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1.
Am J Med Genet A ; : e63843, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39205479

RESUMO

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.

2.
Epilepsia ; 65(8): 2308-2321, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38802989

RESUMO

OBJECTIVES: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders. METHODS: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified-Delphi process. Twenty-eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified-Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%-79% fully or partially agree, <10% disagree. RESULTS: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non-seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep-related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. SIGNIFICANCE: Significant comorbidities are present in most phenotypes of SCN8A-related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long-term management for patients with these comorbidities and provide the basis for future evidence-based studies on optimal treatments of SCN8A-related disorders. Identifying the prognosis of patients with SCN8A-related disorders will also improve care and quality-of-life for patients and their caregivers.


Assuntos
Comorbidade , Consenso , Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.6 , Transtornos do Neurodesenvolvimento , Humanos , Técnica Delphi , Epilepsia/epidemiologia , Epilepsia/genética , Epilepsia/diagnóstico , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Prognóstico
3.
Epilepsia ; 65(8): 2322-2338, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38802994

RESUMO

OBJECTIVE: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. METHODS: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. RESULTS: Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. SIGNIFICANCE: This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.


Assuntos
Consenso , Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.6 , Transtornos do Neurodesenvolvimento , Humanos , Anticonvulsivantes/uso terapêutico , Técnica Delphi , Epilepsia/diagnóstico , Epilepsia/terapia , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/terapia , Fenótipo
4.
Neuropediatrics ; 55(1): 1-8, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37984419

RESUMO

There is insufficient evidence regarding the efficacy of epilepsy surgery in patients with pharmacoresistant focal epilepsy and coexistent DEPDC5 (dishevelled EGL-10 and pleckstrin domain-containing protein 5) pathogenic (P), likely pathogenic (LP), or variance of unknown significance (VUS) variants. To conduct a systematic review on the literature regarding the use and efficacy of epilepsy surgery as an intervention for patients with DEPDC5 variants who have pharmacoresistant epilepsy. A systematic review of the current literature published regarding the outcomes of epilepsy surgery for patients with DEPDC5 variants was conducted. Demographics and individual patient data were recorded and analyzed. Subsequent statistical analysis was performed to assess significance of the findings. A total of eight articles comprising 44 DEPDC5 patients with genetic variants undergoing surgery were included in this study. The articles primarily originated in high-income countries (5/8, 62.5%). The average age of the subjects was 10.06 ± 9.41 years old at the time of study. The most common form of epilepsy surgery was focal resection (38/44, 86.4%). Thirty-seven of the 40 patients (37/40, 92.5%) with reported seizure frequency results had improvement. Twenty-nine out of 38 patients (29/38, 78.4%) undergoing focal resection achieved Engel Score I postoperatively, and two out of four patients achieved International League Against Epilepsy I (50%). Epilepsy surgery is effective in patients with pharmacoresistant focal epilepsy and coexistent DEPDC5 P, LP, or VUS variants.


Assuntos
Epilepsias Parciais , Epilepsia , Malformações do Desenvolvimento Cortical , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Convulsões/genética , Convulsões/cirurgia , Epilepsias Parciais/genética , Epilepsias Parciais/cirurgia , Proteínas Ativadoras de GTPase/genética
5.
Epilepsia ; 61(10): 2234-2243, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33053223

