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Background: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABA A receptors., Objective: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET)., Methods: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo., Results: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder., Conclusion: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The objective was to investigate the efficacy and safety of soticlestat as adjunctive therapy in participants with complex regional pain syndrome (CRPS)., Design: A proof-of-concept phase 2a study, comprising a 15-week randomized, double-blind, placebo-controlled, parallel-group study (part A), and an optional 14-week open-label extension (part B)., Methods: Twenty-four participants (median age 44.5 years [range, 18-62 years]; 70.8% female) with chronic CRPS were randomized (2:1) to receive oral soticlestat or placebo. Soticlestat dosing started at 100 mg twice daily and was titrated up to 300 mg twice daily. In part B, soticlestat dosing started at 200 mg twice daily and was titrated up or down at the investigator's discretion. Pain intensity scores using the 11-point Numeric Pain Scale (NPS) were collected daily. The Patient-Reported Outcomes Measurement Information System (PROMIS)-29, Patients' Global Impression of Change (PGI-C), and CRPS Severity Score (CSS) were completed at screening and weeks 15 and 29., Results: From baseline to week 15, soticlestat treatment was associated with a mean change in 24-hour pain intensity NPS score (95% confidence interval) of -0.75 (-1.55, 0.05) vs -0.41 (-1.41, 0.59) in the placebo group, resulting in a non-significant placebo-adjusted difference of -0.34 (-1.55, 0.88; P = .570). Statistically non-significant numerical changes were observed for the PROMIS-29, PGI-C, and CSS at weeks 15 and 29., Conclusions: Adjunctive soticlestat treatment did not significantly reduce pain intensity in participants with chronic CRPS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: Chromosome 15q duplication (Dup15q) syndrome and cyclin‑dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275)., Methods: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs)., Results: The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported., Conclusions: Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Scott Demarest has served as a paid consultant for BioMarin, Neurogene, Upsher-Smith Laboratories, Taysha Gene Therapies, and Zogenix on unrelated subject matters and for Marinus Pharmaceuticals and Ovid Therapeutics on related subject matters. Furthermore, he has received funding from the US National Institutes of Health, the International Foundation for CDKL5 Research, Mila's Miracle Foundation, and Project 8p. He also serves on the advisory board for the nonprofit foundations FamilieSCN2A, Project 8p, Ring14 USA, and SLC6A1 Connect. Shafali Jeste has served as a consultant for Roche Pharmaceuticals. Nitin Agarwal currently serves on a speaker panel for Livanova. Dimitrios Arkilo is a former employee of Takeda Pharmaceutical Company Limited. Mahnaz Asgharnejad and Samuel Hsiao are employees of Takeda Pharmaceutical Company Limited and own stock or stock options. Ronald Thibert has served as a paid consultant for Ovid Therapeutics, Takeda, and Roche on related subject matters., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452)., Methods: ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs)., Results: ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported., Significance: Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies., (© 2022 Takeda Pharmaceuticals Company Limited and The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Aims: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694)., Methods: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia., Results: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia., Conclusion: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported., (© 2022 Takeda Pharmaceutical Company. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069)., Methods: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD])., Results: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide., Conclusion: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation., (© 2021 Takenda Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE)., Methods: The study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by evaluation of changes in seizure frequency from baseline., Results: Eighteen patients (median age, 28.5 years) were enrolled and randomized, and 14 (78 %) completed the study. In Part A, TEAEs occurred in 71.4 % of soticlestat-treated patients and 100 % of placebo-treated patients. In Part B, the overall incidence of TEAEs was 68.8 %. In Part A, TEAEs that occurred in more than one patient in the soticlestat group were dysarthria (n = 3, 21.4 %), lethargy (n = 2, 14.3 %), upper respiratory tract infection (n = 2, 14.3 %), fatigue (n = 2, 14.3 %), and headache (n = 2, 14.3 %). Four patients discontinued treatment because of TEAEs, of whom two reported drug-related seizure clusters as serious TEAEs. There were no deaths. Pharmacokinetic analysis showed dose-dependent increases in systemic exposure and peak plasma soticlestat concentrations. At the end of Part B, the overall mean percent change from baseline in plasma 24HC was -80.97 %. Changes from baseline in median seizure frequency were +16.71 % and +22.16 % in the soticlestat and placebo groups, respectively, in Part A, and -36.38 % in all participants in Part B., Conclusion: Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome., (Copyright © 2021 Takeda Pharmaceuticals, USA. Published by Elsevier B.V. All rights reserved.)

