William Brian Gallentine

All Publications

• Images: Benign myoclonus of sleep associated with K-complexes on EEG. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Silverman, A., Miglis, M. G., Gallentine, W. 2023

  Abstract

  In this brief case report on paroxysmal sleep-related movements, we describe an adolescent patient's presentation of brief jerking movements during sleep and the accompanying differential diagnosis. In examining the patient's overnight electroencephalogram (EEG), we utilize hallmark sleep architecture to provide reassurance to the patient and her family.

  View details for DOI 10.5664/jcsm.10822

  View details for PubMedID 37772703

• Safe use of the ketogenic diet in an infant with microcephaly, epilepsy, and diabetes syndrome: a case report. BMC pediatrics Zegarra, W. A., Gallentine, W. B., Ruzhnikov, M. R., McAndrews, C. A., Gloyn, A. L., Addala, A. 2023; 23 (1): 453

  Abstract

  BACKGROUND: Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a rare syndromic form of monogenic diabetes caused by bi-allelic loss of function mutations in IER3IP1. In vitro studies have shown that loss of IER31P leads to apoptosis in both neurons and pancreatic beta-cells. Simultaneous management of seizures and diabetes is challenging in patients with MEDS. We present the challenges and successes in the use of ketogenic diet in an infant with insulinopenic diabetes.CASE PRESENTATION: Our term female proband presented at 2 months of age with new onset multifocal seizures followed by the onset of infantile spasms (IS) at 4 months of age. An epilepsy gene panel identified bi-allelic variants, c.239T>G (p.Leu80*) and c.2T>A (initiator codon), in IER3IP1 that were subsequently shown to be inherited in trans. Following initiation of steroid therapy for IS, the patient developed clinically apparent insulin requiring diabetes. Her epilepsy was ultimately refractory to multiple antiseizure medications, thus the ketogenic diet (KD) was initiated. We were able to successfully titrate to a therapeutic KD ratio of 3:1 and maintain a ketotic state without diabetic ketoacidosis (DKA). With intercurrent illnesses, however, the patient had rapid decompensation and mild DKA due to delays in treatment, and for this reason, KD was discontinued after 5 months.CONCLUSIONS: We report two novel IER31P1 mutations in a patient with MEDS and the successful management of the cooccurring conditions of IS and insulinopenic diabetes with the KD. Our experience underscores the importance of careful monitoring during KD as our patient had DKA more easily when on the KD.

  View details for DOI 10.1186/s12887-023-04272-y

  View details for PubMedID 37689631

• Automated Interpretation of Clinical Electroencephalograms Using Artificial Intelligence. JAMA neurology Tveit, J., Aurlien, H., Plis, S., Calhoun, V. D., Tatum, W. O., Schomer, D. L., Arntsen, V., Cox, F., Fahoum, F., Gallentine, W. B., Gardella, E., Hahn, C. D., Husain, A. M., Kessler, S., Kural, M. A., Nascimento, F. A., Tankisi, H., Ulvin, L. B., Wennberg, R., Beniczky, S. 2023

