Pediatric Refractory Epilepsy Research Articles

P.034 Cost-effectiveness of treatment strategies for medically refractory pediatric epilepsy: a systematic review

Background: Medically refractory pediatric epilepsy is a disorder that can cause significant financial and physical burden. Although multiple treatments exist, cost-effectiveness remains unclear. We conducted a systematic review to assess cost-effectiveness of treatments for medically refractory pediatric epilepsy and to summarize key issues and areas for further inquiry. Methods: We searched MEDLINE and 6 other databases up to July 2022. We included partial and full economic evaluations (EEs) on treatments for medically refractory pediatric epilepsy. Pairs of reviewers independently screened the literature, extracted data, and assessed quality using the 24-item Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. We extracted data on study characteristics, health outcomes, model design, costs, and treatment characteristics. Results: We identified 37 eligible studies for analysis, 19 of which were partial EEs and 18 were full EEs. Study quality, outcomes reported, treatment comparators, and factors included in cost calculations were common influential factors in study results. Vagus nerve stimulation and cannabinoid oil were the most consistently cost-effective, in 6 of 7 and 1 of 2 studies, respectively. Other treatments were inconsistently cost-effective. Conclusions: The cost-effectiveness of treatments for medically refractory pediatric epilepsy was not definitive. Consistency in study design and inputs is necessary for future comparison of epilepsy treatment.

Efficacy and safety of a smartphone application-based treatment of ketogenic diet in pediatric refractory epilepsy.

We aimed to find predictors for smartphone application-based ketogenic diet (KD) treatment effectiveness and safety. The efficacy was evaluated according to the reduction in seizure frequency after the intervention of KD; safety was evaluated based on adverse effects. The ordinal logistic regression analysis was used to explore the influencing factors of efficacy. The study sample included 116 males and 65 females with a median age of 2.27 years. The baseline frequency of seizure was more than five times/day in 123 children, 50.83% of them received three or more antiepileptic drugs (AEDs). Seventy-two patients' KD initiation mode was outpatient, and 73 completed the 12-month follow-up. A total of 88 (48.62%) patients had reported a reduction in seizure ≥50%. Compared with 12 months, those who had received KD therapy for only 3 (P = 0.009) and 6 months (P = 0.005) were more likely to show negative outcomes. Outpatient initiation had better outcomes (P = 0.029) than inpatient initiation. For the number of AEDs applied, patients on two AEDs were more likely to achieve better outcomes (P = 0.001). Adverse events had been noted among 77 patients; BMI Z-score at KD initiation was associated with adverse effects (P = 0.003). Our study suggested that outpatient initiation and long-term treatment of KD should be encouraged. Our research shows that the KD is a helpful treatment for children with refractory epilepsy, reducing seizures by more than 50% in nearly half of the cases, with some experiencing complete seizure freedom. We used a smartphone app to improve communication between patients and their healthcare teams, resulting in a high retention, and app usage was linked to reduced adverse effects. We recommend early consideration of KD treatment for patients failing two AED, encourage outpatient initiation, and advocate for longer-term KD use.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark

ObjectiveTo evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. MethodsA review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. ResultsThe median age of epilepsy onset was two years (interquartile range (IQR): 0.0–5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6–1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0–55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: −10.0–+4.0]). Callosotomy resulted in a seizure reduction of 86–99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0–30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). ConclusionHemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

Long-term effectiveness and seizure recurrence risk factors of ketogenic diet for pediatric refractory epilepsy: Experience from a tertiary care center in China.

