Try a new search

Format these results:

Searched for:

in-biosketch:true

person:od4

Total Results:

1066


Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up

Olson, Heather E; Amin, Sam; Bahi-Buisson, Nadia; Devinsky, Orrin; Marsh, Eric D; Pestana-Knight, Elia; Rajaraman, Rajsekar R; Aimetti, Alex A; Rybak, Eva; Kong, Fanhui; Miller, Ian; Hulihan, Joseph; Demarest, Scott
OBJECTIVE:In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS:Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS:Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE/CONCLUSIONS:Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.
PMID: 37950390
ISSN: 1528-1167
CID: 5620332

Wavelet phase coherence of ictal scalp EEG-extracted muscle activity (SMA) as a biomarker for sudden unexpected death in epilepsy (SUDEP)

Gravitis, Adam C; Sivendiran, Krishram; Tufa, Uilki; Zukotynski, Katherine; Chinvarun, Yotin; Devinsky, Orrin; Wennberg, Richard; Carlen, Peter L; Bardakjian, Berj L
OBJECTIVE:Approximately 50 million people worldwide have epilepsy and 8-17% of the deaths in patients with epilepsy are attributed to sudden unexpected death in epilepsy (SUDEP). The goal of the present work was to establish a biomarker for SUDEP so that preventive treatment can be instituted. APPROACH/METHODS:Seizure activity in patients with SUDEP and non-SUDEP was analyzed, specifically, the scalp EEG extracted muscle activity (SMA) and the average wavelet phase coherence (WPC) during seizures was computed for two frequency ranges (1-12 Hz, 13-30 Hz) to identify differences between the two groups. MAIN RESULTS/RESULTS:Ictal SMA in SUDEP patients showed a statistically higher average WPC value when compared to non-SUDEP patients for both frequency ranges. Area under curve for a cross-validated logistic classifier was 81%. SIGNIFICANCE/CONCLUSIONS:Average WPC of ictal SMA is a candidate biomarker for early detection of SUDEP.
PMCID:11361603
PMID: 39208242
ISSN: 1932-6203
CID: 5702002

Timing and location of speech errors induced by direct cortical stimulation

Kabakoff, Heather; Yu, Leyao; Friedman, Daniel; Dugan, Patricia; Doyle, Werner K; Devinsky, Orrin; Flinker, Adeen
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.
PMCID:10948744
PMID: 38505231
ISSN: 2632-1297
CID: 5640502

Michael Duchowny: Mentor and mensch [Letter]

Devinsky, Orrin
PMID: 38044172
ISSN: 1525-5069
CID: 5597562

Adult Phenotype of SYNGAP1-DEE

Rong, Marlene; Benke, Tim; Zulfiqar Ali, Quratulain; Aledo-Serrano, Ángel; Bayat, Allan; Rossi, Alessandra; Devinsky, Orrin; Qaiser, Farah; Ali, Anum S; Fasano, Alfonso; Bassett, Anne S; Andrade, Danielle M
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.
PMCID:10692795
PMID: 38045990
ISSN: 2376-7839
CID: 5597752

Reply to RJ Klement [Comment]

Lieberman, Daniel E; Worthington, Steven; Schell, Laura D; Parkent, Christine M; Devinsky, Orrin; Carmody, Rachel N
PMID: 38044026
ISSN: 1938-3207
CID: 5591042

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

de Boer, Elke; Ockeloen, Charlotte W; Kampen, Rosalie A; Hampstead, Juliet E; Dingemans, Alexander J M; Rots, Dmitrijs; Lütje, Lukas; Ashraf, Tazeen; Baker, Rachel; Barat-Houari, Mouna; Angle, Brad; Chatron, Nicolas; Denommé-Pichon, Anne-Sophie; Devinsky, Orrin; Dubourg, Christèle; Elmslie, Frances; Elloumi, Houda Zghal; Faivre, Laurence; Fitzgerald-Butt, Sarah; Geneviève, David; Goos, Jacqueline A C; Helm, Benjamin M; Kini, Usha; Lasa-Aranzasti, Amaia; Lesca, Gaetan; Lynch, Sally A; Mathijssen, Irene M J; McGowan, Ruth; Monaghan, Kristin G; Odent, Sylvie; Pfundt, Rolph; Putoux, Audrey; van Reeuwijk, Jeroen; Santen, Gijs W E; Sasaki, Erina; Sorlin, Arthur; van der Spek, Peter J; Stegmann, Alexander P A; Swagemakers, Sigrid M A; Valenzuela, Irene; Viora-Dupont, Eléonore; Vitobello, Antonio; Ware, Stephanie M; Wéber, Mathys; Gilissen, Christian; Low, Karen J; Fisher, Simon E; Vissers, Lisenka E L M; Wong, Maggie M K; Kleefstra, Tjitske
PMID: 37658852
ISSN: 1530-0366
CID: 5728302

