Publications by authors named "William D Gaillard"

160 Publications

Functional Connectivity as a Potential Mechanism for Language Plasticity.

Neurology 2021 Nov 18. Epub 2021 Nov 18.

Department of Neuropsychology, Children's National Hospital, Washington DC.

Background And Objectives: Task-fMRI is a clinical tool for language lateralization, but has limitations, and cannot provide information about network-level plasticity. Additional methods are needed to improve the precision of presurgical language mapping. We investigate language resting-state functional connectivity(RS fMRI;FC) in typically developing children and children with epilepsy. Our objectives were to: 1)Understand how FC components differ between typically developing (TD) children and those with epilepsy. 2)Elucidate how the location of disease (frontal/temporal epilepsy foci) effects FC. 3)Investigate the relationship between age and FC.

Methods: Sample includes 55 TD children (mean age 12 years, range 7-18, and 31 patients with focal epilepsy (mean age 13) with same range. All subjects underwent RS fMRI. Using a bilateral canonical language map as target, vertex wise intra-hemispheric FC map and inter-hemispheric FC map for each subject were computed and thresholded at top 10% to compute an FC laterality index (FCLI;((L-R)/(L+R)) of the frontal and temporal regions for both integration (intra-hemispheric FC; FCLI) and segregation (Inter-hemispheric FC; FCLI) maps.

Results: We found FC differences in the developing language network based on disease, seizure foci location, and age. Frontal and Temporal FCLI was different between groups (t(84)=2.82, p<.01; t(84)=4.68, p<.01, respectively). Frontal epilepsy foci had the largest differences from TD (Cohen's D Frontal FCLI=0.84, FCLI=0.51; Temporal FCLI=1.29). Development and disease have opposing influences on the laterality of FC based on groups. In the frontal foci group, FCLI decreased with age (r=-0.42), whereas in the temporal foci group FCLI increased with age (r=0.40). Within the epilepsy group, increases in right frontal integration FCLI relates to increased right frontal task activation in our mostly left language dominant group (r=.52, p<.01). Language network connectivity is associated with higher verbal intelligence in children with epilepsy (r=.45, p<.05).

Discussion: These findings lend preliminary evidence that FC reflects network plasticity in the form of adaptation and compensation, or the ability to recruit support and reallocate resources within and outside of the traditional network to compensate for disease. FC expands on task-based fMRI and provides complementary and potentially useful information about the language network that is not captured using task-based fMRI alone.
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http://dx.doi.org/10.1212/WNL.0000000000013071DOI Listing
November 2021

Virtual reality-based 3-dimensional localization of stereotactic EEG (SEEG) depth electrodes and related brain anatomy in pediatric epilepsy surgery.

Childs Nerv Syst 2021 Oct 30. Epub 2021 Oct 30.

Department of Neurosurgery, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.

Introduction: The increasing use of stereoelectroencephalography (SEEG) in the USA and the need for three-dimensional (3D) appreciation of complex spatial relationships between implanted stereotactic EEG depth electrodes and surrounding brain and cerebral vasculature are a challenge to clinicians who are used to two-dimensional (2D) appreciation of cortical anatomy having been traditionally trained on 2D radiologic imaging. Virtual reality and its 3D renderings have grown increasingly common in the multifaceted practice of neurosurgery. However, there exists a paucity in the literature regarding this emerging technology in its utilization of epilepsy surgery.

Methods: An IRB-approved, single-center retrospective study identifying all SEEG pediatric patients in which virtual reality was applied was observed.

Results: Of the 46 patients identified who underwent an SEEG procedure, 43.5% (20/46) had a 3D rendering (3DR) of their SEEG depth electrodes. All 3DRs were used during patient-family education and discussion among the Epilepsy multidisciplinary team meetings, while 35% (7/20) were used during neuronavigation in surgery. Three successful representative cases of its application were presented.

