Intractable Pediatric Epilepsy Research Articles

Disconnection Surgery in Pediatric Epilepsy: A Single Center's Experience With 185 Cases.

Lobar and multilobar disconnections have gradually become common surgical methods in pediatric epilepsy surgery in recent years. However, the surgical procedures, postoperative epilepsy outcomes, and complications reported by each center are quite different. To review and analyze the clinical data from lobar disconnection in treating intractable pediatric epilepsy and study the characteristics, surgical outcomes, and safety of different disconnection surgeries. This was a retrospective analysis of 185 children with intractable epilepsy who underwent various lobar disconnections at the Pediatric Epilepsy Center, Peking University First Hospital. Clinical information was grouped according to their characteristics. The differences in the abovementioned characteristics among the different lobar disconnections were summarized, and risk factors affecting the surgical outcome and postsurgical complications were explored. Among the 185 patients, 149 patients (80.5%) achieved seizure freedom with a follow-up of 2.1 years. There were 145 patients (78.4%) with malformations of cortical development (MCD). The seizure onset time (median 6 months, P = .001) and surgery time (median 34 months, P = .000) of the MCD group were smaller. Differences were found in etiology, resection of the insular lobe and epilepsy outcome among different disconnection approaches. Both parieto-occipital disconnection ( P = .038, odds ratio = 8.126) and MRI abnormalities larger than the disconnection extent ( P = .030, odds ratio = 2.670) affected the epilepsy outcome. Early postoperative complications were observed in 43 patients (23.3%), and long-term postoperative complications were observed in 5 patients (2.7%). The most common etiology of epilepsy in children undergoing lobar disconnection is MCD, whose onset and operative ages are the youngest. Disconnection surgery obtained good seizure outcomes in the treatment of pediatric epilepsy with a low incidence of long-term complications. With advances in presurgical evaluation, disconnection surgery will play a more important role in young children with intractable epilepsy.

Racial and socioeconomic disparities in the advanced treatment of medically intractable pediatric epilepsy.

Racial and ethnic disparities in healthcare have gained significant importance since the Institute of Medicine published its report on disparities in healthcare. There is a lack of evidence on how race and ethnicity affect access to advanced treatment of pediatric medically intractable epilepsy. In this context, the authors analyzed the latest Kids' Inpatient Database (KID) for racial/ethnic disparities in access to surgical treatment of epilepsy. The authors queried the KID for the years 2016 and 2019 for the diagnosis of medically intractable epilepsy. A total of 29,292 patients were included in the sample. Of these patients, 8.9% (n = 2610) underwent surgical treatment/invasive monitoring. The mean ages in the surgical treatment and nonsurgical treatment groups were 11.73 years (SD 5.75 years) and 9.5 years (SD 6.16 years), respectively. The most common insurance in the surgical group was private/commercial (55.9%) and Medicaid in the nonsurgical group (47.7%) (p < 0.001). White patients accounted for the most common population in both groups, followed by Hispanic patients. African American patients made up 7.9% in the surgical treatment group compared with 12.9% in the nonsurgical group. African American (41.1%) and Hispanic (29.9%) patients had higher rates of emergency department (ED) utilization compared with the White population (24.6%). After adjusting for all covariates, the odds of surgical treatment increased with increasing age (OR 1.06, 95% CI 1.053-1.067; p < 0.001). African American race (OR 0.513, 95% CI 0.443-0.605; p < 0.001), Hispanic ethnicity (OR 0.681, 95% CI 0.612-0.758; p < 0.001), and other races (OR 0.789, 95% CI 0.689-0.903; p = 0.006) had lower surgical treatment odds compared with the White population. Medicaid/Medicare was associated with lower surgical treatment odds than private/commercial insurance (OR 0.603, 0.554-0.657; p < 0.001). Interaction analysis revealed that African American (OR 0.708, 95% CI 0.569-0.880; p = 0.001) and Hispanic (OR 0.671, 95% CI 0.556-0.809; p < 0.001) populations with private insurance had lower surgical treatment odds than White populations with private insurance. Similarly, African American patients, Hispanic patients, and patients of other races with nonprivate insurance also had lower surgical treatment odds than their White counterparts after adjusting for all other covariates. Based on the KID, African American and Hispanic populations had lower surgical treatment rates than their White counterparts, with higher utilization of the ED for pediatric medically intractable epilepsy.