RESUMO

OBJECTIVE: To test whether children with epilepsy have impairments in myocardial mechanics compared to controls without epilepsy. METHODS: Children with refractory epilepsy with epilepsy duration of at least 3 years underwent echocardiography including conventional measurements and speckle tracking to assess longitudinal and circumferential strain. Parent-completed surveys, capturing critical aspects of the children's seizure history and cardiac risk factors, complemented retrospective chart reviews, which also included antiepileptic drug history. Normal echocardiograms from controls, matched for age and gender, were obtained from our institutional database and evaluated for strain. RESULTS: Forty-one patients (median age = 10 years, interquartile range [IQR] = 5-15; 58.5% male) were enrolled. Epilepsy etiology included genetic (n = 26), structural (n = 6), genetic and structural (n = 5), infection (n = 3), and unknown (n = 1). No cardiac structural abnormalities were identified. Both longitudinal and circumferential strain were impaired (P < .03) in patients compared to controls (median [IQR] = 22.7% [21.2-24.2] vs 23.6% [22.2-26.1] and 22.0% [20.3-25.4] vs 24.5% [22.3-27.0], respectively), indicating decreased myocardial deformation/contraction. Shortening fraction was higher in patients (37.6% [35.7-39.7] vs 34.9% [32.5-38.7], P = .009); mitral valve E wave inflow velocity (84.8 cm/s [78.4-92.8] vs 97.2 cm/s [85.9-105.8], P = .005) and tissue Doppler lateral E' wave (13.9 cm/s [12.3-16.1] vs 17.3 cm/s [15.4-18.5], P < .001) were decreased compared to controls. Findings were similar in the pairs with epilepsy patients distinguished by the ability to independently ambulate. There was no difference between patients and controls in ejection fraction. Among the epilepsy patients, there were no associations between cardiac measurements and epilepsy characteristics, including seizure type and frequency and cardiotoxic antiseizure medication exposure after correction for multiple comparisons. SIGNIFICANCE: Children with refractory epilepsy had impaired systolic ventricular strain compared to controls, not correlated with epilepsy history. Further studies are needed to determine the significance of these changes.


Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Contração Miocárdica/fisiologia , Morte Súbita Inesperada na Epilepsia/prevenção & controle , Adolescente , Estudos de Casos e Controles , Criança , Epilepsia Resistente a Medicamentos/epidemiologia , Ecocardiografia Doppler/métodos , Feminino , Cardiopatias/epidemiologia , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Morte Súbita Inesperada na Epilepsia/epidemiologia
6.
Am J Respir Cell Mol Biol ; 59(5): 635-647, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29958015

RESUMO

Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous recombinant human TRIM72 protein (rhT72) demonstrated tissue-mending properties in animal models of tissue injury. Here we examine the mechanisms of rhT72-mediated lung cell protection in vitro and test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator-induced lung injury. In vitro lung cell injury was induced by glass beads and stretching. Ventilator-induced lung injury was modeled by injurious ventilation at 30 ml/kg tidal volume. Affinity-purified rhT72 or control proteins were added into culture medium or applied through nebulization. Cellular uptake and in vivo distribution of rhT72 were detected by imaging and immunostaining. Exogenous rhT72 maintains membrane integrity of alveolar epithelial cells subjected to glass bead injury in a dose-dependent manner. Inhaled rhT72 decreases the number of fatally injured alveolar cells, and ameliorates tissue-damaging indicators and cell injury markers after injurious ventilation. Using in vitro stretching assays, we reveal that rhT72 improves both cellular resilience to membrane wounding and membrane repair after injury. Image analysis detected rhT72 uptake by rat alveolar epithelial cells, which can be inhibited by a cholesterol-disrupting agent. In addition, inhaled rhT72 distributes to the distal lungs, where it colocalizes with phosphatidylserine detection on nonpermeabilized lung slices to label wounded cells. In conclusion, our study showed that inhaled rhT72 accumulates in injured lungs and protects lung tissue from ventilator injury, the mechanisms of which include improving cell resilience to membrane wounding, localizing to injured membrane, and augmenting membrane repair.


Assuntos
Proteínas de Transporte/administração & dosagem , Alvéolos Pulmonares/metabolismo , Proteínas Recombinantes/administração & dosagem , Respiração Artificial/efeitos adversos , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Cicatrização , Administração por Inalação , Animais , Membrana Celular/metabolismo , Células Cultivadas , Humanos , Proteínas de Membrana , Camundongos , Alvéolos Pulmonares/lesões , Alvéolos Pulmonares/patologia , Ratos , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
7.
Am J Respir Cell Mol Biol ; 58(6): 756-766, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29268030

