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.

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.

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.

Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system.

Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation. Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed. Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes. Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

GNAO1-related neurodevelopmental disorder: Literature review and caregiver survey.

Background: GNAO1-related neurodevelopmental disorder is a heterogeneous condition characterized by hypotonia, developmental delay, epilepsy, and movement disorder. This study aims to better understand the spectrum of epilepsy associated with GNAO1 variants and experience with anti-seizure medications, and to review published epilepsy phenotypes in GNAO1. Methods: An online survey was distributed to caregivers of individuals diagnosed with GNAO1 pathogenic variants, and a literature review was conducted. Results: Fifteen respondents completed the survey with the median age of 39 months, including a novel variant p.Q52P. Nine had epilepsy - six had onset in the first week of life, three in the first year of life - but two reported no ongoing seizures. Seizure types varied. Individuals were taking a median of 3 seizure medications without a single best treatment. Our cohort was compared to a literature review of epilepsy in GNAO1. In 86 cases, 38 discrete variants were described; epilepsy is reported in 53 % cases, and a developmental and epileptic encephalopathy in 36 %. Conclusions: While GNAO1-related epilepsy is most often early-onset and severe, seizures may not always be drug resistant or lifelong. Experience with anti-seizure medications is varied. Certain variant "hotspots" may correlate with epilepsy phenotype though genotype-phenotype correlation is poorly understood.

Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

Connectivity increases during spikes and spike-free periods in self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: To understand the impact of interictal spikes on brain connectivity in patients with Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS). METHODS: Electroencephalograms from 56 consecutive SeLECTS patients were segmented into periods with and without spikes. Connectivity between electrodes was calculated using the weighted phase lag index. To determine if there are chronic alterations in connectivity in SeLECTS, we compared spike-free connectivity to connectivity in 65 matched controls. To understand the acute impact of spikes, we compared connectivity immediately before, during, and after spikes versus baseline, spike-free connectivity. We explored whether behavioral state, spike laterality, or antiseizure medications affected connectivity. RESULTS: Children with SeLECTS had markedly higher connectivity than controls during sleep but not wakefulness, with greatest difference in the right hemisphere. During spikes, connectivity increased globally; before and after spikes, left frontal and bicentral connectivity increased. Right hemisphere connectivity increased more during right-sided than left-sided spikes; left hemisphere connectivity was equally affected by right and left spikes. CONCLUSIONS: SeLECTS patient have persistent increased connectivity during sleep; connectivity is further elevated during the spike and perispike periods. SIGNIFICANCE: Testing whether increased connectivity impacts cognition or seizure susceptibility in SeLECTS and more severe epilepsies could help determine if spikes should be treated.

Limited utility of structural MRI to identify the epileptogenic zone in young children with tuberous sclerosis.

BACKGROUND AND PURPOSE: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC. METHODS: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG). RESULTS: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features. CONCLUSIONS: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data.

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.

Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder.

We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients' records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders.

Real-World Preliminary Experience With Responsive Neurostimulation in Pediatric Epilepsy: A Multicenter Retrospective Observational Study.

BACKGROUND: Despite the well-documented utility of responsive neurostimulation (RNS, NeuroPace) in adult epilepsy patients, literature on the use of RNS in children is limited. OBJECTIVE: To determine the real-world efficacy and safety of RNS in pediatric epilepsy patients. METHODS: Patients with childhood-onset drug-resistant epilepsy treated with RNS were retrospectively identified at 5 pediatric centers. Reduction of disabling seizures and complications were evaluated for children (<18 yr) and young adults (>18 yr) and compared with prior literature pertaining to adult patients. RESULTS: Of 35 patients identified, 17 were <18 yr at the time of RNS implantation, including a 3-yr-old patient. Four patients (11%) had concurrent resection. Three complications, requiring additional surgical interventions, were noted in young adults (2 infections [6%] and 1 lead fracture [3%]). No complications were noted in children. Among the 32 patients with continued therapy, 2 (6%) achieved seizure freedom, 4 (13%) achieved ≥90% seizure reduction, 13 (41%) had ≥50% reduction, 8 (25%) had <50% reduction, and 5 (16%) experienced no improvement. The average follow-up duration was 1.7 yr (median 1.8 yr, range 0.3-4.8 yr). There was no statistically significant difference for seizure reduction and complications between children and young adults in our cohort or between our cohort and the adult literature. CONCLUSION: These preliminary data suggest that RNS is well tolerated and an effective off-label surgical treatment of drug-resistant epilepsy in carefully selected pediatric patients as young as 3 yr of age. Data regarding long-term efficacy and safety in children will be critical to optimize patient selection.