Hepatic metabolism of low-clearance compound TAK-041 was studied in two different in vitro model systems using rat, dog, monkey, and human suspended cryopreserved hepatocytes and HepatoPac micropatterned coculture model primary hepatocytes. The aim of this work was to investigate the most appropriate system to assess the biotransformation of TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions for all species, with no metabolites observed in human hepatocytes. However, incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N -acetylation to mercapturic acid and/or conversion to β -lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N -dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest. Furthermore, the model shows its suitability for establishing correlation with in vivo metabolism of low-turnover and extensively metabolized compounds such as TAK-041, displaying an extensive and unusual downstream sequential β -lyase-derived thiol metabolism in preclinical species and human. SIGNIFICANCE STATEMENT: This study investigated the most appropriate in vitro system to assess the biotransformation of the low-turnover and extensively metabolized compound TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. The HepatoPac model was identified and showed its suitability for species comparison and establishing correlation, with in vivo metabolism displaying an extensive and unusual downstream sequential β -lyase-derived thiol metabolism in preclinical species and human., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Objectives: To evaluate emergency department use and outcomes of neuroimaging for headache in a free-standing children's hospital system., Study Design: We prospectively enrolled children aged 6-18 years who presented to the emergency department with a chief complaint of headache from September 2015 to September 2016. Standardized data collection was performed in real time, including telephone follow-up as needed, and imaging outcome was determined through a chart review. Using multivariable logistic regression, we estimated the associations between clinically important patient characteristics and neuroimaging., Results: Of 294 enrolled patients, 53 (18%) underwent neuroimaging (computed tomography or magnetic resonance imaging) and 2 (0.7%) had clinically important intracranial findings. Presenting with abnormal neurologic examination findings (OR, 11.55; 95% CI, 3.24-41.22), no history of similar headaches (OR, 2.13; 95% CI, 1.08-4.18), and white race (OR, 3.04; 95% CI, 1.51-6.12) were significantly associated with an increased odds of undergoing imaging in multivariable regression models., Conclusions: Our observed emergency department imaging rate was 26.5 times higher than our positive result rate, suggesting there is room to decrease unnecessary neuroimaging. Associations for abnormal examination and new headache type are consistent with the American Academy of Neurology clinical imaging recommendations. The increased odds of imaging white patients suggests bias that should be addressed. The low rate of positive findings supports the need for an evidence-based clinical decision tool for neuroimaging in the acute care setting., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a rare disorder caused by duplications of chromosome 15q11.2-q13.1, resulting in a wide range of developmental disabilities in affected individuals. The Dup15q Alliance is an organization that provides family support and promotes research to improve the quality of life of patients living with Dup15q syndrome. Because of the low prevalence of this condition, the establishment of a single research repository would have been difficult and more time consuming without collaboration across multiple institutions., Objective: The goal of this project is to establish a national deidentified database with clinical and survey information on individuals diagnosed with Dup15q syndrome., Methods: The development of a multiclinic site repository for clinical and survey data on individuals with Dup15q syndrome was initiated and supported by the Dup15q Alliance. Using collaborative workflows, communication protocols, and stakeholder engagement tools, a comprehensive database of patient-centered information was built., Results: We successfully established a self-report populating, centralized repository for Dup15q syndrome research. This repository also resulted in the development of standardized instruments that can be used for other studies relating to developmental disorders. By standardizing the data collection instruments, it allows us integrate our data with other national databases, such as the National Database for Autism Research. A substantial portion of the data collected from the questionnaires was facilitated through direct engagement of participants and their families. This allowed for a more complete set of information to be collected with a minimal turnaround time., Conclusions: We developed a repository that can efficiently be mined for shared clinical phenotypes observed at multiple clinic sites and used as a springboard for future clinical and basic research studies., (©Oluwaseun Jessica Ajayi, Ebony Jeannae Smith, Teeradache Viangteeravat, Eunice Y Huang, Naga Satya V Rao Nagisetty, Nora Urraca, Laina Lusk, Brenda Finucane, Dimitrios Arkilo, Jennifer Young, Shafali Jeste, Ronald Thibert, The Dup15q Alliance, Lawrence T Reiter. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 18.10.2017.)

