Publications by authors named "Tristan T Sands"

22 Publications

  • Page 1 of 1

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

Epilepsia 2021 Aug 21. Epub 2021 Aug 21.

Division of Neurology, Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta, Canada.

Objective: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE).

Methods: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM.

Results: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival.

Significance: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.
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http://dx.doi.org/10.1111/epi.17043DOI Listing
August 2021

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

Epilepsia 2021 Sep 12;62(9):2190-2204. Epub 2021 Jul 12.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE.

Methods: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients.

Results: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion.

Significance: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.
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http://dx.doi.org/10.1111/epi.16984DOI Listing
September 2021

Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

Epilepsia 2021 Aug 21;62(8):1907-1920. Epub 2021 Jun 21.

Department of Pediatrics, Saint-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium.

Objective: Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.

Methods: We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.

Results: Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy.

Significance: Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.
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http://dx.doi.org/10.1111/epi.16957DOI Listing
August 2021

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

Pediatr Crit Care Med 2021 Jun 14. Epub 2021 Jun 14.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA. Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, MN. Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI. Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Barcelona, Spain. Division of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain. Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX. Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH. Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, VA. Center for Neuroscience, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC. Departments of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, IL. Division of Pediatric Neurology, Washington University Medical Center, Washington University School of Medicine, Saint Louis, MO. Section of Pediatric Critical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX. Division of Child Neurology, Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY. Division of Pediatric Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, NC. Department of Neurology, Division of Pediatric Neurology, University of Washington, Seattle, WA. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA. Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University. Columbus, OH. Department of Pediatrics, Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland, OR. Division of Critical Care, Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA. Critical Care and Pediatrics, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Department of Child Health, University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ.

Objectives: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients.

Design: Retrospective cohort study with prospectively collected data between June 2011 and January 2019.

Setting: Seventeen academic hospitals in the United States.

Patients: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups.

Interventions: None.

Measurements And Main Results: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments.

Conclusions: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.
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http://dx.doi.org/10.1097/PCC.0000000000002786DOI Listing
June 2021

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

Epilepsia 2021 Jul 26;62(7):e103-e109. Epub 2021 May 26.

Department of Neuropediatrics, APHP Sorbonne University, Trousseau Hospital, Paris, France.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
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http://dx.doi.org/10.1111/epi.16931DOI Listing
July 2021

Time to Treatment in Pediatric Convulsive Refractory Status Epilepticus: The Weekend Effect.

Pediatr Neurol 2021 Jul 26;120:71-79. Epub 2021 Mar 26.

Department of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency.

Methods: We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus.

Results: We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01).

Conclusions: The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.03.009DOI Listing
July 2021

A Novel Kv7.3 Variant in the Voltage-Sensing S Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and Rescue by β-Hydroxybutyrate.

Front Physiol 2020 4;11:1040. Epub 2020 Sep 4.

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States.

Pathogenic variants in and , paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K channel subunits, are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early-onset developmental and epileptic encephalopathy (DEE). variants account for the majority of pedigrees with BFNE and variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits.
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http://dx.doi.org/10.3389/fphys.2020.01040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498716PMC
September 2020

Association of guideline publication and delays to treatment in pediatric status epilepticus.

Neurology 2020 09 1;95(9):e1222-e1235. Epub 2020 Jul 1.

From the Division of Epilepsy and Clinical Neurophysiology (I.S.F., M.A.-G., C.B.A., J.C., M.G.-L., A.V., T.L.), Department of Neurology, and Department of Neurology (R.C.T.), Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Department of Child Neurology (I.S.F.), Hospital Sant Joan de Déu, Universitat de Barcelona, Spain; Division of Neurology (N.S.A.), Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Pediatric Critical Care Medicine (A.A., Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH; University of Virginia Health (J.N.B., H.P.G.), Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.E.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Pediatric Neurology (R.F.-M., K.S.), Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Instituto de Pediatría (M.G.-L.), Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.G., T.M.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric and Developmental Neurology (R.M.G.), Department of Neurology, Washington University School of Medicine, St. Louis, MO; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Pediatrics and Neurology (L.A.M., E.N., M.S.W.), Seattle Children's Hospital, University of Washington; Center for Integrative Brain Research (L.A.M., E.N., M.S.W.), Seattle Children's Research Institute, WA; Department of Neurology (E.P.), Mayo Clinic, Mayo Clinic School of Medicine, Rochester, MN; Department of Neurology (J.P.), Doernbercher Children's Hospital, Oregon Health & Science University, Portland; Department of Neurology (A.O.), Nationwide Children's Hospital, Ohio State University, Columbus; Division of Child Neurology and Institute for Genomic Medicine (T.T.S.), Columbia University Irving Medical Center, New York Presbyterian Hospital, New York; Division of Critical Care Medicine (A.A.T.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Division of Child and Adolescent Neurology (A.V.), Department of Neurology, Mayo Clinic, Rochester, MN; Barrow Neurological Institute (A.W., K.W.), Phoenix Children's Hospital; and Department of Pediatrics (A.W., K.W.), University of Arizona School of Medicine, Phoenix.

