Publications by authors named "Phillip L Pearl"

151 Publications

Presurgical accuracy of dipole clustering in MRI-negative pediatric patients with epilepsy: Validation against intracranial EEG and resection.

Clin Neurophysiol 2021 Mar 26. Epub 2021 Mar 26.

Laboratory of Children's Brain Dynamics, Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Jane and John Justin Neurosciences Center, Cook Children's Health Care System, Fort Worth, TX, USA; School of Medicine, Texas Christian University and University of North Texas Health Science Center, Fort Worth, TX, USA; Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA. Electronic address:

Objective: To assess the utility of interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering in magnetic resonance imaging (MRI)-negative patients with drug resistant epilepsy (DRE).

Methods: We localized spikes in low-density (LD-EEG) and high-density (HD-EEG) electroencephalography as well as magnetoencephalography (MEG) recordings using dipoles from 11 pediatric patients. We computed each dipole's level of clustering and used it to discriminate between clustered and scattered dipoles. For each dipole, we computed the distance from seizure onset zone (SOZ) and irritative zone (IZ) defined by intracranial EEG. Finally, we assessed whether dipoles proximity to resection was predictive of outcome.

Results: LD-EEG had lower clusterness compared to HD-EEG and MEG (p < 0.05). For all modalities, clustered dipoles showed higher proximity to SOZ and IZ than scattered (p < 0.001). Resection percentage was higher in optimal vs. suboptimal outcome patients (p < 0.001); their proximity to resection was correlated to outcome (p < 0.001). No difference in resection percentage was seen for scattered dipoles between groups.

Conclusion: MSI and ESI dipole clustering helps to localize the SOZ and IZ and facilitate the prognostic assessment of MRI-negative patients with DRE.

Significance: Assessing the MSI and ESI clustering allows recognizing epileptogenic areas whose removal is associated with optimal outcome.
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http://dx.doi.org/10.1016/j.clinph.2021.01.036DOI Listing
March 2021

Speech Motor Function and Auditory Perception in Succinic Semialdehyde Dehydrogenase Deficiency: Toward Pre-Supplementary Motor Area (SMA) and SMA-Proper Dysfunctions.

J Child Neurol 2021 Mar 23:8830738211001210. Epub 2021 Mar 23.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This study reviews the fundamental roles of pre-supplementary motor area (SMA) and SMA-proper responsible for speech-motor functions and auditory perception in succinic semialdehyde dehydrogenase (SSADH) deficiency. We comprehensively searched the databases of PubMed, Google Scholar, and the electronic journals Springer, PreQuest, and Science Direct associated with keywords , , , , and with AND operator. Transcranial magnetic stimulation emerged for assessing excitability/inhibitory M1 functions, but its role in pre-SMA and SMA proper dysfunction remains unknown. There was a lack of data on resting-state and task-based functional magnetic resonance imaging (MRI), with a focus on passive and active tasks for both speech and music, in terms of analysis of SMA-related cortex and its connections. Children with SSADH deficiency likely experience a dysfunction in connectivity between SMA portions with cortical and subcortical areas contributing to disabilities in speech-motor functions and auditory perception. Early diagnosis of auditory-motor disabilities in children with SSADH deficiency by neuroimaging techniques invites opportunities for utilizing sensory-motor integration as future interventional strategies.
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http://dx.doi.org/10.1177/08830738211001210DOI Listing
March 2021

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

Epilepsia 2021 Mar 13. Epub 2021 Mar 13.

Department of Neurosurgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, USA.

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
March 2021

Noninvasive Mapping of Ripple Onset Predicts Outcome in Epilepsy Surgery.

Ann Neurol 2021 May 24;89(5):911-925. Epub 2021 Mar 24.