Surgical treatment of pediatric intractable frontal lobe epilepsy due to malformation of cortical development

BackgroundMalformation of cortical development (MCD) is a common cause of intractable epilepsy in children. In this study, the effectiveness of frontal lobe epilepsy (FLE) surgery in children with intractable epilepsy due to MCD was assessed and its prognostic factors were studied.MethodsSeventy-six patients with intractable FLE who received epilepsy surgery between January 2016 and March 2018 in Peking University First Hospital were recruited in this study. All the resected brain tissues were demonstrated to be MCD. All patients were followed up for at least 3 years. The clinical data and prognosis were analyzed retrospectively. Univariate and multivariate analyses were performed to investigate the correlations between clinical variables and prognostic outcome (Engel classification).ResultsSixty (78.9%) patients had Engel class I postoperative outcome. The mean age at surgery was 6.00 ± 4.24 years. Sixty-six patients (86.8%) had daily seizures, 40.2% of the patients had epileptic spasm, and 33% of the patients had extensive interictal EEG abnormalities, which, however, could not provide any helpful information for localizing epileptogenic zones. About 29% of the patients had normal MRI findings even by experienced radiologists, and 26% of the patients had epileptogenic lesion involving adjacent lobes. There was a significant correlation between acute postoperative seizure (APOS) and prognosis (P < 0.05): APOS predicted poor prognosis. There was a significant correlation between pathology and prognosis (P < 0.05): FCD IA and FCD IIB were correlated with a good outcome. Both variables with a significance level of P < 0.05 during univariate analysis, including pathology and APOS, were included in multivariate analysis, which were significant independent predictors of prognosis.ConclusionsThe clinical manifestations of pediatric intractable FLE due to MCD are more complicated than those in adults. Multidisplinary presurgical evaluation in pediatric epilepsy is mandatory. The surgical outcome of pediatric FLE due to MCD could reach a seizure-free rate of 78.9% with the follow-up of at least 3 years. The post-operative pathology and APOS may be related to the prognosis of surgery in this group of pediatric patients.

Vascular endothelial growth factor-C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia.

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor‐C (VEGF‐C) and corresponding receptors VEGFR‐2, VEGFR‐3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF‐C, VEGFR‐2, and VEGFR‐3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF‐C, VEGFR‐2 and VEGFR‐3 was located in the micro‐columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked‐EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor‐ and AMPA receptor‐mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X‐ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF‐C, however, could be antagonized by ki8751, the blocker of VEGFR‐2. These results suggest that VEGF‐C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor–mediated currents.

Development and psychometric evaluation of the Persian version of the Phoneme Recognition Test: A central auditory processing measure.

ObjectivesEpilepsy is the most prevalent chronic neurologic disorder in children. One-third of patients with epilepsy do not respond to antiepileptic drugs. This condition is known as intractable epilepsy. Previous studies have shown the beneficial effects of curcumin in the treatment of epilepsy. There are no randomized controlled clinical trials assessing the use of curcumin in epilepsy. This study aimed to evaluate the effects of nanomicelle curcumin on intractable pediatric epilepsy. Materials & MethodsThis double-blinded randomized crossover clinical trial was performed by a consecutive sampling to select 22 patients with intractable epilepsy divided into two groups. Patients received a daily dose of 4 mg/kg of curcumin or placebo as add-on therapy for 4 weeks. After a 2-week washout period, the treatment was replaced, and the new treatment was given for another 4 weeks. The SPSS software version 16 was used for statistical analysis. The study was approved by the Ethics Committee of Mashhad University of Medical Sciences, Iran.ResultsA total of 22 children were enrolled in this study, 11 of which were boys. The mean age of the patients was 4.28±5 years. A female patient taking a placebo was excluded in the first week of the trial due to parental dissatisfaction. The most common type of seizure among our patients was a generalized myoclonic seizure (42.9%). The mean number of seizure attacks among the subjects was 68.76±69.26 pre-intervention and 39.85±39.41at the end of the intervention, which represents a statistically significant difference (P=0.01).ConclusionNanomicelle curcumin reduced the number of seizures significantly. Our results imply that curcumin treatment can help treat patients with intractable pediatric epilepsy.

Effective application of corpus callosotomy in pediatric intractable epilepsy patients with mitochondrial dysfunction.

