Publications by authors named "Mark P Fitzgerald"

21 Publications

  • Page 1 of 1

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
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http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

Epilepsia 2021 Jul 2;62(7):1617-1628. Epub 2021 Jun 2.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Objective: Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12 months of clinical use in outpatient encounters.

Methods: Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters.

Results: We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n = 121), Lennox-Gastaut syndrome (n = 86), and Dravet syndrome (n = 42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12 months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time.

Significance: Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.
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http://dx.doi.org/10.1111/epi.16934DOI Listing
July 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

Expanding Access to Continuous EEG Monitoring in Neonatal Intensive Care Units.

J Clin Neurophysiol 2020 Jun 9. Epub 2020 Jun 9.

Division of Neurology, Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Purpose: Neonatal seizures are common and difficult to identify clinically because the majority are subclinical and correct identification of electroclinical seizures based on semiology is unreliable. Therefore, continuous EEG monitoring (CEEG) is critical for seizure identification in neonates and is recommended as the gold standard method in American Clinical Neurophysiology Society guidelines. Despite these recommendations, barriers to implementing widespread CEEG exist.

Methods: To expand access to CEEG for at-risk neonates, a framework for providing remote CEEG was established at two network hospital neonatal intensive care units. Utilization and clinical impact were tracked as a quality improvement study.

Results: In a 27-month period from June 2017 through September 2019, 76 neonates underwent CEEG between the two network neonatal intensive care units. Electrographic seizures occurred in about one quarter of records (18/76; 24%), though their incidence varied by CEEG indication. Care notes indicated that CEEG impacted clinical care in three quarters of cases (57/76; 75%). Continuous EEG impacted decisions to treat with anti-seizure medications in approximately one half of patients (impact: 28/57 [49%]; no impact 29/57 [51%]), and CEEG impacted prognostic discussions in approximately two thirds of patients (impact: 39/57 [68%]; no impact 18/57 [32%]).

Conclusions: Establishment of a remote CEEG program for neonates is feasible, effective at identifying seizures, and improves the quality of care provided to neonates hospitalized at these network hospitals.
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http://dx.doi.org/10.1097/WNP.0000000000000730DOI Listing
June 2020

Analyzing 2,589 child neurology telehealth encounters necessitated by the COVID-19 pandemic.

Neurology 2020 09 9;95(9):e1257-e1266. Epub 2020 Jun 9.

From the Division of Neurology (S.C.R., S.E.F., A.K.G., J.X., P.D.G., M.K., M.S.P., U.S., M.P.F., S.E.M., M.P.M., S.K.K., D.J.S.., B.L.B., N.S.A., I.H.), Department of Biomedical and Health Informatics (A.K.G., J.X., P.D.G., M.K., I.H.), and The Epilepsy NeuroGenetics Initiative (A.K.G., J.X., P.D.G., M.K., M.P.F., S.K.K., N.S.A., I.H.), Children's Hospital of Philadelphia; and Departments of Neurology and Pediatrics (S.C.R., S.E.F., M.S.P., M.P.F., S.K.K., N.S.A., I.H.), Department of Biostatistics, Epidemiology and Informatics (N.S.A.), and Department of Anesthesia & Critical Care (N.S.A.), University of Pennsylvania Perelman School of Medicine, Philadelphia.

Objective: To assess the rapid implementation of child neurology telehealth outpatient care with the onset of the coronavirus disease 2019 (COVID-19) pandemic in March 2020.

Methods: This was a cohort study with retrospective comparison of 14,780 in-person encounters and 2,589 telehealth encounters, including 2,093 audio-video telemedicine and 496 scheduled telephone encounters, between October 1, 2019 and April 24, 2020. We compared in-person and telehealth encounters for patient demographics and diagnoses. For audio-video telemedicine encounters, we analyzed questionnaire responses addressing provider experience, follow-up plans, technical quality, need for in-person assessment, and parent/caregiver satisfaction. We performed manual reviews of encounters flagged as concerning by providers.

