Sleep homeostasis, seizures, and cognition in children with focal epilepsy.

AIM: To investigate the link between sleep disruption and cognitive impairment in childhood epilepsy by studying the effect of epilepsy on sleep homeostasis, as reflected in slow-wave activity (SWA). METHOD: We examined SWA from overnight EEG-polysomnography in 19 children with focal epilepsy (mean [SD] age 11 years 6 months [3 years], range 6 years 6 months-15 years 6 months; 6 females, 13 males) and 18 age- and sex-matched typically developing controls, correlating this with contemporaneous memory consolidation task scores, full-scale IQ, seizures, and focal interictal discharges. RESULTS: Children with epilepsy did not differ significantly from controls in overnight SWA decline (p = 0.12) or gain in memory performance with sleep (p = 0.27). SWA was lower in patients compared to controls in the first hour of non-rapid eye movement sleep (p = 0.021), although not in those who remained seizure-free (p = 0.26). Full-scale IQ did not correlate with measures of SWA in patients or controls. There was no significant difference in SWA measures between focal and non-focal electrodes. INTERPRETATION: Overnight SWA decline is conserved in children with focal epilepsy and may underpin the preservation of sleep-related memory consolidation in this patient group. Reduced early-night SWA may reflect impaired or immature sleep homeostasis in those with a higher seizure burden. WHAT THIS PAPER ADDS: The decline in slow-wave activity (SWA) across the night, reflecting global synaptic downscaling, was preserved in children with focal lesional epilepsies. Sleep benefited memory consolidation in this group of patients, as in typically developing children. Reduced early-night SWA was associated with increased likelihood of a subsequent seizure.

Cognitive profiles in pediatric unilobar vs. multilobar epilepsy.

OBJECTIVES: We aimed to determine how cognitive impairment relates to the extent of the presumed epileptogenic zone in pediatric focal epilepsies. We analyzed the cognitive functions in unilobar compared to multilobar focal epilepsy patients that underwent neuropsychological testing at a tertiary epilepsy center. METHODS: We assessed cognitive functions of pediatric focal epilepsy patients with the German version of the Wechsler Intelligence Scales that measures full-scale IQ and subcategories. We assessed differences in IQ and epilepsy-related variables between unilobar and multilobar epilepsy patients. RESULTS: We included 62 patients (37 unilobar, 25 multilobar), aged 10.6 ± 3.7 years. Full-scale IQ values were significantly higher in unilobar (93.6 ± 17.7, 95% CI 87.7-99.6) than in multilobar epilepsy patients (77.3 ± 17.2, 95% CI 69.3-85.0; p = 0.001). In all but one IQ subcategory (working memory), significantly higher values were measured in unilobar than in multilobar epilepsy patients. The proportion of unilobar epilepsy patients with severe cognitive impairment (8.3%) and below-average intelligence (30.5%) was lower compared to multilobar epilepsy patients (47.6% and 61.9%; p = 0.002 and p = 0.021, respectively). Epilepsy onset occurred earlier in multilobar (4.0 years, 95% CI 2.6-5.5, SD ± 3.4 years) than in unilobar epilepsy patients (7.0 years, 95% CI 5.5-8.5, SD ± 4.4 years, p = 0.008). CONCLUSIONS: Pediatric multilobar epilepsy patients face more cognitive issues than unilobar epilepsy patients on average. Our findings should help to identify children and adolescents who are most at risk for impaired cognitive development. A limitation of our study is the simple division into unilobar and multilobar epilepsies, with no specific account being taken of etiology/epilepsy syndrome, which can have a profound effect on cognition.

The future is now: pediatric neuropsychological presurgical epilepsy evaluation in the age of COVID-19.

The objective of this brief report is to review an assessment paradigm for conducting virtual neuropsychological pre-surgical evaluations in the context of the COVID-19 pandemic. A multidisciplinary epilepsy team at a Level 4 epilepsy center within a large children's academic medical center convened to discuss the challenges and possible solutions for Phase II evaluations for pediatric patients with pharmacoresistant epilepsy during the COVID-19 pandemic. The neuropsychologists explored evidence-based methods of virtual evaluation and developed a systematic decision-making process for youth requiring a Phase II evaluation. We propose models of assessment which prioritize teleneuropsychology when possible to reduce the risk of infection: (1) evaluation with directly administered tests through a completely virtual format; (2) virtual/in-person hybrid evaluation; and (3) clinical observation/interview in a virtual format supplemented by survey data. These models are illustrated by three cases. Using virtual assessment models, the team was able to meet the urgent patient care needs and collect useful data while minimizing the risk of virus spread. The paradigms presented may be useful examples for other multidisciplinary surgical teams interested in incorporating teleneuropsychology into their practices.

