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Importance: Molecular testing of the presence of pathogenic genomic variants in a tumor without quantifying the variant allele fraction (VAF) does not differentiate the variation extent among tumors, often resulting in an inconclusive diagnosis because of interpatient variability. Objective: To examine the association between the quantification of VAFs of BRAF V600E and TERT promoter variants and a definitive cancer diagnosis of thyroid tumors. Design, Setting, and Participants: This diagnostic study analyzed a cohort of 378 surgically resected thyroid tumors with a maximum dimension of 1 cm or larger between March 15, 2016, and March 16, 2020, and a separate cohort of 217 residual thyroid fine-needle aspiration (FNA) biopsy specimens obtained from January 22, 2020, to March 2, 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data analysis was conducted between February 1, 2021, and February 1, 2023. Exposures: Quantitative VAF assays of BRAF V600E and TERT promoter variants (C228T and C250T) were performed by digital polymerase chain reaction molecular assays. Main Outcomes and Measures: The VAFs of BRAF V600E and TERT promoter variants were correlated with tumor histologic diagnoses and histopathologic features to delineate the association of VAF assays with tumor malignancy. The receiver operating characteristic curve analysis, sensitivity, specificity, positive predictive value, negative predictive value, and logistic regression analysis based on follow-up histopathologic types were used to determine the diagnostic utility of the quantitative molecular assays. Results: A total of 595 specimens, including 378 surgically resected thyroid tumors and 217 thyroid nodule FNA biopsy specimens, were collected from 580 patients (436 [75.2%] female with a mean [SD] age of 50 [16] years and 144 [24.8%] male with a mean [SD] age of 55 [14] years). Sensitive VAF assays of 378 thyroid tumors revealed the presence of the BRAF V600E variant in 162 tumors (42.9%), with 26 (16.0%) at a low VAF of 1% or less and 136 (84.0%) at a high VAF of greater than 1%, and the presence of TERT promoter variants in 49 tumors (13.0%), including 45 C228T variants (91.8%), 15 (33.3%) of which were quantified as having a low VAF (≤1%) and 30 (66.7%) as having a high VAF (>1%), and 4 C250T variants (8.2%) with VAFs between 40.0% and 47.0%. All tumors detected with BRAF V600E and/or TERT promoter variants, whether at low or high VAFs, received a definitive cancer diagnosis. Further analysis delineated a significant association between high VAFs of either variant individually or different VAF levels for both variants in coexistence and aggressive histopathologic features of tumors. Excluding low VAFs assisted in identifying patients at an intermediate-to-high risk of recurrence (odds ratio, 5.3; 95% CI, 1.9-14.6; P = .001). The VAF assays on the residual FNA biopsy specimens showed a high agreement to those on surgical tissues (κ = 0.793, P < .001) and stratified malignancy in 40 of 183 indeterminate FNA cases (21.9%), with a sensitivity of 93.8% (95% CI, 67.7%-99.7%), specificity of 90.0% (95% CI, 75.4%-96.7%), positive predictive value of 78.9% (95% CI, 53.9%-93.0%), and negative predictive value of 97.3% (95% CI, 84.2%-99.9%). Conclusions and Relevance: This diagnostic study suggests that sensitive quantitative VAF assays of BRAF V600E and TERT promoter variants can elucidate the interpatient variability in tumors and facilitate a definitive cancer diagnosis of thyroid nodules by differentiating the variation extent of genomic variants, even at low VAFs.