Laboratory of Children's Brain Dynamics, Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: Intracranial electroencephalographic (icEEG) studies show that interictal ripples propagate across the brain of children with medically refractory epilepsy (MRE), and the onset of this propagation (ripple onset zone [ROZ]) estimates the epileptogenic zone. It is still unknown whether we can map this propagation noninvasively. The goal of this study is to map ripples (ripple zone [RZ]) and their propagation onset (ROZ) using high-density EEG (HD-EEG) and magnetoencephalography (MEG), and to estimate their prognostic value in pediatric epilepsy surgery.

Methods: We retrospectively analyzed simultaneous HD-EEG and MEG data from 28 children with MRE who underwent icEEG and epilepsy surgery. Using electric and magnetic source imaging, we estimated virtual sensors (VSs) at brain locations that matched the icEEG implantation. We detected ripples on VSs, defined the virtual RZ and virtual ROZ, and estimated their distance from icEEG. We assessed the predictive value of resecting virtual RZ and virtual ROZ for postsurgical outcome. Interictal spike localization on HD-EEG and MEG was also performed and compared with ripples.

Results: We mapped ripple propagation in all patients with HD-EEG and in 27 (96%) patients with MEG. The distance from icEEG did not differ between HD-EEG and MEG when mapping the RZ (26-27mm, p = 0.6) or ROZ (22-24mm, p = 0.4). Resecting the virtual ROZ, but not virtual RZ or the sources of spikes, was associated with good outcome for HD-EEG (p = 0.016) and MEG (p = 0.047).

Interpretation: HD-EEG and MEG can map interictal ripples and their propagation onset (virtual ROZ). Noninvasively mapping the ripple onset may augment epilepsy surgery planning and improve surgical outcome of children with MRE. ANN NEUROL 2021;89:911-925.
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http://dx.doi.org/10.1002/ana.26066DOI Listing
May 2021

Enzyme Replacement Therapy for Succinic Semialdehyde Dehydrogenase Deficiency: Relevance in γ-Aminobutyric Acid Plasticity.

J Child Neurol 2021 Feb 24:883073821993000. Epub 2021 Feb 24.

FM Kirby Neurobiology Center, 1862Boston Children's Hospital, Boston, MA, USA.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the gene), an enzyme essential for metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in broad spectrum encephalopathy including developmental delay, ataxia, seizures, and a heightened risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable intervention for SSADHD. However, before testing enzyme replacement therapy or gene therapy in patients, we must consider its safety and feasibility in the context of early brain development and unique SSADHD pathophysiology. Specifically, a profound use-dependent downregulation of GABA receptors in SSADHD indicates a risk that any sudden SSADH restoration might diminish GABAergic tone and provoke seizures. In addition, the tight developmental regulation of GABA circuit plasticity might limit the age window when SSADH restoration is accomplished safely. Moreover, given SSADH expressions are cell type-specific, targeted instead of global restoration might be necessary. We therefore describe 3 key parameters for the clinical readiness of SSADH restoration: (1) rate, (2) timing, and (3) cell type specificity. Our work focuses on the construction of a novel SSADHD mouse model that allows "on-demand" SSADH restoration for the systematic investigation of these key parameters. We aim to understand the impacts of specific SSADH restoration protocols on brain physiology, accelerating bench-to-bedside development of enzyme replacement therapy or gene therapy for SSADHD patients.
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http://dx.doi.org/10.1177/0883073821993000DOI Listing
February 2021

Magnetic Resonance Imaging (MRI) and Spectroscopy in Succinic Semialdehyde Dehydrogenase Deficiency.

J Child Neurol 2021 Feb 9:883073821991295. Epub 2021 Feb 9.

Contributing authors and affiliations are listed at the end of the article.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.
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http://dx.doi.org/10.1177/0883073821991295DOI Listing
February 2021

Child neurology, COVID-19, and crisis in society.

Authors:
Phillip L Pearl

Dev Med Child Neurol 2020 10;62(10):1113

Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/dmcn.14624DOI Listing
October 2020

Hippocampal Involvement With Vigabatrin-Related MRI Signal Abnormalities in Patients With Infantile Spasms: A Novel Finding.

J Child Neurol 2021 Jan 12:883073820985395. Epub 2021 Jan 12.