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

Patterns and predictors of language representation and the influence of epilepsy surgery on language reorganization in children and young adults with focal lesional epilepsy.

Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery.

Learning difficulties in Japanese schoolchildren with focal epilepsy.

BACKGROUND: Children with epilepsy often show some degree of cognitive impairment. In this study, we investigated their learning skills to clarify the characteristics of the difficulties related to learning in Japanese-speaking children with focal epilepsy. METHODS: The study included 13 boys and 17 girls of mean age 9.7 years (standard deviation 2.61; range 6-14 years) with focal epilepsy and a normal magnetic resonance brain scan. None of the patients had any other neurological disorder. RESULTS: Twenty-two children had "learning difficulties", i.e., an intellectual disability or low scores on a learning abilities task. Significant differences were found in age (P = 0.030), age at onset of epilepsy (P = 0.033), and electroencephalographic findings, as well as between bilateral vs. unilateral (P = 0.028) and right-localized vs. left-localized or bilateral (P = 0.014) involvement between subjects with and without learning difficulties. Seven (88%) of eight children with low scores on a learning abilities task showed abnormalities in reading speed. DISCUSSION: More than half of Japanese-speaking children with focal epilepsy need learning assistance. This finding points to a need for learning support in children with focal epilepsy regardless of language. Measurement of reading speed is useful in children with learning difficulties to identify those who require early intervention.

Neurocognitive and behavioural profile in Panayiotopoulos syndrome.

AIM: To determine neurocognitive performance and behavioural problems in children with Panayiotopoulos syndrome. METHOD: All 18 children (10 females, 8 males; mean age 4y 7mo; SD 1y 10mo) diagnosed with Panayiotopoulos syndrome at the Kempenhaeghe Epilepsy Center in the Netherlands between 2010 and 2017 were analysed retrospectively. All underwent a neuropsychological/behavioural assessment, an academic assessment, and a 24-hour electroencephalogram. RESULTS: Mean full-scale IQ (93.5; range 76-123; p=0.04) and performance IQ (93.2; range 76-126; p=0.04) were within the normal range, although significantly lower compared to the normative mean. Verbal IQ (96.3; range 76-118) and processing speed (96.1; range 74-114) were not significantly lower. Simple auditory/visual reaction times, visual attention, visual-motor integration, and verbal memory were significantly lower compared to normative values. On average, patients with Panayiotopoulos syndrome were 8 months behind in arithmetic speed and 11 months behind in reading speed for the number of months in school. Behavioural questionnaires revealed significantly higher scores on reported internalizing behavioural problems. INTERPRETATION: Children with Panayiotopoulos syndrome demonstrated diffuse cognitive dysfunction in full-scale IQ, performance IQ, visual attention, visual-motor integration, and verbal memory. A high incidence of internalizing behavioural problems was reported. This strongly suggests neuropsychological and behavioural comorbidity in children with Panayiotopoulos syndrome. WHAT THIS PAPER ADDS: Children with Panayiotopoulos syndrome are at risk for cognitive deficits in various cognitive domains. Children with Panayiotopoulos syndrome are also prone to internalizing behavioural problems. Mild-to-severe academic underachievement was present in more than half of the children with Panayiotopoulos syndrome.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Social cognition and executive functions in children and adolescents with focal epilepsy.

