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KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Miceli, Francesco; Millevert, Charissa; Soldovieri, Maria Virginia; Mosca, Ilaria; Ambrosino, Paolo; Carotenuto, Lidia; Schrader, Dewi; Lee, Hyun Kyung; Riviello, James; Hong, William; Risen, Sarah; Emrick, Lisa; Amin, Hitha; Ville, Dorothée; Edery, Patrick; de Bellescize, Julitta; Michaud, Vincent; Van-Gils, Julien; Goizet, Cyril; Willemsen, Marjolein H; Kleefstra, Tjitske; Møller, Rikke S; Bayat, Allan; Devinsky, Orrin; Sands, Tristan; Korenke, G Christoph; Kluger, Gerhard; Mefford, Heather C; Brilstra, Eva; Lesca, Gaetan; Milh, Mathieu; Cooper, Edward C; Taglialatela, Maurizio; Weckhuysen, Sarah
BACKGROUND:Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS:Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS/RESULTS:Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION/CONCLUSIONS:Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING/BACKGROUND:Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.
PMCID:9254340
PMID: 35780567
ISSN: 2352-3964
CID: 5278312

Hospital Emergency Treatment of Convulsive Status Epilepticus: Comparison of Pathways From Ten Pediatric Research Centers

Vasquez, Alejandra; Gaínza-Lein, Marina; Sánchez Fernández, Iván; Abend, Nicholas S; Anderson, Anne; Brenton, J Nicholas; Carpenter, Jessica L; Chapman, Kevin; Clark, Justice; Gaillard, William D; Glauser, Tracy; Goldstein, Joshua; Goodkin, Howard P; Lai, Yi-Chen; Loddenkemper, Tobias; McDonough, Tiffani L; Mikati, Mohamad A; Nayak, Anuranjita; Payne, Eric; Riviello, James; Tchapyjnikov, Dmitry; Topjian, Alexis A; Wainwright, Mark S; Tasker, Robert C
OBJECTIVE:We aimed to evaluate and compare the status epilepticus treatment pathways used by pediatric status epilepticus research group (pSERG) hospitals in the United States and the American Epilepsy Society (AES) status epilepticus guideline. METHODS:We undertook a descriptive analysis of recommended timing, dosing, and medication choices in 10 pSERG hospitals' status epilepticus treatment pathways. RESULTS:One pathway matched the timeline in the AES guideline; nine pathways described more rapid timings. All pathways matched the guideline's stabilization phase in timing and five suggested that first-line benzodiazepine (BZD) be administered within this period. For second-line therapy timing (initiation of a non-BZD antiepileptic drug within 20 to 40 minutes), one pathway matched the guideline; nine initiated the antiepileptic drug earlier (median 10 [range five to 15] minutes). Third-line therapy timings matched the AES guideline (40 minutes) in two pathways; eight suggested earlier timing (median 20 [range 15 to 30] minutes). The first-line BZD recommended in all hospitals was intravenous lorazepam; alternatives included intramuscular midazolam or rectal diazepam. In second-line therapy, nine pathways recommended fosphenytoin. For third-line therapy, eight pathways recommended additional boluses of second-line medications; most commonly phenobarbital. Two pathways suggested escalation to third-line medication; most commonly midazolam. We found variance in dosing for the following medications: midazolam as first-line therapy, fosphenytoin, and levetiracetam as second-line therapy, and phenobarbital as third-line therapy medications. CONCLUSIONS:The pSERG hospitals status epilepticus pathways are consistent with the AES status epilepticus guideline in regard to the choice of medications, but generally recommend more rapid escalation in therapy than the guideline.
PMID: 30075875
ISSN: 1873-5150
CID: 3483402

