Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

OBJECTIVE: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age. METHODS: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin. RESULTS: Of 84 infants enrolled, 12 were screen failures, 4 went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). Fifty-six were randomized to early vigabatrin (n = 29) or placebo (n = 27). Nineteen of 27 in the placebo arm transitioned to open label vigabatrin, with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug-resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups. INTERPRETATION: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children, nor does it delay onset or lower the incidence of focal seizures and drug-resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. ANN NEUROL 2023.

Expanding eligibility for intracranial electroencephalography using Dexmedetomidine Hydrochloride in children with behavioral dyscontrol.

INTRODUCTION: Invasive intracranial electroencephalography (IEEG) is advantageous for identifying epileptogenic foci in pediatric patients with medically intractable epilepsy. Patients with behavioral challenges due to autism, intellectual disabilities, and hyperactivity have greater difficulty tolerating prolonged IEEG recording and risk injuring themselves or others. There is a need for therapies that increase the safety of IEEG but do not interfere with IEEG recording or prolong hospitalization. Dexmedetomidine Hydrochloride's (DH) use has been reported to improve safety in patients with behavioral challenges during routine surface EEG recording but has not been characterized during IEEG. Here we evaluated DH administration in pediatric patients undergoing IEEG to assess its safety and impact on the IEEG recordings. METHODS: A retrospective review identified all pediatric patients undergoing IEEG between January 2016 and September 2022. Patient demographics, DH administration, DH dose, hospital duration, and IEEG seizure data were analyzed. The number of seizures recorded for each patient was divided by the days each patient was monitored with IEEG. The total number of seizures, as well as seizures per day, were compared between DH and non-DH patients via summary statistics, multivariable linear regression, and univariate analysis. Other data were compared across groups with univariate statistics. RESULTS: Eighty-four pediatric patients met the inclusion criteria. Eighteen (21.4 %) received DH treatment during their IEEG recording. There were no statistical differences between the DH and non-DH groups' demographic data, length of hospital stays, or seizure burden. Non-DH patients had a median age of 12.0 years (interquartile range: 7.25-15.00), while DH-receiving patients had a median age of 8.0 years old (interquartile range: 3.00-13.50) (p = 0.07). The non-DH cohort was 57.6 % male, and the DH cohort was 50.0 % male (p = 0.76). The median length of IEEG recordings was 5.0 days (interquartile range: 4.00-6.25) for DH patients versus 6.0 days (interquartile range: 4.00-8.00) for non-DH patients (p = 0.25). Median total seizures recorded in the non-DH group was 8.0 (interquartile range: 5.00-13.25) versus 15.0 in the DH group (interquartile range: 5.00-22.25) (p = 0.33). Median total seizures per day of IEEG monitoring were comparable across groups: 1.50 (interquartile range: 0.65-3.17) for non-DH patients compared to 2.83 (interquartile range: 0.89-4.35) (p = 0.25) for those who received DH. Lastly, non-DH patients were hospitalized for a median of 8.0 days (interquartile range: 6.00-11.25), while DH patients had a median length of stay of 7.00 days (interquartile range: 5.00-8.25) (p = 0.27). No adverse events were reported because of DH administration. CONCLUSIONS: Administration of DH was not associated with adverse events. Additionally, the frequency of seizures captured on the IEEG, as well as the duration of hospitalization, were not significantly different between patients receiving and not receiving DH during IEEG. Incorporating DH into the management of patients with behavioral dyscontrol and intractable epilepsy may expand the use of IEEG to patients who previously could not tolerate it, improve safety, and preserve epileptic activity during the recording period.

Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Antiseizure medication use and medical resource utilization after resective epilepsy surgery in children in the United States: A contemporary nationwide cross-sectional cohort analysis.