RESUMO

The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. This study aimed to explore the role of tripartite motif protein (TRIM) 72 in regulating complement receptor (CR) of the Ig superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Imaging, absorbance quantification, and flow cytometry were used to evaluate in vitro and in vivo AM phagocytosis with normal, or altered, TRIM72 expression. Pulldown, coimmunoprecipitation, and gradient binding assays were applied to examine TRIM72 and CRIg interaction. A pneumonia model was established by intratracheal injection of Pseudomonas aeruginosa. Mortality, lung bacterial burden, and cytokine levels in BAL fluid and lung tissues were examined. Our data show that TRIM72 inhibited CR-mediated phagocytosis, and release of TRIM72 inhibition led to increased AM phagocytosis. Biochemical assays identified CRIg as a binding partner of TRIM72, and TRIM72 inhibited formation of the CRIg-phagosome. Genetic ablation of TRIM72 led to improved pathogen clearance, reduced cytokine storm, and improved survival in murine models of severe pneumonia, specificity of which was confirmed by adoptive transfer of wild-type or TRIM72KO AMs to AM-depleted TRIM72KO mice. TRIM72 overexpression promoted bacteria-induced NF-κB activation in murine alveolar macrophage cells. Our data revealed a quiescent, noninflammatory bacterial clearance mechanism in the lung via AM CRIg, which is suppressed by TRIM72. In vivo data suggest that targeted suppression of TRIM72 in AM may be an effective measure to treat fatal pulmonary bacterial infections.


Assuntos
Proteínas de Transporte/metabolismo , Imunidade Inata/fisiologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Receptores de Complemento 3b/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Membrana , Camundongos Knockout , NF-kappa B/metabolismo , Fagocitose/fisiologia , Fagossomos/metabolismo , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/patologia , Proteínas com Motivo Tripartido
8.
Am J Hum Genet ; 96(4): 675-81, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817015

RESUMO

Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.


Assuntos
Anormalidades Múltiplas/genética , Alanina-tRNA Ligase/genética , Epilepsia/genética , Modelos Moleculares , Bainha de Mielina/patologia , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Anormalidades Múltiplas/patologia , Alanina-tRNA Ligase/química , Sequência de Aminoácidos , Sequência de Bases , Epilepsia/patologia , Genes Recessivos/genética , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Mutação/genética , Doenças do Sistema Nervoso Periférico/patologia , Estudos Prospectivos , Análise de Sequência de DNA , Síndrome , Estados Unidos
9.
Genet Med ; 19(2): 160-168, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27388694

RESUMO

PURPOSE: The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the ß-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). METHODS: Prospective natural history protocol. RESULTS: In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. CONCLUSION: Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.


Assuntos
Deficiências do Desenvolvimento/genética , Glicoproteínas/genética , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Adolescente , Adulto , Albuminas/líquido cefalorraquidiano , Proteínas do Líquido Cefalorraquidiano/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Glicosilação , Humanos , Masculino , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Fenótipo , Adulto Jovem
10.
Epilepsia ; 58(8): 1340-1348, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28555777

RESUMO

OBJECTIVE: Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy described as explosive onset of super refractory status epilepticus (SRSE) in previously healthy children. We describe electroencephalography (EEG) abnormalities in the hyperacute phase of FIRES, with the aim of contributing to the diagnostic characterization of a syndrome otherwise lacking specific biomarkers. METHODS: This is a retrospective single-center, case series of seven children with FIRES. Cases were identified from a Neurocritical Care database. Patient characteristics and clinical course were obtained from electronic medical records. Electroencephalography recordings were reviewed in two segments: the initial 12 h of recording and the 12 h prior to initiation of a medically induced burst suppression (BS). RESULTS: Fourteen 12-h segments of video-electroencephalography (EEG) recordings were analyzed for commonalities. A beta-delta complex resembling extreme delta brush (EDB) occurred in at least one 12-h segment for all patients. In six patients, seizures were brief and relatively infrequent during the first recording, with a gradual evolution to status epilepticus by the second. We observed a characteristic electrographic seizure pattern in six of seven patients with prolonged focal fast activity at onset. Shifting seizures were seen in four of seven patients. SIGNIFICANCE: The diagnosis of FIRES is typically assigned late in a patient's clinical course, which has broad implications for clinical care and research. We retrospectively analyzed acute EEG features in seven patients with FIRES and discovered three common features: gradual increase in seizure burden, presence of a recurrent EDB, and a typical seizure pattern. Recognition of this pattern may facilitate early diagnosis and treatment.


