Do antiepileptic drugs accelerate forgetting?

The majority of patients with epilepsy become seizure-free with antiepileptic drug therapy. However, seizures in approximately one-third of patients with epilepsy are difficult to treat with antiepileptic drugs and require high doses or polytherapy. High dosages increase the risk of cognitive side effects. We retrospectively investigated 162 patients with refractory temporal lobe epilepsy to determine whether the antiepileptic drugs carbamazepine, phenobarbital, and phenytoin affect the acquisition and retention of verbal and visual information. We found that patients with high serum levels of these antiepileptic drugs were selectively impaired in the retention but not acquisition of new information. Intelligence, age, duration of epilepsy, and seizure frequency were controlled for and were not factors in the observed results. There were no differences in favor of a certain drug with respect to memory functioning. Our results suggest that patients with refractory epilepsy with high serum levels of the antiepileptic drugs studied are at higher risk of accelerated forgetting.     

Neuropsychological performance and seizure-related risk factors in patients with temporal lobe epilepsy: a retrospective cross-sectional study

The aim of this study was to identify the neuropsychological features in patients with temporal lobe epilepsy (TLE) and their correlation with seizure-related variables. For this purpose, we carried out a retrospective analysis of data from 65 patients with TLE who had undergone a comprehensive neuropsychological assessment. The results suggest that the majority of patients with TLE were impaired in more than one cognitive domain, and among these patients, the mean proportions with defective semantic memory, language, motor/psychomotor speed, verbal episodic memory, and executive function were > 50% each. Moreover, age at seizure onset was the strongest predictor of general intellectual impairment, and number of antiepileptic drugs and seizure frequency could significantly predict deficits in verbal memory, language, and psychomotor speed. However, epilepsy duration was a less potent predictor of cognitive deficit than has been reported in cross-sectional studies.     

Neuropsychological performance and seizure-related risk factors in patients with temporal lobe epilepsy: A retrospective cross-sectional study

The aim of this study was to identify the neuropsychological features in patients with temporal lobe epilepsy (TLE) and their correlation with seizure-related variables. For this purpose, we carried out a retrospective analysis of data from 65 patients with TLE who had undergone a comprehensive neuropsychological assessment. The results suggest that the majority of patients with TLE were impaired in more than one cognitive domain, and among these patients, the mean proportions with defective semantic memory, language, motor/psychomotor speed, verbal episodic memory, and executive function were > 50% each. Moreover, age at seizure onset was the strongest predictor of general intellectual impairment, and number of antiepileptic drugs and seizure frequency could significantly predict deficits in verbal memory, language, and psychomotor speed. However, epilepsy duration was a less potent predictor of cognitive deficit than has been reported in cross-sectional studies.     

Computerized spectral analysis of the interictal EEG in epilepsy

Eight seizure patients without encephalopathy, frequent seizures, brain lesion, or medication intoxication had significant slowing of alpha-frequency activity, as compared to nonepileptic controls, that was evident in compressed spectral analysis but not in standard EEG. Those patients with cognitive or behavioral problems or taking more than one antiepileptic medication had a greater degree of slowing. Differences between seizure patients with and without cognitive or behavioral symptoms, and between specific antiepileptic drugs, were suggested but could not be assigned significance due to small numbers. The findings suggest that interictal changes in brain function that are not revealed by standard EEG may relate to observed changes in interictal behavior and cognition, and that computerized spectral analysis of the interictal EEG may be of value in the assessment of seizure patients before and during therapy.     

Neuropsychological development in children belonging to BECTS spectrum: Long-term effect of epileptiform activity

Benign epilepsy with centrotemporal spikes (BECTS) is an idiopathic focal epileptic syndrome in childhood. It is called “benign” because the seizure and cognitive outcomes are usually favorable, but a significant number of children with BECTS present heterogeneous cognitive deficits correlated to NREM sleep epileptiform discharges. The atypical evolutions of BECTS form a spectrum of conditions suggesting that slow sleep nocturnal interictal epileptiform discharges (IEDs) specifically determine the neuropsychological deficit.Few follow-up studies of neuropsychological outcome in BECTS are available, and very often, slow sleep has not been recorded throughout night sleep. The present study analyzed the long-term effects of IEDs during NREM sleep on neuropsychological development in children with rolandic spikes. Thirty-three children with a diagnosis of BECTS were monitored for at least two years. Results show that these children are at higher risk for residual verbal difficulties, and the abnormal neuropsychological development is significantly correlated with a greater frequency of NREM sleep discharges, school-age epilepsy onset, and a higher number of antiepileptic drugs (AEDs). The findings are discussed in terms of how slow sleep IEDs affect the consolidation of verbal skills during critical epochs of neuropsychological development.     

Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.     

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.     

Kognitive Beeinträchtigungen unter Add-on-Therapie mit Topiramat

In an open study, 37 epilepsy patients were investigated with regard to cognitive impairments in anticonvulsant add-on therapy with topiramate (TPM). In addition to a preexisting antiepileptic medication, TPM administration was started and increased by 25 mg/week. Cognitive side effects noted by the patient or doctor were assessed by a neuropsychological test battery. In 18/37 patients (49%), cognitive deficits consisting of impaired concentration, psychomotoric slowing, memory deficits, and dysphasia were observed. The adverse effects became apparent at dosages of 50-575 mg TPM/day (average 210 mg). In four patients, they were reversible after reducing the dose of TPM by 25-150 mg/day. In eight patients, the adverse effects led to withdrawal of TPM. In spite of slow titration, the present study showed a higher frequency of cognitive side effects under TPM than was previously reported. In some patients, these side effects led to substantial impairments in daily life and at work. For early recognition of cognitive impairments, neuropsychological baseline and follow-up investigations of verbal fluency, psychomotor processing speed, and verbal memory are recommended.     

Therapy for neurobehavioral disorders in epilepsy

Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.     

Therapy for Neurobehavioral Disorders in Epilepsy

Summary:  Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.     

Postictal Courses of Cognitive Deficits in Focal Epilepsies

Summary: Patients with epileptic seizures frequently complain of long-lasting cognitive impairment after a seizure. We evaluated this issue in 31 patients with epileptic seizures of a frontal (n = 8) or temporal lobe origin [right temporal lobe (RTL) n = 8/left temporal lobe (LTL) n = 151. Seizures were secondarily generalized in 18 patients. Computerized testing of verbal and nonverbal recognition memory was performed before the seizure, directly after postictal reorientation, and 30 min and 1 h later. Repeated testing of 14 healthy persons served as control. The following results were obtained: Depending on seizure generalization, postictal reorientation times were 1–45 min. Frontal lobe seizures showed no effect on postictal memory performances, but verbal and visual recognition memory was significantly decreased after temporal lobe seizures. Decrease in either verbal or visual memory and time of recovery were related to lateralization of seizure onset. Functional recovery after reorientation lasted 30 min to 1 h. The decrease in performance was more severe after generalized seizures. Decision times during memory performance were not significantly affected by the seizures. Temporal lobe seizures lead to circumscribed and long-lasting memory deficits, which can be assumed to affect patients'capabilities seriously. Preand postictal testing is a useful tool for determining postictal cognitive impairment and in determining the site of seizure onset.     

Differences in memory performance and other clinical characteristics in patients with mesial temporal lobe epilepsy with and without hippocampal atrophy

Mesial temporal lobe epilepsy (MTLE) is usually accompanied by memory deficits due to damage to the hippocampal system. In most studies, however, the influence of hippocampal atrophy (HA) is confounded with other variables, such as: type of initial precipitating injury and pathological substrate, effect of lesion (HA) lateralization, history of febrile seizures, status epilepticus, age of seizure onset, duration of epilepsy, seizure frequency, and antiepileptic drugs (AEDs). To investigate the relationship between memory deficits and these variables, we studied 20 patients with MTLE and signs of HA on MRI and 15 MTLE patients with normal high-resolution MRI. The findings indicated that (1) HA, earlier onset of seizures, longer duration of epilepsy, higher seizure frequency, and AEDs (polytherapy) are associated with memory deficits; and (2) there is a close relationship between deficits of verbal memory and left HA, but not between visual memory and right HA.     

Language Disturbances as Side Effects of Topiramate and Zonisamide Therapy

Reversible side effects of two sulfa-containing antiepileptic drugs (AEDs), topiramate (TPM) and zonisamide (ZNS), are reported. These effects differ from those of other AEDs in that language impairment was the predominant cognitive complaint. Information was available for 42 patients exposed to TPM. Twenty-two (52%) complained of adverse effects; 12, specifically of deficits in language-related functions. Brief neuropsychological testing in four patients on TPM confirmed verbal deficits. These deficits could appear shortly after initiating TPM and disappear variably after drug withdrawal. Similar complaints were seen in a pilot study of ZNS monotherapy, administered in supratherapeutic doses, confirmed by neuropsychological testing. TPM and ZNS both contain a sulfa moiety, suggesting that verbal processing is especially sensitive to these sulfa-containing AEDs.     

