Faculty Bibliography

BACKGROUND:Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS:In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS/RESULTS:Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION/CONCLUSIONS:In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING/BACKGROUND:Zogenix.

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn-Tolosa-Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.

BACKGROUND:"Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS:Following surgery, patients received five cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS:Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. 5-year event-free survival (EFS) and overall-survival (OS) rates (±SE) were 46±5% and 62±5% for all patients, 61±8% and 77±7% for localized medulloblastoma, and 35±7% and 52±7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89±6% and 89±6% compared to 26±6% and 53±7% for classic and 38±13% and 46±14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age and sex (p<0.0001). 5-year irradiation-free EFS was 78±8% for ND and 21±5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity with two toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis.IQ and memory scores were within average range overall whereas processing speed and adaptive functioning were low-average. CONCLUSION/CONCLUSIONS:We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy with most patients surviving without irradiation.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.

Researchers, parents, and educators consistently observe a stark mismatch between biologically preferred and socially imposed sleep-wake hours in adolescents, fueling debate about high school start times. We contribute neural evidence to this debate with electroencephalogram (EEG) data collected from high school students during their regular morning, mid-morning and afternoon classes. Overall, student alpha power was lower when class content was taught via videos than through lectures. Students' resting state alpha brain activity decreased as the day progressed, consistent with adolescents being least attentive early in the morning. During the lessons, students showed consistently worse performance and higher alpha power for early morning classes than for mid-morning classes, while afternoon quiz scores and alpha levels varied. Together, our findings demonstrate that both class activity and class time are reflected in adolescents' brain states in a real-world setting, and corroborate educational research suggesting that mid-morning may be the best time to learn.

OBJECTIVES/OBJECTIVE:METHODS: We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy we used separate, nested, case-control designs and matched each case to 3 age-, sex- and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and apolipoprotein ε4 allele status in modifying the association between epilepsy and dementia. RESULTS:= 0.001) compared to controls of the same educational attainment. CONCLUSIONS:There is a bi-directional association between epilepsy and dementia with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.

Background/UNASSIGNED:Equestrian athletes (horse riders) are at high risk for head injury, including concussions. Materials & methods/UNASSIGNED:Adults riders were recruited via social media posting to complete a branching survey collecting data on demographics, riding experience, helmet use, injury history and concussion symptom knowledge. Results are reported as frequencies and percentages, with associations tested using chi-square with significance level p < 0.05. Results/UNASSIGNED:Of the 2598 subjects, about 75% reported always wearing a helmet. Of those who did not, the most common reasons were that helmets are unnecessary (57.4%) or do not fit well (48.6%). Many indicated improper storage conditions and/or did not follow manufacturer's replacement recommendations. Most (75.4%) reported a high level of comfort with recognizing concussion signs, with half experiencing a prior head injury. Conclusion/UNASSIGNED:This information suggests opportunities for intervention to improve helmet use through increased fit, while the responses indicate a need for further education on proper helmet use.