Assuntos
Encefalopatia Aguda Febril/complicações , Ritmo Delta/fisiologia , Epilepsia/complicações , Encefalopatia Aguda Febril/fisiopatologia , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Gravação em Vídeo
11.
Epilepsia ; 58(1): 113-122, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864929

RESUMO

OBJECTIVE: To demonstrate an association between magnetic resonance imaging (MRI) findings and pathologic characteristics in children who had surgery for medically refractory epilepsy due to focal cortical dysplasia (FCD). METHODS: We retrospectively studied 110 children who had epilepsy surgery. Twenty-seven patients with FCD were included. Thirteen had temporal lobe epilepsy (TLE) and 14 had extra-temporal lobe epilepsy (ETLE). Three patients had associated mesial temporal sclerosis. Preoperative 3T MRIs interleaved with nine controls were blindly re-reviewed and categorized according to signal alteration. Pathologic specimens were classified according to the 2011 International League Against Epilepsy (ILAE) classification and compared to MRI studies. RESULTS: Rates of pathology subtypes differed between TLE and ETLE (χ2 (3) = 8.57, p = 0.04). FCD type I was more frequent in TLE, whereas FCD type II was more frequent in ETLE. In the TLE group, nine patients had temporal tip abnormalities. They all exhibited gray-white matter blurring with decreased myelination and white matter hyperintense signal. Blurring involved the whole temporal tip, not just the area of dysplasia. These patients were less likely to demonstrate cortical thickening compared to those without temporal tip findings (χ2 (1) = 9.55, p = 0.002). Three of them had FCD Ib, three had FCD IIa, two had FCD IIIa, and one had FCD IIb; MRI features could not entirely distinguish between FCD subtypes. TLE patients showed more pronounced findings than ETLE on MRI (χ2 (1) = 11.95, p = 0.003, odds ratio [OR] 18.00). In all cases of FCD, isolated blurring was more likely to be associated with FCD II, whereas blurring with decreased myelination was seen with FCD I (χ2 (6) = 13.07, p = 0.042). SIGNIFICANCE: Our study described associations between MRI characteristics and pathology in children with FCD and offered a detailed analysis of temporal lobe tip abnormalities and FCD subtypes in children with TLE. These findings may contribute to the presurgical evaluation of patients with refractory epilepsy.


Assuntos
Encéfalo/patologia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/etiologia , Epilepsia/complicações , Malformações do Desenvolvimento Cortical do Grupo I/complicações , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Lateralidade Funcional , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Lactente , Imageamento por Ressonância Magnética , Masculino , Proteínas de Neurofilamentos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Estudos Retrospectivos , Adulto Jovem
13.
Curr Opin Pediatr ; 26(6): 655-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25313971

RESUMO

PURPOSE OF REVIEW: Status epilepticus is an acute neurologic emergency, the incidence of which is increasing in the United States as the definition evolves and our detection abilities improve. We will present the current definition of status epilepticus, including a recently modified operational definition for use in the clinical setting. We will also provide updates on identifying children in status epilepticus, etiologic considerations, and the rationale for diagnostic testing. RECENT FINDINGS: Recent data reveal the benefits of MRI vs. computed tomography in new-onset status epilepticus, as well as high rates of identification of electrographic seizures in patients with unexplained acute encephalopathy in pediatric ICU settings. Genetic testing should be considered in young children with recurrent status epilepticus. SUMMARY: Prompt recognition and diagnostic evaluation of the child in status epilepticus will help identify causes, which may require specific treatment, and help in the management of this life-threatening condition. Laboratory work, neuroimaging, electroencephalogram or continuous video electroencephalogram, lumbar puncture, and genetic testing may be considered in the evaluation of the child in status epilepticus.


