Brivaracetam for the treatment of refractory epilepsy in patients with prior exposure to levetiracetam: A retrospective outcome analysis.

PURPOSE: To determine whether brivaracetam (BRV) provides an evident improvement in treatment efficacy and a reduction in treatment-emergent adverse events (TEAEs) in patients with refractory epilepsy, who previously failed treatment with levetiracetam (LEV). DESIGN: Retrospective analysis of data extracted from electronic patient files at Epilepsy Centre Kempenhaeghe (Heeze, the Netherlands) from the year 2000 until October 2020. METHODS: The inclusion criteria were met by 407 patients >18 years of age. During data collection, 26 patients were excluded due to too little follow-up information on the use of either LEV or BRV, and two more due to poor medication compliance, leaving a total of 379 patients for further analyses. All had used LEV before they started treatment with BRV. For every patient, data were collected including demographic information, efficacy (positive responder or non-responder) of LEV and BRV, and TEAEs occurring during LEV and BRV treatment. RESULTS: A total of 121 (29.8%) patients had discontinued BRV treatment before the end of data collection. At time of data collection the mean time since first seizure was 25.4 years. Of the 379 patients, 82.8% were diagnosed with focal epilepsy and 9.8% with generalized epilepsy. The median duration of treatment was 39 months for LEV and 20 months for BRV, the mean maximum dose was 1749.9 mg/day for LEV and 144.2 mg/day for BRV, and the mean number of concomitant AEDs was 1.4 at the start of LEV treatment and 2.0 at the start of BRV treatment. LEV was switched directly to BRV in 208 (54.9%) patients; 171 (45.1%) patients had an interval between discontinuation of LEV and the start of BRV. The mean duration of interval was 77.7 months. Of the patients who discontinued BRV, 30 (24.8%) switched back to LEV. Discontinuation of initial LEV treatment was due to TEAEs in 63.6% of patients, including 55.1% because of behavioural TEAEs. Discontinuation of BRV was due to inadequate efficacy in 24.0% of patients, to TEAEs in 47.1% and to both inadequate efficacy and TEAEs in 22.3%. Concerning efficacy, the analysis showed no significant difference between the positive responder rate of LEV and BRV (72.0% vs 69.1%, p>0.05). Of the patients who were positive responders to LEV treatment, 78.0% also had a positive response to BRV treatment. Of the non-responders to LEV treatment, 46.2% did have a positive response to BRV treatment. In comparison to LEV, patients reported significantly fewer TEAEs during BRV treatment (86.5% vs 61.7%, p<0.05). The most substantial difference was seen in the category 'behaviour' (55.1% vs 22.4%, p<0.05). Newly found behavioural TEAEs after switching from LEV to BRV were found in 7.1% of patients. CONCLUSION: Overall BRV was better tolerated than LEV, especially regarding the behavioural TEAEs. Efficacy analyses showed that patients are likely to have a positive response to BRV when they had a positive response to LEV. However, this is not always guaranteed. Lack of response to LEV does not preclude a positive response to BRV. All in all, BRV seems to be an interesting treatment option in patients previously treated with LEV.

Cognitive benefits of the ketogenic diet in patients with epilepsy: A systematic overview.

The ketogenic diet (KD) has been found to be effective in reducing seizures in patients with treatment-refractory epilepsy. Less attention has been paid to additional cognitive benefits of KD. The aim of the present paper was to provide a comprehensive overview of the studies reporting effects on cognition after KD treatment in adults and children with epilepsy. To address this aim, the clinical literature on cognitive effects of KD in patients with epilepsy was reviewed using a systematic approach. We conclude that using subjective assessments of the patient's experience, cognitive improvements are frequently reported during KD treatment in the domains of alertness, attention, and global cognition. Studies that used objective neuropsychological tests confirmed benefits on alertness but found no improvement in global cognition. There are indications that these improvements are caused by both seizure reduction and direct effects of KD on cognition. The improvements appear to be unrelated to medication reduction, age when KD is started, type of KD, and sleep improvement. The findings in the present overview contribute to a better understanding of the beneficial effects of KD in patients with epilepsy.

Chronic antiepileptic drug use and functional network efficiency: A functional magnetic resonance imaging study.

