Interictal magnetic signals in new-onset Rolandic epilepsy may help with timing of treatment selection.

OBJECTIVE: With research progress on Rolandic epilepsy (RE), its "benign" nature has been phased out. Clinicians are exhibiting an increasing tendency toward a more assertive treatment approach for RE. Nonetheless, in clinical practice, delayed treatment remains common because of the "self-limiting" nature of RE. Therefore, this study aimed to identify an imaging marker to aid treatment decisions and select a more appropriate time for initiating therapy for RE. METHODS: We followed up with children newly diagnosed with RE, classified them into medicated and non-medicated groups according to the follow-up results, and compared them with matched healthy controls. Before beginning follow-up visits, interictal magnetic data were collected using magnetoencephalography in treatment-naïve recently diagnosed patients. The spectral power of the whole brain during initial diagnosis was determined using minimum normative estimation combined with the Welch technique. RESULTS: A difference was observed in the magnetic source intensity within the left caudal anterior cingulate and precentral and postcentral gyri in the delta band between the medicated and non-medicated groups. The results revealed good discriminatory ability within the receiver operator characteristic curve. In the medicated group, there was a specific change in the frontotemporal magnetic source intensity, which shifted from high to low frequencies, compared with the healthy control group. SIGNIFICANCE: The intensity of the precentral gyrus magnetic source within the delta band showed good specificity. Considering the rigor of initial treatment, the intensity of the precentral gyrus magnetic source can provide some help as an imaging marker for initial RE treatment, particularly for the timing of treatment initiation.

Perampanel and lacosamide monotherapy in pediatric patients with newly diagnosed focal epilepsy: A prospective study evaluating efficacy, tolerability, and behavior.

PURPOSE: Perampanel (PER) and lacosamide (LCM) are the new third-generation anti-seizure medications (ASMs) that were approved for the monotherapy of focal epilepsy in children over four years of age in China, in 2021. Very few studies have analyzed the application of PER monotherapy among pediatric patients aged ≥four years, and no study compared the efficacy and tolerability of PER monotherapy with LCM monotherapy in pediatric patients with focal epilepsy. The present study aimed to investigate the efficacy, tolerability, and effect on behavior and emotion of PER and LCM as monotherapy in pediatric patients with newly diagnosed focal epilepsy, which is beneficial for clinicians to have more choices to treat pediatric patients with focal epilepsy. METHODS: This was a prospective, single-center, observational study that involved pediatric patients (disease onset age ≥four years) with newly diagnosed focal epilepsy treated with PER or LCM as primary monotherapy. Outcomes included retention, being responders, and seizure-free rates after 3, 6, and 12 months. Adverse events (AEs) were noticed throughout the follow-up period. Behavioral outcomes were evaluated with Achenbach Child Behavior Checklist (CBCL/4-16) at baseline and after three and six months. RESULTS: Using randomization, 60 patients receiving PER (31 females, 29 males, median age: 7.79 [5.34, 10.16] years, median dose: 3.0 [2.0, 4.0] mg/day) and 60 patients receiving LCM (25 females, 35 males, median age: 7.72 [5.91, 10.72] years, median dose: 150.0 [100.0, 200.0] mg/day) were enrolled in the study. At the 12-month follow-up, the retention rates in the PER and LCM groups, both were 90.4%, and the responder rates were 65.4% and 71.2%, while seizure-free rates were 57.7% and 67.3%, respectively. There were no significant differences in the retention, responder and seizure-free rates between the two groups (P > 0.05). There were no significant differences in the responder rates between patients with BECTS, abnormal brain magnetic resonance imaging (MRI), or types of seizure in the two groups (P > 0.05). In the PER group, 28.8% (15/52) of patients experienced AEs, of which the most frequently reported were irritability (n = 7; 13.5%), dizziness (n = 5; 9.6%), somnolence (n = 3; 5.8%), ataxia (n = 1; 1.9%), headache (n = 1; 1.9%), and rash (n = 1; 1.9%). In the LCM group, 15.4% (8/52) of the patients had AEs, including headache (n = 4; 7.5%), dizziness (n = 4; 7.5%), nausea (n = 2; 3.8%), somnolence (n = 2; 3.8%), irritability (n = 1; 1.9%), stomach ache (n = 1; 1.9%), and vomiting (n = 1; 1.9%). The incidence of irritability was significantly higher in the PER group than in the LCM group (13.5% vs. 1.9%, P = 0.031), which occurred mainly within eight weeks after drug administration. Patients with irritability were not dangerous to surrounding people by the assessment of parental observation in the life. And the symptoms were relieved spontaneously within a few months. The outcomes of total scores, internalizing scores, and externalizing scores of the CBCL did not show statistically significant differences in the PER and LCM groups between baseline and three and six months. Characteristics of behavior and emotion did not have substantial changes in patients treated with PER and LCM monotherapy. CONCLUSIONS: The present study documented similar good effectiveness and good tolerance of PER and LCM as monotherapy in pediatric patients with newly diagnosed focal epilepsy and showed no behavioral or emotional impact, as assessed by the CBCL. Though the incidence of irritability with PER monotherapy may be higher than that with LCM monotherapy soon after medication initiation, this side effect appears to resolve spontaneously within a few months. At present, this study was the first research about PER and LCM monotherapy in pediatric patients with newly diagnosed focal epilepsy evaluating efficacy, tolerability, and behavior in China.