This study aimed to assess the long-term effectiveness and seizure recurrence risk in children with drug-resistant epilepsy who achieved seizure freedom on a ketogenic diet (KD). Predictors associated with seizure recurrence were also evaluated. Patients with drug-resistant epilepsy who received KD therapy for at least 3 months between May 2011 and April 2020 were included. The clinical efficacy of the KD was evaluated. Patients who achieved seizure freedom for at least 3 months on the KD were focused. Multivariate Cox regression models were used to explore the risk factors of seizure relapse in patients who achieved seizure freedom. This study included 288 patients (163 males, 125 females). The seizure-free rates of the KD at 3, 6, 12, and 24 months were 9.7%, 16.7%, 14.2%, and 9.0%, respectively. Additionally, the seizure reduction rates between 50% and 99% were 46.5%, 39.9%, 30.2%, and 20.5%, respectively. Patients with Angelman syndrome (AS) showed the highest efficacy rate, followed by those with Dravet syndrome (DS). 51 patients achieved at least 3 months of seizure freedom on the KD. Seizures recurred in 24 (47.1%) patients. None of the patients with AS relapsed, while those with DS had the highest recurrence rate. The etiology of epilepsy, KD maintenance treatment period, and electroencephalography (EEG) abnormalities during follow-up differed significantly between patients with and without recurrence. However, multivariate Cox regression analysis indicated that a KD maintenance treatment period of less than 12 months and the presence of EEG abnormalities during follow-up were significantly correlated with a higher risk of relapse. Epilepsy control was restored in 3 of the 24 (12.5%) patients who experienced relapse. KD appears to be effective in children with various types of drug-resistant epilepsy. A short KD maintenance treatment period and EEG abnormalities during follow-up were associated with an increased risk of seizure recurrence.

Additional Effect of High-output Current and/or High-duty Cycle in Vagus Nerve Stimulation for Adolescent/Adult Intractable Epilepsy.

A vagus nerve stimulation (VNS) device delivers electrical pulses to the vagus nerve at a rhythm defined by the duty cycle. The standard therapeutic range is advocated for an output current of 1.5-2.25 mA and a duty cycle of 10%. As the optimal settings vary from patient to patient, some patients may benefit from additional seizure reduction when stimulated beyond the standard range. A total of 74 patients (15 children aged <12 years and 59 adolescents/adults) who underwent VNS implantation between 2011 and 2020 and who were followed up for at least 2 years were included in this retrospective study. Stimulation parameters exceeding 2.25 mA of output current, 25% of duty cycle, and 0.5625 (2.25 mA × 25%) of current × duty cycle were defined as high stimulation. The proportion achieved an additional seizure reduction of 20%, and the 50% seizure reduction rate at the last follow-up was compared between adolescents/adults and children. Approximately 40% of patients in adolescents/adults treated with high stimulation experienced an additional acute effect, resulting in a 50% or greater reduction in seizures in almost all patients. Moreover, in adolescents/adults, 22.2%-41.9% of the patients were treated with high stimulation, and the responder rate was 69.5%. Conversely, the responder rate in children was 26.7%, significantly worse than that in adolescents/adults, despite higher stimulation. VNS with high-stimulation settings is effective for adolescent and adult patients with intractable epilepsy. Even high stimulation may not be effective in extremely refractory pediatric epilepsy with a high seizure frequency.

Analysis of the efficacy and safety of inpatient and outpatient initiation of KD for the treatment of pediatric refractory epilepsy using generalized estimating equations.

To compare the efficacy and safety of inpatient and outpatient initiation ketogenic diet (KD) protocol of pediatric refractory epilepsy. Eligible children with refractory epilepsy were randomly assigned to receive KD with inpatient and outpatient initiation. The generalized estimation equation (GEE) model was used to analyze the longitudinal variables of seizure reduction, ketone body, weight, height, body mass index (BMI), and BMI Z-score at different follow-up times between the two groups. Between January 2013 and December 2021, 78 and 112 patients were assigned to outpatient and inpatient KD initiation groups, respectively. There were no statistical differences between the two groups based on baseline demographics and clinical characteristics (all Ps > 0.05). The GEE model indicated that the rate of reduction of seizures≥50% in the outpatient initiation group was higher than that of the inpatient initiation group (p = 0.049). A negative correlation was observed between the seizure reduction and blood ketone body at 1, 6, and 12 months (all Ps < 0.05). There were no significant differences in height, weight, BMI, and BMI Z-score between the two groups over the 12-month period by the GEE models (all Ps > 0.05). Adverse events were reported by 31 patients (43.05%) in the outpatient KD initiation group and 46 patients (42.20%) in the inpatient KD initiation group, but these differences were not statistically significant (p = 0.909). Our study shows that outpatient KD initiation is a safe and effective treatment for children with refractory epilepsy.