Objective: To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review.

Methods: We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE.

Results: We studied 328 patients (56% male) with median (25th-75th percentile [p-p]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p-p) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes, = 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes, = 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes, = 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%], = 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3], = 0.0005).

Conclusion: Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival.
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http://dx.doi.org/10.1212/WNL.0000000000010174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538224PMC
September 2020

Rasmussen Encephalitis: An Update.

Semin Neurol 2020 Apr 17;40(2):201-210. Epub 2020 Mar 17.

Department of Neurology, Columbia University Irving Medical Center, New York, New York.

Rasmussen encephalitis (RE) is a rare, devastating, progressive pediatric epilepsy. First described 60 years ago, RE continues to present challenges in diagnosis and management. RE causes a unilateral focal epilepsy in children that typically becomes medically refractory, results in significant hemiparesis, and causes progressive cognitive decline. The etiology is a cell-mediated immune attack on one cerebral hemisphere, though the inciting antigen remains unknown. While the underlying histopathology is unilateral and RE is described as "unihemispheric," studies have demonstrated (1) atrophy of the unaffected hemisphere, (2) electroencephalographic abnormalities (slowing and spikes) in the unaffected hemisphere, and (3) cognitive decline referable to the unaffected hemisphere. These secondary contralateral effects likely reflect the impact of uncontrolled epileptic activity (i.e., epileptic encephalopathy). Hemispheric disconnection (HD) renders 70 to 80% of patients seizure free. While it has the potential to limit the influence of seizures and abnormal electrical activity emanating from the pathological hemisphere, HD entails hemiparesis and hemianopia, as well as aphasia for patients with dominant HD. With the recent expansion of available immunomodulatory therapies, there has been interest in identifying an alternative to HD, though evidence for disease modification is limited to date. We review what is known and what remains unknown about RE.
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http://dx.doi.org/10.1055/s-0040-1708504DOI Listing
April 2020

Autism and developmental disability caused by KCNQ3 gain-of-function variants.

Ann Neurol 2019 08 26;86(2):181-192. Epub 2019 Jun 26.

Division of Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objective: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms.

Methods: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording.

Results: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects.

Interpretation: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.
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http://dx.doi.org/10.1002/ana.25522DOI Listing
August 2019

Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

CNS Drugs 2019 01;33(1):47-60

Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks.

Objective: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy.

Methods: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures.

Results: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free.

Conclusion: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.
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http://dx.doi.org/10.1007/s40263-018-0589-2DOI Listing
January 2019

The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria.

Hum Mutat 2018 11;39(11):1476-1484

Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.
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http://dx.doi.org/10.1002/humu.23632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418072PMC
November 2018

NBEA: Developmental disease gene with early generalized epilepsy phenotypes.

Ann Neurol 2018 11 25;84(5):788-795. Epub 2018 Oct 25.

Department of Pediatrics, University of Washington, Seattle, WA.

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.
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http://dx.doi.org/10.1002/ana.25350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249120PMC
November 2018

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

Am J Med Genet A 2018 11 8;176(11):2259-2275. Epub 2018 Sep 8.

Carle Physician Group, Urbana, Illinois.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
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http://dx.doi.org/10.1002/ajmg.a.40472DOI Listing
November 2018

Lack of response to quinidine in KCNT1-related neonatal epilepsy.

Epilepsia 2018 10 4;59(10):1889-1898. Epub 2018 Sep 4.

Department of Neurology, University of California San Francisco, San Francisco, California.

Objective: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro.

Methods: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings.

Results: Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine.

Significance: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.
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http://dx.doi.org/10.1111/epi.14551DOI Listing
October 2018

Neonatal epilepsies: Clinical management.

Semin Fetal Neonatal Med 2018 06 31;23(3):204-212. Epub 2018 Jan 31.

Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA. Electronic address:

Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. Here, we address the elements differentiating neonatal-onset epilepsies from acute symptomatic seizures. We review some common neonatal-onset epilepsies and emphasize how pathognomonic electro-clinical phenotypes such as the ones associated with KCNQ2 or KCNT1 gene mutation, when recognized early, can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
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http://dx.doi.org/10.1016/j.siny.2018.01.004DOI Listing
June 2018

Genetic Testing in Pediatric Epilepsy.

Curr Neurol Neurosci Rep 2017 May;17(5):45

Division of Child Neurology, Columbia University Medical Center, 180 Fort Washington Avenue, New York, NY, 10032, USA.