De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy

Berkovic, Samuel F.; Dixon-Salazar, Tracy; Goldstein, David B.; Heinzen, Erin L.; Laughlin, Brandon L.; Lowenstein, Daniel H.; Lubbers, Laura; Milder, Julie; Stewart, Randall; Whittemore, Vicky; Angione, Kaitlin; Bazil, Carl W.; Bier, Louise; Bluvstein, Judith; Brimble, Elise; Campbell, Colleen; Chambers, Chelsea; Choi, Hyunmi; Cilio, Maria Roberta; Ciliberto, Michael; Cornes, Susannah; Delanty, Norman; Demarest, Scott; Devinsky, Orrin; Dlugos, Dennis; Dubbs, Holly; Dugan, Patricia; Ernst, Michelle E.; Gallentine, William; Gibbons, Melissa; Goodkin, Howard; Grinton, Bronwyn; Helbig, Ingo; Jansen, Laura; Johnson, Kaleas; Joshi, Charuta; Lippa, Natalie C.; Makati, Mohamad A.; Marsh, Eric; Martinez, Alejandro; Millichap, John; Moskovich, Yuliya; Mulhern, Maureen S.; Numis, Adam; Park, Kristen; Poduri, Annapurna; Porter, Brenda; Sands, Tristan T.; Scheffer, Ingrid E.; Sheidley, Beth; Singhal, Nilika; Smith, Lacey; Sullivan, Joseph; Riviello, James J., Jr.; Taylor, Alan; Tolete, Patricia
Purpose: As part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.
ISI:000425939300013
ISSN: 1098-3600
CID: 3406052

Children with new-onset refractory status epilepticus from a multicenter US registry [Meeting Abstract]

Sculier, C; Gainza-Lein, M; Gaspard, N; Fernandez, I S; Abend, N S; Anderson, A; Arya, R; Brenton, J N; Carpenter, J L; Chapman, K E; Gaillard, W; Glauser, T A; Goldstein, J L; Goodkin, H P; Mikati, M A; Nayak, A; Peariso, K; Riviello, J J; Tasker, R C; Tchapyjnikov, D; Topjian, A A; Wainwright, M S; Wilfong, A; Williams, K; Loddenkemper, T
Introduction: We describe the clinical presentation of new-onset refractory status epilepticus of unknown etiology in children. Methods: We analyzed patients within the pediatric Status Epilepticus Research Group (pSERG) cohort with the following inclusion criteria: 1) age 1-21 years; 2) first episode of RSE requiring more than 2 anti-seizure medications (ASM); 3) RSE episode between 06/2011 and 10/2016. We excluded patients with a history of developmental delay and/or epilepsy. We compare these patients to those with a first refractory status epilepticus (RSE) due to an identified etiology. Results: Fifty four patients were eligible. The median age was 5 years (IQR 1.9, 10.6). The most frequent etiologies were infection (15%), febrile status epilepticus (15%) and acute brain lesions (13%). No etiology was found in 18 patients (33%). In the group with unknown etiology, 15 patients (83%) required intubation and the median duration of ICU stay was 4.8 days (IQR 2, 49). These patients received a median of 3 ASM (IQR 2, 4) and 1 continuous infusion (IQR 0, 3). Compared to patients with an etiology, patients with unknown etiology received a larger number of immunotherapies (8 vs 5 patients; p = 0.02), were more often treated with the ketogenic diet (7 vs 2; p = 0.004) and were more likely to have a family history of epilepsy (6 vs 3; p = 0.045). The mean duration of RSE in the group with unknown etiology (12.25 h) was longer than in the group with etiology (4.25 h; p = 0.4). Fifty five percent of the patients with unknown etiology failed to return to baseline function at discharge compared to 36% in patients with an etiology (p = ns). Conclusions: One third of children with a first episode of RSE had an unknown etiology and seemed more likely to have a family history of epilepsy. These patients were more likely to receive immunotherapies and ketogenic diet
EMBASE:619068735
ISSN: 1532-2130
CID: 2777912