Results: There were no differences in patient age and major ICD-10 codes before and after transition. Clinicians considered telemedicine satisfactory in 93% (1,200 of 1,286) of encounters and suggested telemedicine as a component for follow-up care in 89% (1,144 of 1,286) of encounters. Technical challenges were reported in 40% (519 of 1,314) of encounters. In-person assessment was considered warranted after 5% (65 of 1,285) of encounters. Patients/caregivers indicated interest in telemedicine for future care in 86% (187 of 217) of encounters. Participation in telemedicine encounters compared to telephone encounters was less frequent among patients in racial or ethnic minority groups.

Conclusions: We effectively converted most of our outpatient care to telehealth encounters, including mostly audio-video telemedicine encounters. Providers rated the vast majority of telemedicine encounters to be satisfactory, and only a small proportion of encounters required short-term in-person follow-up. These findings suggest that telemedicine is feasible and effective for a large proportion of child neurology care. Additional strategies are needed to ensure equitable telemedicine use.
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http://dx.doi.org/10.1212/WNL.0000000000010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538222PMC
September 2020

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

Am J Hum Genet 2020 04 26;106(4):467-483. Epub 2020 Mar 26.

Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address:

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118584PMC
April 2020

RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells.

J Cell Physiol 2020 10 17;235(10):7261-7272. Epub 2020 Mar 17.

Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont.

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial-to-mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal-like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA-seq on the CD24 versus CD24 MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFβ1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24 and CD24 MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human-specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFβ for 5 days followed by a 7-day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence.
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http://dx.doi.org/10.1002/jcp.29625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415511PMC
October 2020

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat.

Neurobiol Dis 2020 07 13;140:104836. Epub 2020 Mar 13.

Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, United States; Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States. Electronic address:

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.
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http://dx.doi.org/10.1016/j.nbd.2020.104836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814471PMC
July 2020

Further delineation of the phenotypic spectrum of nevus comedonicus syndrome to include congenital pulmonary airway malformation of the lung and aneurysm.

Am J Med Genet A 2020 04 21;182(4):746-754. Epub 2020 Jan 21.

Division of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Nevus comedonicus syndrome (NCS) is a rare epidermal nevus syndrome characterized by ocular, skeletal, and central nervous system anomalies. We present a 23-month-old boy with a history of a congenital pulmonary airway malformation (CPAM) of the lung and a congenital cataract who developed progressive linear and curvilinear plaques of dilated follicular openings with keratin plugs (comedones) on parts of his scalp, face, and body consistent with nevus comedonicus. MRI of the brain demonstrated an aneurysm of the right internal carotid artery. Genetic testing identified NEK9 c.1755_1757del (p.Thr586del) at mean allele frequency of 28% in the nevus comedonicus. This same mutation was present in the CPAM tissue. This is the first case of a CPAM in a patient with an epidermal nevus syndrome. This case expands the phenotype of nevus comedonicus syndrome to include CPAM and vascular anomalies.
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http://dx.doi.org/10.1002/ajmg.a.61490DOI Listing
April 2020

Collodion Remover Can Degrade Plastic-Containing Medical Devices Commonly Used in the Intensive Care Unit.

Neurodiagn J 2019 14;59(3):163-168. Epub 2019 Aug 14.

Division of Neurology, Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania , Philadelphia , Pennsylvania.

Collodion remover, a solvent blend used to remove collodion glue after long-term video EEG monitoring, was implicated as a potential causative factor in patient safety events at our institution during which damage to plastic components of medical devices was noted in the intensive care unit. We sought to determine experimentally whether collodion remover could lead to degradation of multiple plastic-containing medical devices commonly used in the intensive care unit to determine whether workflow changes were needed during electrode removal. We exposed devices to collodion remover for brief, intermediate, and prolonged durations. We report that collodion remover is capable of degrading the hard plastic components of multiple medical devices after prolonged exposure; however, intermediate duration exposure was also capable of producing damage to clave connectors used with intravenous and central lines, which could plausibly lead to adverse events given the widespread use of these devices. These data suggest a pathway-based approach to collodion remover use might be beneficial in minimizing the potential impact of this solvent on plastic-containing medical devices.
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http://dx.doi.org/10.1080/21646821.2019.1649516DOI Listing
February 2020

Treatment Responsiveness in KCNT1-Related Epilepsy.