OBJECTIVES: Deficits in facial emotion recognition and Theory of Mind are frequent in patients with epilepsy. Although this evidence, studies on pediatric age are few and the relation between these abilities and other cognitive domain remains to be better elucidated. The purpose of our study is to evaluate facial emotion recognition and Theory of Mind in children and adolescents with focal epilepsy, and correlate them with intelligence and executive functions. MATERIALS AND METHODS: Our work is a cross-sectional observational study. Sixty-two children and adolescents aged between 7-16 years diagnosed by focal epilepsy and 32 sex/age-matched controls were recruited. All participants were administered a standardized battery tests to assess social cognition (NEPSY-II), executive functions (EpiTrack Junior) and cognitive non-verbal level (Raven Progressive Matrices). RESULTS: Emotion recognition mean score was significantly lower in the epilepsy group than in the controls to Student's t-test (p<0.05). Epilepsy group showed an impairment in happiness, sadness, anger and fear recognition, compared to controls (p<0.05). Theory of Mind mean score was also significantly lower in epilepsy group than controls (p<0.05). Deficits in emotion recognition seemed to be related to low age at onset of epilepsy, long duration of disease, low executive functions and low non-verbal intelligence. Deficits in Theory of Mind seemed to be related to a high seizure frequency. CONCLUSIONS: Our results suggest that children and adolescents with focal epilepsy had deficit in facial emotion recognition and Theory of Mind, compared to their peer. Both these difficulties seem to be related to some features of epilepsy itself. Our results also suggest that deficits in facial emotion recognition are potentially related to difficulties in executive functions and non-verbal intelligence. More studies are needed to confirm these hypotheses.

Which seizure elements do patients memorize? A comparison of history and seizure documentation.

OBJECTIVE: People with epilepsy (PWE) are frequently unable to recall the core manifestation of their disease, epileptic seizures. This means that seizure frequency is often underestimated by practitioners and that seizure classification based on reports of patients or their relatives is difficult because seizure semiology remains unclear. The purpose of this study, therefore, was to prospectively explore patients' memory regarding seizure elements and to assess the role of seizure types. METHOD: Ninety patients diagnosed with focal epilepsy undergoing diagnostic electroencephalography (EEG)-video monitoring were included. The ability to memorize individual seizure elements was assessed using a questionnaire. Patient knowledge was then compared to the findings of subsequent seizure documentation during EEG-video monitoring. Seizure elements were categorized in four groups: subjective, motor, autonomic, and postictal elements. RESULTS: In all categories, the number of documented seizure elements during monitoring strongly exceeded the number of elements that were recalled. Only 45.6% of subjective elements, 5.4% of motor phenomena, 11.9% of autonomic findings, and 2.1% of postictal impairments were recalled. The ability to recall seizure elements varied significantly depending on seizure types (secondarily generalized tonic-clonic seizures [SGTCS] < complex partial seizures [CPS] < simple partial seizures [SPS]), but not on the relative timing of the element during the seizure. SIGNIFICANCE: Patients' memory of seizure semiology is almost always fragmentary. Although the rate of correctly remembered seizure elements depends on the seizure type, complete recall of a seizure is almost never obtained. Consequently, 89 of 90 patients in this cohort would only have had seizures classified as a seizure with "impaired awareness" according to the new International League Against Epilepsy (ILAE) seizure classification. The involvement of brain areas involved in memory encoding and consolidation and in the context of seizure classification schemes.

Behavioral phenotypes of childhood idiopathic epilepsies.

OBJECTIVE: To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies. METHODS: The parents of 290 youth (age = 8-18 years) with epilepsy (n = 183) and typically developing participants (n = 107) completed the Child Behavior Checklist for children aged 6-18 from the Achenbach System of Empirically Based Assessment. The eight behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. To characterize the external validity and co-occurring comorbidities of the identified subgroups, we examined demographic features (age, gender, handedness), cognition (language, perception, attention, executive function, speed), academic problems (present/absent), clinical epilepsy characteristics (epilepsy syndrome, medications), familial factors (parental intelligence quotient, education, employment), neuroimaging features (cortical thickness), parent-observed day-to-day executive function, and number of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses. RESULTS: Hierarchical clustering identified three behavioral phenotypes, which included no behavioral complications (Cluster 1, 67% of epilepsy cohort [n = 122]), nonexternalizing problems (Cluster 2, 11% of cohort [n = 21]), and combined internalizing and externalizing problems (Cluster 3, 22% of cohort [n = 40]). These behavioral phenotypes were characterized by orderly differences in personal characteristics, neuropsychological status, history of academic problems, parental status, cortical thickness, daily executive function, and number of lifetime-to-date DSM-IV diagnoses. Cluster 1 was most similar to controls across most metrics, whereas Cluster 3 was the most abnormal compared to controls. Epilepsy syndrome was not a predictor of cluster membership. SIGNIFICANCE: Youth with new and recent onset epilepsy fall into three distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

Adaptive behavior and its related factors in children with focal epilepsy.