Increased Perirolandic Cortical Excitability May Facilitate Sensory Motor Mapping in Children (P13-1.003)

<h3>Objective:</h3> We are hereby describing a case of refractory pediatric epilepsy where resection of perirolandic seizure foci was performed successfully under neurophysiologic guidance. <h3>Background:</h3> Pediatric neurophysiologic sensory-motor mapping is frequently unsuccessful, due to inability to localize central sulcus (CS) and primary motor cortex (M1). These shortcomings result from poor somatosensory evoked potentials (SSEP) and high M1 depolarization thresholds respectively, both reflections of the immaturity of the central nervous system. <h3>Design/Methods:</h3> Case report <h3>Results:</h3> An 8-year-old boy with developmental delay, debilitating focal epilepsy and epileptic encephalopathy underwent phase 2 video EEG monitoring. The recordings showed seizures with early involvement of several depth electrodes located within the right parieto-frontal regions, and an early motor semiology involving the left arm. The patient underwent neurophysiologically guided resection of the seizure foci under general anesthesia. Pre-resection electrocorticography (ECoG) via a 64 contact grid showed abundant perirolandic epileptiform discharges (ED), maximal postcentrally. Cortical recordings of high amplitude median SSEP and a low depolarization threshold led to successful CS localization and identification of M1, respectively. A subdural strip electrode placed over the precentral gyrus and secured in position, allowed simultaneous ECoG and motor monitoring during the resection of the postcentral foci. Initially, ECoG showed near continuous runs of ED, unchanged by cortical electrical stimulation. Under steady state anesthesia, at a constant propofol infusion rate, this activity decreased in frequency and stopped altogether towards the end stages of the resection, as the M1 threshold increased by 7 mA. Post-resection fronto-parietal ECoG recordings were quiet. Post-operatively, the patient became seizure free, showed cognitive improvement and no motor deficits. <h3>Conclusions:</h3> Increased cortical excitability may lead to successful functional mapping in children. Under steady anesthetic conditions, increases in the M1 threshold during resection of nearby epileptic foci may be an early sign of decrease in the abnormal regional cortical excitability. <b>Disclosure:</b> Dr. Alzahrany has nothing to disclose. Dr. Simon has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Risk Management Foundation of the Harvard Institutions Incorporated. Dr. Simon has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for MCIC Vermont. Dr. Simon has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Aaronson, Rappaport, Feinstein&amp; Deutch. Dr. Simon has received publishing royalties from a publication relating to health care. Dr. Simon has received personal compensation in the range of $0-$499 for serving as a Speaker with American Clinical Neurophysiology Society . Dr. Simon has a non-compensated relationship as a Speaker with International Society of Intraoperative Neurophysiology that is relevant to AAN interests or activities. Dr. Simon has a non-compensated relationship as a Speaker with Brazilian Congress of Neurology that is relevant to AAN interests or activities.

Graph Theory-Based Electroencephalographic Connectivity via Phase-Locking Value and Its Association with Ketogenic Diet Responsiveness in Patients with Focal Onset Seizures.

