Faculty Bibliography

Cortical regions supporting speech production are commonly established using neuroimaging techniques in both research and clinical settings. However, for neurosurgical purposes, structural function is routinely mapped peri-operatively using direct electrocortical stimulation. While this method is the gold standard for identification of eloquent cortical regions to preserve in neurosurgical patients, there is lack of specificity of the actual underlying cognitive processes being interrupted. To address this, we propose mapping the temporal dynamics of speech arrest across peri-sylvian cortices by quantifying the latency between stimulation and speech deficits. In doing so, we are able to substantiate hypotheses about distinct region-specific functional roles (e.g. planning versus motor execution). In this retrospective observational study, we analysed 20 patients (12 female; age range 14-43) with refractory epilepsy who underwent continuous extra-operative intracranial EEG monitoring of an automatic speech task during clinical bedside language mapping. Latency to speech arrest was calculated as time from stimulation onset to speech arrest onset, controlling for individual speech rate. Most instances of motor-based arrest (87.5% of 96 instances) were in sensorimotor cortex with mid-range latencies to speech arrest with a distributional peak at 0.47 s. Speech arrest occurred in numerous regions, with relatively short latencies in supramarginal gyrus (0.46 s), superior temporal gyrus (0.51 s) and middle temporal gyrus (0.54 s), followed by relatively long latencies in sensorimotor cortex (0.72 s) and especially long latencies in inferior frontal gyrus (0.95 s). Non-parametric testing for speech arrest revealed that region predicted latency; latencies in supramarginal gyrus and in superior temporal gyrus were shorter than in sensorimotor cortex and in inferior frontal gyrus. Sensorimotor cortex is primarily responsible for motor-based arrest. Latencies to speech arrest in supramarginal gyrus and superior temporal gyrus (and to a lesser extent middle temporal gyrus) align with latencies to motor-based arrest in sensorimotor cortex. This pattern of relatively quick cessation of speech suggests that stimulating these regions interferes with the outgoing motor execution. In contrast, the latencies to speech arrest in inferior frontal gyrus and in ventral regions of sensorimotor cortex were significantly longer than those in temporoparietal regions. Longer latencies in the more frontal areas (including inferior frontal gyrus and ventral areas of precentral gyrus and postcentral gyrus) suggest that stimulating these areas interrupts a higher-level speech production process involved in planning. These results implicate the ventral specialization of sensorimotor cortex (including both precentral and postcentral gyri) for speech planning above and beyond motor execution.

BACKGROUND AND OBJECTIVES/UNASSIGNED: METHODS/UNASSIGNED:variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden. RESULTS/UNASSIGNED:de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger. DISCUSSION/UNASSIGNED:-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

Febrile seizures affect 2-5% of U.S. children and are considered benign although associated with an increased risk of epilepsy and rarely, sudden unexplained death. We compared rates of mortality, neurodevelopmental disorders, and neuropathology in young children with simple and complex febrile seizures to healthy controls. We systematically reviewed studies of 3-72-month-old children with simple or complex febrile seizures <30 minutes. We searched studies with outcome measures on mortality, neurodevelopment, or neuropathology through July 18, 2022. Bias risk was assessed per study design. Each outcome measure was stratified by study design. Prospero registration is CRD42022361645. Twenty-six studies met criteria reporting mortality (11), neurodevelopment (11), and neuropathology (13), including 2665 children with febrile seizures and 1206 seizure-free controls. Study designs varied; 15 cohort, 2 cross sectional, 3 case-control, 5 series and 1 case report. Mortality outcomes showed stark contrasts. Six cohort studies following children after febrile seizure (n= 1348) reported no deaths, while four child death series and case report identified 24.1% (108/449) deaths associated with simple (n=104) and complex (n=3) febrile seizures <30 minutes. Minor hippocampal histopathological anomalies were common in sudden deaths with or without febrile seizure history. Most EEG studies were normal. Neuroimaging studies suggested increased right hippocampal volumes. When present, neurodevelopmental problems usually preexisted febrile seizure onset. Risk bias was medium or high in 95%(18/19) cohort and case-control studies versus medium to low across remaining studies designs. Research on outcomes after simple or brief complex febrile seizures is limited. Cohort studies suffered from inadequate sample size, bias risk and limited follow-up durations to make valid conclusions on mortality, neurodevelopment, and neuropathology. Sudden death registries, focused on a very small percentage of all cases, strongly suggest simple febrile seizures are associated with increased mortality. While most children with febrile seizures have favorable outcomes, longer-term prospective studies are needed.

OBJECTIVE:This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS:This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS:A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE/CONCLUSIONS:The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.

BACKGROUND:Although human diets varied considerably before the spread of agriculture, public perceptions of preagricultural diets have been strongly influenced by the Paleo Diet, which prescribes percentage calorie ranges of 19-35% protein, 22-40% carbohydrate, and 28-47% fat, and prohibits foods with added sugar, dairy, grains, most starchy tubers, and legumes. However, the empirical basis for Paleolithic nutrition remains unclear, with some of its assumptions challenged by the archaeological record and theoretical first principles. OBJECTIVES/OBJECTIVE:We assessed the variation in diets among tropical hunter-gatherers, including the effect of collection methods on implied macronutrient percentages. METHODS:We analyzed data on animal food, plant food, and honey consumption by weight and kcal from 15 high-quality published ethnographic studies representing 11 recent tropical hunter-gatherer groups. We used Bayesian analyses to perform inference and included data collection methods and environmental variables as predictors in our models. RESULTS:Our analyses reveal high levels of variation in animal versus plant foods consumed and in corresponding percentages of protein, fat, and carbohydrates. In addition, studies that weighed food items consumed in and out of camp and across seasons and years reported higher consumption of animal foods, which varied with annual mean temperature. CONCLUSIONS:The ethnographic evidence from tropical foragers refutes the concept of circumscribed macronutrient ranges modeling preagricultural diets.

Noncommunicable diseases (NCDs) are on the rise worldwide. Obesity, cardiovascular disease, and type 2 diabetes are among a long list of "lifestyle" diseases that were rare throughout human history but are now common. The evolutionary mismatch hypothesis posits that humans evolved in environments that radically differ from those we currently experience; consequently, traits that were once advantageous may now be "mismatched" and disease causing. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit "genotype by environment" (GxE) interactions, with different health effects in "ancestral" versus "modern" environments. To identify such loci, we advocate for combining genomic tools in partnership with subsistence-level groups experiencing rapid lifestyle change. In these populations, comparisons of individuals falling on opposite extremes of the "matched" to "mismatched" spectrum are uniquely possible. More broadly, the work we propose will inform our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and cultures.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults < 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8 × 106 or 2.7 × 106 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6-11 months and 1-5, 6-10, 11-17, 18-35, and 36-61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6-61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group (P ≥ 0.17). There were no significant differences between vaccinees and controls with respect to the rates or severity of unsolicited AEs or laboratory abnormalities. Development of antibodies to P. falciparum circumsporozoite protein occurred in 67/69 vaccinees (97%) and 0/15 controls. Median antibody levels were highest in infants and 1-5-year-olds and declined progressively with age. Antibody responses in children were greater than in adults protected against controlled human malaria infection. Robust immunogenicity, combined with a benign AE profile, indicates children are an ideal target for immunization with PfSPZ Vaccine.