OBJECTIVE: We aimed to clarify the strengths and weaknesses in adaptive behavior in children with focal epilepsy and show children-associated factors related to adaptive behavior. MATERIALS AND METHODS: Sixty-three children with focal epilepsy aged 5-18 years with intellectual quotient (IQ) ranging from 67 to 135 were enrolled in this study. Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). The children performed continuous performance test and tests of reading, writing, and IQ; parents answered questionnaires regarding attention-deficit hyperactivity disorder and autism spectrum disorder (ASD). Participants were categorized into four groups based on IQ and adaptive behavior scores for statistical comparisons. RESULTS AND DISCUSSION: Children with low adaptive behavior were more likely to show a reduction in daily living skills, and those with both low adaptive behavior and IQ were more likely to show a reduction in daily living skills and communication. Lower adaptive behavior was related to more severe autistic symptoms, lower academic achievement in children with IQ > 85, and lower executive function in children with IQ ≤ 85. There was a qualitative difference of cognitive dysfunction in adaptive behavior between both groups. CONCLUSIONS: There were differences in VABS-II domain and subdomain characteristics between children with focal epilepsy and those with ASD; however, it was more difficult for children with more severe ASD and coexisting focal epilepsy to show age-equivalent adaptive behavior.

Pleiotropy of polygenic factors associated with focal and generalized epilepsy in the general population.

Epilepsy is clinically heterogeneous, and neurological or psychiatric comorbidities are frequently observed in patients. It has not been tested whether common risk variants for generalized or focal epilepsy are enriched in people with other disorders or traits related to brain or cognitive function. Here, we perform two brain-focused phenome association studies of polygenic risk scores (PRS) for generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) with all binary brain or cognitive function-related traits available for 334,310 European-ancestry individuals of the UK Biobank. Higher GE-PRS were associated with not having a college or university degree (P = 3.00x10-4), five neuroticism-related personality traits (P<2.51x10-4), and having ever smoked (P = 1.27x10-6). Higher FE-PRS were associated with several measures of low educational attainment (P<4.87x10-5), one neuroticism-related personality trait (P = 2.33x10-4), having ever smoked (P = 1.71x10-4), and having experienced events of anxiety or depression (P = 2.83x10-4). GE- and FE-PRS had the same direction of effect for each of the associated traits. Genetic factors associated with GE or FE showed similar patterns of correlation with genetic factors associated with cortical morphology in a subset of the UKB with 16,612 individuals and T1 magnetic resonance imaging data. In summary, our results suggest that genetic factors associated with epilepsies may confer risk for other neurological and psychiatric disorders in a population sample not enriched for epilepsy.

Positive illusions determine quality of life in drug-resistant epilepsy.

OBJECTIVE: Humans use a complex system of protective cognitive biases or "positive illusions" that foster emotional well-being and subjective quality of life. This study examined the role of positive illusions in patient adjustment to drug-resistant epilepsy and its surgical treatment. METHODS: One hundred fifty people participated, including 93 focal epilepsy patients being evaluated for surgery and 57 sociodemographically matched healthy controls. We purpose-built computer software, "Living With Epilepsy," to assess the impact of positive illusions on patient perceptions of their current life, and administered well-validated questionnaires of depression (Neurological Disorders Depression Inventory for Epilepsy), anxiety (Patient Health Questionnaire for Generalized Anxiety Disorder-7 items), and health-related quality of life (HRQOL; Epilepsy Surgery Inventory-55) before and at 3 and 12 months after surgery. RESULTS: We identified two patient groups: those with "high positive illusions" (53%) about their epilepsy and those with "low positive illusions" (47%), with no differences between sociodemographic or epilepsy variables (all P > .05). Before epilepsy surgery, patients with high positive illusions exhibited fewer symptoms of depression (P < .001) and anxiety (P = .002) and higher HRQOL (P ≥ .002 ≤ 0.046) than those with low positive illusions. A subset of patients proceeded with surgery (n = 34 at 3 months; n = 26 at 12 months). They showed that the beneficial impact of having high positive illusions re-emerged 12 months postsurgery, with patients reporting lower depression and anxiety (P = .006) and elevated HRQOL (P = .036) compared to low positive illusions patients, independent of seizure outcome (P > .05). SIGNIFICANCE: These findings point to an active psychological process in drug-resistant patients, where approximately half generate strong positive illusions about their life with epilepsy, maintaining their mood and subjective well-being. Those who use this psychological mechanism show better adjustment 12 months postsurgery independent of seizure outcome, providing a potential new target for psychological treatment in patients with epilepsy.

Efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of six randomized studies.

OBJECTIVE: This post hoc analysis of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2-12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic-clonic (PGTC) seizures. METHODS: Adolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs). RESULTS: The Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients. CONCLUSIONS: Adjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy.

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

OBJECTIVES: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.

Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study.

PURPOSE: Clinical trials have demonstrated the efficacy of perampanel for the treatment of epilepsy. However, patients treated with this and other antiepileptic drugs often exhibit aggressive behaviors. We investigated the clinical factors contributing to aggression in patients with refractory focal epilepsy during 6 months of adjunctive perampanel treatment. METHODS: This was a single-center longitudinal study involving patients treated with perampanel (starting dose, 2 mg/day; maximal dose, 12 mg/day). Patients were assessed with an aggression questionnaire (Korean version of Aggression Questionnaire [AQ-K]) and the hospital anxiety depression scale (HADS) at the beginning of the study and after receiving treatment for 6 months. Paired t-tests were used to compare AQ-K and HADS scores at the beginning of the study with those recorded at the end, and stepwise linear regression models were applied to identify predictive factors. RESULTS: Thirty-two patients (mean age, 42.4 ±â€¯10.3 years) successfully completed the 6-month study. The AQ-K and HADS scores increased after 6 months of adjunctive perampanel treatment (p < .1). The HADS scores related to depression at baseline predicted changes in total AQ-K scores, whereas the change in this HADS score was a predictor of physical and verbal aggression. A perampanel dose of ≥8 mg was a predictive factor for changes in anger and HADS scores related to depression after 6 months. Unexpectedly, concomitant use of topiramate had protective effects on AQ-K scores (including for verbal aggression and anger) in patients receiving perampanel. CONCLUSION: Depressive symptoms and a high dose of perampanel are potential predictors for aggression, whereas concomitant use of topiramate is protective against aggression in patients receiving perampanel for focal epilepsy.

Contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy.

"My memory is terrible!" is a common refrain among people with epilepsy, but such complaints are not reliably linked to poor performances on standard tests of memory. Negative affect like depression and anxiety are the most robust predictor of these complaints; however, neither do they entirely account for the phenomenon. The contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy has not been well-explored despite autobiographic memory impairments being common in patients with epilepsy, and the face validity of relating day-to-day memory failings to such a personally relevant form of memory. The current study sought to clarify whether autobiographic memory dysfunction contributes to subjective complaints in epilepsy, above and beyond negative affect, objective memory impairment, and epileptological factors in a large sample of patients with drug-resistant focal epilepsy relative to healthy controls (N = 135). Patients were stratified into groups with mesial temporal (MT; n = 40) versus nonmesial temporal (NMT; n = 46) foci. Compared to controls (n = 46), both patient groups reported more bitter subjective memory complaints (p < 0.001, large effect size), demonstrated poorer episodic (p = 0.001, large effect size) and semantic autobiographical recall (p = 0.004, medium effect size), and had higher levels of depressive symptomatology (p = 0.011, medium effect size), and trait neuroticism (p = 0.015, medium effect size). Contrary to expectations, multiple regression analyses revealed that autobiographic memory function was not an independent predictor of subjective memory complaints in either group with epilepsy. In people with epilepsy with MT foci, objective verbal memory dysfunction, neuroticism, and female gender predicted memory complaints (R2 = 0.70, p = 0.015), whereas only neuroticism predicted memory complaints in people with epilepsy with NMT foci (R2 = 0.21, p = 0.001). Although patients' poor recall of their autobiographical memories did not contribute to their concerns about their day-to-day memory function, the findings indicate that the location of the epileptogenic focus can provide clues as to the underlying contributors to subjective memory complaints in focal epilepsy. Important clinical implications to stem from these findings include the need for clinicians to adopt a patient-tailored, multifactorial lens when managing memory complaints in people with epilepsy, taking into account both psychological and cognitive factors.