Neuroradiology Division, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: In a subset of infants exhibiting typical vigabatrin-related magnetic resonance imaging (MRI) changes, the authors observed additional hippocampal signal abnormalities. The authors investigated occurrence and significance of additional signal abnormalities.

Methods: A retrospective review of infantile spasms patients with typical vigabatrin-related MRI abnormalities was performed. Atypical features included signal changes unilaterally or at previously unreported sites. Comparisons were made between patients with and without atypical features.

Results: In all, 26/55 (47%) exhibited typical vigabatrin-related MRI changes, with additional signal abnormalities in the hippocampi in 6 of 26. On follow-up, evolution of hippocampal signal changes paralleled changes at typical locations in 4 patients. Two patients, clinically well, without follow-up MRI. Patients with and without additional hippocampal signal changes did not differ with respect to clinical factors, including seizure status. One patient had unilateral thalamic/cerebral peduncle signal abnormality along with typical vigabatrin changes.

Conclusions: Hippocampal changes seen in subset of patients with typical vigabatrin-related changes may be attributable to vigabatrin exposure in the appropriate circumstance.
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http://dx.doi.org/10.1177/0883073820985395DOI Listing
January 2021

Succinic Semialdehyde Dehydrogenase Deficiency: Review of the Natural History Study.

J Child Neurol 2021 Jan 4:883073820981262. Epub 2021 Jan 4.

Department of Pharmacotherapy, Washington State University, Spokane, WA, USA.

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity.

Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort.

Results: At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months-40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls.

Conclusions: The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.
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http://dx.doi.org/10.1177/0883073820981262DOI Listing
January 2021

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

J Inherit Metab Dis 2021 Jan 1;44(1):178-192. Epub 2020 Dec 1.

Department of Pediatrics Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
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http://dx.doi.org/10.1002/jimd.12332DOI Listing
January 2021

Pediatric and adult neurologist perspectives on the challenges of sustaining a transfer clinic.

Neurol Clin Pract 2020 Aug;10(4):356-361

Department of Neurology (TAF), The Ottawa Hospital, Ontario, Canada; Department of Neurology (CSJ), Massachusetts General Hospital; Department of Neurology (CDG, AMB, PLP), Boston Children's Hospital; and Department of Neurology (CDG, TAM, BAD), Brigham and Women's Hospital, Boston, MA.

We present a novel epilepsy fellow-driven transfer clinic model and discuss the challenges experienced in finding sustainability; this is timely as many pioneering transition clinics are dissolving across North America. The goal of this clinic was to improve patient care and satisfaction, as measured by a post-visit telephone survey. Unfortunately, our transfer clinic model proved unsustainable due to several factors, broadly categorized as (1) cultural-societal differences between the pediatric and adult health care environments, (2) staffing issues, (3) lack of an established standardized process for transfer of care, and (4) financial and administrative barriers. We suggest potential solutions to these challenges, but the fate of transition and transfer of care clinics may ultimately depend on implementation of practice, policy, and/or financial guidelines.
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http://dx.doi.org/10.1212/CPJ.0000000000000727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508345PMC
August 2020

Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency.

Orphanet J Rare Dis 2020 09 23;15(1):261. Epub 2020 Sep 23.

Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences Building Room 210C, Washington State University, 412 E. Spokane Falls Boulevard, Spokane, WA, 99202-2131, USA.

Background: Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Samples (mixed sex) included: patients (n = 21 unique samples, 1-39.5 yrs) and parallel controls (n = 9 unique samples, 8.4-34.8 yrs). Archival control data (DBS only; n = 171, 0.5-39.9 yrs) was also included.