Discussion: Our institution's experience regarding virtual reality in the 3D representation of SEEG depth electrodes and the application to pre-surgical planning, patient-family education, multidisciplinary communication, and intraoperative neuronavigation demonstrate its applicability in comprehensive epilepsy patient care.
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http://dx.doi.org/10.1007/s00381-021-05403-5DOI Listing
October 2021

Hypothalamic Hamartomas: Evolving Understanding and Management.

Neurology 2021 Nov 4;97(18):864-873. Epub 2021 Oct 4.

From the Center for Neuroscience Research (N.T.C., W.D.G.), Children's National Hospital, The George Washington University School of Medicine, Washington, DC; UCL NIHR BRC Great Ormond Street Institute of Child Health (J.H.C.), Member of ERN-EpiCARE, London; Great Ormond Street Hospital for Children (J.H.C.), NHS Trust, London; Young Epilepsy (J.H.C.), Lingfield, Surrey, UK; Department of Pediatric Clinical Epileptology (A.A.), Sleep Disorders and Functional Neurology, Member of ERN-EpiCARE; HFME (A.A.), Hospices Civils de Lyon, France; Epilepsy Research Unit (A.A.), Barcelona's Children Hospital San Juan de Dios, Member of the ERN EpiCARE, Spain; Epilepsy Research Centre (S.F.B.), University of Melbourne, Australia; Division of Pediatric Neurology (J.F.K.), Barrow Neurological Institute at Phoenix Children's Hospital; Hope for Hypothalamic Hamartomas (I.P.M., E.W., L.S.), Phoenix, AZ; Epilepsy Surgery Program (A.C.), Clinica de Epilepsia de Sao Paulo, Brazil; Department of Epidemiology (D.K.H.), Columbia University Medical Center, New York, NY; RTI International (B.L.K.), Rockville, MD; Department of Neurology (C.B.S.), Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Epilepsy Center (A.S.-B.), Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Germany.

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
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http://dx.doi.org/10.1212/WNL.0000000000012773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610628PMC
November 2021

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

Epilepsia 2021 Nov 12;62(11):2707-2718. Epub 2021 Sep 12.

Division of Neurosurgery, Department of Surgery, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom.

Methods: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method.

Results: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique.

Significance: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.
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http://dx.doi.org/10.1111/epi.17021DOI Listing
November 2021

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

Epilepsia 2021 Nov 21;62(11):2766-2777. 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
November 2021

Human herpesvirus 6 and epilepsy.

Epilepsia Open 2021 Jul 29. Epub 2021 Jul 29.

Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS.
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http://dx.doi.org/10.1002/epi4.12531DOI Listing
July 2021

Comparative Effectiveness of Initial Treatment for Infantile Spasms in a Contemporary US Cohort.

Neurology 2021 Jul 15. Epub 2021 Jul 15.

University of Michigan, Ann Arbor, MI.

Objective: Compare the effectiveness of initial treatment for infantile spasms.

Methods: The National Infantile Spasms Consortium prospectively followed children with new onset infantile spasms that began at age 2-24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.

Results: Freedom from treatment failure rates were: ACTH 88/190 (46%), oral steroids 42/95 (44%), vigabatrin 32/87 (37%), and non-standard therapy 4/51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% CI 34-54]). Changing from non-standard therapy to ACTH would improve response from 8% to 39 [17-67]%, and to oral steroids from 8% to 38 [15-68]%. There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42 [15-75]%), vigabatrin to oral steroids (29% to 42 [28-57]%), and non-standard therapy to vigabatrin (8% to 20 [6-50]%). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p<0.05) CONCLUSION: Compared to non-standard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between ACTH / oral steroids and non-standard therapy, though the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.

Classification Of Evidence: This study provides Class III evidence that for children with new onset infantile spasms, ACTH or oral steroids were superior to non-standard therapies.
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http://dx.doi.org/10.1212/WNL.0000000000012511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480478PMC
July 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

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

Seizure 2021 Oct 31;91:150-158. Epub 2021 May 31.

Division of Neuroimmunology and Neurovirology, NINDS, NIH, Bethesda, MD, United States.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection.

Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation.

Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels.

Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.
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http://dx.doi.org/10.1016/j.seizure.2021.05.022DOI Listing
October 2021

Cardiac-based detection of seizures in children with epilepsy.

Epilepsy Behav 2021 09 17;122:108129. Epub 2021 Jun 17.

RTI International, Technology Advancement and Commercialization, United States.

Introduction: We evaluated a multi-parametric approach to seizure detection using cardiac and activity features to detect a wide range of seizures across different people using the same model.

Methods: Electrocardiogram (ECG) and accelerometer data were collected from a chest-worn sensor from 62 children aged 2-17 years undergoing video-electroencephalogram monitoring for clinical care. ECG data from 5 adults aged 31-48 years who experienced focal seizures were also analyzed from the PhysioNet database. A detection algorithm was developed based on a combination of multiple heart rhythm and motion parameters.

Results: Excluding patients with multiple seizures per hour and myoclonic jerks, 25 seizures were captured from 18 children. Using cardiac parameters only, 11/12 generalized seizures with clonic or tonic activity were detected as well as 7/13 focal seizures without generalization. Separately, cardiac parameters were evaluated using electrocardiogram data from 10 complex partial seizures in the PhysioNet database of which 7 were detected. False alarms averaged one per day. Movement-based parameters did not identify any seizures missed by cardiac parameters, but did improve detection time for 4 of the generalized seizures.

Conclusion: Our data suggest that cardiac measures can detect seizures with bilateral motor features with high sensitivity, while detection of focal seizures depends on seizure duration and localization and may require customization of parameter thresholds.
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http://dx.doi.org/10.1016/j.yebeh.2021.108129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429110PMC
September 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

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

Epilepsia 2021 07 6;62(7):1629-1642. Epub 2021 Jun 6.

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

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE).

Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever.

Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function.

Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.
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http://dx.doi.org/10.1111/epi.16950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362203PMC
July 2021

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

Pediatr Neurol 2021 07 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

Responsive neurostimulation for the treatment of medically refractory epilepsy in pediatric patients: strategies, outcomes, and technical considerations.

J Neurosurg Pediatr 2021 Apr 30:1-8. Epub 2021 Apr 30.

3Department of Neurosurgery, Children's National Hospital, Washington, DC.

Objective: Children with medically refractory partial-onset epilepsy arising from eloquent cortex present a therapeutic challenge, as many are not suitable for resective surgery. For these patients, responsive neurostimulation may prove to be a potential tool. Although responsive neurostimulation has demonstrated utility in adults, little has been discussed regarding its utility in the pediatric population. In this study, the authors present their institution's experience with responsive neurostimulation via the RNS System through a case series of 5 pediatric patients.

Methods: A single-center retrospective study of patients who underwent RNS System implantation at Children's National Hospital was performed.

Results: Five patients underwent RNS System implantation. The mean patient age at treatment was 16.8 years, and the average follow-up was 11.2 months. All patients were considered responders, with a seizure frequency reduction of 64.2% without adverse events.

Conclusions: All 5 patients experienced medium-term improvements in seizure control after RNS System implantation with decreases in seizure frequency > 50% from baseline preoperative seizure frequency. The authors demonstrated two primary configurations of electrode placement: hippocampal or amygdala placement via an occipitotemporal trajectory, as well as infratemporal surface electrodes and surface electrodes on the primary motor cortex. No adverse events were experienced in this case series.
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http://dx.doi.org/10.3171/2020.11.PEDS20660DOI Listing
April 2021

Functional connectivity hemispheric contrast (FC-HC): A new metric for language mapping.

Neuroimage Clin 2021 1;30:102598. Epub 2021 Mar 1.