Ketogenic diets (KDs) are a promising alternative therapy for pediatric refractory epilepsy. Several predictors of KD responsiveness have been identified, including biochemical parameters, seizure types, and electroencephalography (EEG) examinations. We hypothesized that graph theory-based EEG functional connectivity could explain KD responses in patients presenting focal onset seizure (FOS). A total of 17 patients aged 0-30 years old with focal onset seizures (FOS) were recruited as a study group between January 2015 and July 2021. Twenty age-matched children presenting headache with no intracranial complications nor other medical issues were enrolled as a control group. Data were obtained at baseline and at 12 months after initiating KD therapy (KDT) using the child behavior checklist (CBCL) and brain functional connectivity parameters based on phase-locking value from 19 scalp EEG signals, including nodal strength, global efficiency, clustering coefficient, and betweenness centrality. Compared with age-matched controls, patients presenting FOS with right or bilateral EEG lateralization presented higher baseline functional connectivity, including parameters such as global efficiency, mean cluster coefficient and mean nodal strength in the delta and beta frequency bands. In patients presenting FOS with right or bilateral EEG lateralization, the global efficiency of functional connectivity parameters in the delta and theta frequency bands was significantly lower at 12 months after KDT treatment than before KDT. Those patients also presented a significantly lower mean clustering coefficient and mean nodal strength in the theta frequency band at 12 months after KDT treatment. Changes in brain functional connectivity were positively correlated with social problems, attention, and behavioral scores based on CBCL assessments completed by parents. This study provides evidence that KDT might be beneficial in the treatment of patients with FOS. Graph theoretic analysis revealed that the observed effects were related to decreased functional connectivity, particularly in terms of global efficiency. Our findings related to brain connectivity revealed lateralization to the right (non-dominant) hemisphere; however, we were unable to define the underlying mechanism. Our data revealed that in addition to altered brain connectivity, KDT improved the patient's behavior and emotional state.

Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis

Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs. Cannabidiol (CBD) has recently been approved as ASM for three refractory epilepsy syndrome indications in children and adults. In this study, we evaluated the overall clinical potential of an oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 16 weeks. A subgroup analysis by syndrome and CBD with or without concomitant clobazam was conducted. The key outcomes were reduction in seizure frequency, differences in 50% responder rates, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be more efficacious compared to placebo (OR = 2.45, 95% CI =1.81–3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38–3.70), LGS (OR = 2.98, 95% CI:1.83–4.85) and TSC (OR = 1.99, 95% CI = 1.06–3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33–2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63–5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD. In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessments, and therapeutic management guidelines are warranted.

Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: A single-center retrospective study

ObjectiveWe explored the efficacy and safety profile of cenobamate as an adjunctive therapy in patients with refractory focal-onset epilepsy in the pediatric population. MethodsThis was a retrospective, single-center study of cenobamate used as an adjunctive medication in pediatric patients with refractory focal-onset epilepsy . We measured seizure reduction, median reduction in seizure frequency, median dose, responder rate, and treatment-emergent adverse events. ResultsWe studied the efficacy and safety profile of cenobamate in 21 pediatric patients (mean age 15.9). Cenobamate was up titrated using the prescribed starter pack with final doses ranging from 100 mg to 400 mg daily. The mean and median dose of cenobamate was 209.8 mg (±98.87 mg) and 200 mg (175–275), respectively. For patients weighing less than 50 kg, mean and median dose was 4.0 mg/kg/day (3.20–4.63) and 4.32 mg/kg/day, respectively. Mean and median baseline seizure frequency per month in this cohort was 15.38 and 16, respectively, prior to the introduction of cenobamate. After the adjunctive use of cenobamate, mean and median seizure frequency per month reduced to 7.29 and 1, respectively; median reduction in seizure frequency was 93.7%. Seizure reduction of at least 50% (responder rate) was noted in 13 (62.5%) patients and a seizure reduction of at least 75% noted in 11 (52.4%) patients, similar to that seen in adults. Four patients (19%) achieved seizure freedom. Of the 21 pediatric patients, 9 (42.8%) patients had treatment-emergent adverse events (TEAE) with the most commonly reported symptom being ataxia (5, 23.8%) and sedation (2, 9.5%). Three (14.3%) patients discontinued early due to these side effects. No children developed drug rash with eosinophilia and systemic symptoms (DRESS). ConclusionCenobamate demonstrates similar efficacy rates and safety profile within the pediatric population when compared to the published adult data, making it an effective, safe, and tolerable adjunctive medication for children with refractory focal-onset epilepsy, even at the maximum daily dose.