The fate of spikes in self-limited epilepsy with centrotemporal spikes: Are clinical and baseline EEG features effective?

OBJECTIVE: The aim of this study is to evaluate the effects of clinical and electroencephalographic features on spike reduction with a focus on the first EEG characteristics in self-limited epilepsy with centrotemporal spikes (SeLECTS). METHODS: This retrospective study was conducted on SeLECTS patients of with at least five years follow-up and at least two EEG recordings in which spike wave indexes (SWI) were calculated. RESULTS: 136 patients were enrolled. Median SWI in the first and last EEGs were 39% (7.6-89%) and 0 (0-112%). Gender, seizure onset age, psychiatric diseases, seizure characteristics (semiology, duration, and relationship to sleep), last EEG time, and spike lateralization in the first EEG did not have a statistically significant effect on the SWI change. Multinomial logistic regression analysis revealed that presence of phase reversal, interhemispheric generalization, and SWI percentage had a significant effect on spike reduction. The frequency of seizures was also significantly decreased in patients with a greater decrease in SWI. Both valproate and levetiracetam were statistically superior in suppressing SWI, with no significant difference between them. CONCLUSION: Interhemispheric generalization and phase reversal in the first EEG in SeLECTS had negative effects on the spike reduction. The most effective ASMs in reducing spikes were valproate and levetiracetam.

Clinical and electrophysiological predictors of behavioral disorders in patients with benign childhood epilepsy with centrotemporal spikes.

PURPOSE: Long-term seizure and developmental outcomes of benign childhood epilepsy with centrotemporal spikes (BECTS) are thought to be good. Studies have shown that behavioral disorders may accompany BECTS. We aimed to investigate the frequency of behavioral disorders in patients with BECTS and evaluate their relationship to epilepsy features. METHODS: Data for 41 patients with BECTS followed up at our clinic between December 2019 and June 2020 were analyzed. Behavioral disorders and intelligence were evaluated by the Turgay Diagnostic and Statistical Manual of Mental Disorders 4th Edition - Disruptive Behaviour Disorders Rating Scale and Wechsler Intelligence Scale for Children Revised, respectively. Patients with a diagnosis of BECTS were divided into 2 groups: children with a behavioral disorder and children without a behavioral disorder. Demographic characteristics, clinical and electroencephalography (EEG) findings, and intelligence level were compared between the two groups. RESULTS: Twelve of the patients (29%) were classified as having attention-deficit/hyperactivity disorder (ADHD) and 2 (5%) were classified as having oppositional defiant disorder (ODD). The age at seizure onset was earlier in patients with behavioral disorders (p = 0.023). Bilateral interictal epileptic discharges (IEDs) were more common in children with behavioral disorders than children without behavioral disorders (p = 0.039). The most preferred antiseizure medication was carbamazepine, followed by levetiracetam and valproic acid. The intelligence score of the patients with BECTS was in the normal range in both groups. The total, verbal, and performance scores were lower in patients with a behavioral disorder than in patients without a behavioral disorder, but there was no statistically significant difference between the two groups. CONCLUSION: Behavioral disorders may be present in approximately one-third of patients with BECTS. Early onset of seizures and the presence of bilateral IEDs may be risk factors for behavioral disorders in children with BECTS.