Department of Neurology, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, United States. Electronic address:

Development of a task-free method for presurgical mapping of language function is important for use in young or cognitively impaired patients. Resting state connectivity fMRI (RS-fMRI) is a task-free method that may be used to identify cognitive networks. We developed a voxelwise RS-fMRI metric, Functional Connectivity Hemispheric Contrast (FC-HC), to map the language network and determine language laterality through comparison of within-hemispheric language network connections (Integration) to cross-hemispheric connections (Segregation). For the first time, we demonstrated robustness and efficacy of a RS-fMRI metric to map language networks across five groups (total N = 243) that differed in MRI scanning parameters, fMRI scanning protocols, age, and development (typical vs pediatric epilepsy). The resting state FC-HC maps for the healthy pediatric and adult groups showed higher values in the left hemisphere, and had high agreement with standard task language fMRI; in contrast, the epilepsy patient group map was bilateral. FC-HC has strong but not perfect agreement with task fMRI and thus, may reflect related and complementary information about language plasticity and compensation.
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http://dx.doi.org/10.1016/j.nicl.2021.102598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102641PMC
July 2021

Response: Let us not miss the forest for the trees. Reply to "Echocardiography in epilepsy: A tool to be explored".

Epilepsia 2021 05 23;62(5):1287-1288. Epub 2021 Mar 23.

Division of Neurology, Children's National Hospital, Washington, DC, USA.

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http://dx.doi.org/10.1111/epi.16881DOI Listing
May 2021

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

Epilepsia 2021 05 13;62(5):1064-1073. Epub 2021 Mar 13.

Department of Pediatrics, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy.

Methods: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques.

Results: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom.

Significance: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.
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http://dx.doi.org/10.1111/epi.16861DOI Listing
May 2021

Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration.

J Pediatr 2021 05 20;232:220-228.e3. Epub 2021 Jan 20.

Department of Pediatrics & Neurology, University of Colorado, Aurora, CO.

Objectives: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US.

Study Design: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables.

Results: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs.

Conclusions: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.032DOI Listing
May 2021

Risk factors, etiologies, and comorbidities in urban pediatric epilepsy.

Epilepsy Behav 2021 02 11;115:107716. Epub 2021 Jan 11.

Children's National Hospital, Center for Neuroscience, 111 Michigan Avenue NW, Washington, DC 20010, USA.

The Seizures and Outcomes Study in Children (SOS-KIDS) identifies risk factors, etiologies, and comorbidities in a pediatric epilepsy population in a major city with diversity in socioeconomic levels. A thorough understanding of the range of issues impacting children with epilepsy is critical to establishing treatment that will produce better health outcomes. SOS-KIDS is a cross-sectional cohort study of pediatric epilepsy patients who live in Washington D.C. and are evaluated at Children's National Hospital. Families were recruited at the time of the child's routine clinic appointment or inpatient visit. Information was extracted from participants' electronic medical records (EMR) and parent reports; participants were screened for comorbidities using standardized screening measures. Data were collected from 289 participants (47% female, 53% male), and mean age was 7.9 years (2 months to 17 years). Twenty-nine percent of participants had primary generalized epilepsy, 63% focal epilepsy, 0.3% combined generalized and focal epilepsy, and 8% could not be distinguished. There were a variety of epilepsy risk factors including prematurity (10%), intraventricular hemorrhage (7%), neonatal seizures (8%), and febrile seizures (17%). The most common etiologies were cerebral malformations (13%) and genetic disorders (25%). Numerous participants had documented comorbidities including developmental delay (56%), intellectual disability (20%), headaches (16%), attention-deficit hyperactivity disorder (23%), and autism (7%). Of participants aged six years and older, depression, and anxiety were reported in 5% and 6% within the EMR, 14% and 19% in parent surveys, and 22% and 33% with standardized screening measures. We identified a wide variety of risk factors and etiologies among urban pediatric epilepsy patients, with genetic and structural being the most common. Neurologic and psychiatric comorbidities were common, but the prevalence of several psychiatric disorders reported within the EMR was substantially lower compared to that found when using parent surveys and standardized screening measures.
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http://dx.doi.org/10.1016/j.yebeh.2020.107716DOI Listing
February 2021

Design and implementation of electronic health record common data elements for pediatric epilepsy: Foundations for a learning health care system.

