be easily defined. Early detection of cognitive effects is based on actively eliciting reports of symptoms. This can be complemented by a screening battery in case of suspicion.     

药物治疗：有希望解决儿童精神认知问题

Subclinical electroencephalogram discharges in children with psycho-cognitive problems are not uncommon. However, the clinical importance and relationship to cognitive deficits, as well as indications for medical treatment, are not well understood. Transient cognitive impairment, which accompanies electroencephalogram discharges, could negatively influence cognitive abilities over time. Studies have suggested that treatment with antiepileptic drugs normalizes electroencephalogram results, thereby preventing electrical paroxysmal discharges that could be harmful to the developing brain. Physicians should attempt to differentiate between corresponding factors, such as subtle seizures, nature of underlying etiology, stable cognitive deficits, seizure-inducing effects, and potential side effects of antiepileptic drugs prior to initiation of medical treatment for definitive diagnosis of transient cognitive impairment and its consequences. Therefore, appropriate criteria for patient selection and proper guidelines for medical therapy, should be addressed in future studies.     

Kognitive Nebenwirkungen neuer Antikonvulsiva

In the treatment of epilepsy adverse effects of medication must be recognized as being as important as seizure freedom. Cognitive deficits often occur in chronic epilepsy and may sometimes reflect adverse effects of antiepileptic drugs. However, the successful treatment of seizures frequently outweighs these adverse cognitive effects. Adverse cognitive effects of medication mostly concern certain cognitive domains, such as attention or executive functions but memory and language disturbances may also occur. Psychiatric comorbidity, e.g. depression has detrimental effects on cognition which should be considered when mood stabilizing drugs are withdrawn. With the exception of topiramate, most of the newer antiepileptic drugs seem to have a favorable profile of adverse effects on cognition; however, only few studies have directly compared cognition between newer and classic antiepileptic drug treatment. In the individual patient, standardized neuropsychological assessment may help to detect even subtle signs of cognitive decline and to improve the evaluation of the cause of (subjective) cognitive decline.     

Antiepileptic Drugs, Cognitive Function, and Behavior in Children: Evidence from Recent Studies

Summary: The effects of antiepileptic drugs (AEDs) on cognitive function and behavior in children are reviewed on the basis of published studies. Individual AEDs have been shown to differ–the deleterious effects of phenytoin generally contrasting with the relatively minimal effects of valproate and carbamazepine. Some of the differences between results may be attributed to the psychological tests used and to age differences. However, there appears to be a dissociation between AEDs that affect higher cognitive function, e.g., phenytoin, and those mainly affecting motor function, e.g., carbamazepine, which appears to increase speed of performance. AEDs should be prescribed with care in children with epilepsy, taking account of their differing effects on cognitive function and behavior.     

Treatment of epilepsy in adults. Options and strategies

Currently, epilepsy can be treated with antiepileptic drugs and, in patients with focal and/or secondarily generalized seizures (focal epilepsy), by means of surgery and vagus nerve stimulation. In the choice of monotherapy possible negative drug related effects on cognitive, endocrine, and psychic symptoms must be considered. Newly developed antiepileptic drugs help to establish an individualized strategy, especially in antiepileptic drug monotherapy. Additionally these antiepileptic drugs have proven to be effective and well tolerated when combined with other antiepileptic drugs. Surgery of focal epilepsy offers the chance of complete cure. Vagus nerve stimulation is a nonmedical treatment option used in addition to antiepileptic drugs in patients with focal epilepsy. Tolerability and safety data should be considered to establish a long-term medical treatment tolerated and accepted by the patient.     

Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress

Conventional antiepileptic drugs fail to adequately control seizures and predispose to cognitive impairment and oxidative stress with chronic usage in a significant proportion of patients with epilepsy. Coenzyme Q10 (CoQ10), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. To evaluate the neuroprotective effects of CoQ10 in rats against the observed oxidative stress during seizures induced by pilocarpine, and to study its interactions with the conventional antiepileptic drug phenytoin, two experiments were performed. Experiment 1 was conducted to test the effect of phenytoin, CoQ10, or both on seizure severity and oxidative markers in the pilocarpine model of epilepsy. Experiment 2 was conducted to test the effect of 2 weeks of chronic treatment with phenytoin, CoQ10, or both on oxidative markers and behavioral tests in rats. Overall, CoQ10 reduced the severity of pilocarpine-induced seizures and the severity of oxidative stress. Moreover, it potentiated the antiepileptic effects afforded by phenytoin treatment, with the potential safety and efficacy in ameliorating oxidative stress and cognitive impairment caused by chronic phenytoin therapy. Our findings strongly suggest that CoQ10 can be considered a safe and effective adjuvant to phenytoin therapy in epilepsy both to ameliorate seizure severity and to protect against seizure-induced oxidative damage by reducing the cognitive impairment and oxidative stress associated with chronic use of phenytoin.     

认知功能评定方法在癫中的应用

癫是一种慢性疾病,因其疾病的特殊性质及抗癫药物的长期应用,患者常合并有程度不等的认知功能障碍。认知功能是癫的重要预后指标之一,对认知功能障碍程度的评定既可用于判断预后和指导康复治疗,也可为相关临床科研工作提供统一量化、有较好可比性的数据。对癫患者的认知功能评定越来越引起临床和科研工作者的注意,2011年国际抗癫联盟(ILAE)发布了癫神经心理并发症的治疗指南,其中包括癫相关的认知功能异常评估和处理指南,强调应向癫患者及家属宣教认知功能的相关知识,并应由专业的临床神经心理学者对癫患者进行认知功能评定。本文复习癫认知评定方法的有关文献,对近年在此方面的研究作介绍。     

Management of epilepsy in mentally retarded children using the newer antiepileptic drugs, vagus nerve stimulation, and surgery

Clusters of seizures, prolonged seizures, and status epilepticus occur more frequently in children with multiple disabilities, and chronic seizures are more likely to be refractory to treatment. In many patients, the seizures appear to contribute to the mental retardation. Thus, if the lives of these children are to improve, seizure control is essential. However, medical treatment can interfere with cognition and cause behavioral disturbances, making life very difficult for the child and the child's family. With the introduction of 10 new antiepileptic drugs in the last decade, the treatment of epilepsy in multiply handicapped children has significantly advanced. These new antiepileptic drugs may improve seizure control, medication tolerance, or both. Although the ultimate therapeutic goal is to keep children seizure free and alert, compromises regarding medication choice and dosage are still necessary in many cases. Novel treatment options, such as the vagus nerve stimulator, may decrease seizure frequency without behavioral or cognitive side effects. In carefully selected children with specific epilepsy syndromes, epilepsy surgery can provide partial or complete relief from seizures.     

Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients

Multiple factors-including the efficacy of the antiepileptic drug for the particular seizure type, availability of pediatrics-friendly formulations, the ease of dosing and titration, and tolerability issues, such as possible drug interactions and adverse events-affect the selection of the best antiepileptic drug for a child with epilepsy. Behavioral problems are common in children with epilepsy and can be aggravated or initiated by antiepileptic drug therapy. The types and frequencies of antiepileptic drug-associated behavioral events can influence a clinician's drug selection, drug management, and counseling of parents. Unfortunately, appreciating differences among antiepileptic drugs in behavioral adverse event profiles is problematic because, among other reasons, methodologies for reporting, collecting, and analyzing adverse events are not uniform across trials, and there is marked heterogeneity in study design among trials. This review summarizes incidence rates for behavioral and psychiatric adverse events taken from studies of children with epilepsy. These rates are reported for the 10 most commonly prescribed antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, lamotrigine, phenytoin, levetiracetam, oxcarbazepine, topiramate, zonisamide, and gabapentin), grouped according to their predominant mechanism of action. Despite the numerous methodologic inconsistencies, some similarities in adverse event profiles among antiepileptic drugs that share mechanisms of action are apparent. Moreover, the overwhelming body of data on the behavioral effects of phenobarbital should convince clinicians that, whenever possible, it should not be used as the initial-or even the second-monotherapy in children with epilepsy.     