The attention networks in benign epilepsy with centrotemporal spikes: A long-term follow-up study.

PURPOSE: To evaluate the long-term prognosis of attention deficit in children with newly diagnosed benign childhood epilepsy with centrotemporal spikes (BECTS). METHODS: Attention network test (ANT) was performed over a period of 7 years on 42 patients who were newly diagnosed with BECTS, in the Department of Neurology of Anhui Provincial Children's Hospital. RESULTS: In the patients' group, the accuracy of ANT was lower (P = 0.000), the total response time was longer (P = 0.000), and the efficiency of orienting (P = 0.000) and alerting (P = 0.041) networks was lower than that of the control group. Accuracy was positively correlated with age of onset (b = 1.184) and negatively correlated with number of seizures (b = -1.321). After 7 years, there was no significant difference in the accuracy (P = 0.385); total response time (P = 0.661); and alerting (P = 0.797), orienting (P = 0.709), and executive control (P = 0.806) network efficiencies between the patients and controls. Accuracy was positively correlated with age of onset (b = 0.8583) and negatively correlated with number of seizures (b = -1.017) and duration of antiepileptic drugs therapy (b = -3.203). CONCLUSIONS: In our study, the newly diagnosed BECTS patients had impaired attention network, mainly in the alerting and orienting domains. Age of onset, number of seizures, and time of antiepileptic treatment may affect the attention networks. With the remission of BECTS, the attention network dysfunction was reversed.

Evaluation of eating behaviors in childhood epilepsy with centrotemporal spikes: Case-control study.

BACKGROUND: Psychosocial and behavioral disorders have been reported in childhood epilepsy with centrotemporal spikes (CECTS). We aimed to identify the symptoms of eating disorders in CECTS. METHODS: Patients with CECTS were recruited from the pediatric neurology outpatient clinic between September 2019 and July 2020. The Children's Eating Behaviour Questionnaire (CEBQ) was administered to 39 patients and 31 controls. Patients' scores were compared with those of healthy subjects. RESULTS: There was no significant difference between the CEBQ of patients with CECTS and the control group (p > 0.05). There was no significant difference between the BMI of the patients with CECTS and the control group. In the patient group with CECTS, no significant difference was found in terms of CEBQ according to the antiepileptic drug used and EEG findings (p > 0.05). CONCLUSION: No difference was found in the eating habits of patients with CECTS compared with the healthy control group.

Anti-seizure medication correlated changes of cortical morphology in childhood epilepsy with centrotemporal spikes.

To investigate the morphological changes of cerebral cortex correlating with anti-seizure medication in Childhood Epilepsy with Centrotemporal Spikes (CECTS), and their relationships with seizure control. This study included a total of 188 children, including 62 patients with CECTS taking anti-seizure drugs, 56 patients with drug-naive, and 70 healthy controls. A portion of cases were also followed-up for longitudinal analysis. Cortical morphological parameters were quantitatively measured by applying surface-based morphometry analysis to high-resolution three-dimension T1 weighted images. Among the three groups, the morphological indices were compared to quantify any cortical changes affected by seizures and medication. The relationships among anti-seizure medication, seizure controls and cortical morphometry were investigated using causal mediator analysis. The Rolandic cortex of the drug-naive patients showed abnormal cortical thickness by comparing with that of healthy controls, and thinning by comparing with that of patients with medication. The cortical thickness in the Rolandic regions was negatively correlated with duration of medication and duration of seizure-free. Longitudinal analysis further demonstrated that the thickness of Rolandic cortex thinned in post-medication state relative to the pre-medication state. Mediation analysis revealed that morphological alteration of the Rolandic cortex might act as a mediator in the path of anti-seizure medication on seizure control. Our findings highlighted that anti-seizure medication was associated with regression of abnormal increment of cortical thickness in the Rolandic regions in CECTS. The neuroanatomical alteration might be a mediating factor in the process of seizure control by anti-seizure medication.