Epilepsia 2021 01 24;62(1):198-216. Epub 2020 Dec 24.

Department of Neurology, St Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Objective: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy.

Methods: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types.

Results: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center.

Significance: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy.
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http://dx.doi.org/10.1111/epi.16733DOI Listing
January 2021

Establishing criteria for pediatric epilepsy surgery center levels of care: Report from the ILAE Pediatric Epilepsy Surgery Task Force.

Epilepsia 2020 12 14;61(12):2629-2642. Epub 2020 Nov 14.

Department of Neurology, Nicklaus Children's Hospital, Miami, FL, USA.

Presurgical evaluation and surgery in the pediatric age group are unique in challenges related to caring for the very young, range of etiologies, choice of appropriate investigations, and surgical procedures. Accepted standards that define the criteria for levels of presurgical evaluation and epilepsy surgery care do not exist. Through a modified Delphi process involving 61 centers with experience in pediatric epilepsy surgery across 20 countries, including low-middle- to high-income countries, we established consensus for two levels of care. Levels were based on age, etiology, complexity of presurgical evaluation, and surgical procedure. Competencies were assigned to the levels of care relating to personnel, technology, and facilities. Criteria were established when consensus was reached (≥75% agreement). Level 1 care consists of children age 9 years and older, with discrete lesions including hippocampal sclerosis, undergoing lobectomy or lesionectomy, preferably on the cerebral convexity and not close to eloquent cortex, by a team including a pediatric epileptologist, pediatric neurosurgeon, and pediatric neuroradiologist with access to video-electroencephalography and 1.5-T magnetic resonance imaging (MRI). Level 2 care, also encompassing Level 1 care, occurs across the age span and range of etiologies (including tuberous sclerosis complex, Sturge-Weber syndrome, hypothalamic hamartoma) associated with MRI lesions that may be ill-defined, multilobar, hemispheric, or multifocal, and includes children with normal MRI or foci in/abutting eloquent cortex. Available Level 2 technologies includes 3-T MRI, other advanced magnetic resonance technology including functional MRI and diffusion tensor imaging (tractography), positron emission tomography and/or single photon emission computed tomography, source localization with electroencephalography or magnetoencephalography, and the ability to perform intra- or extraoperative invasive monitoring and functional mapping, by a large multidisciplinary team with pediatric expertise in epilepsy, neurophysiology, neuroradiology, epilepsy neurosurgery, neuropsychology, anesthesia, neurocritical care, psychiatry, and nursing. Levels of care will improve safety and outcomes for pediatric epilepsy surgery and provide standards for personnel and technology to achieve these levels.
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http://dx.doi.org/10.1111/epi.16698DOI Listing
December 2020

Children with refractory epilepsy demonstrate alterations in myocardial strain.

Epilepsia 2020 10 14;61(10):2234-2243. Epub 2020 Oct 14.

Department of Neurology, Children's National Hospital, Washington, District of Columbia, USA.

Objective: To test whether children with epilepsy have impairments in myocardial mechanics compared to controls without epilepsy.

Methods: Children with refractory epilepsy with epilepsy duration of at least 3 years underwent echocardiography including conventional measurements and speckle tracking to assess longitudinal and circumferential strain. Parent-completed surveys, capturing critical aspects of the children's seizure history and cardiac risk factors, complemented retrospective chart reviews, which also included antiepileptic drug history. Normal echocardiograms from controls, matched for age and gender, were obtained from our institutional database and evaluated for strain.