OBJECTIVE: Antiseizure drug (ASD) therapy can significantly impact quality of life for pediatric patients whose epilepsy remains refractory to medications and who experience neuropsychological side effects manifested by impaired cognitive and social development. Contemporary patterns of ASD reduction after pediatric epilepsy surgery across practice settings in the United States are sparsely reported outside of small series. We assessed timing and durability of ASD reduction after pediatric epilepsy surgery and associated effects on health care utilization. METHODS: We performed a retrospective analysis of 376 pediatric patients who underwent resective epilepsy surgery between 2007 and 2016 in the United States using the Truven MarketScan database. Filled ASD prescriptions during the pre- and postoperative periods were compared. Univariate and multivariate analyses identified factors associated with achieving a stable discontinuation of or reduction in number of ASDs. Health care utilization and costs were systematically compared. RESULTS: One hundred seventy-one patients (45.5%) achieved a >90-day ASD-free period after surgery, and 84 (22.3%) additional patients achieved a stable reduction in number of ASDs. Achieving ASD freedom was more common in patients undergoing total hemispherectomy (n = 21, p = .002), and less common in patients with tuberous sclerosis (p = .003). A higher number of preoperative ASDs was associated with a greater likelihood of achieving ASD reduction postoperatively (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 1.50-2.28), but was not associated with a significant difference in the likelihood of achieving ASD freedom (0.83, 95% CI: 0.49-1.39). Achieving an ASD-free period was associated with fewer hospital readmissions within the first year after surgery. SIGNIFICANCE: Patterns of ASD use and discontinuation after pediatric epilepsy surgery provide an unbiased surgical outcome endpoint extractable from administrative databases, where changes in seizure frequency are not captured. This quantitative measure can augment traditional surgical outcome scales, incorporating a significant clinical parameter associated with improved quality of life.

Caregivers' impression of epilepsy surgery in patients with tuberous sclerosis complex.

Epilepsy surgery is successful in the majority of patients with tuberous sclerosis complex (TSC), with high rates of postoperative seizure reduction and even seizure freedom. Epilepsy surgery is recommended after failing two appropriate antiseizure medication trials; however, this is rare in clinical practice. We hypothesized that following surgery, caregivers' perspectives on the path they took to epilepsy surgery would inform changes in clinical practice and future research to increase utilization and early use of surgery. A questionnaire was developed to explore caregivers' perspectives on their child's path to epilepsy surgery. All 46 caregivers that filled out the majority of the survey were glad that their child underwent epilepsy surgery. Fourteen of 34 caregivers that commented on surgery timing wished their child had undergone epilepsy surgery earlier. Epilepsy with a duration of 23.5 months [interquartile range (IQR), 11.1 to 32.2 months, N = 14] prior to surgery was associated with caregiver dissatisfaction and was twice as long compared with caregivers who were satisfied with the timing of surgery (10 months, IQR, 7 to 17.3 months, p = 0.03). Caregivers were willing to accept a lower likelihood of seizure freedom and improvement than what they felt was likely from the preoperative discussions with their physicians. Forty caregivers rated various neurology physician factors as very important in their decision to undergo surgery: neurologist's attitude toward epilepsy surgery, experience with epilepsy surgery, and discussions around the risks of having and not having epilepsy surgery. Optimizing the caregiver-physician relationship can help facilitate early surgery referral and caregiver perception of surgery, potentially preventing delays to surgery and improved caregiver satisfaction.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Delay in pediatric epilepsy surgery: A caregiver's perspective.

The timing of epilepsy surgery is complex, and there is not a structured pathway to help families decide whether to continue medical management or pursue surgical treatment. We surveyed caregivers of pediatric epilepsy surgery patients. Fifty-eight respondents answered the majority of questions. Thirty caregivers wished their child had undergone epilepsy surgery earlier compared with twenty who felt surgery was done at the appropriate time, and eight were unsure. In retrospect, caregivers who wished their child's surgery had been performed sooner had a significantly longer duration of epilepsy prior to the surgery [44.1±71.7 (months±standard deviation (SD), N=27)], compared with those who felt content with the timing of the surgery [12.8±14.1 (months±SD, N=20), p=0.0034]. Caregivers were willing to accept a lower likelihood of seizure freedom than their physician reported was likely. Most caregivers were willing to accept deficits in all domains surveyed; caregivers had high acceptance of motor deficits, cognitive deficits, behavioral change, and language loss. Future studies are needed to focus on how to improve the education of caregivers and neurologists about the benefits and risks of epilepsy surgery and accelerate the pipeline to epilepsy surgery to improve caregiver satisfaction.