Neurotherapeutics 2019 07;16(3):848-857

Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA.

Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
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http://dx.doi.org/10.1007/s13311-019-00739-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694367PMC
July 2019

Interrater and Intrarater Agreement in Neonatal Electroencephalogram Background Scoring.

J Clin Neurophysiol 2019 Jan;36(1):1-8

Department of Pediatrics (Neurology), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.

Purpose: Many neonates undergo electroencephalogram (EEG) monitoring to identify and manage acute symptomatic seizures. Information about brain function contained in the EEG background data may also help predict neurobehavioral outcomes. For EEG background features to be useful as prognostic indicators, the interpretation of these features must be standardized across electroencephalographers. We aimed at determining the interrater and intrarater agreement among electroencephalographers interpreting neonatal EEG background patterns.

Methods: Five neonatal electroencephalographers reviewed 5-to-7.5-minute epochs of EEG from full-term neonates who underwent continuous conventional EEG monitoring. The EEG assessment tool used to classify background patterns was based on the American Clinical Neurophysiology Society's guideline for neonatal EEG terminology. Interrater and intrarater agreement were measured using Kappa coefficients.

Results: Interrater agreement was consistently highest for voltage (binary: substantial, kappa = 0.783; categorical: moderate, kappa = 0.562), seizure presence (fair-substantial; kappa = 0.375-0.697), continuity (moderate; kappa = 0.481), burst voltage (moderate; kappa = 0.574), suppressed background presence (moderate-substantial; kappa = 0.493-0.643), delta activity presence (fair-moderate; kappa = 0.369-0.432), theta activity presence (fair-moderate; kappa = 0.347-0.600), presence of graphoelements (fair; kappa = 0.381), and overall impression (binary: moderate, kappa = 0.495; categorical: fair-moderate, kappa = 0.347, 0.465). Agreement was poor or inconsistent for all other patterns. Intrarater agreement was variable, with highest average agreement for voltage (binary: substantial, kappa = 0.75; categorical: substantial, kappa = 0.714) and highest consistent agreement for continuity (moderate-substantial; kappa = 0.43-0.67) and overall impression (moderate-substantial; kappa = 0.42-0.68).

Conclusions: This study demonstrates substantial variability in neonatal EEG background interpretation across electroencephalographers, indicating a need for educational and technological strategies aimed at improving performance.
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http://dx.doi.org/10.1097/WNP.0000000000000534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322680PMC
January 2019

High electroencephalographic seizure exposure is associated with unfavorable outcomes in neonates with hypoxic-ischemic encephalopathy.

Seizure 2018 Oct 11;61:221-226. Epub 2018 Sep 11.

Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States; Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.

Purpose: Electroencephalographic seizures (ES) are common among neonates with hypoxic-ischemic encephalopathy (HIE), and they represent a treatable complication that might improve neurodevelopmental outcomes. We aimed to establish whether higher ES exposure was predictive of unfavorable outcomes while adjusting for other important clinical and electroencephalographic parameters.

Methods: We performed a single-center, retrospective study of consecutive neonates with HIE managed with therapeutic hypothermia from June 2010 through December 2016. Neonates underwent continuous electroencephalographic (cEEG) monitoring during and after therapeutic hypothermia. Outcome measures included abnormal MRIs after rewarming and abnormal motor and language development.