Spike wave characteristics and temporal spike evolution on serial EEG in childhood epilepsy with centrotemporal spikes.

PURPOSE: To assess the spike characteristics and temporal spike evolution on serial EEG of children with childhood epilepsy with centrotemporal spikes (CECTS) treated with anti-seizure medication. METHODS: The study cohort consisted of 127 children with CECTS divided into three groups based on anti-seizure medication responsiveness: group I: seizure-free with monotherapy (n: 61, 48%), group II: seizure-controlled with monotherapy (n: 52, 41%) and group III: seizure-controlled with dual therapy (n: 14, 11%). The clinical profiles and sequential four-year follow-up visual EEG recordings of the children were evaluated. Each EEG was reanalyzed with three spike characteristics on the epochs: (1) spike-wave rate, (2) spike topography, and (3) spike localization. We calculated the spike clearance velocity, which is defined as a decrease in the spike-wave rate over time in four-year sequential follow-up EEGs. RESULTS: There was no statistical significance across the study groups with respect to initial EEG spike characteristics (spike-wave rate, spike localization, and spike topography). Seizure recurrence occurred in 15 patients (12.8%) who discontinued anti-seizure medication. There was no statistically significant difference between the spike characteristics on EEG just before the discontinuation of anti-seizure medication and seizure recurrence. However, the spike clearance velocity was significantly slower in group III than in group I in four-year sequential follow-up EEGs (p = 0.002). A statistically significant decrease in the mean spike-wave rate was observed in group I in the first year of anti-seizure medication (p<0.001). The spike clearance velocity was also more prominent during the second year of treatment in group II and the third year of treatment in group III. However, the spike clearance velocity was not different across the anti-seizure medication groups (oxcarbazepine, valproic acid, and levetiracetam). CONCLUSION: Spike clearance velocity might be a valuable EEG marker to guide anti-seizure medication in children with CECTS.

A Systematic Review of Seizure-Freedom Rates in Patients With Benign Epilepsy of Childhood With Centrotemporal Spikes Receiving Antiepileptic Drugs.

OBJECTIVES: The objective of this study was to evaluate seizure remission rates in patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) receiving antiepileptic drugs. METHODS: PubMed and Web of Science were searched for studies on pharmacotherapy in patients with BECTS using free search terms or Medical Subject Headings. Only studies that used seizure-freedom rates as an indicator for pharmaceutical efficacy were considered. Different antiepileptic drugs were compared using the Fisher exact test for seizure-freedom rates. RESULTS: A total of 19 studies were included, 6 of them being randomized controlled trials. The randomized controlled trials included a total of 308 patients and covered sulthiame (n = 52), topiramate (n = 45), levetiracetam (n = 43), oxcarbazepine (n = 31), carbamazepine (n = 68), and clobazam (n = 18) as well as placebo (n = 35) and untreated control groups (n = 16). Treatment success rates were significantly higher in those children treated with sulthiame, levetiracetam, and clobazam compared with the children treated with carbamazepine, oxcarbazepine, or topiramate. CONCLUSIONS: The available literature suggests the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of BECTS.

Effects of levetiracetam and oxcarbazepine monotherapy on intellectual and cognitive development in children with benign epilepsy with centrotemporal spikes.