Assuntos
Estado Epiléptico/diagnóstico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Eletroencefalografia/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Estados Unidos
14.
Pediatr Neurol ; 159: 48-55, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39121557

RESUMO

BACKGROUND: This retrospective clinical study performed at a single clinical center aimed to identify the prevalence of seizures in individuals with urea cycle disorders (UCDs) with and without hyperammonemic (HA) crises. In addition, we sought to correlate the utility of biochemical markers and electroencephalography (EEG) in detecting subclinical seizures during HA. METHODS: Medical records of individuals with UCDs enrolled in Urea Cycle Disorders Consortium Longitudinal Study (UCDC-LS) (NCT00237315) at Children's National Hospital between 2006 and 2022 were reviewed for evidence of clinical and subclinical seizuress during HA crises, and initial biochemical levels concurrently. RESULTS: Eighty-five individuals with UCD were included in the analyses. Fifty-six of the 85 patients (66%) experienced HA crises, with a total of 163 HA events. Seizures are observed in 13% of HA events. Among all HA events with concomitant EEG, subclinical seizures were identified in 27% of crises of encephalopathy without clinical seizures and 53% of crises with clinical seizures. The odds of seizures increases 2.65 (95% confidence interval [CI], 1.51 to 4.66) times for every 100 µmol/L increase in ammonia and 1.14 (95% CI, 1.04 to 1.25) times for every 100 µmol/L increase in glutamine. CONCLUSIONS: This study highlights the utility of EEG monitoring during crises for patients presenting with clinical seizures or encephalopathy with HA. During HA events, measurement of initial ammonia and glutamine can help determine risk for seizures and guide EEG monitoring decisions.


Assuntos
Amônia , Eletroencefalografia , Hiperamonemia , Convulsões , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Convulsões/diagnóstico , Hiperamonemia/diagnóstico , Hiperamonemia/sangue , Feminino , Masculino , Estudos Retrospectivos , Distúrbios Congênitos do Ciclo da Ureia/complicações , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Amônia/sangue , Criança , Pré-Escolar , Lactente , Adolescente , Estudos Longitudinais
15.
Neurol Genet ; 9(3): e200060, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37152443

RESUMO

Background and Objectives: Pathogenic variants at the voltage-gated sodium channel gene, SCN8A, are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the clinic. In this study, we develop a predictive modeling approach to classify variants based on clinical features present at initial diagnosis. Methods: We performed an exhaustive search for individuals deemed to carry SCN8A GOF and LOF variants by means of in vitro studies in heterologous cell systems, or because the variant was classified as truncating, and recorded clinical features. This resulted in a total of 69 LOF variants: 34 missense and 35 truncating variants, including 9 nonsense, 13 frameshift, 6 splice site, 6 indels, and 1 large deletion. We then assembled a truth set of variants with known functional effects, excluding individuals carrying variants at other loci associated with epilepsy. We then trained a predictive model based on random forest using this truth set of 45 LOF variants and 45 GOF variants randomly selected from a set of variants tested by in vitro methods. Results: Phenotypic categories assigned to individuals correlated strongly with GOF or LOF variants. All patients with GOF variants experienced early-onset seizures (mean age at onset = 4.5 ± 3.1 months) while only 64.4% patients with LOF variants had seizures, most of which were late-onset absence seizures (mean age at onset = 40.0 ± 38.1 months). With high accuracy (95.4%), our model including 5 key clinical features classified individuals with GOF and LOF variants into 2 distinct cohorts differing in age at seizure onset, development of seizures, seizure type, intellectual disability, and developmental and epileptic encephalopathy. Discussion: The results support the hypothesis that patients with SCN8A GOF and LOF variants represent distinct clinical phenotypes. The clinical model developed in this study has great utility because it provides a rapid and highly accurate platform for predicting the functional class of patient variants during SCN8A diagnosis, which can aid in initial treatment decisions and improve prognosis.