Background:Whether epilepsy surgery, such as corpus callosotomy is effective in patients with pediatric intractable epilepsy with mitochondrial dysfunction is controversial, and there is a paucity of literature on this issue.Objective:This study aimed to assess and describe the effective application of corpus callosotomy for treating pediatric patients with intractable epilepsy with mitochondrial dysfunction in a single institution in Korea.Methods:This was a retrospective study of pediatric patients with intractable epilepsy and mitochondrial dysfunction who underwent corpus callosotomy in a single tertiary care center. Ten patients with intractable epilepsy with mitochondrial dysfunction were included, and 10 patients with intractable epilepsy with non-mitochondrial dysfunctions were included as a control group. The outcomes of corpus callosotomy in the two groups were evaluated and compared.Results:Corpus callosotomy was safely performed and was efficacious in reducing seizure frequency in both groups. The group with non-mitochondrial dysfunction showed slightly better treatment outcomes, with greater reductions in overall seizures, traumatic falling seizures, and electroencephalography improvements, but the differences in treatment effects were not statistically significant.Conclusions:Our study is meaningful as it identified the use of corpus callosotomy as a means to save lives and improve quality of life by reducing the frequency of seizures and those associated with traumatic falling in pediatric patients with intractable epilepsy with mitochondrial dysfunction. Larger multicenter studies are necessary to confirm the efficacy of the procedure.

The Effectiveness of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment for Pediatric Intractable Epilepsy Other than Infantile Spasms, Case-Series

The Effectiveness of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment for Pediatric Intractable Epilepsy Other than Infantile Spasms, Case-Series

Patient Characteristics Associated with Seizure Freedom after Vagus Nerve Stimulation in Pediatric Intractable Epilepsy: An Analysis of “Super-Responders”

AbstractClinical responses to vagus nerve stimulation (VNS) therapy for intractable epilepsy can be unpredictable, and factors that predict response to therapy are elusive. Minority of children undergoing VNS achieve seizure freedom. The current study aimed to characterize this exceptional patient population, defined as “super-responders” (SRs). Retrospective data were collected from 150 children who underwent VNS at a single pediatric institution. The patients' mean age at VNS device implantation was 12.0 years (range, 3.09–17.9 years). Ten SRs (6.7%) were identified who achieved and maintained seizure freedom for longer than 1 year following implantation. The interval between epilepsy onset and VNS device implantation was significantly shorter in SRs than in the other children (mean epilepsy duration 5.72 vs. 8.44 years, respectively; p = 0.032). SRs also had a significantly shorter proportion of life with epilepsy compared with the other children (mean ratio of epilepsy duration to age at implantation 0.52 vs. 0.71, respectively; p = 0.023). SRs reported their seizure freedom relatively early (six patients within 6 months and all patients within 12 months after implantation) at relatively low device settings (mean output current 0.81 mA at their last follow-up). Compared with conventional models, responsive VNS models with autostimulation features did not increase the ratio of SRs. No other clinical or imaging characteristic difference between SRs and the other children was found in this cohort. The current study showed a significant association between shorter epilepsy duration and shorter proportion of life with epilepsy and seizure freedom after VNS.

Impairment of Cardiac Autonomic Nerve Function in Pre-school Children With Intractable Epilepsy.

Objective: Intractable epilepsy and uncontrolled seizures could affect cardiac function and the autonomic nerve system with a negative impact on children's growth. The aim of this study was to investigate the variability and complexity of cardiac autonomic function in pre-school children with pediatric intractable epilepsy (PIE).Methods: Twenty four-hour Holter electrocardiograms (ECGs) from 93 patients and 46 healthy control subjects aged 3–6 years were analyzed by the methods of traditional heart rate variability (HRV), multiscale entropy (MSE), and Kurths–Wessel symbolization entropy (KWSE). Receiver operating characteristic (ROC) curve analysis was used to estimate the overall discrimination ability. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) models were also analyzed.Results: Pre-school children with PIE had significantly lower HRV measurements than healthy controls in time (Mean_RR, SDRR, RMSSD, pNN50) and frequency (VLF, LF, HF, LF/HF, TP) domains. For the MSE analysis, area 1_5 in awake state was lower, and areas 6_15 and 6_20 in sleep state were higher in PIE with a significant statistical difference. KWSE in the PIE group was also inferior to that in healthy controls. In ROC curve analysis, pNN50 had the greatest discriminatory power for PIE. Based on both NRI and IDI models, the combination of MSE indices (wake: area1_5 and sleep: area6_20) and KWSE (m = 2, τ = 1, α = 0.16) with traditional HRV measures had greater discriminatory power than any of the single HRV measures.Significance: Impaired HRV and complexity were found in pre-school children with PIE. HRV, MSE, and KWSE could discriminate patients with PIE from subjects with normal cardiac complexity. These findings suggested that the MSE and KWSE methods may be helpful for assessing and understanding heart rate dynamics in younger children with epilepsy.