Levetiracetam (LEV) and oxcarbazepine (OXC) are commonly used in the treatment of epilepsy, but their efficacy and safety have seldom been compared for the treatment of children with benign epilepsy with centrotemporal spikes (BECTS). We thus assessed the efficacy of LEV and OXC monotherapy in the treatment of children with BECTS, and the effect of this treatment on children's intelligence and cognitive development. This was a randomized, single-center trial. Children with BECTS were randomized (1:1) into LEV and OXC groups, and were assessed at 1, 3 and 6 months after treatment. The primary outcomes were the frequency of seizures and changes in intelligence and cognitive function. Secondary outcomes were electroencephalogram (EEG) results and safety. Seventy children were enrolled and randomized to the LEV group or the OXC group, and 32 of the 35 children in each group completed the study. After 6 months, the effective treatment rate of the OXC group was significantly higher than that of the LEV group (78.12 vs. 53.12%, p = 0.035). However, no significant inter-group difference was observed in EEG improvement (p = 0.211). In terms of intelligence and cognitive development, children in the OXC group exhibited significantly improved choice reaction time, mental rotation, and Wisconsin Card Sorting Test results (all p < 0.05). Both LEV and OXC were well tolerated, with 18.75 and 21.88% of children reporting mild adverse events (p = 0.756). OXC monotherapy was more effective than LEV for children with BECTS. In addition, children with OXC monotherapy had higher improvements in children's intelligence and cognitive function than those with LEV monotherapy.

Outcome analysis of children with rolandic discharges on EEG: A real-world study.

OBJECTIVE: To evaluate the efficacy of drugs for patients with central mid-temporal (rolandic) discharges detected by electroencephalogram (EEG). METHODS: This retrospective study enrolled 430 patients with rolandic discharges, who were treated at the Neuroelectrophysiology Center of the Children's Hospital of Nanjing Medical University from February 2015 to February 2018. Patients were divided into three groups according to medication: levetiracetam (LEV), oxcarbazepine (OXC) and sodium valproate (VPA). All patients were followed up for at least 2 years, and the seizure frequency, EEG results and side effects of drugs were recorded. RESULTS: Rolandic epilepsy (RE) occurred in 398/430 patients. Rolandic discharges were also found in those with febrile seizures, tic disorders, and attention deficit hyperactivity disorder. Thirty-one patients experienced only one seizure and no relapse, while 367 patients experienced more than two seizures (including 364 receiving drug treatment). The failure rate of LEV as initial therapy was significantly higher than those of OXC and VPA. The overall efficacy of OXC was higher than that of LEV. However, none of the three medications could control rolandic discharges. Moreover, the side effects of the three drugs were mild. CONCLUSIONS: Rolandic discharges are common in children with RE and other diseases, such as febrile seizures, tic disorders, and attention deficit hyperactivity disorder. Patients with only one seizure need no treatment. Those with multiple seizures can be treated with OXC, LEV, and VPA. OXC serves as the initial antiepileptic drug with a lower failure rate and significant efficacy.

Oxcarbazepine monotherapy in children with benign epilepsy with centrotemporal spikes improves quality of life.