Safety and efficacy of responsive neurostimulation in the pediatric population: Evidence from institutional review and patient-level meta-analysis

BackgroundResponsive neurostimulation (RNS) is a novel technology for drug-resistant epilepsy rising from bilateral hemispheres or eloquent cortex. Although recently approved for adults, its safety and efficacy for pediatric patients is under investigation. MethodsA comprehensive literature search (Pubmed/Medline, Scopus, Cochrane) was conducted for studies on RNS for pediatric epilepsy (<18 y/o) and supplemented by our institutional series (4 cases). Reduction in seizure frequency at last follow-up compared to preoperative baseline comprised the primary endpoint. ResultsA total of 8 studies (49 patients) were analyzed. Median age at implant was 15 years (interquartile range [IQR] 12–17) and 63% were males. A lesional MRI was noted in 64% (14/22). Prior invasive EEG recording was performed in the majority of patients (90%) and the most common modality was stereoelectroencephalography (57%). The most common implant location (total of 94 RNS leads) was the frontal lobe (27%), followed by mesial temporal structures (23%) and thalamus (17%). At a median follow-up of 22 months, median seizure frequency reduction was 75% (IQR: 50–88%) and 80% were responders (>50% seizure reduction). Responses ranged from 50% for temporal lobe epilepsy to 81–93% for frontal, parietal, and multilobar epilepsy. Four infections were observed (8%) and there were no hematomas or postoperative neurological deficits. ConclusionCurrent evidence, albeit limited by potential publication bias, supports the promising safety and efficacy profile of RNS for medically refractory pediatric epilepsy. Randomized controlled trial data are needed to further establish the role of this intervention in preoperative discussions with patients and their families.

Simultaneously Acquired MRI Arterial Spin-Labeling and Interictal FDG-PET Improves Diagnosis of Pediatric Temporal Lobe Epilepsy.

Interictal FDG-PET scans are a routine diagnostic technique for the identification of epileptogenic foci in the presurgical work-up of medically refractory pediatric epilepsy. With the advent of PET/MR imaging, it has become possible to simultaneously acquire FDG-PET and arterial spin-labeling perfusion data. The objective of this study was to evaluate whether the incorporation of arterial spin-labeling data with interictal FDG-PET could improve the diagnostic performance metrics of FDG-PET for identification of epileptogenic foci. Forty-five pediatric patients with a mean age of 10.8 years were retrospectively included in this study. These patients all underwent PET/MR imaging to diagnose suspected focal epilepsy. When compared to interpretations of interictal FDG findings alone, FDG combined with arterial spin-labeling findings resulted in significantly decreased sensitivity (0.64 versus 0.52, P = .02), significantly increased specificity (0.50 versus 0.75, P = .04), and an increased positive predictive value (0.59 versus 0.75). The decreased sensitivity was found to be primarily driven by patients with extratemporal lobe epilepsy, as a subgroup analysis showed decreased sensitivity for patients with extratemporal epilepsy (0.52 versus 0.38, P = .04), but not for temporal epilepsy (0.83 versus 0.75, P = .16). Additionally, substantial agreement between focal FDG hypometabolism and arterial spin-labeling hypoperfusion was demonstrated with the Cohen κ (0.70, P < .01). These findings suggest that simultaneously acquired interictal FDG-PET and arterial spin-labeling data can improve the diagnosis of epileptogenic foci, especially in the setting of temporal lobe epilepsy where they improve specificity and positive predictive value, with preservation of sensitivity.

Immunological approach to refractory pediatric epilepsy from a clinician's point of view

Immunological approach to refractory pediatric epilepsy from a clinician's point of view

Neuroprotection by the Ketogenic Diet: Evidence and Controversies.

The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.

The ketogenic diet alters the expression of chromatin modifying enzymes in GBM to potentiate the effects of chemotherapy and radiotherapy