A comparison of glutamic acid decarboxylase serum autoantibody levels in pediatric intractable and non-intractable epilepsy

ObjectiveThe purpose of this study was to compare autoantibodies to glutamic acid decarboxylase serum levels in children suffering from intractable and non-intractable epilepsy at Dr. Soetomo General Hospital Surabaya, Indonesia. MethodsA case–control study was conducted with children suffering from intractable and non-intractable epilepsy from November to December 2018 in the pediatric neurology outpatient clinic. Autoantibodies to glutamic acid decarboxylase serum levels were examined from both groups using ELISA; statistical analysis was performed using the Mann–Whitney U test non-parametric tests. ResultA sample of 80 children was divided into two groups of 40 children each. Their average age was 5.4 years (range of 4 months–17 years). The average anti-epileptic drug treatment duration was 2.3 years (3 months–13 years). Glutamic acid decarboxylase autoantibody levels in the intractable group were higher compared to levels in the non-intractable group, ranging from 140 to 410ng/ml (median 243.3) and 10–120ng/ml (median 98.10) respectively with p values<0.05. ConclusionChildren suffering from intractable epilepsy have higher levels of GAD-Ab compared to children with non-intractable epilepsy.

Cultural conformity and cannabis care in the wake of intractable pediatric epilepsy

Biomedicine controls seizures for many children with epilepsy – but not all. In such cases, parents struggle in the wake of various structural, cultural, and corporeal ruptures. Continued use of ineffective medications can lead, iatrogenically, to frightening and serious symptoms and debilitations whose effects, along with those of uncontrolled seizures, ripple outward in challenging ways. Using data from 25 Californian (US) parents who favored providing cannabis to their ill children to meet the iatrogenic burdens of biomedical epilepsy treatments in 2015, well before cannabis’s present destigmatization, this paper explores parental refiguration of the effects of clinical iatrogenesis as inevitable – and as productive of evidence necessary to finding better options. In attending to the generative dimensions of iatrogenesis, this paper strives to help clarify the dilemma for parents who critique biomedicine’s isolating, materialist, and sometimes apparently haphazard approach to their children, but depend on biomedical and associated systems for their family’s well-being nonetheless. Along the way, this paper underscores raced and gendered dimensions of their experiences. Rather than rejecting biomedicine, most hung on tightly, blaming the uncontrolled seizures and their aftermath on a lag in ‘the science’ and pointing to the cultural idea that every child is unique in explaining their own children’s non-responsiveness to treatment thus far. Likewise, they worked to determine effective cannabis regimens with scientised rigour. However, in the end – and in keeping with a culture of (male) Whiteness – stigmatisation, fatigue from chronic care provision, faith in science, and a need for a biomedically-mediated form of social belonging underwrote a majority desire for cannabis’s incorporation into the official biomedical pharmacopeia.

Cannabichromene, Related Phytocannabinoids, and 5-Fluoro-cannabichromene Have Anticonvulsant Properties in a Mouse Model of Dravet Syndrome.