Results: Forty-one patients (median age = 10 years, interquartile range [IQR] = 5-15; 58.5% male) were enrolled. Epilepsy etiology included genetic (n = 26), structural (n = 6), genetic and structural (n = 5), infection (n = 3), and unknown (n = 1). No cardiac structural abnormalities were identified. Both longitudinal and circumferential strain were impaired (P < .03) in patients compared to controls (median [IQR] = 22.7% [21.2-24.2] vs 23.6% [22.2-26.1] and 22.0% [20.3-25.4] vs 24.5% [22.3-27.0], respectively), indicating decreased myocardial deformation/contraction. Shortening fraction was higher in patients (37.6% [35.7-39.7] vs 34.9% [32.5-38.7], P = .009); mitral valve E wave inflow velocity (84.8 cm/s [78.4-92.8] vs 97.2 cm/s [85.9-105.8], P = .005) and tissue Doppler lateral E' wave (13.9 cm/s [12.3-16.1] vs 17.3 cm/s [15.4-18.5], P < .001) were decreased compared to controls. Findings were similar in the pairs with epilepsy patients distinguished by the ability to independently ambulate. There was no difference between patients and controls in ejection fraction. Among the epilepsy patients, there were no associations between cardiac measurements and epilepsy characteristics, including seizure type and frequency and cardiotoxic antiseizure medication exposure after correction for multiple comparisons.

Significance: Children with refractory epilepsy had impaired systolic ventricular strain compared to controls, not correlated with epilepsy history. Further studies are needed to determine the significance of these changes.
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http://dx.doi.org/10.1111/epi.16652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191539PMC
October 2020

Language representation and presurgical language mapping in pediatric epilepsy: A narrative review.

Iran J Child Neurol 2020 ;14(3):7-18

Professor of Neurology and Pediatrics, George Washington University, Center for Neuroscience and Behavioral Health, Children's National Medical Center, Washington DC. USA.

As one of the most common neurological diseases in children, epilepsy affects 0.9-2% of children. Complex interactions among the etiologies of epilepsy, interictal discharges, seizures, and antiepileptic drugs lead to cognitive impairments in children with epilepsy. Since epilepsy is considered as a network disorder, in which seizures have a widespread impact on many parts of the brain, childhood epilepsy can even affect the normal development of language. About 25% of children with epilepsy do not respond to medications; therefore, brain surgery is considered as a treatment option for some of them. Presurgical neuropsychological evaluations including language mapping are recommended to preserve cognitive and language abilities of patients after surgery. Functional magnetic resonance imaging as a non-invasive technique for presurgical language mapping has been widely recommended in many epileptic centers. The present study reviewed language representation and presurgical language mapping in children with epilepsy. Mapping language in children with epilepsy helps to localize the epileptogenic zone, and also, to predict the cognitive outcome of epilepsy surgery and possible cognitive rehabilitation. This review collected information about language representation and language mapping in pediatric epilepsy settings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468084PMC
January 2020

First-line medication dosing in pediatric refractory status epilepticus.

Neurology 2020 11 10;95(19):e2683-e2696. Epub 2020 Sep 10.

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

Objective: To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.

Methods: This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.

Results: We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95).

Conclusion: BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.

Classification Of Evidence: This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.
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http://dx.doi.org/10.1212/WNL.0000000000010828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713738PMC
November 2020

The neural basis of language development: Changes in lateralization over age.

Proc Natl Acad Sci U S A 2020 09 8;117(38):23477-23483. Epub 2020 Sep 8.

Center for Brain Plasticity and Recovery, Georgetown University Medical Center and MedStar National Rehabilitation Hospital, Washington, DC 20057;

We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca's area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.
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http://dx.doi.org/10.1073/pnas.1905590117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519388PMC
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

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

J Neurosurg Pediatr 2020 Mar 20:1-8. Epub 2020 Mar 20.

4Neuroscience Research, and.

Objective: The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning.

Methods: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test.

Results: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted.

Conclusions: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.
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http://dx.doi.org/10.3171/2020.1.PEDS19695DOI Listing
March 2020

Measure thrice, cut twice: On the benefit of reoperation for failed pediatric epilepsy surgery.

Epilepsy Res 2020 03 11;161:106289. Epub 2020 Feb 11.

Division of Child Neurology, Children's National Hospital, Washington, DC, United States.

Objective: To determine whether clinical outcomes are improved after repeat surgery for medically refractory epilepsy in children.