Results: Clinical data from the perinatal period were available for 116 neonates. Follow-up data were available for 93 of 116 (80%) neonates who survived to discharge, with a median follow-up period of 23 months (interquartile range 1236 months). Multivariate analysis demonstrated that high ES exposure (OR 5.2, 95% CI 1.3-21.2, p = 0.02) and moderate/severely abnormal EEG background (OR 8.3, 95% CI 1.6-43.9, p = 0.01) were independent predictors of abnormal motor development. High ES exposure was an independent predictor of abnormal language development (OR 4.2, 95% CI 1.1-15.9, p = 0.04). High ES exposure (OR 7.0, 95% CI 2.2-22.5, p = 0.01) and severe encephalopathy (OR 7.9, 95% CI 1.5-42.7, p = 0.02) were independent predictors of abnormal MRIs.

Conclusions: Among neonates with HIE managed with therapeutic hypothermia, high ES exposure was the most important predictor of abnormal developmental and neuroimaging outcomes, even after adjustment for multiple clinical and EEG variables. Adequate identification and management of ES with judicious use of anti-seizure medications may optimize outcomes.
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http://dx.doi.org/10.1016/j.seizure.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168337PMC
October 2018

The phenotype of developmental and epileptic encephalopathy.

Neurology 2018 09 31;91(12):e1112-e1124. Epub 2018 Aug 31.

From the Department of Clinical Neurophysiology (E.G., S.B.), Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (E.G., K.M.J., R.S.M.), University of Southern Denmark, Odense, Denmark; Neuroscience Department (C.M., R.G., M.M.), Children's Hospital A. Meyer, University of Florence; Department of Neuroscience (M.T., N.S., F.V.), Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Division of Neurology (M.P.F., I.H.), The Children's Hospital of Philadelphia; Departments of Pediatrics and Neurology (M.P.F., I.H.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Universitätskinderklinik Tübingen (M.A., M.W.), Germany; Department of Neurology (K.H.), Royal Children's Hospital Melbourne; Department of Paediatrics (K.H.), University of Melbourne; Australia Neurosciences Group (K.H.), Murdoch Children's Research Institute, Melbourne, Australia; Servizio di Neuropsichiatria Infantile (F.D., E.F.), Policlinico G.B. Rossi, Universita Degli Studi di Verona; Department of Child Neurology (S.S., G.A.), Ospedale Pediatrico G. Salesi-Ospedali Riuniti, Ancona, Italy; Division of Clinical Neurophysiology (B.B.), Children's Research Center, University Children's Hospital Zurich, Switzerland; Brain and Behaviour Department (S.M.), University of Pavia; Department of Pediatric Neuroradiology (A.P.), IRCCS "C. Mondino" National Neurological Institute, Pavia, Italy; Department of Epilepsy Genetics (K.J., R.S.M.), Danish Epilepsy Centre Dianalund; Department of Child Neurology (B.J.), Danish Epilepsy Centre, Dianalund, Denmark; Cytogenetic and Molecular Genetic Laboratory (S.R., F.C.), Istituto Auxologico Italiano, IRCCS, Milano, Italy; Department of Adult Neurology (G.R.), Danish Epilepsy Centre, Dianalund; University of Copenhagen (G.R.), Denmark; Struttura Complessa di Neurologia Pediatrica Ospedale Vittore Buzzi (P.V.), Milano; Dipartimento di Scienze Biomediche e Cliniche L. Sacco (P.V.), Università di Milano, Italy; Århus University (S.B.), Denmark; Department of Child Neurology (I.E.S.), University of Melbourne, Austin Health, Florey Institute; and Department of Child Neurology (I.E.S.), The Royal Children's Hospital, Melbourne, Australia.

Objective: To delineate the electroclinical features of infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558).

Methods: Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment.

Results: Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes (8/22), cortical myoclonus (8/22), and myoclonic absences (1/22). FS typically clustered and were prolonged (<20 minutes) with (1) cyanosis, hypomotor, and vegetative semiology, sometimes unnoticed, followed by (2) tonic-vibratory and (3) (hemi)-clonic manifestations ± evolution to a bilateral tonic-clonic seizure. FS had posterior-temporal/occipital onset, slowly spreading and sometimes migrating between hemispheres. Brain MRI showed progressive parenchymal atrophy and restriction of the optic radiations.