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Proteínas Proto-Oncogénicas B-raf , Telomerasa , Neoplasias de la Tiroides , Nódulo Tiroideo , Femenino , Humanos , Masculino , Mutación , Ontario , Proteínas Proto-Oncogénicas B-raf/genética , Telomerasa/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/genética , Nódulo Tiroideo/patología , Adulto , Persona de Mediana Edad , AncianoRESUMEN
Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction. Muscle respiratory chain enzymology was unremarkable. Whole-genome sequencing identified a maternally inherited NDUFV1 missense variant [NM_007103.4 (NDUFV1):c.1157G > A; p.(Arg386His)] and a paternally inherited synonymous variant [NM_007103.4 (NDUFV1):c.1080G > A; (p.Ser360=)]. RNA sequencing demonstrated aberrant splicing. This case emphasizes the diagnostic odyssey of a patient in whom a confirmed diagnosis was elusive because of atypical features and normal muscle respiratory chain enzyme (RCE) activities, along with a synonymous variant, which are often filtered out from genomic analyses. It also illustrates the following points: (1) complete resolution of magnetic resonance imaging changes may be part of the picture in mitochondrial disease; (2) analysis for synonymous variants is important for undiagnosed patients; and (3) RNA-seq is a powerful tool to demonstrate pathogenicity of putative splicing variants.
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Imagen por Resonancia Magnética , Músculos , Humanos , RNA-Seq , Secuenciación Completa del Genoma , Encéfalo , Complejo I de Transporte de Electrón/genéticaRESUMEN
Objectives To identify features of mental health services that affect the uptake of services among parents of children with chronic medical conditions, to inform the design of pathways into mental health care. Methods A discrete choice experiment in which participants made choices between hypothetical mental health services described in terms of service features: cost, wait time, provider knowledge of chronic medical conditions, recommendations, opening hours, and travel time. Participants were parents of children attending The Royal Children's Hospital outpatient clinics for the management of a chronic medical condition who completed the online survey between August 2020 and January 2021. The uptake of mental health services with differing features was predicted based on regression models examining the relationship between choice and service features, and accounting for participant characteristics and unobserved heterogeneity. Results The sample comprised 112 parents, of whom 52% reported unmet needs. The most influential service features were wait times, cost, recommendation from medical specialists, and mental health provider knowledge of chronic medical conditions. Predicted uptake of a realistic service showed inequalities across income, parental education, and single parent status. A service comprising preferred features was predicted to eliminate these inequalities. Conclusions Reducing cost and wait time for mental health services could reduce unmet need among children with chronic medical conditions. Specific approaches to tackle the high levels of unmet needs in this group include equipping medical specialists to recommend mental health providers and training mental health providers on the impacts of chronic medical conditions on children. Offering preferred services could increase uptake and reduce inequalities in mental health care.
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Servicios de Salud Mental , Padres , Niño , Humanos , ViajeRESUMEN
Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
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Epilepsia , Pruebas Genéticas , Humanos , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Estudios Transversales , Pruebas Genéticas/métodos , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Convulsiones/genéticaRESUMEN
Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.
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Ciliopatías , Hamartoma , Enfermedades Hipotalámicas , Ciliopatías/genética , Hamartoma/genética , Proteínas Hedgehog/metabolismo , Humanos , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/genética , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: To explore parent perspectives on accessing mental healthcare for children with a chronic physical health condition. DESIGN: Qualitative research using semistructured interviews and Framework Analysis. Rankings were used to select attributes for a Discrete Choice Experiment (DCE). SETTING: Four specialty outpatient clinics (diabetes, epilepsy, bronchiectasis unrelated to cystic fibrosis and epidermolysis bullosa) at an Australian tertiary paediatric hospital. PARTICIPANTS: Eighteen parents of children with a chronical physical health condition. RESULTS: Most parents identified the child's general practitioner and/or hospital team as an initial pathway to seek help if they were worried about their child's mental health. Parents see mental healthcare as part of care for the whole child and want the outpatient clinics to proactively discuss child and family mental health, as well as refer to appropriate services as needed. The hospital being a familiar, child-friendly environment was identified as a key reason the hospital might be a desired place to access mental healthcare, as previous research has found. Six attributes of mental health services were identified as important and will be included in an upcoming DCE: travel time, cost, wait time, available hours, knowledge of physical health condition, and recommendation. CONCLUSIONS: This study highlights the opportunity presented in specialist outpatient clinics to address the often unmet mental healthcare needs of children with chronic physical health conditions. Parents identified practical ways for outpatient clinics to better facilitate access to mental healthcare. These will be further explored through a quantitative study of parent preferences.