  Abstract

  Electroencephalograms (EEGs) are a fundamental evaluation in neurology but require special expertise unavailable in many regions of the world. Artificial intelligence (AI) has a potential for addressing these unmet needs. Previous AI models address only limited aspects of EEG interpretation such as distinguishing abnormal from normal or identifying epileptiform activity. A comprehensive, fully automated interpretation of routine EEG based on AI suitable for clinical practice is needed.To develop and validate an AI model (Standardized Computer-based Organized Reporting of EEG-Artificial Intelligence [SCORE-AI]) with the ability to distinguish abnormal from normal EEG recordings and to classify abnormal EEG recordings into categories relevant for clinical decision-making: epileptiform-focal, epileptiform-generalized, nonepileptiform-focal, and nonepileptiform-diffuse.In this multicenter diagnostic accuracy study, a convolutional neural network model, SCORE-AI, was developed and validated using EEGs recorded between 2014 and 2020. Data were analyzed from January 17, 2022, until November 14, 2022. A total of 30 493 recordings of patients referred for EEG were included into the development data set annotated by 17 experts. Patients aged more than 3 months and not critically ill were eligible. The SCORE-AI was validated using 3 independent test data sets: a multicenter data set of 100 representative EEGs evaluated by 11 experts, a single-center data set of 9785 EEGs evaluated by 14 experts, and for benchmarking with previously published AI models, a data set of 60 EEGs with external reference standard. No patients who met eligibility criteria were excluded.Diagnostic accuracy, sensitivity, and specificity compared with the experts and the external reference standard of patients' habitual clinical episodes obtained during video-EEG recording.The characteristics of the EEG data sets include development data set (N = 30 493; 14 980 men; median age, 25.3 years [95% CI, 1.3-76.2 years]), multicenter test data set (N = 100; 61 men, median age, 25.8 years [95% CI, 4.1-85.5 years]), single-center test data set (N = 9785; 5168 men; median age, 35.4 years [95% CI, 0.6-87.4 years]), and test data set with external reference standard (N = 60; 27 men; median age, 36 years [95% CI, 3-75 years]). The SCORE-AI achieved high accuracy, with an area under the receiver operating characteristic curve between 0.89 and 0.96 for the different categories of EEG abnormalities, and performance similar to human experts. Benchmarking against 3 previously published AI models was limited to comparing detection of epileptiform abnormalities. The accuracy of SCORE-AI (88.3%; 95% CI, 79.2%-94.9%) was significantly higher than the 3 previously published models (P < .001) and similar to human experts.In this study, SCORE-AI achieved human expert level performance in fully automated interpretation of routine EEGs. Application of SCORE-AI may improve diagnosis and patient care in underserved areas and improve efficiency and consistency in specialized epilepsy centers.

  View details for DOI 10.1001/jamaneurol.2023.1645

  View details for PubMedID 37338864

• Survey of Pediatric ICU EEG Monitoring-Reassessment After a Decade. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Fung, F. W., Carpenter, J. L., Chapman, K. E., Gallentine, W., Giza, C. C., Goldstein, J. L., Hahn, C. D., Loddenkemper, T., Matsumoto, J. H., Press, C. A., Riviello, J. J., Abend, N. S. 2023

  Abstract

  In 2011, the authors conducted a survey regarding continuous EEG (CEEG) utilization in critically ill children. In the interim decade, the literature has expanded, and guidelines and consensus statements have addressed CEEG utilization. Thus, the authors aimed to characterize current practice related to CEEG utilization in critically ill children.The authors conducted an online survey of pediatric neurologists from 50 US and 12 Canadian institutions in 2022.The authors assessed responses from 48 of 62 (77%) surveyed institutions. Reported CEEG indications were consistent with consensus statement recommendations and included altered mental status after a seizure or status epilepticus, altered mental status of unknown etiology, or altered mental status with an acute primary neurological condition. Since the prior survey, there was a 3- to 4-fold increase in the number of patients undergoing CEEG per month and greater use of written pathways for ICU CEEG. However, variability in resources and workflow persisted, particularly regarding technologist availability, frequency of CEEG screening, communication approaches, and electrographic seizure management approaches.Among the surveyed institutions, which included primarily large academic centers, CEEG use in pediatric intensive care units has increased with some practice standardization, but variability in resources and workflow were persistent.

  View details for DOI 10.1097/WNP.0000000000001006

  View details for PubMedID 36930237

• Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy. American journal of medical genetics. Part A Harris, S. C., Chong, K., Chitayat, D., Gilmore, K. L., Jorge, A. A., Freire, B. L., Lerario, A., Shannon, P., Cope, H., Gallentine, W. B., Le Guyader, G., Bilan, F., Létard, P., Davis, E. E., Vora, N. L. 2023

  Abstract

  Exome sequencing is a powerful tool in prenatal and postnatal genetics and can help identify novel candidate genes critical to human development. We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32, including four fetal probands in three unrelated pedigrees and three pediatric probands in unrelated pedigrees. We also report clinical comparisons with seven previously published patients. Index probands were identified through an ongoing prenatal exome sequencing study and through an online data sharing platform (Gene Matcher™). A literature review was also completed. TBC1D32 is involved in the development and function of cilia and is expressed in the developing hypothalamus and pituitary gland. We provide additional data to expand the phenotype correlated with TBC1D32 variants, including a severe prenatal phenotype associated with life-limiting congenital anomalies.