BACKGROUND: Benign epilepsy with centrotemporal spikes (BECTS) is the most common type of childhood idiopathic focal epilepsy. BECTS is associated with pervasive cognitive deficits and behavior problems. While seizures can be easily controlled, it is crucial to select anti-epileptic drugs that do not impair cognition, do not cause psychosocial effects, and improve the quality of life. Previous studies showed effects of oxcarbazepine (OXC) monotherapy on the cognitive and psychosocial profiles of patients with BECTS. Here, we studied the effects of OXC monotherapy on the neuropsychologic profiles and quality of life in patients with BECTS in China. METHODS: Thirty-one patients aged 6 to 12 years newly diagnosed with BECTS were recruited. A psychometric assessment was performed before and during the follow-up of OXC monotherapy with Cognitive Computerized Task Battery, Depression Self-Rating Scale for children, Screen for Child Anxiety Related Emotional Disorders, and Quality of Life in Epilepsy-31 (QOLIE-31). The results of the assessments were compared to explore the effect of OXC monotherapy in patients with BECTS. RESULTS: Thirty children with BECTS completed the study. Five of ten cognitive test scores improved after treatment via OXC monotherapy, including visual tracing (F = 14.480, P < 0.001), paired associated learning (language) (F = 6.292, P < 0.001), paired associated learning (number) (F = 9.721, P < 0.05), word semantic (F = 6.003, P < 0.05), and simple subtraction (F = 6.229, P < 0.05). Of the neuropsychology data concerning the quality of life, statistically significant improvements were observed in emotion (F = 4.946, P < 0.05), QOLIE-social (F = 5.912, P < 0.05), and QOLIE-total (F = 14.161, P < 0.001). CONCLUSIONS: OXC is safe and does not impair neuropsychologic functions, with no obvious mood burden on children with BECTS. Most importantly, OXC has positive impacts on children's perception of quality of life, especially in terms of happiness and life satisfaction.

Clinical and electroencephalographic features of benign childhood epilepsy with centrotemporal spikes comorbidity with attention-deficit hyperactivity disorder in Southwest China.

PURPOSE: This study was conducted to analyze the clinical and electroencephalographic (EEG) features of attention-deficit hyperactivity disorder (ADHD) in children with benign partial epilepsy with centrotemporal spikes (BECTS) in Southwest China, to address the question of what the risk factors are for patients with BECTS who suffer from ADHD. METHODS: Overall 118 right-handed children with BECTS were included from two medical centers. Of them, 29 patients were with diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) at baseline, and the remaining were considered as typical BECTS. Clinical and EEG characteristics were collected at baseline and follow-up endpoint of one year. All the patients completed an eight-hour video-electroencephalogram (VEEG) without sedation at those two time points using a digital system with international 10-20 array electrode placement. At the follow-up endpoint, we also evaluated the intelligence level of all patients using the Wechsler Intelligence Scale for Children-IV (WISC-IV). Multivariate logistical regression model was performed to assess the risk factors of ADHD in BECTS patients. RESULTS: Compared with typical BECTS, patients with BECTS-ADHD had an earlier age of onset, a longer disease course and tended to have lower intelligence quotient (IQ) scores. Their epileptiform discharges were more likely to diffuse to one or both hemispheres, and a higher percentage of patients with BECTS-ADHD patients needed multitherapy to control seizures. Multivariate analysis showed that age of onset, disease course, intelligence score, number of antiepileptic drugs (AEDs), and bilateral or diffusing discharges were independently associated with the occurrence of ADHD in patients with BECTS (p < .05). Additionally, we found that delayed diagnosis (37.3%) and nonadherence to treatment (16.1%) were the main reasons of a long disease course. CONCLUSION: Benign partial epilepsy with centrotemporal spikes with ADHD has the characteristics of early age of onset, long course of disease and low intelligence score. In addition, the epileptiform discharges of BECTS-ADHD were prone to be bilateral or diffuse, and polypharmacological treatment is also common in this group.

Seizures in self-limited epilepsy with centrotemporal spikes: video-EEG documentation.

PURPOSE: Self-limited epilepsy with centrotemporal spikes, formerly called benign epilepsy with centrotemporal spikes, or rolandic epilepsy, is an age-related and well-defined epileptic syndrome. Since seizures associated with rolandic spikes are infrequent and usually occur during sleep, and repetitive or prolonged EEG recording for diagnostic purposes is not necessary for diagnosis, reports of ictal video-electroencephalographic seizures in this syndrome are rare. We aimed to show ictal video-EEG of typical rolandic seizures. METHODS: We report the ictal video-EEG recordings of two children with rolandic epilepsy who presented typical rolandic seizures during routine recording. RESULTS: Case 1: A 9-year-old boy, with normal development, had his first seizure at 8 years old, characterized by paresthesia in his left face, blocking of speech, and drooling. Carbamazepine was started with seizure control. Case 2: A 10-year-old boy, with normal development, started with focal seizures during sleep, characterized by eye and perioral deviation, and speech arrest at age of 7. He started using oxcarbazepine. Both patients underwent routine electroencephalography for electroclinical diagnosis and presented a seizure. CONCLUSION: Although self-limited epilepsy with centrotemporal spikes is a very common epileptic syndrome, seizure visualization is very difficult, and these videos may bring didactical information for recognition of this usual presentation of benign childhood focal epilepsy.