Use of Anesthesia for Imaging Studies and Interventional Procedures in Children

Huang, Yolanda Y; Li, Lucy; Monteleone, Matthew; Ferrari, Lynne; States, Lisa J; Riviello, James J; Kernie, Steven G; Mencin, Ali A; Gupta, Sumit; Sun, Lena S
Ongoing investigation from the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study hopes to examine the long-term effect on cognitive and language development of a single anesthetic exposure in children undergoing inguinal hernia repair. The fifth PANDA Symposium, held in April 2016, continued the mission of previous symposia to examine evidence from basic science and clinical studies on potential neurotoxic effects of anesthetics on developing brain. At the 2016 Symposium, a panel of specialists from nonsurgical pediatric disciplines including anesthesiology, radiology, neurology, gastroenterology, oncology, cardiology, and critical care reviewed use of anesthesia in their practices, including how concern over possible neurodevelopmental effects of early childhood anesthetic exposure has changed discussion with patients and families regarding risks and benefits of imaging studies and interventional procedures involving sedation or anesthesia. This paper summarizes presentations from nonsurgical pediatric specialists at the 2016 PANDA Symposium.
PMID: 27564559
ISSN: 1537-1921
CID: 5376652

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

Glauser, Tracy; Shinnar, Shlomo; Gloss, David; Alldredge, Brian; Arya, Ravindra; Bainbridge, Jacquelyn; Bare, Mary; Bleck, Thomas; Dodson, W Edwin; Garrity, Lisa; Jagoda, Andy; Lowenstein, Daniel; Pellock, John; Riviello, James; Sloan, Edward; Treiman, David M
CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.
PMCID:4749120
PMID: 26900382
ISSN: 1535-7597
CID: 2025712

Consensus Statement on Continuous EEG in Critically Ill Adults and Children, Part II: Personnel, Technical Specifications, and Clinical Practice

Herman, Susan T; Abend, Nicholas S; Bleck, Thomas P; Chapman, Kevin E; Drislane, Frank W; Emerson, Ronald G; Gerard, Elizabeth E; Hahn, Cecil D; Husain, Aatif M; Kaplan, Peter W; LaRoche, Suzette M; Nuwer, Marc R; Quigg, Mark; Riviello, James J; Schmitt, Sarah E; Simmons, Liberty A; Tsuchida, Tammy N; Hirsch, Lawrence J
INTRODUCTION: Critical Care Continuous EEG (CCEEG) is a common procedure to monitor brain function in patients with altered mental status in intensive care units. There is significant variability in patient populations undergoing CCEEG and in technical specifications for CCEEG performance. METHODS: The Critical Care Continuous EEG Task Force of the American Clinical Neurophysiology Society developed expert consensus recommendations on the use of CCEEG in critically ill adults and children. RECOMMENDATIONS: The consensus panel describes the qualifications and responsibilities of CCEEG personnel including neurodiagnostic technologists and interpreting physicians. The panel outlines required equipment for CCEEG, including electrodes, EEG machine and amplifier specifications, equipment for polygraphic data acquisition, EEG and video review machines, central monitoring equipment, and network, remote access, and data storage equipment. The consensus panel also describes how CCEEG should be acquired, reviewed and interpreted. The panel suggests methods for patient selection and triage; initiation of CCEEG; daily maintenance of CCEEG; electrode removal and infection control; quantitative EEG techniques; EEG and behavioral monitoring by non-physician personnel; review, interpretation, and reports; and data storage protocols. CONCLUSION: Recommended qualifications for CCEEG personnel and CCEEG technical specifications will facilitate standardization of this emerging technology.
PMCID:4434600
PMID: 25626777
ISSN: 1537-1603
CID: 1556292

Consensus statement on continuous EEG in critically ill adults and children, part I: indications