  View details for DOI 10.1002/ajmg.a.63150

  View details for PubMedID 36826837

• Delineating the Epilepsy Phenotype of NGLY1 Deficiency. Journal of inherited metabolic disease Levy, R. J., Frater, C. H., Gallentine, W. B., Phillips, J. M., Ruzhnikov, M. R. 2022

  Abstract

  To delineate the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort.We collected detailed clinical and electroencephalographic data from 29 individuals with bi-allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in-person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping.Of 29 individuals (mean 11.4 years, range 3-27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. EEGs were abnormal in 80% (12/15) of participants with or without epilepsy, though encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays.Epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12494

  View details for PubMedID 35243670

• Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis. JAMA neurology Nosadini, M., Eyre, M., Molteni, E., Thomas, T., Irani, S. R., Dalmau, J., Dale, R. C., Lim, M., International NMDAR Antibody Encephalitis Consensus Group, Anlar, B., Armangue, T., Benseler, S., Cellucci, T., Deiva, K., Gallentine, W., Gombolay, G., Gorman, M. P., Hacohen, Y., Jiang, Y., Lim, B. C., Muscal, E., Ndondo, A., Neuteboom, R., Rostasy, K., Sakuma, H., Sartori, S., Sharma, S., Tenembaum, S. N., Van Mater, H. A., Wells, E., Wickstrom, R., Yeshokumar, A. K. 2021

  Abstract

  Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear.Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score.Data Sources: Systematic search in PubMed from inception to January 1, 2019.Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data.Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models.Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset).Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P<.001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P=.006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P=.05).Conclusions and Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

  View details for DOI 10.1001/jamaneurol.2021.3188

  View details for PubMedID 34542573

• International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Nosadini, M., Thomas, T., Eyre, M., Anlar, B., Armangue, T., Benseler, S. M., Cellucci, T., Deiva, K., Gallentine, W., Gombolay, G., Gorman, M. P., Hacohen, Y., Jiang, Y., Lim, B. C., Muscal, E., Ndondo, A., Neuteboom, R., Rostasy, K., Sakuma, H., Sharma, S., Tenembaum, S. N., Van Mater, H. A., Wells, E., Wickstrom, R., Yeshokumar, A. K., Irani, S. R., Dalmau, J., Lim, M., Dale, R. C. 2021; 8 (5)

  Abstract

  OBJECTIVE: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).METHODS: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement).RESULTS: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.CONCLUSION: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

  View details for DOI 10.1212/NXI.0000000000001052

  View details for PubMedID 34301820

• Psychiatric Phenotypes of Pediatric Patients With Seropositive Autoimmune Encephalitis. Hospital pediatrics Adams, A. V., Van Mater, H., Gallentine, W., Mooneyham, G. C. 2021

  Abstract

  OBJECTIVES: Patients with autoimmune encephalitis (AE) often present with symptoms that are broadly characterized as psychiatric or behavioral, yet little attention is given to the precise symptomatology observed. We sought to more fully define the psychiatric symptoms observed in patients with anti-N-methyl-D-aspartate receptor (NMDAR), anti-glutamic-acid-decarboxylase 65 (GAD65), and anti-voltage-gated-potassium-channel complex (VGKC) antibody-mediated AE using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition nomenclature.METHODS: We present a case series (n = 25) using a retrospective chart review of 225 patients evaluated for AE in a tertiary care academic medical center between 2014 and 2018. The included patients were ≤18 years old with anti-NMDAR AE (n = 13), anti-GAD65 AE (n = 7), or anti-VGKC AE (n = 5). The frequency of neuropsychiatric symptoms present at the onset of illness and time to diagnosis were compared across groups.RESULTS: Psychiatric symptoms were seen in 92% of patients in our cohort. Depressive features (72%), personality change (64%), psychosis (48%), and catatonia (32%) were the most common psychiatric symptoms exhibited. On average, patients experienced impairment in ≥4 of 7 symptom domains. No patients had isolated psychiatric symptoms. The average times to diagnosis were 1.7, 15.5, and 12.4 months for anti-NMDAR AE, anti-GAD65 AE, and anti-VGKC AE, respectively (P < .001).CONCLUSIONS: The psychiatric phenotype of AE in children is highly heterogenous. Involving psychiatry consultation services can be helpful in differentiating features of psychosis and catatonia, which may otherwise be misidentified. Patients presenting with psychiatric symptoms along with impairments in other domains should prompt a workup for AE, including testing for all known antineuronal antibodies.