Conclusions: developmental and epileptic encephalopathy has strikingly consistent electroclinical features, suggesting a global progressive brain dysfunction primarily affecting the temporo-occipital regions. Both uncontrolled epilepsy and developmental compromise contribute to the profound impairment (increasing risk of death) during early childhood, but stabilization occurs in late childhood.
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http://dx.doi.org/10.1212/WNL.0000000000006199DOI Listing
September 2018

Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor.

Mol Cancer Res 2018 12 6;16(12):1952-1964. Epub 2018 Aug 6.

Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont.

Breast cancer remains the most common malignant disease in women worldwide. Despite advances in detection and therapies, studies are still needed to understand the mechanisms underlying this cancer. Cancer stem cells (CSC) play an important role in tumor formation, growth, drug resistance, and recurrence. Here, it is demonstrated that the transcription factor RUNX1, well known as essential for hematopoietic differentiation, represses the breast cancer stem cell (BCSC) phenotype and suppresses tumor growth . The current studies show that BCSCs sorted from premalignant breast cancer cells exhibit decreased RUNX1 levels, whereas ectopic expression of RUNX1 suppresses tumorsphere formation and reduces the BCSC population. RUNX1 ectopic expression in breast cancer cells reduces migration, invasion, and tumor growth (57%) in mouse mammary fat pad. Mechanistically, RUNX1 functions to suppress breast cancer tumor growth through repression of CSC activity and direct inhibition of ZEB1 expression. Consistent with these cellular and biochemical results, clinical findings using patient specimens reveal that the highest RUNX1 levels occur in normal mammary epithelial cells and that low RUNX1 expression in tumors is associated with poor patient survival. IMPLICATIONS: The key finding that RUNX1 represses stemness in several breast cancer cell lines points to the importance of RUNX1 in other solid tumors where RUNX1 may regulate CSC properties.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289193PMC
December 2018

Early discontinuation of antiseizure medications in neonates with hypoxic-ischemic encephalopathy.

Epilepsia 2017 06 12;58(6):1047-1053. Epub 2017 Apr 12.

Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.

Objective: Neonates with hypoxic-ischemic encephalopathy (HIE) managed with therapeutic hypothermia (TH) often experience acute symptomatic seizures, prompting treatment with antiseizure medications (ASMs). Because the risk of seizure occurrence after hospital discharge is unknown, the optimal ASM treatment duration is unclear. We aimed to determine the risk of seizure occurrence after hospital discharge and the impact of ASM treatment duration on this outcome.

Methods: We performed a single-center, retrospective study of consecutive neonates with HIE managed with TH who received ASMs for acute symptomatic seizures from June 2010 through December 2014. Neonates were monitored with continuous electroencephalography (EEG) during TH.

Results: Follow-up data were available for 59 (82%) of 72 neonates who survived to discharge, with a median follow-up period of 19 months (interquartile range [IQR] 11-25). Acute symptomatic seizures occurred in 35 neonates (59%), including electrographic seizures in 21 neonates (36%). ASMs were continued upon discharge in 17 (49%) of 35 neonates. Seizures occurred in follow-up in four neonates (11%). No patient for whom ASMs were discontinued prior to discharge experienced seizures during the follow-up period.

Significance: Among neonates with HIE, seizures after hospital discharge were rare in those with acute symptomatic seizures and did not occur in neonates without acute symptomatic seizures. ASM discontinuation prior to discharge did not increase the risk of seizures during the follow-up period, suggesting that ASMs may be discontinued in many neonates prior to discharge.
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http://dx.doi.org/10.1111/epi.13745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462843PMC
June 2017

An NXF1 mRNA with a retained intron is expressed in hippocampal and neocortical neurons and is translated into a protein that functions as an Nxf1 cofactor.