Methods: This is a single-center retrospective cohort analysis of all patients who received repeat resective surgery for ongoing seizures from 2000-2017. From a total of 251 consecutive individual epilepsy surgical patients for focal resection, 53 patients met study inclusion criteria and had adequate follow-up documented.

Results: Median age of seizure-onset was 2.0-years-old (IQR 0.3-5.5 years). The median age at first epilepsy surgery was 6.3-years-old (IQR 2.9-9.2 years) and at second epilepsy surgery was 8.4-years-old (IQR 4.7-12.6 years). Overall, 53 % (n = 28) of this series achieved Engel Class I (seizure freedom); with improved seizure control (Engel Class I-II) in 83 % (n = 44) of the cohort. 64 % (n = 34) had one reoperation; 26 % (n = 14) had two; and 9% (n = 5) had three. Pathology: 58 % (n = 31) had focal cortical dysplasia; 13 % (n = 10) tumor; 9% (n = 5) encephalitis; 6% (n = 3) gliosis; 4% (n = 2) mesial temporal sclerosis; and 2% (n = 1) hemimegalencephaly. Tumor pathology was associated with increased chance (p = 0.01) for seizure freedom (90 % of tumor patients had Engel Class I outcome). MTS had worse outcome with both patients having ongoing seizures (Engel II-IV). There were 6 patients who developed post-operative hemiparesis; one was unplanned but resolved.

Significance: Reoperation for pediatric epilepsy surgery can lead to seizure freedom in many cases and improved seizure control in most cases. Reoperation for brain tumor pathology is associated with a high rate of seizure freedom.
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March 2020

A multi-disciplinary clinic for SCN8A-related epilepsy.

Epilepsy Res 2020 01 23;159:106261. Epub 2019 Dec 23.

Children's National Medical Center, Department of Neurology, 111 Michigan Ave NW, Washington, DC, 20010, USA. Electronic address:

Objective: We endeavored to evaluate a cohort of patients diagnosed with SCN8A-related epilepsy in a multi-disciplinary clinic and to create a bio-repository.

Methods: We recruited patients with epilepsy due to SCN8A variants at Children's National Medical Center, through family organizations, or SCN8A.net. Study procedures included medical record review, review of EEG and MRI data, clinical evaluation, the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), DNA extraction, and preparation of peripheral blood mononuclear cells.

Results: Seventeen patients (9 months - 19 years) completed the study. Age at seizure onset was 1 day to 4 years old (median age 4 months). Epilepsy phenotype ranged from mild epilepsy to severe developmental and epileptic encephalopathy. Medications targeting the voltage-gated sodium channel were most often effective, while levetiracetam resulted in worsening seizures and/or developmental regression in 7/16 (p < 0.05). VABS-3 scores were below age expectations for most children; older children had lower scores. Neurological examination revealed hypotonia (13), spastic quadriparesis (1), ataxia (9), dyskinesia (2)/ dystonia (7), and four non-ambulatory.

Conclusions: This is the first report of a large series of patients with epilepsy due to SCN8A variants evaluated in a single multi-disciplinary clinic. By utilizing a more comprehensive and consistent evaluation, we clarify specific seizure and epilepsy types, describe a distinct epilepsy phenotype in a patient with a nonsense variant, delineate patterns of developmental delay, language, and swallow function (specifically anomic aphasia and flaccid dysarthria), identify and characterize movement disorders, report common findings on physical exam, and demonstrate clinical worsening with levetiracetam.
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January 2020

Putting value back into the "V" of wRVU.

Neurology 2020 01 24;94(2):57-58. Epub 2019 Dec 24.

From the Department of Neurology (W.D.G.), Children's National Health System, George Washington University School of Medicine, Washington, DC; and Department of Neurology and Pediatrics (H.P.G.), UVA Health, University of Virginia School of Medicine, Charlottesville.

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http://dx.doi.org/10.1212/WNL.0000000000008796DOI Listing
January 2020
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