Predictors of neuropsychological impairment in seizure-free epilepsy patients

Persons with epilepsy are at increased risk of cognitive deficits as a result of various factors like etiology, structural brain lesions, seizure frequency, seizure type, age at onset of epilepsy, hereditary factors, psychosocial factors, and possible adverse effects of antiepileptic drugs (AEDs). Despite the fact that the majority of epilepsy patients are seizure-free, previous studies on the relationship between epilepsy-related variables and cognitive function have mainly been conducted on patients with persisting seizures. In this study 158 adults with epilepsy on AED monotherapy and without epileptic seizures for at least 2 years were investigated with a neuropsychological test battery in addition to a neurological examination, MRI and EEG. The major findings were that the group had education and employment status similar to the population mean and neuropsychological function in the normal range. In the patient group without idiopathic generalized epilepsy known cerebral etiology was found to be a highly significant predictor of neuropsychological deficit. For patients with idiopathic generalized epilepsy, early seizure debut at < or =18 years was a powerful predictor of neuropsychological impairment.     

Education and Epilepsy: Assessment and Remediation

Summary: Learning difficulties in children with epilepsy may be caused by brain damage and should be investigated. In many cases, however, seizures and/or electroencephalographic (EEG) findings are the only signs of pathology. Frequency and type of seizures may be determining factors that should, if necessary, be evaluated by long-term EEG monitoring, preferably during school performance or in conjunction with neuropsychological assessment. This may prove that subclinical epileptiform discharges in the EEG can adversely affect the child's performance. Secondary psychological problems in epilepsy patients, combined with side effects of antiepileptic drugs, may cause or heighten learning problems. Prophylactic control of seizures with one appropriate drug may alleviate learning problems. Computerized neuropsychological testing with simultaneous EEG recording may reveal the influence of epileptiform discharges on cognitive function and also help to evaluate the effects of antiepileptic drugs. Objective assessment of subclinical epileptiform activity makes it easier to treat the pathology identified by the EEG with optimal dosage of the most appropriate drug. A balance is required because epileptiform discharges and even occasional seizures may be less disabling than side effects from large doses of several drugs. Information to the school and the parents concerning the patient's abilities and limitations may be as important as seizure control. Specialized teaching should be started early, when necessary, with the patient integrated into a normal school if possible. However, good functioning in a special school is preferable to marginal functioning in a normal school.     

Learning Disabilities in Epilepsy: Neurophysiological Aspects

Summary: Subclinical generalized spike-wave discharges are often accompanied by transitory cognitive impairment, demonstrable by psychological testing during EEG recording. Transitory cognitive impairment is demonstrated most readily by difficult tasks and during generalized regular spike-wave bursts lasting for more than 3 s, but can also be found during briefer and even focal discharges. That this is not simply a consequence of global inattention is shown by the fact that focal discharges exhibit some specificity: left-sided focal spiking is more likely to produce errors on verbal tasks, for instance, whereas right-sided discharges are more often accompanied by impairment in handling nonverbal material. Both learning difficulties in general and specific abnormal patterns of cognitive functioning are well documented in children with epilepsy and are most pronounced in those with frequent interictal discharges. However, there is now evidence that intermittent cognitive impairment due to the discharges themselves contributes significantly to such neurophysiological abnormalities. The significance of transitory cognitive impairment accompanying subclinical EEG discharges for everyday functioning is uncertain, but there is experimental evidence that subclinical discharges may be accompanied by disruption of educational skills in children or by impairment of driving performance in motorists. In some individuals, suppression of discharges by antiepileptic drugs has demonstrably improved psychological function, but further work is required to determine the indications for such treatment     

Attention deficit hyperactivity disorder in children with epilepsy

Attention deficit hyperactivity disorder (ADHD) is more frequent in children with epilepsy than in general pediatric population. Several factors may contribute to this comorbidity, including the underlying brain pathology, the chronic effects of seizures and of the epileptiform EEG discharges, and the effects of antiepileptic drugs. Symptoms of ADHD are more common in some specific types of epilepsies, such as frontal lobe epilepsy, childhood absence epilepsy and Rolandic epilepsy, and may antedate seizure onset in a significant proportion of cases. In epileptic children with symptoms of ADHD, treatment might become a challenge for child neurologists, who are forced to prescribe drugs combinations, to improve the long-term cognitive and behavioral prognosis. Treatment with psychotropic drugs can be initiated safely in most children with epilepsy and ADHD symptoms.     