Results: Metabolites assessed included amino acids (plasma, DBS) and acylcarnitines, creatine, creatinine, and guanidinoacetate (DBS only). Age-related negative correlations for glycine (plasma, DBS) and sarcosine (N-methylglycine, plasma) were detected, accompanied by elevated proline and decreased levels of succinylacetone, argininosuccinate, formaminoglutamate, and creatinine. Significantly low acylcarnitines were detected in patients across all chain lengths (short-, medium- and long-chain). Significant age-dependent positive correlations for selected acylcarnitines (C6-, C12DC(dicarboxylic)-, C16-, C16:1-, C18:1-, C18:2OH-carnitines) were detected in patients and absent in controls. Receiver operating characteristic (ROC) curves for all binary comparisons revealed argininosuccinate and succinylacetone to be the most discriminating biomarkers (area > 0.92).

Conclusions: Age-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA. Our study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism.
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http://dx.doi.org/10.1186/s13023-020-01522-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510106PMC
September 2020

Novel variants and genotype: Phenotype correlation in SSADH deficiency.

Neurology 2020 11 4;95(19):e2675-e2682. Epub 2020 Sep 4.

From the Department of Neurology (M.L.D., P.L.P.) and Neurodevelopmental Core (E.H.), Boston Children's Hospital, Harvard Medical School, MA; Metabolic Unit, Department of Clinical Chemistry, Vrije Universiteit Amsterdam (A.P., G.S.S.), and Department of Genetic Metabolic Diseases, Emma Children's Hospital, University of Amsterdam (G.S.S.), Amsterdam Neuroscience and Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, the Netherlands; and College of Pharmacy, Department of Pharmacotherapy (J.-B.R., K.M.G.), Washington State University, Spokane.

Objective: To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency.

Methods: variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.

Results: Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence ( = 0.003) and severity ( = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) ( = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype.

Conclusions: Seven novel pathogenic and one previously unpublished benign variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.
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http://dx.doi.org/10.1212/WNL.0000000000010730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713737PMC
November 2020

A Missense Variant in Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Genes (Basel) 2020 09 2;11(9). Epub 2020 Sep 2.

Department of Population Health and Reproduction, University of California Davis, Davis, CA 95616, USA.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 () gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. -related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.
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http://dx.doi.org/10.3390/genes11091033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565783PMC
September 2020

Reply to Russo and Trabacca.

Pediatr Neurol 2020 11 22;112. Epub 2020 Jul 22.

President, CNS, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374118PMC
November 2020

How the jazz medium can inform interprofessional health care teams in improving patient care.

Med Teach 2020 12 17;42(12):1337-1342. Epub 2020 Aug 17.

Department of Pediatrics, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Introduction: Interprofessional Health Care Teams (IPHCTs) are essential to provide cost-effective and efficient care to patients with complex illnesses, requiring the skills and expertise of many health care professionals. The jazz medium presents an instructive non-medical analogy.

Methods: We present evidence-based models to compare how effective groups perform in both health care teams and jazz ensembles.

Results: The jazz ensemble has implicit dependence on the salient features of leadership, individual attributes, creativity, synchronization, comprehension, communication, self-improvement, group dynamics, and economy of means.

Conclusions: Features of jazz parallel those of the IPHCT and inform medicine how teams can thrive at the highest levels, using characteristics attributed to effective team functioning. Incorporating jazz educators and their approaches to music into IPHCT training may be a strategy to improve patient outcomes.
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http://dx.doi.org/10.1080/0142159X.2020.1805102DOI Listing
December 2020

A Standardized Electrode Nomenclature for Stereoelectroencephalography Applications.

J Clin Neurophysiol 2020 Jul 23. Epub 2020 Jul 23.

Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, U.S.A.

Purpose: Stereoelectroencephalography (SEEG) is widely performed on individuals with medically refractory epilepsy for whom invasive seizure localization is desired. Despite increasing adoption in many centers across the world, no standardized electrode naming convention exists, generating confusion among both clinical and research teams.

Methods: We have developed a novel nomenclature, named the Standardized Electrode Nomenclature for SEEG Applications system. Concise, unique, informative, and unambiguous labels provide information about entry point, deep targets, and relationships between electrodes. Inter-rater agreement was evaluated by comparing original electrode names from 10 randomly sampled cases (including 136 electrodes) with those prospectively assigned by four additional blinded raters.