16.
Neurocrit Care ; 17(1): 31-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22565632

RESUMO

OBJECTIVES: In this study, we aimed to determine the incidence of electrographic seizures among patients in a pediatric intensive care unit (PICU) presenting with acute encephalopathy. Risk factors and duration of continuous EEG monitoring needed to capture electrographic seizures were also assessed. STUDY DESIGN: Based on a NeuroICU clinical care pathway, all patients with acute encephalopathy admitted to the PICU are monitored with continuous video electroencephalogram (cVEEG) for 48 h or until the encephalopathy improves. Ninety-four consecutive patients included on the pathway over a year were identified. Mean age was 6.7 years (range 32 days-17.9 years). Data pertaining to patient clinical information and electrographic seizures, including non-convulsive seizures (NCS) and non-convulsive status epilepticus (NCSE), were extracted from a prospective database. RESULTS: Thirty percent (28/94) had seizures captured on cVEEG including 17 patients (18%) with NCSE. Variables associated with electrographic seizures were age <24 months and clinical seizure(s) prior to EEG placement. The first seizure captured on cVEEG occurred in the first 24 h for the majority of patients (97%). Acute brain injury and electrographic seizures were associated with worse outcome. CONCLUSIONS: Electrographic seizures are common in pediatric patients with acute encephalopathy. This study supports the practice of cVEEG monitoring for at least 24 h in pediatric patients with acute encephalopathy, particularly if they are less then 24 months of age and/or if a clinical event suspicious for seizure precedes the encephalopathy.


Assuntos
Lesões Encefálicas/diagnóstico , Cuidados Críticos/métodos , Eletroencefalografia/métodos , Unidades de Terapia Intensiva Pediátrica , Estado Epiléptico/diagnóstico , Gravação em Vídeo/métodos , Doença Aguda , Adolescente , Lesões Encefálicas/epidemiologia , Criança , Pré-Escolar , Procedimentos Clínicos , Feminino , Humanos , Incidência , Lactente , Masculino , Monitorização Fisiológica/métodos , Estudos Prospectivos , Fatores de Risco , Estado Epiléptico/epidemiologia
17.
J Pediatr Pharmacol Ther ; 27(6): 558-563, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36042959

RESUMO

OBJECTIVE: We hypothesized that serum cannabidiol (CBD) concentrations would be higher in patients taking pharmaceutical- versus artisanal-CBD oil, and higher serum CBD concentrations would correlate with increased side effects and decreased seizure frequency. METHODS: This was a retrospective chart review. We included patients with pharmacoresistant epilepsy, treated with artisanal-CBD or pharmaceutical-CBD (Epidiolex), and with quantitative serum CBD concentrations. We tracked epilepsy diagnosis, artisanal-CBD dosage, pharmaceutical-CBD dose, serum CBD concentration, clobazam concentration, N-desmethylclobazam concentration, seizure history (frequency of motor seizures), response to medication (percentage reduction in motor seizures), and side effects. RESULTS: Forty-two patients met inclusion criteria. Mean serum CBD concentration was 51.1 ng/mL (artisanal group) and 124 ng/mL (pharmaceutical group) (p = 0.022). Patients receiving artisanal-CBD had no change in median overall seizures (IQR, -50% to 50%); the pharmaceutical-CBD group had median 50% reduction (IQR, -90% to no change) (p = 0.199). CONCLUSIONS: Pharmaceutical-CBD achieves higher serum CBD concentrations than artisanal-CBD in pediatric patients with refractory epilepsy. These higher CBD concentrations are associated with increased reported adverse effects, but no detectable difference in seizure frequency.