Abstract Aims Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12-14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved ineffective due, in part, to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained much attention. The therapeutic ketogenic diet (KD) is a high fat, low carbohydrate and adequate protein diet. It has been recognized as a treatment for refractory paediatric epilepsy for decades. Recent studies have shown that a KD reduced tumour growth and potentiated the effects of therapy in some glioma animal models. However, the underlying mechanism(s) is still unclear. Thus, the aim of this study was to understand the mechanism of action behind the KD’s effects in inhibiting tumour growth and potentiating chemotherapy and radiotherapy. Method To unravel the mechanism of action, we analyzed the expression of genes encoding chromatin modifying enzymes in brain tumour samples from mice fed either a KD or standard diet (SD), using the Mouse Epigenetic Chromatin Modification Enzyme PCR Array (Qiagen, Germany). The expression of genes of interest selected from the array were validated by qRT-PCR. Human GBM cell lines and primary cells from GBMs were used to validate the results of the GBM mouse model. Beta-hydroxybutyrate, the main physiological ketone body found in the circulation of patients during KD, was used in in vitro experiments to mimic the in vivo physiological effect of a KD. The effect of protein arginine methyltransferase 8 (PRMT8) overexpression in GBM cells was studied using a lentiviral system. Cell proliferation was measured by Sulforhodamine B assay (Sigma, USA). Spheroid growth and invasion was measured in GBM spheroids cultured in Matrigel matrix (Corning, USA). Results Our results highlighted changes in the expression of a number of key chromatin modifying enzymes in mice fed a KD compared to those fed a SD. PRMT8, a gene highly downregulated in GBM, was upregulated in tumors from mice fed a KD, with corresponding downregulation of its target genes, dihydrofolate reductase (DHFR) and C-X-C chemokine receptor type 4 (CXCR4). Our results also showed that overexpression of PRMT8 in GBM cells reduced cell proliferation and invasiveness. Conclusion PRMT8, DHFR and CXCR4 have been shown to play key roles in tumour growth, invasion, migration and chemo/radio-resistance. Moreover, therapeutic strategies to downregulate these genes have been investigated in the form of methotrexate for DHFR inhibition and small molecule inhibitors of CXCR4. Thus, our results suggest that one mechanism through which the KD exerts its therapeutic effects may be through altering the expression of chromatin modifying enzymes. This provides additional support for the use of a KD as an adjuvant in combination with existing therapeutic approaches.

An Ultrafast Ultrahigh-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for Cannabidiol Monitoring in Pediatric Refractory Epilepsy.

Cannabidiol (CBD) is a nonpsychoactive natural product that has been increasingly used as a promising new drug for the management of neurological conditions such as refractory epilepsy. Development of rapid and sensitive methods to quantitate CBD is essential to evaluate its pharmacokinetics in humans, particularly in children. The objective of this work was to develop and validate an ultrafast ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for CBD quantitation that is capable of detecting major CBD and tetrahydrocannabinol (THC) metabolites in the plasma of pediatric refractory epilepsy patients. Eight-point CBD calibration curves were prepared using 60 µL of plasma from healthy volunteers. Samples were analyzed in a Shimadzu Nexera X2 UHPLC system, which was coupled to a Sciex QTRAP 6500 mass spectrometer. Chromatography was optimized in acetonitrile (ACN)/water with a 70%-90% gradient of ACN in 2 minutes. Multiple reaction monitoring transitions of major CBD and THC metabolites were optimized in patient plasma. The optimized UHPLC-MS/MS method was validated for the linear range (1-300 ng/mL) of CBD (r2 = 0.996). The limit of quantification and limit of detection were 0.26 and 0.86 ng/mL, respectively. Accuracy and precision met the acceptable validation limits. CBD recovery and matrix effects were 83.9 ± 13.9% and 117.4 ± 4.5%, respectively. The method was successfully applied to quantify CBD and detect the major CBD and THC metabolites in clinical samples. 7-COOH-CBD was the most intensely detected metabolite followed by glucuronide conjugates. A simple and sensitive method for rapidly monitoring CBD and identifying relevant metabolites was developed. Its applicability in samples from children treated for epilepsy was demonstrated, making it an excellent alternative for performing pharmacokinetic studies.

Vagus Nerve Stimulation and Seizure Outcomes in Pediatric Refractory Epilepsy: Systematic Review and Meta-analysis.