Cannabis-based products are increasingly being used to treat refractory childhood epilepsies such as Dravet syndrome. Cannabis contains at least 140 terpenophenolic compounds known as phytocannabinoids. These include the known anticonvulsant compound cannabidiol (CBD) and several molecules showing emergent anticonvulsant properties in animal models. Cannabichromene (CBC) is a phytocannabinoid frequently detected in artisanal cannabis oils used in the community by childhood epilepsy patients. Here we examined the brain and plasma pharmacokinetic profiles of CBC, cannabichromenic acid (CBCA), cannabichromevarin (CBCV), and cannabichromevarinic acid (CBCVA) following intraperitoneal administration in mice. The anticonvulsant potential of each was then tested against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome. All phytocannabinoids within the CBC series were readily absorbed and showed substantial brain penetration (brain-plasma ratios ranging from 0.2 to 5.8). Anticonvulsant efficacy was evident with CBC, CBCA, and CBCVA, each significantly increasing the temperature threshold at which Scn1a+/- mice had a generalized tonic-clonic seizure. We synthesized a fluorinated derivative of CBC (5-fluoro-CBC), which showed improved brain penetration relative to the parent CBC molecule but not any greater anticonvulsant effect. Since CBC and derivatives are anticonvulsant in a model of intractable pediatric epilepsy, they may constitute part of the mechanism through which artisanal cannabis oils are anticonvulsant in patients.

Randomized Controlled Trial of Vagal Nerve Stimulation for Younger Pediatric Patients with Intractable Epilepsy

Background: Vagal nerve stimulation (VNS) may control seizures of pediatric intractable epilepsy (PIE) as a clinically adjunctive therapy. However, high-evidence level data for younger children are needed. Methods: In this multicenter, double-blind, randomized controlled trial (VNS-PIE), we recruited children aged 3-6 years with PIE from eleven hospitals specialized in epilepsy in China. Enrolled children underwent computer-generated randomization at 1:1 ratio. Within first 12-week double-blind period, children in stimulation group received active electrical stimulation while others in control group received sham treatment. Children, their parents and investigators assessing outcomes were masked to random allocation; unmasked investigators were responsible for stimulation parameter programming. After unblinding, all children received active electrical stimulation for the subsequent 12 weeks. The primary outcome was the reduction percentage of seizure frequency between two groups at the end of the double-blind period. Findings: Between Sep 29, 2017, and May 29, 2018, 93 children were enrolled and randomly assigned to 47(51%) in stimulation group and 46(49%) in control group (Dropout: one (2%) in stimulation group). At the end of the double-blind period, the median reduction in seizure from baseline was 40·0%(IQR:[0, 71·7%]) in stimulation group, compared to 21·2%(IQR:[-15·9, 68·0%]) in control group (Adjusted median difference(AMD), 12·6%; 95% CI, 10·3% to 34·7%; p=0·23; n=93, FAS); Between-group difference of seizure decrease significantly favored electrical stimulation with respect to subgroup analysis without surgery honeymoon effect (AMD: 21·6 %; 95% CI, -4·2% to 43·3%; p=0·043; n=78, PPS). There was no significant difference in the efficacy of mental development on Gesell scale. Incision infection was common in 9 severe adverse events and cough was most frequent in 41 adverse events. Interpretation: The results from this trial of VNS supported its clinical use for younger children with PIE. Trial Registration: This trial was registered with ClinicalTrials.gov, number NCT03062514. Funding: Pins Medical Ltd; NKRDPC; NSFC; SICRP. Declaration of Interests: ZY, JD, XYQ, TYC, XF, YY and ZYW reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study. TYJ, QZL, JXL, FY, YHC, LPZ, BML, YXG, XMS, SPH, FG, JML, SFL, JP, SWS, JW, CC, WXS, MQT, LY, YH, YPH, YW, HX, LXC and YWJ reports institution remunerated for recruitment of patients from Pins Medical during the conduct of the study. HWH reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study; grants for advisory broad outside the submitted work. LML reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study; grants for neuromodulation research outside the submitted work. Ethics Approval Statement: The trial was approved by each ethical committee of participating hospitals (Trial protocol number: G112L31101; version date: 7/31/2017) and was performed in accordance with the principles of the Declaration of Helsinki.

Vagal nerve stimulation is effective in pre-school children with intractable epilepsy: A report of two cases

There is lack of prospective evidence regarding vagal nerve stimulator (VNS) in younger children with intractable epilepsy. Here, we report the outcomes of using VNS in two pre-school patients for pediatric intractable epilepsy (VNS-PIE) study. Medical treatment was ineffective in both the patients, and they underwent VNS implantation. Seizure frequency, score on the Gesell scale, and heart rate variability (HRV) were assessed following VNS therapy. After 6 months VNS treatment, the seizure frequency in the two patients decreased by 50% from that at baseline, based on the records in their epileptic diary. Video electroencephalography (EEG) examinations showed that abnormal fast waves diminished in the background in Patient 1, and captured seizure frequency in Patient 2 remarkably decreased. The adaptability, language, and individual and social interaction on their Gesell scales increased slightly, suggesting that VNS had a positive effect on the development of these two children. Moreover, the changes in the different HRV indices indicated improved cardiac autonomic function. In conclusion, these two cases indicated that VNS may not only be a superior therapy for pre-school children with intractable epilepsy, but also may exert a positive effect on their mental development and cardiac autonomic function.