  View details for DOI 10.1542/hpeds.2020-005298

  View details for PubMedID 34103402

• Alterations in coordinated EEG activity precede the development of seizures in comatose children. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Vakorin, V. A., Nita, D. A., Payne, E. T., McBain, K. L., Frndova, H., Go, C., Ribary, U., Abend, N. S., Gallentine, W. B., Nash, K. B., Hutchison, J. S., Parshuram, C. S., Snead, O. C., van Straaten, I. E., Stam, C. J., Doesburg, S. M., Hahn, C. D. 2021; 132 (7): 1505-1514

  Abstract

  OBJECTIVE: We aimed to test the hypothesis that computational features of the first several minutes of EEG recording can be used to estimate the risk for development of acute seizures in comatose critically-ill children.METHODS: In a prospective cohort of 118 comatose children, we computed features of the first five minutes of artifact-free EEG recording (spectral power, inter-regional synchronization and cross-frequency coupling) and tested if these features could help identify the 25 children who went on to develop acute symptomatic seizures during the subsequent 48 hours of cEEG monitoring.RESULTS: Children who developed acute seizures demonstrated higher average spectral power, particularly in the theta frequency range, and distinct patterns of inter-regional connectivity, characterized by greater connectivity at delta and theta frequencies, but weaker connectivity at beta and low gamma frequencies. Subgroup analyses among the 97 children with the same baseline EEG background pattern (generalized slowing) yielded qualitatively and quantitatively similar results.CONCLUSIONS: These computational features could be applied to baseline EEG recordings to identify critically-ill children at high risk for acute symptomatic seizures.SIGNIFICANCE: If confirmed in independent prospective cohorts, these features would merit incorporation into a decision support system in order to optimize diagnostic and therapeutic management of seizures among comatose children.

  View details for DOI 10.1016/j.clinph.2021.03.015

  View details for PubMedID 34023630

• Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurology(R) neuroimmunology & neuroinflammation Cellucci, T., Van Mater, H., Graus, F., Muscal, E., Gallentine, W., Klein-Gitelman, M. S., Benseler, S. M., Frankovich, J., Gorman, M. P., Van Haren, K., Dalmau, J., Dale, R. C. 2020; 7 (2)

  Abstract

  OBJECTIVE: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.METHODS: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.RESULTS: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.CONCLUSIONS: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

  View details for DOI 10.1212/NXI.0000000000000663

  View details for PubMedID 31953309

• Evaluation of Diagnostic Criteria for Hashimoto's Encephalopathy Among Children and Adolescents. Pediatric neurology Adams, A. V., Mooneyham, G. C., Van Mater, H., Gallentine, W. 2020

  Abstract

  BACKGROUND: The recently proposed adult diagnostic criteria for the Hashimoto's encephalopathy (HE) include a requirement of subclinical or mild thyroid disease. However, most case reports indicate that most children treated for HE do not have evidence of thyroid disease. We aim to evaluate the impact of applying the current adult diagnostic criteria to pediatric patients.METHODS: Pediatric patients with HE were evaluated at time of symptom onset and follow up at least 1 year after initiation of immunomodulatory treatment for degree of impairment within the neuropsychiatric domains of cognition, language, psychiatric disturbance, seizure, movement disorder, sleep disruption, and overall functionality. We compared the response to treatment among patients stratified by the presence or absence of subclinical or mild thyroid disease using the Modified Rankin Scale, the Liverpool Outcome Score, and a novel multidomain scale designed for the population with pediatric autoimmune brain disorders.RESULTS: Of 17 pediatric patients treated for HE, 6 met full adult diagnostic criteria, whereas 11 patients did not meet criteria solely owing to the absence of thyroid disease. Using our novel scale, the 6 patients meeting full criteria had statistically significant improvement from time of onset of disease to follow up in the domain of cognition. The 11 patients who did not meet full criteria based on their absence of thyroid disease exhibited statistically significant improvement from time of onset of disease to follow up in the domains of cognition, language, psychiatric disturbance, movement, and sleep.CONCLUSIONS: Rigidly applying the current diagnostic criteria to pediatric patients with suspected HE may result in the failure to treat potential responders. We propose a set of diagnostic criteria for HE in children, which does not require thyroid disease but include abrupt onset cognitive regression with deficits in one or more other neuropsychiatric domains in the setting of antithyroid antibodies.