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

OBJECTIVE: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. METHODS: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. RESULTS: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. SIGNIFICANCE: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.

Interictal network synchrony and local heterogeneity predict epilepsy surgery outcome among pediatric patients.

OBJECTIVE: Epilepsy is a disorder of aberrant cortical networks. Researchers have proposed that characterizing presurgical network connectivity may improve the surgical management of intractable seizures, but few studies have rigorously examined the relationship between network activity and surgical outcome. In this study, we assessed whether local and global measures of network activity differentiated patients with favorable (seizure-free) versus unfavorable (seizure-persistent) surgical outcomes. METHODS: Seventeen pediatric intracranial electroencephalography (IEEG) patients were retrospectively examined. For each patient, 1,200 random interictal epochs of 1-s duration were analyzed. Functional connectivity networks were constructed using an amplitude-based correlation technique (Spearman correlation). Global network synchrony was computed as the average pairwise connectivity strength. Local signal heterogeneity was defined for each channel as the variability of EEG amplitude (root mean square) and absolute delta power (µV2 /Hz) across epochs. A support vector machine learning algorithm used global and local measures to classify patients by surgical outcome. Classification was assessed using the Leave-One-Out (LOO) permutation test. RESULTS: Global synchrony was increased in the seizure-persistent group compared to seizure-free patients (Student's t-test, p = 0.006). Seizure-onset zone (SOZ) electrodes exhibited increased signal heterogeneity compared to non-SOZ electrodes, primarily in seizure-persistent patients. Global synchrony and local heterogeneity measures were used to accurately classify 16 (94.1%) of 17 patients by surgical outcome (LOO test, iterations = 10,000, p < 0.001). SIGNIFICANCE: Measures of global network synchrony and local signal heterogeneity represent promising biomarkers for assessing patient candidacy in pediatric epilepsy surgery.

Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.

Mutations in the SLC13A5 gene that codes for the Na(+)/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In the present study we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improve transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, our study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na(+)/citrate transporters.

A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy.

Head trauma and vascular injuries are known risk factors for acquired epilepsy. The sequence of events that lead from the initial injury to the development of epilepsy involves complex plastic changes and circuit rewiring. In-depth, comprehensive understanding of the epileptogenic process is critical for the identification of disease-modifying targets. Here we review the complex interactions of cellular and extracellular components that may promote epileptogenesis, with an emphasis on the role of astrocytes. Emerging evidence demonstrates that astrocytes promptly respond to brain damage and play a critical role in the development of postinjury epilepsy. Astrocytes have been shown to regulate extracellular matrix (ECM) remodeling, which can affect plasticity and stability of synapses and, in turn, contribute to the epileptogenic process. From these separate lines of evidence, we present a hypothesis suggesting a possible role for astrocyte-regulated remodeling of ECM and perineuronal nets, a specialized ECM structure around fast-spiking inhibitory interneurons, in the development and progression of posttraumatic epilepsies. © 2016 Wiley Periodicals, Inc.

Plasma taurine levels are not affected by vigabatrin in pediatric patients.

Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.

Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy.

OBJECTIVE: Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model. METHODS: Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREB(IR) ) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video-electroencephalography (EEG) to assess the effect of CREB suppression on seizures. RESULTS: Our findings indicate that activation of CREB(IR) shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREB(IR) induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREB(IR) , supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation. SIGNIFICANCE: Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy.