Changes in color vision after a single dose of vigabatrin or carbamazepine in healthy volunteers

In patients with epilepsy the older antiepileptic drugs induce distinct electroencephalographic changes and may also alter visual function. Although the effects of the newer antiepileptic drugs on the electroencephalogram remain less clear, long-term treatment with vigabatrin (VGB) has been reported to induce severe and permanent visual impairment. Our aim in this study was to investigate the effects of a single oral dose of VGB and carbamazepine (CBZ) on visual function in normal healthy volunteers randomly assigned to three groups according to a single-blind, placebo-controlled design. All subjects underwent color visual evoked potential tests and color perimetry at baseline and after receiving placebo, VGB (2,000 mg) or CBZ (400 mg). Whereas CBZ induced a mild overall impairment of the chromatic and achromatic systems, VGB induced a selective blue impairment. The differential changes the two antiepileptic drugs induced in visual tests presumably depend on their different mechanisms of action. The selective blue impairment in color visual tests in VGB-treated healthy subjects is consistent with gamma-aminobutyric acid (GABA)-ergic inhibition also at retinal level. Hence, color visual tests may be suitable to detect initial visual abnormalities in VGB-treated patients with epilepsy.     

The effect of seizure type and medication on cognitive and behavioral functioning in children with idiopathic epilepsy

Antiepileptic drugs have been reported to have a variety of adverse effects on behavior and performance in children with epilepsy. Previous studies investigating these side effects, however, have not controlled for the baseline status of the child (e.g. underlying neurological condition, seizure type, socioeconomic status, family variables), making it difficult to determine whether changes in function are attributable to the use of medication. We investigated the cognitive and behavioral profiles of 43 children, aged from 4 to 16 years, with new onset, idiopathic seizures. Twenty-six of these children participated in a 6-month follow-up study, and 12 in a 12-month follow-up study, investigating the effects of antiepileptic medications on psychological functioning. The children were of average intelligence (mean 1Q108) and had not previously been treated with antiepileptic medication. Children were classified as having either generalized convulsive, generalized non-convulsive (absence), simple partial, or complex partial seizures. Prior to the initiation of treatment, children with partial seizures were found to perform better than children with generalized seizures on measures of cognitive functioning. Children with convulsive seizures obtained significantly higher cognitive scores than those with non-convulsive seizures. Children with generalized non-convulsive seizures had lower cognitive scores than subjects with other types of seizure. No differences were found between groups at baseline prior to the initiation of antiepileptic medications. Analysis of subjects' performance after 6 and 12 months of antiepileptic therapy showed no significant deterioration attributable to medication. The differences in cognitive performance of the four seizure groups at baseline were not apparent at the time of follow-up. These results indicate that intrinsic and environmental variables may play a more significant role in predisposing certain children to cognitive and learning problems than do antiepileptic medications.     

Epilepsie und Gedächtnisbeeinträchtigungen

Many patients with epilepsy complain memory deficits that may impair their quality of life. The authors briefly review the concepts of memory diagnostics. Specific memory deficits have to be distinguished from other cognitive disturbances like attention deficits or slowing of mental speed. The influence of structural lesions on memory especially within the mesial temporal lobes is discussed. The authors also consider effects of antiepileptic drugs and epileptic brain activity on memory. Moreover, the risks and benefits of epilepsy surgery on memory functions are described. If memory is at risk due to an epileptogenic lesion, epileptic neuronal activity, or antiepileptic drugs, diagnostics and therapy should consider the complex issue of memory distortions.