Long-term outcomes of ketogenic diet in patients with tuberous sclerosis complex-derived epilepsy

ObjectiveFor epilepsy with tuberous sclerosis complex (TSC), ketogenic diet (KD) therapy has been consistently reported to be more beneficial than the average KD therapy response. Herein, we aimed to investigate the long-term outcomes of a KD on patients with TSC and intractable epilepsy. MethodsThis study included 31 patients with intractable epilepsy and TSC who were treated with the KD, and an intention-to-treat analysis was performed. ResultsOverall, 21 of the 31 patients (67.7%) had >50% reduction in seizures at 3 months after initiating the KD. Thirteen of the 31 patients (41.9%) were seizure-free for at least 3 months, but 10 of these 13 patients (76.9%) experienced seizure recurrence during the 24-month follow-up period. Finally, at 24 months of the KD observational period, there was >50% response in 10 of the 31 patients (32.3%), including seizure-free patients (6 of 31 patients, 19.4%). Most of the patients (12 of 13, 92.3%) who experienced seizure freedom had >50% reduction in seizures within 1 month after initiating the KD, and this result was the only factor associated with seizure freedom in the current study. ConclusionThe KD appeared to be an effective therapeutic modality for intractable pediatric epilepsy in TSC, but it did not exhibit guaranteed efficacy over a long-term period.

Differential Expression Hallmarks of Interneurons in Different Types of Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is the main cause of medically intractable pediatric epilepsy. Previous studies have suggested that alteration of cortical interneurons and abnormal cytoarchitecture have been linked to initiation and development for seizure. However, whether each individual subpopulation of cortical interneurons is linked to distinct FCD subtypes remains largely unknown. Here, we retrospectively analyzed both control samples and epileptic specimens pathologically diagnosed with FCD types Ia, IIa, or IIb. We quantified three major interneuron (IN) subpopulations, including parvalbumin (PV)-, somatostatin (Sst)-, and vasoactive intestinal peptide (Vip)-positive INs across all the subgroups. Additionally, we calculated the ratio of the subpopulations of INs to the major INs (mINs) by defining the total number of the PV-, Sst-, and Vip-INs as mINs. Compared with the control, the density of the PV-INs in FCD type IIb was significantly lower, and the ratio of PV/mINs was lower in the superficial part of the cortex of the FCD type Ia and IIb groups. Interestingly, we found a significant increase in the ratio of Vip/mINs only in FCD type IIb. Overall, these results suggest that in addition to a reduction in PV-INs, the increase in Vip/mINs may be related to the initiation of epilepsy in FCD type IIb. Furthermore, the increase in Vip/mINs in FCD type IIb may, from the IN development perspective, indicate that FCD type IIb forms during earlier stages of pregnancy than FCD type Ia.

Internalizing symptoms in intractable pediatric epilepsy: Structural and functional brain correlates

Internalizing disorders (i.e., depression and anxiety) are common comorbidities in people with epilepsy. In adults with epilepsy, comorbid depression or anxiety is associated with worse seizure control and reduced quality of life, and may be linked to specific neural biomarkers. Less is known about brain correlates of internalizing symptoms in pediatric populations. In the current study, we performed a retrospective analysis of 45 youth between the ages of 6 and 18 years old with intractable epilepsy. Individuals were evaluated for internalizing symptoms on the Child Behavior Checklist (CBCL) and underwent magnetic resonance (MR) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging as part of the clinical evaluation for surgical treatment of epilepsy. Forty-two percent of patients experienced clinically significant internalizing symptoms based on parent report. Compared with individuals who scored in the normal range, youth with clinical levels of internalizing problems showed overall reductions in cortex volume, as well as widespread reductions in cortical thickness and functional activation in the bilateral occipital/parietal lobe, left temporal regions, and left inferior frontal cortex on MR and PET scans. There were no group differences in amygdala or hippocampus volumes, nor other patient- or illness-related variables such as age, sex, or the type, lateralization, or duration of epilepsy. Results suggest that high rates of internalizing disorders are present in youth with refractory epilepsy. Multifocal reductions in cortical thickness and function may be nonspecific risk factors for clinically meaningful internalizing symptoms in youth with chronic epilepsy. As such, the presence of broad cortical thinning and reduced glucose uptake upon radiological examination may warrant more focused clinical evaluation of psychological symptoms.