  View details for DOI 10.1016/j.pediatrneurol.2019.12.011

  View details for PubMedID 32173161

• Subacute Neuropsychiatric Syndrome in Girls With SHANK3 Mutations Responds to Immunomodulation. Pediatrics Bey, A. L., Gorman, M. P., Gallentine, W. n., Kohlenberg, T. M., Frankovich, J. n., Jiang, Y. H., Van Haren, K. n. 2020; 145 (2)

  Abstract

  Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

  View details for DOI 10.1542/peds.2019-1490

  View details for PubMedID 32015180

• Institutional Pediatric Convulsive Status Epilepticus Protocol Decreases Time to First and Second Line Anti-Seizure Medication Administration. Seizure Trau, S. P., Sterrett, E. C., Feinstein, L. n., Tran, L. n., Gallentine, W. B., Tchapyjnikov, D. n. 2020; 81: 263–68

  Abstract

  Convulsive status epilepticus (CSE) is a medical emergency associated with high rates of morbidity and mortality. Although guidelines for CSE management recommend rapid treatment of seizures, prior studies show that compliance with these guidelines is low. In this study, we assessed if implementation of a paper-based clinical pathway for the treatment of CSE improves the timeliness and appropriate dosing of first and second line anti-seizure medications (ASM).A non-digital CSE treatment protocol was implemented as part of a quality improvement initiative in 2016. A retrospective analysis was subsequently conducted on cases of CSE originating in the pediatric emergency department (ED) from 2012-2019. Standard descriptive statistics were used to assess patient demographics as well as the timing and dosing of the first and second line ASMs used in our protocol (lorazepam [LZP] and fosphenytoin [FOS]). Statistical process control charts (XmR charts) were used to assess the variation in time to drug administration before and after implementation of the protocol.153 cases of CSE were identified (72 prior to and 81 after protocol implementation). Among patients who were actively having seizures on arrival to the ED (n = 44), the median time from arrival to ASM administration decreased from 15 to 11 minutes for the first LZP dose (p = 0.23), 23 to 10 minutes for the second LZP dose (p = 0.06), and 40 to 25 minutes for the PHE dose (p = 0.04). There was no improvement in time to LZP administration after seizure onset among those with seizure onset after hospital arrival (5 minutes before/after implementation for the first LZP dose and 15 to 14 minutes for second LZP dose); however, the time to FOS decreased from 42 to 22 minutes (p = 0.86). Statistical process control charts showed a universal decrease in variation for time to each drug administration after protocol implementation. Whereas FOS dosing was largely appropriate before and after protocol implementation, appropriate dosing of LZP did not improve, with only about half of patients receiving the recommended dose.The implementation of a paper-based treatment protocol for CSE was associated with a decreased time to ASM administration among patients who arrived to the ED, particularly for the second-line ASM. Approaches for improving appropriate benzodiazepine dosing are needed.

  View details for DOI 10.1016/j.seizure.2020.08.011

  View details for PubMedID 32916380

• Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies AMERICAN JOURNAL OF HUMAN GENETICS Khan, T. N., Khan, K., Sadeghpour, A., Reynolds, H., Perilla, Y., McDonald, M. T., Gallentine, W. B., Baig, S. M., Davis, E. E., Katsanis, N., Task Force Neonatal Genomics 2019; 104 (1): 94–111

  Abstract

  The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.