Mol Biol Cell 2016 12 5;27(24):3903-3912. Epub 2016 Oct 5.

Myles H. Thaler Center for AIDS and Human Retrovirus Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908

The Nxf1 protein is a major nuclear export receptor for the transport of mRNA, and it also is essential for export of retroviral mRNAs with retained introns. In the latter case, it binds to RNA elements known as constitutive transport elements (CTEs) and functions in conjunction with a cofactor known as Nxt1. The NXF1 gene also regulates expression of its own intron-containing RNA through the use of a functional CTE within intron 10. mRNA containing this intron is exported to the cytoplasm, where it can be translated into the 356-amino acid short Nxf1(sNxf1) protein, despite the fact that it is a prime candidate for nonsense-mediated decay (NMD). Here we demonstrate that sNxf1 is highly expressed in nuclei and dendrites of hippocampal and neocortical neurons in rodent brain. Additionally, we show that sNxf1 localizes in RNA granules in neurites of differentiated N2a mouse neuroblastoma cells, where it shows partial colocalization with Staufen2 isoform SS, a protein known to play a role in dendritic mRNA trafficking. We also show that sNxf1 forms heterodimers in conjunction with the full-length Nxf1 and that sNxf1 can replace Nxt1 to enhance the expression of CTE-containing mRNA and promote its association with polyribosomes.
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http://dx.doi.org/10.1091/mbc.E16-07-0515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170612PMC
December 2016

Poster 463 Unexpected Transverse Myelitis after Dinutuximab Therapy for Relapsed Neuroblastoma: A Case Report.

PM R 2016 Sep 24;8(9S):S311. Epub 2016 Sep 24.

Hospital of University of Pennsylvania, Philadelphia, PA, United States.

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http://dx.doi.org/10.1016/j.pmrj.2016.07.384DOI Listing
September 2016

Genome-Wide Studies Reveal that H3K4me3 Modification in Bivalent Genes Is Dynamically Regulated during the Pluripotent Cell Cycle and Stabilized upon Differentiation.

Mol Cell Biol 2016 02 7;36(4):615-27. Epub 2015 Dec 7.

Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont, USA

Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1 phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1 transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency.
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http://dx.doi.org/10.1128/MCB.00877-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751694PMC
February 2016

Acute psychosis presenting in a patient with systemic lupus erythematosus: Questions and Answers.

Pediatr Nephrol 2016 Feb 30;31(2):227-31. Epub 2015 Jan 30.

Division of Nephrology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA, 19104, USA.

A 17-year-old girl recently diagnosed with systemic lupus erythematosus (SLE) presented to the Emergency Room with acute onset of psychosis. A variety of potential etiologies, including those related to SLE, to the treatment of her SLE, or to another psychiatric condition, are discussed. In addition, the work-up and management decisions for this patient are reviewed in detail.
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http://dx.doi.org/10.1007/s00467-015-3052-3DOI Listing
February 2016

Tolerance for error and computational estimation ability.

Psychol Rep 2004 Jun;94(3 Pt 2):1393-403

Department of Psychology, University of Scranton, PA 18510, USA.

Previous investigators have suggested that the personality variable tolerance for error is related to success in computational estimation. However, this suggestion has not been tested directly. This study examined the relationship between performance on a computational estimation test and scores on the NEO-Five Factor Inventory, a measure of the Big Five personality traits, including Openness, an index of tolerance for ambiguity. Other variables included SAT-I Verbal and Mathematics scores and self-rated mathematics ability. Participants were 65 college students. There was no significant relationship between the tolerance variable and computational estimation performance. There was a modest negative relationship between Agreeableness and estimation performance. The skepticism associated with the negative pole of the Agreeableness dimension may be important to pursue in further understanding of estimation ability.
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http://dx.doi.org/10.2466/pr0.94.3c.1393-1403DOI Listing
June 2004