Adolescent behavioral abnormalities in a Scn1a+/− mouse model of Dravet syndrome

Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with Dravet syndrome also exhibit delays in reaching normal developmental milestones in attentional, emotional, and cognitive function. These developmental delays manifest in autistic-like social withdrawal and compulsive behavior. Additionally, cognitive impairments including deficits in sensorimotor processing and memory function are present. Several mouse models utilizing heterozygous deletion of Scn1a (Scn1a+/− mice) have been generated that recapitulate many aspects of Dravet syndrome. Studies in these mouse models of Dravet syndrome have characterized behavioral phenotypes in adult mice. In the present study, we characterized the behavioral phenotype of Scn1a+/− mice generated by targeted deletion of Scn1a exon 1 (Scn1atm1Kea) during adolescence. Identifying behavioral deficits in adolescent mice would more closely model the early onset of attentional, emotional, and cognitive delays observed in patients with Dravet syndrome. The behaviors of adolescent Scn1a+/− and wildtype (WT) mice were compared across several behavioral domains. We assessed motor function (open-field test), sociability and social recognition memory (three-chambered social preference and social interaction tests), memory function (novel object recognition, Barnes maze, fear conditioning paradigm), anxiety-related behavior (elevated plus maze and open-field thigmotaxis), startle reflex and sensorimotor gating (prepulse inhibition of startle (PPI) tests), and repetitive compulsive behavior (marble burying test). Adolescent Scn1a+/− mice exhibited normal locomotor activity, marble burying behavior, sociability, and sensorimotor gating. However, adolescent Scn1a+/− mice displayed increased anxiety-related thigmotactic behavior, atypical fear expression, blunted acoustic startle responses, and impaired social recognition and spatial memory. Our results show that Scn1a+/− mice display various behavioral impairments during adolescence, which provides a foundation for testing early intervention therapies targeting developmental delays modeled in Dravet syndrome mice.

Alteration of the anatomical covariance network after corpus callosotomy in pediatric intractable epilepsy.

PurposeThis study aimed to use graph theoretical analysis of anatomical covariance derived from structural MRI to reveal how the gray matter connectivity pattern is altered after corpus callosotomy (CC).Materials and methodsWe recruited 21 patients with epilepsy who had undergone CC. Enrollment criteria were applied: (1) no lesion identified on brain MRI; (2) no history of other brain surgery; and (3) age not younger than 3 years and not older than 18 years at preoperative MRI evaluation. The most common epilepsy syndrome was Lennox-Gastaut syndrome (11 patients). For voxel-based morphometry, the normalized gray matter images of pre-CC and post-CC patients were analyzed with SPM12 (voxel-level threshold of p<0.05 [familywise error-corrected]). Secondly, the images of both groups were subjected to graph theoretical analysis using the Graph Analysis Toolbox with SPM8. Each group was also compared with 32 age- and sex-matched control patients without brain diseases.ResultsComparisons between the pre- and post-CC groups revealed a significant reduction in seizure frequency with no change in mean intelligence quotient/developmental quotient levels. There was no relationship among the three groups in global network metrics or in targeted attack. A regional comparison of betweenness centrality revealed decreased connectivity to and from the right middle cingulate gyri and medial side of the right superior frontal gyrus and a partial shift in the distribution of betweenness centrality hubs to the normal location. Significantly lower resilience to random failure was found after versus before CC and versus controls (p = 0.0450 and p = 0.0200, respectively).ConclusionGraph theoretical analysis of anatomical covariance derived from structural imaging revealed two neural network effects of resection associated with seizure reduction: the reappearance of a structural network comparable to that in healthy children and reduced connectivity along the median line, including the middle cingulate gyrus.

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study

IntroductionSeveral works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time. MethodsThis phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests. ResultsSixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved. ConclusionsPTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.