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Enfermedad Crónica/psicología , Accesibilidad a los Servicios de Salud , Servicios de Salud Mental , Adolescente , Adulto , Niño , Enfermedad Crónica/terapia , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Servicios de Salud Mental/organización & administración , Evaluación de Necesidades , Padres , Investigación Cualitativa , Adulto JovenRESUMEN
Background: Outpatient thyroid surgery is gaining popularity as it can reduce length of hospital stay, decrease costs of care, and increase patient satisfaction. There remains a significant variation in the use of this practice including a perceived knowledge gap with regards to the safety of outpatient thyroidectomies and how to go about implementing standardized institutional protocols to ensure safe same-day discharge. This review summarizes the information available on the subject based on existing published studies and guidelines. Methods: This is a scoping review of the literature focused on the safety, efficacy and patient satisfaction associated with outpatient thyroidectomies. The review also summarizes and editorializes the most recent American Thyroid Association guidelines. Results: In total, 11 studies were included in the analysis: 6 studies were retrospective analyses, 3 were retrospective reviews of prospective data, and 2 were prospective studies. The relative contraindications to outpatient thyroidectomy have been highlighted, including: complex medical conditions, anticipated difficult surgical dissection, patients on anticoagulation, lack of home support, and patient anxiety toward an outpatient procedure. Utilizing these identified features, an outpatient protocol has been proposed. Conclusion: The salient features regarding patient safety and selection criteria and how to develop a protocol implementing ambulatory thyroidectomies have been identified and reviewed. In conclusion, outpatient thyroidectomy is safe, associated with high patient satisfaction and decreased health costs when rigorous institutional protocols are established and implemented. Successful outpatient thyroidectomies require standardized preoperative selection, clear discharge criteria and instructions, and interprofessional collaboration between the surgeon, anesthetist and same-day nursing staff.
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Procedimientos Quirúrgicos Ambulatorios/normas , Tiempo de Internación/estadística & datos numéricos , Pacientes Ambulatorios/estadística & datos numéricos , Enfermedades de la Tiroides/cirugía , Tiroidectomía/métodos , Estudios de Factibilidad , Humanos , Enfermedades de la Tiroides/patologíaRESUMEN
Background: non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a ß-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods: immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto's thyroiditis (LTs). Results: cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions (p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs (p = 0.016) and benign nodules (p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions: our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.
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OBJECTIVE: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD). METHODS: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG. RESULTS: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication. CONCLUSION: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.
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Corteza Cerebral/cirugía , Epilepsia/cirugía , Malformaciones del Desarrollo Cortical de Grupo I/cirugía , Adolescente , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Niño , Epilepsia/diagnóstico por imagen , Epilepsia/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Malformaciones del Desarrollo Cortical de Grupo I/diagnóstico por imagen , Malformaciones del Desarrollo Cortical de Grupo I/fisiopatología , Monitoreo Fisiológico , Procedimientos Neuroquirúrgicos/métodos , Cuidados Preoperatorios , Resultado del TratamientoRESUMEN
This study aimed to investigate the prevalence of fractures and non-fracture injuries, including associated risk factors, in children with epilepsy prescribed antiseizure medications (ASM). A controlled, cross-sectional study was conducted in a hospital outpatient setting, comparing children with epilepsy prescribed ASMs with their non-epileptic siblings. Information was collected by questionnaire included history of fractures, non-fracture injuries and epilepsy, comorbidities and ASM use. 261 participants completed the questionnaire, 133 children with epilepsy (aged 10.7 ± 3.5 years, mean ± SD) and 128 siblings (10.1 ± 3.7 years). There were 49 non-seizure-related fractures in 34 ASM patients while prescribed ASMs, compared with 21 lifetime fractures in 15 controls, giving a 2.7 (95% CI 1.3-5.3, p = 0.007) times greater fracture prevalence in children treated with ASMs compared to healthy siblings. The rates of non-fracture injuries were similar across groups, except that concussion was more common in children taking ASMs (9.0% vs 1.6%, p = 0.026). Duration of ASM use and generalized tonic-clonic seizures (GTCS) were independent predictors of fractures (OR 1.55; 95% CI 1.03-2.31, p = 0.03; OR 2.50; 95% CI 1.05-5.94, p = 0.04, respectively). Fewer than 20% of participants and/or their families were aware that ASM use was related to bone health. Children with epilepsy treated with ASMs had a higher fracture prevalence than their sibling controls. Duration of ASM treatment and GTCS were associated with fracture risk. Longitudinal prospective studies are required to further explore risk and the direct impact of epilepsy on bone health.