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.     

Psychopathology and pediatric complex partial seizures: seizure-related, cognitive, and linguistic variables

PURPOSE: This study examined the role of cognition, language, seizure-related, and demographic variables in the psychopathology of children with complex partial seizure disorder (CPS) of average intelligence. METHODS: One-hundred one CPS and 102 normal children, aged 5.1 to 16.9 years, had a structured psychiatric interview and cognitive and language testing. Parents provided demographic, perinatal, and seizure-related information, as well as behavioral information through the Child Behavior Checklist (CBCL) and a structured psychiatric interview about the child. RESULTS: Significantly more CPS patients had psychopathology, cognitive deficits, and linguistic deficits than did those in the normal group. Among the patients, Verbal IQ predicted the presence of a psychiatric diagnosis, as well as CBCL scores in the borderline/clinical range. Seizure, linguistic, and demographic variables were unrelated to psychopathology. The cognitive and linguistic deficits of the CPS group, however, were predicted by seizure factors (e.g., prolonged seizures/febrile convulsions; seizure frequency/number of antiepileptic drugs) and demographic factors (e.g., minority status). CONCLUSIONS: Because subtle verbal cognitive deficits predict behavioral disturbances in pediatric CPSs, the study's findings highlight the importance of assessing behavior, cognition, and language in these children. They also underscore the negative impact of prolonged seizures, febrile convulsions, seizure frequency, and antiepileptic drug polytherapy on cognition and language in pediatric CPSs.     

The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.

Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.     

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.     

Cognitive skills in children with intractable epilepsy: comparison of surgical and nonsurgical candidates

PURPOSE: To compare neuropsychological performance of two groups of children with intractable epilepsy: those who are surgical candidates, and those who are not. METHODS: Intelligence, verbal memory, visual memory, academic skills, and sustained attention were measured in children aged 6-18 years. The effects of number of antiepileptic drugs (AEDs), seizure frequency, age at seizure onset, and duration of seizure disorder were examined. RESULTS: Both groups had high rates of impairment. Group differences were found only on the verbal memory task. Children who experienced seizures in clusters had higher IQ, reading comprehension, and arithmetic scores. Age at seizure onset and proportion of life with seizures were related to IQ. Performance did not vary with AED monotherapy versus polytherapy. CONCLUSIONS: Few differences exist in cognitive performance between children with intractable seizures who are and those who are not surgical candidates. These findings suggest that children who are not surgical candidates can serve as good controls in studies on cognitive outcome of surgery.     

Accelerated cognitive decline in a rodent model for temporal lobe epilepsy

ObjectiveCognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy.MethodsNeurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance.ResultsRats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits.SignificanceThe effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy.     

Cognitive Consequences of Two-Thirds Anterior Temporal Lobectomy on Verbal Memory in 144 Patients: A Three-Month Follow-Up Study

Previous studies have shown that left temporal lobectomy for intractable epilepsy can lead to verbal memory deficits. However, patients with left temporal lobe epilepsy (LTLE) frequently have impaired verbal memory preoperativel. The present analysis of 144 patients who underwent temporal lobe resections for either left (n = 68) or right (n = 76) temporal lobe epilepsy (LTLE, RTLE) addressed the questions of (a) whether a left two-thirds anterior temporal lobectomy (ATL) increases deficits in these qualitative aspects of verbal memory already impaired preoperatively, and (b) whether other aspects of verbal memory are additionally affected. We also evaluated possible determinants of preoperative abilities and postoperative changes, using multiple regression analysis. Preoperatively, patients with LTLE differed from patients with RTLE only in poorer performance on measures of long-term consolidation/retrieval (delayed recall). This was related to hippocampal pathology and seizure severity. Only left temporal lobe resections resulted in significant deterioration in verbal learning and memory. Acquisition over learning trials and recognition deteriorated most markedly, whereas performance in long-term consolidation/retrieval showed only minor changes. Preoperative performance levels, chronological age, the extent of the en bloc resection, preoperative performance on figural memory, and preoperative seizure severity were valuable determinants of postoperative changes in acquisition and recognition. In contrast, changes in consolidation/retrieval related only to preoperative ability. Left two-thirds ATL leads to new impairment in addition to preexisting memory deficits. The finding that left temporal lobectomy affects verbal acquisition and recognition more than long-term consolidatiodretrieval, including the different determinants of these changes, most likely reflects the differential effects of surgery on mesial temporal and neocortical temporal functions.