Resting state signal latency assesses the propagation of intrinsic activations and estimates anti-epileptic effect of levetiracetam in Rolandic epilepsy.

PURPOSE: We assessed the potential of resting-state fMRI lag analysis (RSLA) in detecting epileptic activation and in estimating anti-epileptic effects of Levetiracetam (LEV) in Rolandic epilepsy. METHODS: Forty-three children with Rolandic epilepsy underwent simultaneous EEG-fMRI. They were grouped into LEV vs drug-naïve groups according to their medication, and into patients who showed or did not show central-temporal spike (CTS) discharges during scans. We calculated the lag structure of rs-fMRI for all patients and assessed interactions with drug (LEV vs. drug-naïve) and CTS status (CTS vs. no-CTS). We furthermore assessed correlations between lag values and number of CTS and medication conditions. RESULTS: RSLA analysis indicated earlier intrinsic activations in bilateral Rolandic areas when CTS occurred. More frequent epileptic discharges were correlated with earlier intrinsic activations (r=-0.46, p = 0.03 left Rolandic). Patients with LEV therapy, on the other hand, displayed delayed intrinsic activity in Rolandic areas compared to drug-naïve patients CONCLUSION: Our RSLA analysis indicated an association between centro-temporal spikes and earlier hemodynamic activations in epileptogenic regions in Rolandic epilepsy, which were counteracted by LEV treatment. As it allows for the mapping of propagation features of intrinsic activity and drug-effects, our findings suggest potential of lag based analyses in detecting focus localization and estimating treatment effects.

Novel variant in CHRNA4 with benign childhood epilepsy with centrotemporal spikes and contribution to precise medicine.

BACKGROUND: Benign childhood epilepsy with centrotemporal spikes (BECTS) or benign rolandic epilepsy is the most common epileptic syndrome in school-age children. Genetics is an important factor in BECTS pathogenesis, and <10 genes were associated with BECTS. This study aimed to identify novel genetic causes of BECTS. METHODS: We conducted whole-exome sequencing on a patient with BECTS and validated the findings by Sanger sequencing in a pedigree with three patients. RESULTS: CHRNA4 c.1007G>A was identified in three patients with BECTS in a pedigree. Carbamazepine, which should be carefully used in BECTS, was observed to be effective in the treatment of our atypical BECTS proband based on the molecular diagnosis of CHRNA4. CONCLUSION: This is the first study on CHRNA4 variant in BECTS, which widened the genetic spectrum of BECTS and contributed to precise medicine in BECTS.

Focal cortical hypermetabolism in atypical benign rolandic epilepsy.

OBJECTIVE: Atypical benign rolandic epilepsy (BRE) is an underrecognized and poorly understood manifestation of a common epileptic syndrome. Most consider it a focal epileptic encephalopathy in which frequent, interictal, centrotemporal spikes lead to negative motor seizures and interfere with motor and sometimes speech and cognitive abilities. We observed focal cortical hypermetabolism on PET in three children with atypical BRE and investigated the spatial and temporal relationship with their centrotemporal spikes. METHODS: EEG, MRI and PET were performed clinically in three children with atypical BRE. The frequency and source localization of centrotemporal spikes was determined and compared with the location of maximal metabolic activity on PET. RESULTS: Cortical hypermetabolism on thresholded PET t-maps and current density reconstructions of centrotemporal spikes overlapped in each child, in the central sulcus region, the distances between the "centers of maxima" being 2 cm or less. Hypermetabolism was not due to recent seizures or frequent centrotemporal spikes at the time of FDG uptake. SIGNIFICANCE: The findings suggest that localized, increased cortical activity, in the region of the EEG focus, underlies the negative clinical manifestations of atypical BRE. Similar findings are reported in the broader group of epileptic encephalopathies associated with electrical status epilepticus in sleep.