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Epilepsia , Fracturas Óseas , Anticonvulsivantes/efectos adversos , Niño , Estudios Transversales , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Fracturas Óseas/tratamiento farmacológico , Fracturas Óseas/epidemiología , Humanos , Estudios Prospectivos , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiologíaRESUMEN
BACKGROUND: Superficial parotidectomy has a potential to be performed as an outpatient procedure. The objective of the study is to evaluate the safety and selection profile of outpatient superficial parotidectomy compared to inpatient parotidectomy. METHODS: A retrospective review of individuals who underwent superficial parotidectomy between 2006 and 2016 at a tertiary care center was conducted. Primary outcomes included surgical complications, including transient/permanent facial nerve palsy, wound infection, hematoma, seroma, and fistula formation, as well as medical complications in the postoperative period. Secondary outcome measures included unplanned emergency room visits and readmissions within 30 days of operation due to postoperative complications. RESULTS: There were 238 patients included (124 in outpatient and 114 in inpatient group). There was no significant difference between the groups in terms of gender, co-morbidities, tumor pathology or tumor size. There was a trend towards longer distance to the hospital from home address (111 Km in inpatient vs. 27 in outpatient, mean difference 83 km [95% CI,- 1 to 162 km], p = 0.053). The overall complication rates were comparable between the groups (24.2% in outpatient group vs. 21.1% in inpatient, p = 0.56). There was no difference in the rate of return to the emergency department (3.5% vs 5.6%, p = 0.433) or readmission within 30 days (0.9% vs 0.8%, p = 0.952). CONCLUSION: Superficial parotidectomy can be performed safely as an outpatient procedure without elevated risk of complications.
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Procedimientos Quirúrgicos Ambulatorios , Procedimientos Quirúrgicos Otorrinolaringológicos/métodos , Enfermedades de las Parótidas/cirugía , Glándula Parótida/cirugía , Complicaciones Posoperatorias/epidemiología , Centros Médicos Académicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Pacientes Internos , Masculino , Persona de Mediana Edad , Ontario , Pacientes Ambulatorios , Readmisión del Paciente/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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Discapacidades del Desarrollo/epidemiología , Epilepsias Mioclónicas/epidemiología , Espasmos Infantiles/epidemiología , Anticonvulsivantes/uso terapéutico , Preescolar , Estudios de Cohortes , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/fisiopatología , Progresión de la Enfermedad , Electroencefalografía , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/etiología , Epilepsias Mioclónicas/fisiopatología , Síndromes Epilépticos/tratamiento farmacológico , Síndromes Epilépticos/epidemiología , Síndromes Epilépticos/etiología , Síndromes Epilépticos/fisiopatología , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Síndrome de Lennox-Gastaut/epidemiología , Síndrome de Lennox-Gastaut/etiología , Síndrome de Lennox-Gastaut/fisiopatología , Masculino , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/epidemiología , Malformaciones del Desarrollo Cortical/cirugía , Mortalidad , Índice de Severidad de la Enfermedad , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/etiología , Espasmos Infantiles/fisiopatología , Victoria/epidemiologíaRESUMEN
AIMS: Severe behavioural problems (SBP) are a major contributor to morbidity in children with intellectual disability (ID). Medications used to treat SBP in ID are associated with a high risk of side effects. Cannabidiol has potential therapeutic effects in SBP. This pilot study aimed to investigate the feasibility of conducting a randomised placebo-controlled trial of cannabidiol to reduce SBP in children with ID. METHODS: This is a double-blind, placebo-controlled, two-armed, parallel-design, randomised controlled trial of cannabidiol in children aged 8-16 years with ID and SBP. Participants were randomised 1:1 to receive either 98% cannabidiol in oil (Tilray, Canada) or placebo orally for 8 weeks. The dose was up-titrated over 9 days to 20 mg/kg/day in two divided doses, with a maximum dose of 500 mg twice/day. The feasibility and acceptability of all study components were assessed. RESULTS: Eight children were randomised, and all completed the full study protocol. There were no serious adverse events or drop-outs. Protocol adherence for key study components was excellent: study visits 100%, medication adherence 100%, blood tests 92% and questionnaire completion 88%. Parents reported a high degree of acceptability with the study design. All parents reported they would recommend the study to other families with children with similar problems. There was an efficacy signal in favour of active drug. CONCLUSIONS: The findings suggest that the study protocol is feasible and acceptable to patients with ID and SBP and their families.