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.

Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder.

Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient's seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients' chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.

Lacosamide-Induced Dyskinesia in Children With Intractable Epilepsy.

Lacosamide, an antiepileptic drug prescribed for children with refractory focal epilepsy, is generally well tolerated, with dose-dependent adverse effects. We describe 4 children who developed a movement disorder in conjunction with the initiation and/or uptitration of lacosamide. Three patients developed dyskinesias involving the face or upper extremity whereas the fourth had substantial worsening of chronic facial tics. The patients all had histories suggestive of opercular dysfunction: 3 had seizure semiologies including hypersalivation, facial and upper extremity clonus while the fourth underwent resection of polymicrogyria involving the opercula. Onset, severity, and resolution of dyskinesias correlated with lacosamide dosing. These cases suggest that pediatric patients with dysfunction of the opercular cortex are at increased risk for developing drug-induced dyskinesias on high-dose lacosamide therapy. Practitioners should be aware of this potential side effect and consider weaning lacosamide or video electroencephalography (EEG) for differential diagnosis, particularly in pediatric patients with underlying opercular dysfunction.

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Robot-guided pediatric stereoelectroencephalography: single-institution experience.

OBJECTIVEStereoelectroencephalography (SEEG) has increased in popularity for localization of epileptogenic zones in drug-resistant epilepsy because safety, accuracy, and efficacy have been well established in both adult and pediatric populations. Development of robot-guidance technology has greatly enhanced the efficiency of this procedure, without sacrificing safety or precision. To date there have been very limited reports of the use of this new technology in children. The authors present their initial experience using the ROSA platform for robot-guided SEEG in a pediatric population.METHODSBetween February 2016 and October 2017, 20 consecutive patients underwent robot-guided SEEG with the ROSA robotic guidance platform as part of ongoing seizure localization and workup for medically refractory epilepsy of several different etiologies. Medical and surgical history, imaging and trajectory plans, as well as operative records were analyzed retrospectively for surgical accuracy, efficiency, safety, and epilepsy outcomes.RESULTSA total of 222 leads were placed in 20 patients, with an average of 11.1 leads per patient. The mean total case time (± SD) was 297.95 (± 52.96) minutes and the mean operating time per lead was 10.98 minutes/lead, with improvements in total (33.36 minutes/lead vs 21.76 minutes/lead) and operative (13.84 minutes/lead vs 7.06 minutes/lead) case times/lead over the course of the study. The mean radial error was 1.75 (± 0.94 mm). Clinically useful data were obtained from SEEG in 95% of cases, and epilepsy surgery was indicated and performed in 95% of patients. In patients who underwent definitive epilepsy surgery with at least a 3-month follow-up, 50% achieved an Engel class I result (seizure freedom). There were no postoperative complications associated with SEEG placement and monitoring.CONCLUSIONSIn this study, the authors demonstrate that rapid adoption of robot-guided SEEG is possible even at a SEEG-naïve institution, with minimal learning curve. Use of robot guidance for SEEG can lead to significantly decreased operating times while maintaining safety, the overall goals of identification of epileptogenic zones, and improved epilepsy outcomes.