Results: The Standardized Electrode Nomenclature for SEEG Application system was prospectively implemented in 40 consecutive patients undergoing SEEG monitoring at our institution, creating unique electrode names in all cases, and facilitating implantation design, SEEG recording and mapping interpretation, and treatment planning among neurosurgeons, neurologists, and neurophysiologists. The inter-rater percent agreement for electrode names among two neurosurgeons, two epilepsy neurologists, and one neurosurgical fellow was 97.5%.

Conclusions: This standardized naming convention, Standardized Electrode Nomenclature for SEEG Application, provides a simple, concise, reproducible, and informative method for specifying the target(s) and relative position of each SEEG electrode in each patient, allowing for successful sharing of information in both the clinical and research settings. General adoption of this nomenclature could pave the way for improved communication and collaboration between institutions.
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http://dx.doi.org/10.1097/WNP.0000000000000724DOI Listing
July 2020

Corpus Callosotomy for Refractory Epilepsy in Aicardi Syndrome: Case Report and Focused Review of the Literature.

World Neurosurg 2020 10 9;142:450-455. Epub 2020 Jul 9.

Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Aicardi syndrome is a severe neurodevelopmental disorder that occurs primarily in females and is characterized by seizures, agenesis of the corpus callosum, and chorioretinal lacunae, which occur together in the majority of affected individuals. Seizures begin in infancy and tend to progress in intensity and are often refractory to standard multimodal medication treatments.

Case Description: We present here a unique case of a 12-year-old girl with partial agenesis of the corpus callosum who underwent a corpus callosotomy for treatment of medically refractory epilepsy. In so doing, we also review the literature with regard to the neurosurgical management of these unique patients.

Conclusions: For the subset of children who present with partial, rather than complete, agenesis of the corpus callosum, corpus callosotomy should be considered as a treatment option to reduce seizure burden.
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http://dx.doi.org/10.1016/j.wneu.2020.06.230DOI Listing
October 2020

EEG features of brain injury during extracorporeal membrane oxygenation in children.

Neurology 2020 09 6;95(10):e1372-e1380. Epub 2020 Jul 6.

From the Division of Epilepsy and Neurophysiology (A.J.S., M.L.D., T.L. , P.L.P., M.H.L.), Department of Anesthesiology, Critical Care and Pain Medicine (A.A.-A., R.C.T.), Department of Neurology (K.L., T.L., M.J.R., P.L.P., M.H.L., R.C.T.), Department of Psychiatry and Radiology (M.J.R.), and Department of Cardiology, Division of Cardiovascular Critical Care (R.R.T.), Boston Children's Hospital, MA.

Objective: To examine EEG features of major pathophysiology in children undergoing extracorporeal membrane oxygenation (ECMO).

Methods: This was a single-center, retrospective study of 201 pediatric patients on ECMO, using the first 24 hours of continuous EEG (cEEG) monitoring, collating background activity and electrographic seizures (ES) with imaging, ECMO type, and outcome.

Results: Severely abnormal cEEG background occurred in 12% (25/201), and was associated with death (sensitivity 0.23, specificity 0.97). ES occurred in 16% (33/201) within 3.2 (0.6-20.3) hours (median [interquartile range]) of cEEG commencement, and higher ES burden was associated with death. ES was always associated with ipsilateral injury ( = 0.006), but occurred in only one-third of cases with abnormal imaging. In 28 patients with isolated hemisphere lesion, type of arterial ECMO cannulation was associated with side of injury: right carotid cannulation was associated with right hemisphere lesions, and ascending aorta cannulation with left hemisphere lesions (odds ratio, 0.29 [95% confidence interval, 0.08-0.98], = 0.03).