We synthesized evidence for effectiveness of vagus nerve stimulation (VNS) as adjuvant therapy in pediatric drug-resistant epilepsy (DRE) by obtaining pooled estimates for seizure outcomes and analyzing their determinants. MEDLINE, EMBASE, and Cochrane databases were searched up to July 2019 for original research on VNS in pediatric (≤18 years of age) epilepsy. The primary outcome was 50% responder rate (50% RR), the proportion of patients with ≥50% seizure reduction, at the last reported follow-up. Other outcomes included a 50% RR and proportion of seizure-free patients at additional reported time points. A random-effects meta-analysis with restricted maximum likelihood estimation was performed to obtain pooled effect estimates. Meta-regression using multiple linear models was performed to obtain determinants of seizure outcomes and sources of heterogeneity. A total of 101 studies were included. The pooled prevalence estimates for a 50% RR and seizure freedom at last follow-up (mean 2.54 years) were 56.4% (95% confidence intervals [CIs] 52.4, 60.4) and 11.6% (95% CI 9.6, 13.9), respectively. Fewer antiseizure medications (ASMs) tried before VNS and later age at onset of seizures were associated with better seizure outcomes following VNS implantation. An effect of sex distribution of studies on long-term outcomes and a potential publication bias for short-term outcomes were also observed. Pooled evidence supports possible effectiveness of VNS in pediatric DRE, although complete seizure freedom is less common. Early referral (fewer trials of ASMs) may be a modifiable factor for desirable seizure outcomes with VNS from a clinical perspective.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia

ObjectiveFocal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. MethodsA retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. ResultsFifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SignificanceLarger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Convolutional Neural Networks for Pediatric Refractory Epilepsy Classification Using Resting-State Functional Magnetic Resonance Imaging

This study aims to evaluate the performance of convolutional neural networks (CNNs) trained with resting-state functional magnetic resonance imaging (rfMRI) latency data in the classification of patients with pediatric epilepsy from healthy controls. Preoperative rfMRI and anatomic magnetic resonance imaging scans were obtained from 63 pediatric patients with refractory epilepsy and 259 pediatric healthy controls. Latency maps of the temporal difference between rfMRI and the global mean signal were calculated using voxel-wise cross-covariance. Healthy control and epilepsy latency z score maps were pseudorandomized and partitioned into training data (60%), validation data (20%), and test data (20%). Healthy control individuals and patients with epilepsy were labeled as negative and positive, respectively. CNN models were then trained with the designated training data. Model hyperparameters were evaluated with a grid-search method. The model with the highest sensitivity was evaluated using unseen test data. Accuracy, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve were used to evaluate the ability of the model to classify epilepsy in the test data set. The model with the highest validation sensitivity correctly classified 74% of unseen test patients with 85% sensitivity, 71% specificity, F1 score of 0.56, and an area under the receiver operating characteristic curve of 0.86. Using rfMRI latency data, we trained a CNN model to classify patients with pediatric epilepsy from healthy controls with good performance. CNN could serve as an adjunct in the diagnosis of pediatric epilepsy. Identification of pediatric epilepsy earlier in the disease course could decrease time to referral to specialized epilepsy centers and thus improve prognosis in this population.

Emerging Role of the Ketogenic Dietary Therapies beyond Epilepsy in Child Neurology.

Ketogenic dietary therapies (KDTs) have been in use for refractory paediatric epilepsy for a century now. Over time, KDTs themselves have undergone various modifications to improve tolerability and clinical feasibility, including the Modified Atkins diet (MAD), medium chain triglyceride (MCT) diet and the low glycaemic index treatment (LGIT). Animal and observational studies indicate numerous benefits of KDTs in paediatric neurological conditions apart from their evident benefits in childhood intractable epilepsy, including neurodevelopmental disorders such as autism spectrum disorder, rarer neurogenetic conditions such as Rett syndrome, Fragile X syndrome and Kabuki syndrome, neurodegenerative conditions such as Pelizaeus-Merzbacher disease, and other conditions such as stroke and migraine. A large proportion of the evidence is derived from individual case reports, case series and some small clinical trials, emphasising the vast scope for research in this avenue. The term 'neuroketotherapeutics' has been coined recently to encompass the rapid strides in this field. In the 100th year of its use for paediatric epilepsy, this review covers the role of the KDTs in non-epilepsy neurological conditions among children.