AIM: To increase our insight in the neuronal mechanisms underlying cognitive side-effects of antiepileptic drug (AED) treatment. METHODS: The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients with epilepsy with a different risk profile for developing cognitive side effects were included: A "low risk" category (lamotrigine or levetiracetam, n = 16), an "intermediate risk" category (carbamazepine, oxcarbazepine, phenytoin, or valproate, n = 34) and a "high risk" category (topiramate, n = 5). Brain connectivity was assessed using resting state functional magnetic resonance imaging and graph theoretical network analysis. The Computerized Visual Searching Task was used to measure central information processing speed, a common cognitive side effect of AED treatment. RESULTS: Central information processing speed was lower in patients taking AEDs from the intermediate and high risk categories, compared with patients from the low risk category. The effect of risk category on global efficiency was significant (P < 0.05, ANCOVA), with a significantly higher global efficiency for patient from the low category compared with the high risk category (P < 0.05, post-hoc test). Risk category had no significant effect on the clustering coefficient (ANCOVA, P > 0.2). Also no significant associations between information processing speed and global efficiency or the clustering coefficient (linear regression analysis, P > 0.15) were observed. CONCLUSION: Only the four patients taking topiramate show aberrant network measures, suggesting that alterations in functional brain network organization may be only subtle and measureable in patients with more severe cognitive side effects.

Glutamate concentrations vary with antiepileptic drug use and mental slowing.

OBJECTIVE: Although antiepileptic drugs (AEDs) are effective in suppressing epileptic seizures, they also induce (cognitive) side effects, with mental slowing as a general effect. This study aimed to assess whether concentrations of MR detectable neurotransmitters, glutamate and GABA, are associated with mental slowing in patients with epilepsy taking AEDs. METHODS: Cross-sectional data were collected from patients with localization-related epilepsy using a variety of AEDs from three risk categories, i.e., AEDs with low, intermediate, and high risks of developing cognitive problems. Patients underwent 3T MR spectroscopy, including a PRESS (n=55) and MEGA-PRESS (n=43) sequence, to estimate occipital glutamate and GABA concentrations, respectively. The association was calculated between neurotransmitter concentrations and central information processing speed, which was measured using the Computerized Visual Searching Task (CVST) and compared between the different risk categories. RESULTS: Combining all groups, patients with lower processing speeds had lower glutamate concentrations. Patients in the high-risk category had a lower glutamate concentration and lower processing speed compared with patients taking low-risk AEDs. Patients taking intermediate-risk AEDs also had a lower glutamate concentration compared with patients taking low-risk AEDs, but processing speed did not differ significantly between those groups. No associations were found between the GABA concentration and risk category or processing speed. CONCLUSIONS: For the first time, a relation is shown between glutamate concentration and both mental slowing and AED use. It is suggested that the reduced excitatory action, reflected by lowered glutamate concentrations, may have contributed to the slowing of information processing in patients using AEDs with higher risks of cognitive side effects.

The Cognitive Profile of Ethosuximide in Children.

INTRODUCTION: Although ethosuximide is one of the oldest antiepileptic drugs (AEDs), little information is available about the cognitive side effects of ethosuximide. OBJECTIVE: The aim of this study was to investigate the cognitive profile of ethosuximide. METHODS: In this cross-sectional study, we used an extensive neuropsychological test battery in patients with epilepsy aged 6-16 years who were treated with monotherapy ethosuximide. We evaluated the efficacy of the drug by seizure frequency (seizure free or not). RESULTS: We included 61 patients with a mean age of 9.4 years [standard deviation (SD) 2.7] who used on average 686 mg/day (SD 245) ESM as monotherapy. ESM was effective in the majority of the patients (70 % were seizure free for at least 6 months at moment of inclusion). The total study population showed impairments of intelligence, visuomotor, and attentional function including activation/alertness. Comparisons between the well-controlled patients and patients who were not in remission showed significantly lower intelligence values and lower performance on the visual-perceptual and attentional tasks for the group with ongoing seizures. Our results suggested that the higher order cognitive dysfunctions (such as intelligence and visual-perceptual functions) may be regarded as seizure or aetiology effects and that the impaired fluid cognitive functions, such as activation/alertness, sustained auditory attention and attentional control or switching, were due to ESM. CONCLUSION: This study suggests the attentional dysfunction resulting in psychomotor slowing and alertness deficits may be regarded as effects of ethosuximide. Although no untreated baseline assessment was available, these effects are comparable to those of other AEDs, and ethosuximide may therefore be considered an AED with only mild effects on cognition. As ethosuximide is a first-line therapy for absence seizures in childhood, and drug-induced cognitive impairment may interfere with development, learning, and academic achievement, these findings are of interest to clinicians who prescribe this drug, especially when informing parents.

Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial.

PURPOSE: The ketogenic diet (KD) is increasingly used for the treatment of refractory epilepsy in childhood because of the beneficial effect on seizure reduction. The aim of the current study was to objectively assess cognition and aspects of behavior during the first 4months of a randomized controlled study in children and adolescents. METHODS: Participants from a tertiary epilepsy center were randomized to a KD group (intervention) or a care-as-usual (CAU) group (control). Follow-up assessments on cognition and behavior were performed approximately 4months after initiation of the KD with a combination of parent report questionnaires and individually administered psychological tests for the children. RESULTS: A total of 50 patients were enrolled in this study, 28 patients from the KD group and 22 patients from the CAU group. The KD group showed lower levels of anxious and mood-disturbed behavior and was rated as more productive. Cognitive test results showed an improvement of activation in the KD group. CONCLUSIONS: This study showed a positive impact of the KD on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, an activated mood and cognitive activation were observed in patients treated with the KD.

Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review.

As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects.

Behavioral side-effects of levetiracetam in children with epilepsy: a systematic review.

PURPOSE: Children with epilepsy are more likely to have behavioral problems compared to children without epilepsy. Literature suggests that levetiracetam leads to behavioral side-effects in children with epilepsy. The objective of this study is to provide a better overview of the frequency and variety of behavioral side-effects, which can be initiated by levetiracetam therapy in children with epilepsy. METHOD: Electronic databases used in the search were PubMed, Medline, Cochrane and Embase. Studies were eligible for inclusion when they included children from one month to 18 years of age with a diagnosis of epilepsy, used levetiracetam, had other AEDs on a stable regimen for at least two months, reported about behavioral side-effects and had a follow-up of at least two weeks. Quality assessments and data collection were carried out for all eligible studies. RESULTS: Thirteen studies, including 727 patients using levetiracetam, were included in this systematic review. Three randomized controlled trials showed a total of 62 behavioral side-effects in 203 patients, effects which led to discontinuation of levetiracetam in only two of 102 patients (2.0%). Hostility, nervousness and aggression were reported mostly. Meta-analysis showed a statistically significant relative risk of 2.18 for the total number of behavioral side-effects for levetiracetam versus placebo. Observational studies showed mixed results with both behavioral deteriorations and improvements following levetiracetam. CONCLUSION: Based on the findings in this systematic review, children using levetiracetam have a risk of developing several behavioral side-effects such as aggression, hostility and nervousness compared to children who do not use levetiracetam.

Cognitive side-effects of antiepileptic drugs in children.

Although the causes of cognitive impairment in patients with epilepsy have not been completely elucidated, three factors are clearly involved: the underlying etiology of epilepsy, the effects of seizures or the epileptiform EEG discharges themselves, and the central nervous system effects of antiepileptic drugs (AEDs). All commonly used AEDs have some effect on cognitive function, and the effect may be substantial when crucial functions are involved, such as learning in children. With phenobarbital, there is a high risk for serious cognitive effects impacting attention and memory. Phenytoin may affect mental speed, mainly in higher dosing and polytherapy. Moderate monotherapy doses do not seem to induce much effect. Valproate does not seem to impair cognition if sufficiently controlled for hyperammonemia. For carbamazepine, there are conflicting reports, which may be due to selection bias or dosing. For oxcarbazepine, there is no evidence for any detrimental change compared to valproate but mild improvements on attentional tests. For topiramate, there is clear evidence for topiramate-induced cognitive impairment (attention, memory, and language function) in adults and children. Although data is sketchy, levetiracetam does not seem to have a negative impact on cognition. For lamotrigine, there is evidence of a cognitive-enhancing effect on attention. No evidence for cognitive side-effects has been found for vigabatrin. Ethosuximide is not associated with cognitive impairment although the evidence is sketchy. For gabapentin, tiagabine, zonisamide, and rufinamide no studies in children are available.

Cognitive and behavioural findings in children with frontal lobe epilepsy.

BACKGROUND: Frontal Lobe Epilepsy (FLE) is the second most frequent type of partial epilepsy and its onset is generally in childhood. Though cognitive and behavioural impairments have been described as co-morbid disorders in epilepsy, their extent in FLE, particularly in children, remains unknown. AIMS: In this study, we assess cognitive skills and behaviour in a cohort of paediatric FLE patients. METHODS: We measured the performance of 71 children with cryptogenic FLE on intelligence tests, neuropsychological tests, and behavioural questionnaires. Age-dependent normative values were used for reference. Results were related to epilepsy-factors including age at epilepsy onset, duration of epilepsy, seizure frequency, localisation of the epileptic focus and drug load. RESULTS: Paediatric FLE patients performed worse on intellectual and neuropsychological tests compared to reference values, and had a delay in school achievement. The performance of patients was typically worse on tasks measuring visual-spatial functions, memory, psychomotor speed and alertness. High seizure frequency was associated with lower scores on the arithmetic subtest of the intelligence scale; the other epilepsy-factors had no statistically significant influence on intelligence test or neuropsychological test outcome. Behavioural problems included attention problems, anxiety and internalising behaviour. These were not significantly related to epilepsy-factors. CONCLUSIONS: Children with cryptogenic FLE show a broad range of cognitive and behavioural impairments, compared to reference values. While high seizure frequency may affect performance on selected cognitive measures, other epilepsy-factors do not seem to influence cognition and behaviour. Study of micro-structural or functional brain abnormalities that underlie these cognitive and behavioural impairments are warranted.