Conclusions: After starting ECMO, cEEG background activity has the potential to inform prognosis. Type of arterial (carotid vs aortic) ECMO correlates with side of focal cerebral injury, which in ≈33% is associated with presence of ES. We hypothesize that the differential distribution reflects abnormal flow dynamics or embolic injury.
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http://dx.doi.org/10.1212/WNL.0000000000010188DOI Listing
September 2020

Management of Infantile Spasms During the COVID-19 Pandemic.

J Child Neurol 2020 10 23;35(12):828-834. Epub 2020 Jun 23.

Department of Neurology, 1862Boston Children's Hospital, Boston, MA, USA.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.
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http://dx.doi.org/10.1177/0883073820933739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315378PMC
October 2020

Epileptic Activity Intrinsically Generated in the Human Cerebellum.

Ann Neurol 2020 08 5;88(2):418-422. Epub 2020 Jun 5.

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

Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020;88:418-422.
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http://dx.doi.org/10.1002/ana.25779DOI Listing
August 2020

Practical Bioethics during the Exceptional Circumstances of a Pandemic.

Pediatr Neurol 2020 07 22;108:3-4. Epub 2020 Apr 22.

President, CNS, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175873PMC
July 2020

Scalp ripples as prognostic biomarkers of epileptogenicity in pediatric surgery.

Ann Clin Transl Neurol 2020 03 25;7(3):329-342. Epub 2020 Feb 25.

Laboratory of Children's Brain Dynamics, Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Objective: To assess the ability of high-density Electroencephalography (HD-EEG) and magnetoencephalography (MEG) to localize interictal ripples, distinguish between ripples co-occurring with spikes (ripples-on-spike) and independent from spikes (ripples-alone), and evaluate their localizing value as biomarkers of epileptogenicity in children with medically refractory epilepsy.

Methods: We retrospectively studied 20 children who underwent epilepsy surgery. We identified ripples on HD-EEG and MEG data, localized their generators, and compared them with intracranial EEG (icEEG) ripples. When ripples and spikes co-occurred, we performed source imaging distinctly on the data above 80 Hz (to localize ripples) and below 70 Hz (to localize spikes). We assessed whether missed resection of ripple sources predicted poor outcome, separately for ripples-on-spikes and ripples-alone. Similarly, predictive value of spikes was calculated.

Results: We observed scalp ripples in 16 patients (10 good outcome). Ripple sources were highly concordant to the icEEG ripples (HD-EEG concordance: 79%; MEG: 83%). When ripples and spikes co-occurred, their sources were spatially distinct in 83-84% of the cases. Removing the sources of ripples-on-spikes predicted good outcome with 90% accuracy for HD-EEG (P = 0.008) and 86% for MEG (P = 0.044). Conversely, removing ripples-alone did not predict outcome. Resection of spike sources (generated at the same time as ripples) predicted good outcome for HD-EEG (P = 0.036; accuracy = 87%), while did not reach significance for MEG (P = 0.1; accuracy = 80%).

Interpretation: HD-EEG and MEG localize interictal ripples with high precision in children with refractory epilepsy. Scalp ripples-on-spikes are prognostic, noninvasive biomarkers of epileptogenicity, since removing their cortical generators predicts good outcome. Conversely, scalp ripples-alone are most likely generated by non-epileptogenic areas.
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http://dx.doi.org/10.1002/acn3.50994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086004PMC
March 2020

Ictal and interictal source imaging on intracranial EEG predicts epilepsy surgery outcome in children with focal cortical dysplasia.

Clin Neurophysiol 2020 03 20;131(3):734-743. Epub 2020 Jan 20.

Laboratory of Children's Brain Dynamics, Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Fetal-Neonatal Neuroimaging Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Jane and John Justin Neurosciences Center, Cook Children's Health Care System, Fort Worth, TX, USA; Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA. Electronic address:

Objective: To localize the seizure onset zone (SOZ) and irritative zone (IZ) using electric source imaging (ESI) on intracranial EEG (iEEG) and assess their clinical value in predicting epilepsy surgery outcome in children with focal cortical dysplasia (FCD).