Are Brief Febrile Seizures Benign? A Systematic Review and Narrative Synthesis

Gould, Laura; Delavale, Victoria; Plovnick, Caitlin; Wisniewski, Thomas; Devinsky, Orrin
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.
PMID: 37466925
ISSN: 1528-1167
CID: 5535782

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial

Sullivan, Joseph; Lagae, Lieven; Cross, J Helen; Devinsky, Orrin; Guerrini, Renzo; Knupp, Kelly G; Laux, Linda; Nikanorova, Marina; Polster, Tilman; Talwar, Dinesh; Ceulemans, Berten; Nabbout, Rima; Farfel, Gail M; Galer, Bradley S; Gammaitoni, Arnold R; Lock, Michael; Agarwal, Anupam; Scheffer, Ingrid E; ,
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.
PMID: 37543865
ISSN: 1528-1167
CID: 5619022

Association between changes in carbohydrate intake and long term weight changes: prospective cohort study

Wan, Yi; Tobias, Deirdre K; Dennis, Kristine K; Guasch-Ferré, Marta; Sun, Qi; Rimm, Eric B; Hu, Frank B; Ludwig, David S; Devinsky, Orrin; Willett, Walter C
OBJECTIVE:To comprehensively examine the associations between changes in carbohydrate intake and weight change at four year intervals. DESIGN:Prospective cohort study. SETTING:Nurses' Health Study (1986-2010), Nurses' Health Study II (1991-2015), and Health Professionals Follow-Up Study (1986-2014). PARTICIPANTS:136 432 men and women aged 65 years or younger and free of diabetes, cancer, cardiovascular disease, respiratory disease, neurodegenerative disorders, gastric conditions, chronic kidney disease, and systemic lupus erythematosus before baseline. MAIN OUTCOME MEASURE:Weight change within a four year period. RESULTS:The final analyses included 46 722 women in the Nurses' Health Study, 67 186 women in the Nurses' Health Study II, and 22 524 men in the Health Professionals Follow-up Study. On average, participants gained 1.5 kg (5th to 95th centile -6.8 to 10.0) every four years, amounting to 8.8 kg on average over 24 years. Among men and women, increases in glycemic index and glycemic load were positively associated with weight gain. For example, a 100 g/day increase in starch or added sugar was associated with 1.5 kg and 0.9 kg greater weight gain over four years, respectively, whereas a 10 g/day increase in fiber was associated with 0.8 kg less weight gain. Increased carbohydrate intake from whole grains (0.4 kg less weight gain per 100 g/day increase), fruit (1.6 kg less weight gain per 100 g/day increase), and non-starchy vegetables (3.0 kg less weight gain per 100 g/day increase) was inversely associated with weight gain, whereas increased intake from refined grains (0.8 kg more weight gain per 100 g/day increase) and starchy vegetables (peas, corn, and potatoes) (2.6 kg more weight gain per 100 g/day increase) was positively associated with weight gain. In substitution analyses, replacing refined grains, starchy vegetables, and sugar sweetened beverages with equal servings of whole grains, fruit, and non-starchy vegetables was associated with less weight gain. The magnitude of these associations was stronger among participants with overweight or obesity compared with those with normal weight (P<0.001 for interaction). Most of these associations were also stronger among women. CONCLUSIONS:The findings of this study highlight the potential importance of carbohydrate quality and source for long term weight management, especially for people with excessive body weight. Limiting added sugar, sugar sweetened beverages, refined grains, and starchy vegetables in favor of whole grains, fruit, and non-starchy vegetables may support efforts to control weight.
PMCID:10523278
PMID: 37758268
ISSN: 1756-1833
CID: 5725302