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Cannabidiol , Discapacidad Intelectual , Problema de Conducta , Adolescente , Canadá , Niño , Método Doble Ciego , Humanos , Discapacidad Intelectual/tratamiento farmacológico , Proyectos PilotoRESUMEN
OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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Encefalopatías/diagnóstico por imagen , Encefalopatías/genética , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Variación Genética/genética , Canales de Potasio Shab/genética , Adolescente , Adulto , Encefalopatías/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía/tendencias , Epilepsia/fisiopatología , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy. METHODS: The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight. CONCLUSION: These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions.
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Cannabidiol , Epilepsia Refractaria , Anticonvulsivantes/uso terapéutico , Teorema de Bayes , Cannabidiol/uso terapéutico , Niño , Método Doble Ciego , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- ß1) and anchors it on the cell surface; this anchoring is required for activation of TGF-ß1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-ß1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-ß1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-ß1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-ß1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-ß1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.
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Encefalopatías/genética , Calcinosis/genética , Variación Genética/genética , Proteínas de Unión a TGF-beta Latente/genética , Enfermedades Neurodegenerativas/genética , Factor de Crecimiento Transformador beta1/genética , Alelos , Femenino , Células HEK293 , Humanos , Lactante , Macrófagos/patología , Masculino , Microglía/patologíaRESUMEN
INTRODUCTION: Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP. However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID. METHODS AND ANALYSIS: This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8-16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group. ETHICS AND DISSEMINATION: This protocol has received ethics approval from the Royal Children's Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media. TRIAL REGISTRATION NUMBER: ACTRN12618001852246.
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Cannabidiol/uso terapéutico , Trastornos de la Conducta Infantil/tratamiento farmacológico , Trastornos de la Conducta Infantil/epidemiología , Discapacidad Intelectual/epidemiología , Adolescente , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Niño , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
INTRODUCTION: Children with epilepsy report lower health-related quality of life (QOL) compared with healthy children and those with other chronic disorders. This study piloted the recently published Pediatric Quality of Life Inventory (PedsQL) Epilepsy Module (PedsQL-EM) in an ambulatory setting and studied epilepsy-related factors contributing to QOL in children with epilepsy. METHODS: Children with epilepsy aged 8-18â¯years who were ambulant and verbal were recruited from pediatric neurology clinics. Children and their caregivers completed age-appropriate versions of the PedsQL-EM (8-12 or 13-18â¯years) in the clinic waiting area. Treating neurologists completed medical questionnaires about their patients' epilepsy. RESULTS: We collected 151 parent-report and 127 self-report PedsQL-EMs. Administration time was 5-10â¯min with some children receiving assistance from the researcher. Mean age of children was 12.9+/-3.0, with 77 females (51%). Parents reported lower mean QOL scores across all subdomains compared with their children. Parents reported significantly lower QOL for children with earlier age at epilepsy onset, longer epilepsy duration, presence of seizures during the last month, more severe epilepsy, increased number of antiepileptic drugs (AEDs), and cognitive comorbidity. The same factors impacted on child self-reporting, but with more variability across subdomains. CONCLUSIONS: The PedsQL-EM is an epilepsy-specific measure of QOL that is quick and easy to administer and is sensitive to the clinical factors reported to impact on QOL in pediatric epilepsy.