  View details for DOI 10.1016/j.ajhg.2018.11.017

  View details for Web of Science ID 000454775500011

  View details for PubMedID 30609410

• De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy GENETICS IN MEDICINE Berkovic, S. F., Dixon-Salazar, T., Goldstein, D. B., Heinzen, E. L., Laughlin, B. L., Lowenstein, D. H., Lubbers, L., Milder, J., Stewart, R., Whittemore, V., Angione, K., Bazil, C. W., Bier, L., Bluvstein, J., Brimble, E., Campbell, C., Chambers, C., Choi, H., Cilio, M., Ciliberto, M., Cornes, S., Delanty, N., Demarest, S., Devinsky, O., Dlugos, D., Dubbs, H., Dugan, P., Ernst, M. E., Gallentine, W., Gibbons, M., Goodkin, H., Grinton, B., Helbig, I., Jansen, L., Johnson, K., Joshi, C., Lippa, N. C., Makati, M. A., Marsh, E., Martinez, A., Millichap, J., Moskovich, Y., Mulhern, M. S., Numis, A., Park, K., Poduri, A., Porter, B., Sands, T. T., Scheffer, I. E., Sheidley, B., Singhal, N., Smith, L., Sullivan, J., Riviello, J. J., Taylor, A., Tolete, P., Epilepsy Genetics Initiative 2018; 20 (2): 275–81

  Abstract

  PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A-an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made.

  View details for DOI 10.1038/gim.2017.100

  View details for Web of Science ID 000425939300013

  View details for PubMedID 29121005

  View details for PubMedCentralID PMC5823708

• Development and validation of a seizure prediction model in critically ill children SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Yang, A., Arndt, D. H., Berg, R. A., Carpenter, J. L., Chapman, K. E., Dlugos, D. J., Gallentine, W. B., Giza, C. C., Goldstein, J. L., Hahn, C. D., Lerner, J. T., Loddenkemper, T., Matsumoto, J. H., Nash, K. B., Payne, E. T., Fernandez, I. S., Shults, J., Topjian, A. A., Williams, K., Wusthoff, C. J., Abend, N. S. 2015; 25: 104-111

  Abstract

  Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children.We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category.The model has fair to good discrimination ability and overall performance. At the optimal cut-off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources.Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures).

  View details for DOI 10.1016/j.seizure.2014.09.013

  View details for Web of Science ID 000349881100019

  View details for PubMedCentralID PMC4315714

• Development and validation of a seizure prediction model in critically ill children. Seizure Yang, A., Arndt, D. H., Berg, R. A., Carpenter, J. L., Chapman, K. E., Dlugos, D. J., Gallentine, W. B., Giza, C. C., Goldstein, J. L., Hahn, C. D., Lerner, J. T., Loddenkemper, T., Matsumoto, J. H., Nash, K. B., Payne, E. T., Sánchez Fernández, I., Shults, J., Topjian, A. A., Williams, K., Wusthoff, C. J., Abend, N. S. 2015; 25: 104-111

  Abstract

  Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children.We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category.The model has fair to good discrimination ability and overall performance. At the optimal cut-off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources.Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures).

  View details for DOI 10.1016/j.seizure.2014.09.013

  View details for PubMedID 25458097

  View details for PubMedCentralID PMC4315714

• Reorganization and stability for motor and language areas using cortical stimulation: case example and review of the literature. Brain sciences Serafini, S., Komisarow, J. M., Gallentine, W., Mikati, M. A., Bonner, M. J., Kranz, P. G., Haglund, M. M., Grant, G. 2013; 3 (4): 1597-1614

  Abstract

  The cerebral organization of language in epilepsy patients has been studied with invasive procedures such as Wada testing and electrical cortical stimulation mapping and more recently with noninvasive neuroimaging techniques, such as functional MRI. In the setting of a chronic seizure disorder, clinical variables have been shown to contribute to cerebral language reorganization underscoring the need for language lateralization and localization procedures. We present a 14-year-old pediatric patient with a refractory epilepsy disorder who underwent two neurosurgical resections of a left frontal epileptic focus separated by a year. He was mapped extraoperatively through a subdural grid using cortical stimulation to preserve motor and language functions. The clinical history and extensive workup prior to surgery is discussed as well as the opportunity to compare the cortical maps for language, motor, and sensory function before each resection. Reorganization in cortical tongue sensory areas was seen concomitant with a new zone of ictal and interictal activity in the previous tongue sensory area. Detailed neuropsychological data is presented before and after any surgical intervention to hypothesize about the extent of reorganization between epochs. We conclude that intrahemispheric cortical plasticity does occur following frontal lobe resective surgery in a teenager with medically refractory seizures.

  View details for DOI 10.3390/brainsci3041597

  View details for PubMedID 24961623

  View details for PubMedCentralID PMC4061887