Purpose Of Review: This article summarizes the emerging landscape of pediatric epilepsy, highlighting genetic contributions, and reviews approaches to genetic evaluation for pediatric epilepsy in this context.

Recent Findings: Advances in understanding the genetic basis for epilepsy over the last several years have been due in large part to the identification of de novo genetic variation underlying sporadic severe epilepsy in children; the genetic underpinnings of the more common epilepsies remain largely unknown. Next-generation sequencing approaches have been added to the repertoire of clinical tests for the evaluation of pediatric epilepsy, improving our ability to make positive diagnoses. Yields of over 50% are now being reported in selected groups of patients. Genetic variation contributing to the risk for pediatric epilepsy spans continua of scale and influence. The highest yield of genetic testing is currently in children with sporadic severe epilepsy caused by de novo variation. The approach to genetic evaluation and interpretation of results requires an understanding of (1) the epilepsy phenotype and (2) the particular advantages and limitations of the different genetic tests available. Our understanding of genetic variation will continue to improve over time and "negative" results are best conceptualized as "unresolved" or "negative for now."
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http://dx.doi.org/10.1007/s11910-017-0753-yDOI Listing
May 2017

Rapid and safe response to low-dose carbamazepine in neonatal epilepsy.

Epilepsia 2016 12 26;57(12):2019-2030. Epub 2016 Nov 26.

Department of Neurology, University of California San Francisco, San Francisco, California, U.S.A.

Objective: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE).

Methods: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes.

Results: Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2-5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months-16 years).

Significance: This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.
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http://dx.doi.org/10.1111/epi.13596DOI Listing
December 2016

Recent Advances in Neonatal Seizures.

Curr Neurol Neurosci Rep 2016 10;16(10):92

Division of Child Neurology, Columbia University Medical Center, 180 Fort Washington Avenue, New York, NY, 10032, USA.

Purpose Of Review: This article strives to review and summarize selected recent literature and topics contributing to a greater understanding of the diagnosis and treatments of neonatal seizures that have emerged in the past several years.

Recent Findings: Continuous EEG is recommended as the gold standard for neonatal seizure monitoring as it can provide additional information that may stratify patients by etiology, as well as identify at-risk groups of newborns for neuromonitoring. Investigations are moving beyond traditional antiepileptic agents in search of treatments with better efficacy and with less concern for developmental effects. Targeted therapies for seizures resulting from particular genetic conditions are increasing, highlighting the importance of early genetic diagnosis. Better understanding of the risk of post-neonatal epilepsy based on etiology is emerging with new epidemiological studies. Evidence is growing for deleterious effects of seizures on outcomes, elevating the importance of seizure detection and effective treatment. Advances in utilization of continuous EEG monitoring have improved the accuracy of seizure detection and have identified at-risk groups of newborns for neuromonitoring. Ultimately, the goal in management of neonatal seizures is not only clinical stabilization in the acute period but also to influence neurodevelopmental outcome and modify the risk of future epilepsy.
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http://dx.doi.org/10.1007/s11910-016-0694-xDOI Listing
October 2016

Focal seizures in children with anti-NMDA receptor antibody encephalitis.

Epilepsy Res 2015 May 16;112:31-6. Epub 2015 Feb 16.

The University of San Francisco, Benioff Children's Hospital-San Francisco, Neurology, Mailstop 0137, 550 16th Street, 4th Floor, San Francisco, CA 94158-2549, United States. Electronic address:

Objective: We investigated the electroclinical features of seizures occurring in children with anti-NMDA receptor antibody encephalitis.

Methods: Clinical features and video EEG recordings were analyzed from pediatric patients with anti-NMDA receptor antibody encephalitis at our center over a six year period.

Results: We identified eight pediatric patients with anti-NMDA receptor antibody encephalitis. Video EEG captured multiple focal seizures in four patients. Ictal onset in all four patients consisted of a focal rhythmic sharpened 6-12Hz activity that subsequently spread to one or both hemispheres. When there was a clinical correlate, seizure semiology was limb posturing with or without dyscognitive features. While background abnormalities were noted at presentation in three cases, the initial EEG background was normal in five, including three patients presenting with seizures. The EEG background deteriorated with clinical progression.

Conclusions: Focal seizures are common in pediatric patients with anti-NMDA receptor antibody encephalitis and have a characteristic ictal onset pattern. Anti-NMDA receptor antibody encephalitis should be considered in the differential diagnosis of a child presenting with new onset focal seizures, irrespective of the EEG background, especially if accompanied by dyskinesia, psychiatric symptoms or impaired cognition.
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http://dx.doi.org/10.1016/j.eplepsyres.2015.02.010DOI Listing
May 2015

Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors.

J Biol Chem 2003 Dec 22;278(49):49279-85. Epub 2003 Sep 22.

Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist.
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http://dx.doi.org/10.1074/jbc.M304034200DOI Listing
December 2003
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