Herman, Susan T; Abend, Nicholas S; Bleck, Thomas P; Chapman, Kevin E; Drislane, Frank W; Emerson, Ronald G; Gerard, Elizabeth E; Hahn, Cecil D; Husain, Aatif M; Kaplan, Peter W; LaRoche, Suzette M; Nuwer, Marc R; Quigg, Mark; Riviello, James J; Schmitt, Sarah E; Simmons, Liberty A; Tsuchida, Tammy N; Hirsch, Lawrence J
INTRODUCTION: Critical Care Continuous EEG (CCEEG) is a common procedure to monitor brain function in patients with altered mental status in intensive care units. There is significant variability in patient populations undergoing CCEEG and in technical specifications for CCEEG performance. METHODS: The Critical Care Continuous EEG Task Force of the American Clinical Neurophysiology Society developed expert consensus recommendations on the use of CCEEG in critically ill adults and children. RECOMMENDATIONS: The consensus panel recommends CCEEG for diagnosis of nonconvulsive seizures, nonconvulsive status epilepticus, and other paroxysmal events, and for assessment of the efficacy of therapy for seizures and status epilepticus. The consensus panel suggests CCEEG for identification of ischemia in patients at high risk for cerebral ischemia; for assessment of level of consciousness in patients receiving intravenous sedation or pharmacologically induced coma; and for prognostication in patients after cardiac arrest. For each indication, the consensus panel describes the patient populations for which CCEEG is indicated, evidence supporting use of CCEEG, utility of video and quantitative EEG trends, suggested timing and duration of CCEEG, and suggested frequency of review and interpretation. CONCLUSION: CCEEG has an important role in detection of secondary injuries such as seizures and ischemia in critically ill adults and children with altered mental status.
PMCID:4435533
PMID: 25626778
ISSN: 1537-1603
CID: 1556302

Episodic Epileptic Verbal Auditory Agnosia in Landau Kleffner Syndrome Treated With Combination Diazepam and Corticosteroids

Devinsky, Orrin; Goldberg, Rina; Miles, Daniel; Bojko, Aviva; Riviello, James Jr
We report 2 pediatric patients who presented initially with seizures followed by subacute language regression characterized by a verbal auditory agnosia. These previously normal children had no evidence of expressive aphasia during their symptomatic periods. Further, in both cases, auditory agnosia was associated with sleep-activated electroencephalographic (EEG) epileptiform activity, consistent with Landau-Kleffner syndrome. However, both cases are unique since the episodic auditory agnosia and sleep-activated EEG epileptiform activity rapidly responded to combination therapy with pulse benzodiazepine and corticosteroids. Further, in each case, recurrences were characterized by similar symptoms, EEG findings, and beneficial responses to the pulse benzodiazepine and corticosteroid therapy. These observations suggest that pulse combination high-dose corticosteroid and benzodiazepine therapy may be especially effective in Landau-Kleffner syndrome.
PMID: 24453158
ISSN: 0883-0738
CID: 817102

Electroencephalography in the pediatric emergency department: when is it most useful?

Fernandez, Ivan Sanchez; Loddenkemper, Tobias; Datta, Anita; Kothare, Sanjeev; Riviello, James J Jr; Rotenberg, Alexander
This study aimed to identify the indications in which electroencephalography in the pediatric emergency department is most useful. We retrospectively reviewed the influence that the results of the emergent electroencephalogram had on the eventual disposition of patients at our pediatric emergency department. Sixty-eight children (mean age, 7.3 years; 32 males) underwent 70 emergent electroencephalograms. Fifty-seven emergent electroencephalograms were performed for the suspicion of ongoing seizures or status epilepticus. Thirteen of the 22 children (59.1%) discharged from the emergency department were sent home mainly based on the results of the emergent electroencephalogram, which prevented an admission. In particular, 11 of 38 children with frequent and recurrent paroxysmal events concerning for seizures and 2 of 19 children with suspected ongoing status epilepticus were discharged after excluding an epileptic disturbance. The emergent electroencephalogram provided meaningful clinical information that influenced disposition, especially in patients with ongoing events in which the clinical picture was clarified by a rapidly acquired electroencephalogram.
PMID: 23594820
ISSN: 0883-0738
CID: 953032