Methods: We analyzed iEEG data from 25 children with FCD-associated medically refractory epilepsy (MRE) who underwent surgery. We performed ESI on ictal onset to localize SOZ (ESI-SOZ) and on interictal discharges to localize IZ (ESI-IZ). We tested whether resection of ESI-SOZ and ESI-IZ predicted good surgical outcome (Engel 1). We further compared the prediction performance of ESI-SOZ and ESI-IZ to those of SOZ and IZ defined using conventional methods, i.e. by identifying iEEG-contacts showing ictal onsets (conventional-SOZ) or being the most interictally active (conventional-IZ).

Results: The proximity of ESI-SOZ (p = 0.043, odds-ratio = 3.9) and ESI-IZ (p = 0.011, odds-ratio = 7.04) to resection has higher effect on patients' outcome than proximity of conventional-SOZ (p = 0.17, odds-ratio = 1.7) and conventional-IZ (p = 0.038, odds-ratio = 2.6). Resection of ESI-SOZ and ESI-IZ presented higher discriminative power in predicting outcome (68% and 60%) than conventional-SOZ and conventional-IZ (48% and 53%).

Conclusions: Localizing SOZ and IZ via ESI on iEEG offers higher predictive value compared to conventional-iEEG interpretation.

Significance: iEEG-ESI may help surgical planning and facilitate prognostic assessment of children with FCD-associated MRE.
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http://dx.doi.org/10.1016/j.clinph.2019.12.408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093832PMC
March 2020

Noninvasive Localization of High-Frequency Oscillations in Children with Epilepsy: Validation against Intracranial Gold-Standard.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:1555-1558

Introduction: Patients with medically refractory epilepsy (MRE) need surgical resection of the epileptogenic zone (EZ) to gain seizure-freedom. High-frequency oscillations (HFOs, > 80 Hz) are promising biomarkers of the EZ that are typically localized using intracranial electroencephalography (icEEG). The goal of this study was to localize the cortical generators of HFOs non-invasively using high-density (HD) EEG and magnetoencephalography (MEG) and validate the localization against the gold-standard given by the icEEGdefined HFO-zone.

Methods: We analyzed simultaneous HDEEG and MEG data from six children with MRE who underwent icEEG and surgery. We detected interictal HFOs (80-160 Hz) on HD-EEG and MEG separately, using an inhouse automatic detector followed by visual human review, and distinguished between HFOs with and without spikes. We localized the cortical generators of each HFO on HD-EEG or MEG using the wavelet Maximum Entropy on the Mean (wMEM). For the HFOs localized in the brain area covered by icEEG, we estimated the localization error (E) with respect to the gold-standard, and classified them as either concordant (E≤15mm) or not.

Results: We found that: (i) HD-EEG presented a higher rate of HFOs than MEG (1 vs 0.5 HFOs/min, p=0.031); (ii) HFOs without spikes were more likely to be localized outside the brain regions of interest (i.e. covered by icEEG) than HFOs with spikes; and (iii) both HD-EEG and MEG showed high precision to the gold-standard (92% and 96%).

Conclusion: We reported quantitative evidence that HDEEG and MEG can localize the HFO cortical generators with high precision to the icEEG gold-standard in children with MRE, suggesting that they may possibly limit the need for icEEG prior to surgery. We also showed that HFOs with spikes on HD-EEG/MEG are more likely to be epileptogenic than those independent from spikes, which may represent physiological events from normal brain.
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http://dx.doi.org/10.1109/EMBC.2019.8857793DOI Listing
July 2019

Assessing the localization accuracy and clinical utility of electric and magnetic source imaging in children with epilepsy.

Clin Neurophysiol 2019 04 31;130(4):491-504. Epub 2019 Jan 31.

Laboratory of Children's Brain Dynamics, Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Fetal-Neonatal Neuroimaging Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Objective: To evaluate the accuracy and clinical utility of conventional 21-channel EEG (conv-EEG), 72-channel high-density EEG (HD-EEG) and 306-channel MEG in localizing interictal epileptiform discharges (IEDs).