Perineuronal net degradation in epilepsy.

OBJECTIVE: We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE. METHODS: The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)-induced seizures were assessed. RESULTS: The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure. SIGNIFICANCE: Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility.

Approach, complications, and outcomes for 37 consecutive pediatric patients undergoing laser ablation for medically refractory epilepsy at Stanford Children's Health.

OBJECTIVE: The objective of this study was to better understand the safety and efficacy of laser interstitial thermal therapy (LITT) for children with medically refractory epilepsy. METHODS: Thirty-seven consecutive pediatric epilepsy patients at a single pediatric center who underwent LITT ablation of epileptogenic foci between May 2017 and December 2021 were retrospectively reviewed. Patient demographics, medication use, seizure frequency, prior surgical interventions, procedural details, and pre- and postoperative seizure history were analyzed. RESULTS: Thirty-seven pediatric patients (24 male, 13 female) with severe medically refractory epilepsy were included; all underwent stereo-electroencephalography (SEEG) prior to LITT. The SEEG electrode placement was based on the preoperative workup and tailored to each patient by the epileptologist and neurosurgeons working together to identify the epileptic network and hopefully quiet borders. Seizure onset was at a mean age of 2.70 ± 2.82 years (range 0.25-12 years), and the mean age at the time of LITT was 9.46 ± 5.08 years (range 2.41-17.86 years). Epilepsy was lesional in 23 patients (18 tuberous sclerosis, 4 focal cortical dysplasia, 1 gliosis) and nonlesional in 14. Eighteen patients had prior surgical interventions including open resections (n = 13: 11 single and 2 multiple), LITT (n = 4), or both (n = 1). LITT targeted a region adjacent to the previous target in 5 cases. The median number of lasers placed during the procedure was 3 (range 1-5). Complications occurred in 14 (37.8%) cases, only 3 (8.11%) of which resulted in a permanent deficit: 1 venous hemorrhage requiring evacuation following laser ablation, 1 aseptic meningitis, 2 immediate postoperative seizures, and 10 neurological deficits (7 transient and 3 permanent). Postoperatively, 22 (59.5%) patients were seizure free at the last follow-up (median follow-up 18.35 months, range 7.40-48.76 months), and the median modified Engel class was I (Engel class I in 22 patients, Engel class II in 2, Engel class III in 2, and Engel class IV in 11). Patients having tried a greater number of antiseizure medications before LITT were less likely to achieve seizure improvement (p = 0.046) or freedom (p = 0.017). Seizure improvement following LITT was associated with a shorter duration of epilepsy prior to LITT (p = 0.044), although postoperative seizure freedom was not associated with a shorter epilepsy duration (p = 0.667). Caregivers reported postoperative neurocognitive improvement in 17 (45.9%) patients. CONCLUSIONS: In this large single-institution cohort of pediatric patients with medically refractory seizures due to various etiologies, LITT was a relatively safe and effective surgical approach for seizure reduction and seizure freedom at 1 year of follow-up.

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.

MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.

Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

Focal cortical dysplasia is more common in boys than in girls.

Genetics and environment likely contribute to the development of medically intractable epilepsy; however, in most patients the specific combination of etiologies remains unknown. Here, we undertook a multicenter retrospective cohort study of sex distribution in pediatric patients undergoing epilepsy surgery and carried out a secondary analysis of the same population subdivided by histopathologic diagnosis. In the multicenter cohort of patients with intractable epilepsy undergoing surgery regardless of etiology (n=206), 63% were boys, which is significantly more boys than expected for the general population (Fisher exact two-tailed p=0.017). Subgroup analysis found that of the 90 patients with a histopathologic diagnosis of focal cortical dysplasia, 72% were boys, giving an odds ratio (OR) of 2.5 (95% CI, 1.34 to 4.62) for male sex. None of the other etiologies had a male sex predominance. Future studies could examine the biological relevance and potential genetic and pathophysiological mechanisms of this observation.