Background: The ketogenic diet is an effective non-pharmacologic treatment for medically resistant epilepsy. The aim of this study was to identify any predictors that may influence the response of ketogenic diet., Methods: A retrospective chart review for all patients with medically resistant epilepsy was performed at a tertiary care epilepsy center from 1996 to 2012. Patient- and diet-related variables were evaluated with respect to seizure reduction at 1, 3, 6, 9 and 12-month intervals and divided into four possible outcome classes., Results: Sixty-three patients met inclusion. Thirty-seven (59%) reported >50% seizure reduction at 3 months with 44% and 37% patients benefiting at 6-month and 12-month follow up, respectively. A trend toward significant seizure improvement was noted in 48% patients with seizure onset >1 year at 12-month (p = 0.09) interval and in 62% patients with >10 seizure/day at 6-month interval (p = 0.054). An ordinal logistic regression showed later age of seizure to have higher odds of favorable response at 1-month (p = 0.005) and 3-month (p = 0.013) follow up. Patients with non-fasting diet induction were more likely to have a favorable outcome at 6 months (p = 0.008) as do females (p = 0.037) and those treated with higher fat ratio diet (p = 0.034)., Conclusion: Our study reports the effectiveness of ketogenic diet in children with medically resistant epilepsy. Later age of seizure onset, female gender, higher ketogenic diet ratio and non-fasting induction were associated with better odds of improved seizure outcome. A larger cohort is required to confirm these findings., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha–delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12–15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To review our clinical experience with intravenous (iv) lacosamide (LCM) in children less than 12 years old., Background: Use of LCM to treat children with epilepsy has been supported by multiple studies with limited information on iv use in children., Designs/methods: All children given iv LCM were identified from 2009 to 2015. Records were audited for demographics, seizure classification, etiology, EEG, imaging, indication. Baseline seizure frequency was based on parental reporting, continuous video EEG and direct observation., Results: 47 patients were identified with median age 6.5 years, 18 less than 3 years old, including 8 younger than 12 months. LCM was an adjunctive therapy of ≥2 antiepileptic drugs (AEDs). LCM was administered intravenously to treat epilepsia partialis continua (n = 3, dose range 5-10 mg/kg), status epilepticus (n = 11, median dose 7.2 mg/kg, range 4-11 mg/kg), and acute exacerbation of seizure frequency (n = 18, median dose 4.5 mg/kg, range 1-11 mg/kg). Parenteral form was substituted for oral form for 10 children treated with maintenance LCM unable to ingest/tolerate enteral medication and 5 who were given iv LCM to initiate maintenance treatment (median dose 4 mg/kg, range: 2-10 mg/kg). The infusion was effective for 24 out of 37 children (65%) naive to LCM. Sedation (one with ataxia) was noted in 5/36 children (14%), without any other identified adverse events., Conclusion: This is the first published retrospective study of very young critically ill children receiving iv LCM. The acute tolerability at this dosing range represents a positive trend and need confirmation from larger studies., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess pregnancy outcomes on women exposed to monotherapy with antiepileptic agents., Methods: Questionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on monotherapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to valproate., Results: There were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamotrigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate., Conclusion: Our pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

A 15-year-old girl with maternal inheritance of neurofibromatosis type 1 (NF1) and paternal inheritance of tuberous sclerosis complex (TSC) developed intractable epilepsy at age 5. Her seizures were refractory to adequate doses of four antiepileptic medications until felbamate was initiated at age 7. She has since remained seizure-free on felbamate monotherapy. Although felbamate has multiple mechanisms of action, it is thought to have its most potent antiepileptic effects through inhibition of the N-methyl-D-aspartate receptor (NMDAR). Previous studies have shown that the NMDAR is altered in varying epilepsy syndromes and notably in the cortical tubers found in TSC. The aim of this paper is to examine how felbamate monotherapy was able to achieve such robust antiepileptic effects in a unique patient and possibly offer a novel therapeutic approach to patients suffering from TSC- and NF-related epilepsy.

We report 3 previously normal children that presented for evaluation of new onset seizures. Case 1, a 7-year-old female, presented with refractory left frontal lobe seizures associated with right arm simple motor seizures refractory to 6 antiepileptic medications at sufficient doses and levels. Case 2, a 15-year-old female, presented with left frontotemporal lobe seizures and nonconvulsive seizures, associated with neuropsychiatric symptoms refractory to 5 antiepileptic medications. Both patients received intravenous steroids and intravenous immunoglobulin. Case 3, an 11-year-old male, presented with a generalized tonic clonic seizure and worsening hallucinations responding to intravenous corticosteroids and 1 antiepileptic medication. All 3 patients had extensive infectious and metabolic evaluation and were found to be serum immunoglobulin M positive for mycoplasma pneumoniae. Despite their prolonged severe symptoms, all patients had virtually complete recovery with excellent seizure control after aggressive seizure management with immunotherapy and antiepileptic medication.

Our objective was to assess the time interval that is required for the return to baseline of the background rhythm in the electroencephalogram (EEG) after ictal electrographic activity. We completed a retrospective EEG review of 28 adults and 13 children admitted to the epilepsy monitoring unit at Massachusetts General Hospital. EEG background rhythm on admission was considered the baseline rhythm per patient. In children the maximum time interval that was required for background rhythm to return to its baseline was 300 min, with average time of 120 min compared to a maximum of 420 min, with average time of 84 min for adults. Background slowing was shorter for frontal lobe seizures and longer for temporal lobe seizures. This study of patients with epilepsy shows that the time required for postictal slowing to resolve is short, and on average background rhythm returns to baseline within 2 h., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study evaluates the outcome of urgent neurologic referrals. This was a retrospective review of all referrals to the Floating Hospital for Children in 1 month. The total number of patients referred to our center was 223. Amongst those, 108 were new patients and 195 were follow-up visits; 30 patients were deemed urgent, yet 6 of them did not present to their visit. Urgent and routinely scheduled patients were compared based on the need for further evaluation or medication initiation following their visit. The frequency of visit outcomes was statistically similar between urgently and nonurgently referred patients. We did observe though, that diagnostic testing and medication were initiated more frequently for the patients urgently referred for seizure compared with those routinely scheduled patients for seizure evaluation. For this reason, we suggest that pediatric neurologists preferentially should hold clinic space open for urgent referrals for patients with new-onset seizure.