Methods: Twenty-four children who underwent epilepsy surgery were studied. IEDs on conv-EEG, HD-EEG, MEG and intracranial EEG (iEEG) were localized using equivalent current dipoles and dynamical statistical parametric mapping (dSPM). We compared the localization error (E) with respect to the ground-truth Irritative Zone (IZ), defined by iEEG sources, between non-invasive modalities and the distance from resection (D) between good- (Engel 1) and poor-outcomes. For each patient, we estimated the resection percentage of IED sources and tested whether it predicted outcome.

Results: MEG presented lower E than HD-EEG and conv-EEG. For all modalities, D was shorter in good-outcome than poor-outcome patients, but only the resection percentage of the ground-truth IZ and MEG-IZ predicted surgical outcome.

Conclusions: MEG localizes the IZ more accurately than conv-EEG and HD-EEG. MSI may help the presurgical evaluation in terms of patient's outcome prediction. The promising clinical value of ESI for both conv-EEG and HD-EEG prompts the use of higher-density EEG-systems to possibly achieve MEG performance.

Significance: Localizing the IZ non-invasively with MSI/ESI facilitates presurgical evaluation and surgical prognosis assessment.
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http://dx.doi.org/10.1016/j.clinph.2019.01.009DOI Listing
April 2019

Age-related phenotype and biomarker changes in SSADH deficiency.

Ann Clin Transl Neurol 2019 01 3;6(1):114-120. Epub 2018 Dec 3.

Department of Neurology Boston Children's Hospital Harvard Medical School Boston Massachusetts.

Objective: Succinic Semialdehyde Dehydrogenase (SSADH) deficiency is a disorder of elevated gamma-amino butyric acid (GABA) and gamma hydroxybutyric acid (GHB) and a complex neuropsychiatric profile. Adult reports suggest worsening epilepsy and high SUDEP risk.

Methods: Subjects with confirmed SSADH deficiency were recruited into a longitudinal study. Plasma thyroid hormone and total GABA/GHB were quantified by standard clinical chemistry methodologies and mass spectrometry, respectively.

Results: A total of 133 subjects with SSADH deficiency are enrolled in the registry; 49 participated in the longitudinal study. The age range of the population is 8 weeks to 63 years (median 7.75 year; 44% male). There is a significant difference in proportions among the age groups in subjects affected with hypotonia, compulsive behavior, sleep disturbances, and seizures. Epilepsy is present in 50% of the total population, and more prevalent in subjects 12 years and older ( = 0.001). The median age of onset for absence seizures was 2 years, and 12 years for generalized tonic-clonic seizures ( < 0.01). The SUDEP rate in adults was 12% (4/33). There was a significant age-dependent negative correlation between GABA and T levels.

Interpretation: There is an age-dependent association with worsening of epilepsy, behavioral disturbances including obsessive-compulsive behavior, and sleep disturbances with age in SSADH deficiency. There is a high risk of SUDEP. We have observed more absence seizures in younger patients, compared to tonic-clonic in the older cohort, which correlates with age-related changes in GABA and GHB concentration and thyroid function, as well as the natural history of seizures in the murine model.
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http://dx.doi.org/10.1002/acn3.696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331944PMC
January 2019

GABA Transaminase Deficiency With Survival Into Adulthood.

J Child Neurol 2019 03 15;34(4):216-220. Epub 2019 Jan 15.

3 Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

γ-Aminobutyric acid (GABA)-transaminase deficiency is an ultra-rare disorder of GABA metabolism that was described for decades as an early-onset epileptic encephalopathy plus movement disorder and hypersomnolence with mortality in early childhood. We report 2 affected siblings in adolescence and adulthood, both with profound developmental impairment, intractable epilepsy, movement disorder, and behavioral fluctuations. This considerably expands the phenotype and longevity of this inherited neurotransmitter disease.
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http://dx.doi.org/10.1177/0883073818823359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292229PMC
March 2019