Temporal trends in incidence of Rolandic epilepsy, prevalence of comorbidities and prescribing trends: birth cohort study.

OBJECTIVE: To examine temporal trends in incidence of Rolandic epilepsy (RE), prevalence of comorbidities and antiepileptic drug (AED) prescribing patterns. DESIGN: Retrospective cohort study. SETTING: The UK. PATIENTS: Children aged 0-16 years born 1994-2012 were followed from birth until September 2017, transfer to another general practitioner practice or death or practice withdrawal from The Health Improvement Network (THIN), whichever occurred first. MAIN OUTCOME MEASURES: Incidence of RE, prevalence of comorbidity and AED prescribing patterns. Read codes for comorbidities and AEDs were adapted from other UK population-based epilepsy studies. RESULTS: There were 379 children with first RE event recorded between 2000 and 2014 from active THIN practices with available mid-year population counts. Crude annual incidence across all years was 5.31/100 000 (95% CI 4.81 to 5.88). There was no significant time trend in adjusted incidence rate ratios (aIRR) (0.99/year, 95% CI 0.96 to 1.02). Males had higher aIRR (1.48, 95% CI 1.20 to 1.82) as did children aged 6-8 and 9-11 years compared with 4-5 years (aIRR 2.43, 95% CI 1.73 to 3.40; aIRR 2.77, 95% CI 1.97 to 3.90, respectively). There was recorded comorbidity in 12% with 6% with a recorded diagnosis of pervasive developmental disorder. Half of children with RE had a record of being prescribed AEDs. CONCLUSIONS: UK incidence of RE has remained stable with crude incidence of 5/100 000/year. Carers and clinicians need to be aware that comorbidities may exist, particularly pervasive developmental disorders. Carbamazepine is consistently the most commonly prescribed AED for RE in the UK.

TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model.

Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations.

Cognitive profile in BECTS treated with levetiracetam: A 2-year follow-up.

INTRODUCTION: Benign epilepsy with centrotemporal spikes (BECTS) is a common epileptic syndrome in childhood, characterized by brief and infrequent partial motor seizures, with or without generalization and mostly recurring during sleep. Because of its favorable efficacy, tolerability, and safety profile, levetiracetam (LEV) monotherapy is often administered in these patients. Long-term effects of LEV therapy and its influence on cognitive functions remain controversial. PURPOSE: This evaluated the changes in the cognitive profile of children with BECTS treated with LEV monotherapy for 2 years, compared with a control group of children with specific learning disabilities. METHOD: Our patient cohort included 20 children aged 8-14 years diagnosed as having BECTS and administered LEV monotherapy and 10 age/sex-matched controls with specific learning disabilities. All participants underwent a standardized test for assessing cognitive profile (Wechsler Intelligence Scale for Children - Fourth Edition [WISC-IV]) before drug therapy and after 2 years of treatment. Average LEV blood level and electroencephalographic (EEG) recordings were periodically monitored. Several factors such as age, sex, response to therapy, and EEG pattern changes were considered. Statistical analysis was performed using Student's t-test for paired and independent samples. p < 0.05 was considered statistically significant. RESULTS: Children administered LEV for 24 months showed a mild but statistically significant improvement in overall cognitive abilities. Verbal skills, visual-perceptual reasoning, working memory, and processing speed showed slight but significant improvement. In the control group, cognitive profile remained substantially unchanged at 2-year follow-up. CONCLUSIONS: Not only do our data suggest a nonworsening of the cognitive profile in BECTS with LEV but, on the contrary, cognitive scores also improved over time, unlike the control group.