18.
Ther Adv Rare Dis ; 3: 26330040221076861, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-37180417

RESUMO

Recent developments in technology and exigencies of the COVID-19 pandemic have spurred innovations for telehealth in patients with rare epilepsies. This review details the many ways telehealth may be used in the diagnosis and management of rare, pharmacoresistant epilepsy and documents our experience as measured by surveying caregivers of pediatric patients with epilepsy. Most components of the epilepsy evaluation, including history and examination, neuroimaging, and electroencephalogram (EEG) can be performed or reviewed remotely, assuming similar technique and quality of diagnostic studies. Seizure and epilepsy diagnosis is enhanced through the assistance of caregiver smart phone video recordings and 'ambulatory' EEG. Monitoring patient seizure frequency through paper seizure diaries is now increasingly being replaced by electronic diaries in both clinical and research settings. Electronic seizure diaries have numerous advantages such as data durability, increased accessibility, real-time availability, and easier analysis. Telehealth enhances access to specialized epilepsy care, which has been shown to reduce mortality and improve patient compliance and outcomes. Telehealth can also enable evaluation of patients with rare epilepsy in centers of excellence and enhance enrollment in clinical trials. Reducing mortality risk in patients with epilepsy can be accomplished through remote counseling and addressing psychiatric co-morbidities. Findings from surveying caregivers of children with epilepsy treated at Children's National Hospital showed that 54/56 (96.4%) found that not having to commute to the appointment positively contributed to their telemedicine experience. Overall, most respondents had a positive experience with their telemedicine visit. Almost all respondents (98%) were either 'very happy' or 'happy' with their telemedicine visit and their ability to communicate over telemedicine with the provider and either 'very likely' or 'likely' to want to use telemedicine for some future clinic visits. Telehealth in rare epilepsies is feasible and, in many ways, comparable with traditional evaluation and management.


Telehealth for patients with rare epilepsies Recent technological advancements and constraints caused by the COVID-19 pandemic have spurred innovations for telehealth in patients with rare epilepsies. This review details the many ways telehealth may be used in the diagnosis and management of rare, drug-resistant epilepsy and documents our experience as measured by surveying caregivers of pediatric patients with epilepsy. Most components of the epilepsy evaluation can be performed or reviewed remotely, assuming similar technique and quality of diagnostic studies. Seizure and epilepsy diagnosis is enhanced through the assistance of caregiver smart phone video recordings and 'ambulatory' electroencephalogram (EEG). Monitoring patient seizure frequency through paper seizure diaries is now increasingly being replaced by electronic diaries in both clinical and research settings. Electronic seizure diaries have numerous advantages such as data durability, increased accessibility, real-time availability, and easier analysis. Telehealth enhances access to specialized epilepsy care, which has been shown to reduce mortality and improve patient compliance and outcomes. Telehealth can also enable evaluation of patients with rare epilepsy in centers of excellence and enhance enrollment in clinical trials. Reducing mortality risk in patients with epilepsy can be accomplished through remote counseling and addressing related mental health issues. Findings from surveying caregivers of children with epilepsy treated at Children's National Hospital showed that most respondents found not having to commute to the appointment positively contributed to their telemedicine experience. Almost all respondents were either 'very happy' or 'happy' with their telemedicine visit and their ability to communicate over telemedicine with the provider and either 'very likely' or 'likely' to want to use telemedicine for some future clinic visits. Telehealth in rare epilepsies is feasible and, in many ways, comparable with traditional evaluation and management.

19.
Curr Neurol Neurosci Rep ; 11(2): 195-204, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21174176

RESUMO

Refractory status epilepticus (RSE) is characterized by a prolonged seizure that persists despite adequate initial management. RSE accounts for almost one quarter of all status epilepticus and carries significant risk for morbidity and mortality. Treatment varies widely between institutions regarding medication choice, dose, and monitoring. Several agents including nonanesthetic antiepileptic drugs (AEDs), anesthetic AEDs, enteral AEDs, and other therapies have been used in RSE. We review the current treatment strategies for RSE, focusing on patient selection, monitoring, optimal dosing and administration of medications, efficacy, adverse effects, and treatment duration.


Assuntos
Anticonvulsivantes/uso terapêutico , Estado Epiléptico/fisiopatologia , Estado Epiléptico/terapia , Anticonvulsivantes/administração & dosagem , Criança , Eletroconvulsoterapia , Humanos , Resultado do Tratamento
20.
Pediatr Neurol ; 121: 28-32, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139551

RESUMO

BACKGROUND: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders. METHODS: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants. RESULTS: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects. CONCLUSIONS: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong.


Assuntos
Epilepsia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Cuidadores , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidade do Paciente
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