Neurofeedback impacts cognition and quality of life in pediatric focal epilepsy: An exploratory randomized double-blinded sham-controlled trial.

OBJECTIVE: Children with epilepsy experience cognitive deficits and well-being issues that have detrimental effects on their development. Pharmacotherapy is the standard of care in epilepsy; however, few interventions exist to promote cognitive development and to mitigate disease burden. We aimed to examine the impact of two different modalities of neurofeedback (NFB) on cognitive functioning and quality-of-life (QOL) measurements in children and adolescents with controlled focal epilepsy. The study also explored the effects of NFB on clinical outcomes and electroencephalography (EEG) quantitative analysis. METHODS: Participants (n = 44) with controlled focal epilepsy were randomized to one of three arms: sensorimotor rhythm (SMR) NFB (n = 15), slow cortical potentials (SCP) NFB (n = 16), or sham NFB (n = 13). All participants received 25 sessions of intervention. The attention switching task (AST), Liverpool Seizure Severity Scale (LSSS), seizure frequency (SF), EEG power spectrum, and coherence were measured at baseline, postintervention, and at 3-month follow-up. RESULTS: In children and adolescents with controlled focal epilepsy, SMR training significantly reduced reaction time in the AST (p = 0.006), and this was correlated with the difference of change for theta power on EEG (p = 0.03); only the SMR group showed a significant decrease in beta coherence (p = 0.03). All groups exhibited improvement in QOL (p = <0.05). CONCLUSIONS: This study provides the first data on two NFB modalities (SMR and SCP) including cognitive, neurophysiological, and clinical outcomes in pediatric epilepsy. Sensorimotor rhythm NFB improved cognitive functioning, while all the interventions showed improvements in QOL, demonstrating a powerful placebo effect in the sham group.

Generalized quasiperiodic epileptiform activity in sleep is associated with cognitive impairment in children with drug-resistant focal lesional epilepsy.

OBJECTIVE: To evaluate the impact of generalized quasiperiodic epileptiform discharges ("hurdles") observed in non-rapid eye movement (NREM) sleep on cognitive function in children with intractable focal epilepsy. "Hurdles" pattern does not meet the criteria of the electrical status epilepticus in slow-wave sleep (ESES). METHODS: In a retrospective analysis, 24 patients with "hurdles" and their 24 peers matched for demographic and epilepsy-related variables were compared in terms of neuropsychological domains and electroencephalography (EEG)-derived quantifiers. Both "hurdles" and controls were children between 2 and 19 years of age who had intractable focal epilepsy evaluated as candidates of resective epilepsy surgery. RESULTS: Full-scale intelligence quotient/developmental quotient (FSIQ/DQ) (P = .002) and visuoconstructional skills (P = .004) were significantly lower in children with "hurdles" compared to controls. Patients with "hurdles" presented with higher interictal spike indexes in sleep (P < .001, median difference -0.9, 95% confidence interval [CI] -1.4, -0.6) and wakefulness (P < .001, median difference -0.3, 95% CI -0.5, -1). Relative time of sleep spindles in NREM sleep was significantly reduced (P < .001, median difference 0.1, 95% CI 0.0, 0.1) in the "hurdles" group. The time proportion of sleep spindles represented a significant positive (P = .008) and spike index of generalized spikes in sleep a significant negative explanatory variable (P = .004) of FSIQ/DQ scores. The proportion of seizure-free patients 2 years after epilepsy surgery did not differ significantly between the two groups (P = .19). SIGNIFICANCE: Although the "hurdles" pattern does not fulfill the criteria of ESES, it is associated with a pronounced cognitive dysfunction. Disturbed sleep structure marked by reduced sleep spindles and generalized spiking in sleep is associated with worse cognitive performance. Despite having a generalized nature, we did not find a lower probability of postsurgical seizure freedom in patients with "hurdles" pattern.