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1.
Brain ; 144(12): 3635-3650, 2021 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-34114611

RESUMO

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and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished).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


Assuntos
Epilepsia/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio Ativados por Sódio/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Adulto Jovem
2.
Epilepsy Behav ; 114(Pt A): 107636, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309428

RESUMO

Paroxysmal events are usually not directly observed by physicians. The diagnosis remains challenging and relies mostly on the description of witnesses. The effectiveness of videos for seizure diagnosis has been validated by several studies, but their place in clinical practice is not yet clear. The aim of our study was to evaluate the real-life use of videos by child neurologists. We conducted a three-month prospective study in which child neurologists were asked to use a short questionnaire to evaluate all videos that were watched in their clinical practice for an initial diagnosis or during follow-up. A click-off meeting during the French pediatric neurology meeting allowed to recruit participants. A total of 165 questionnaires were completed by 15 physicians over the study period. The physicians were child neurologists working in secondary and tertiary/university hospitals, consulting children with epilepsy. Based on the evaluation of child neurologists, 51% of the videos consisted of epileptic seizures; 40%, nonepileptic paroxysmal events; and 9%, psychogenic nonepileptic seizures. Most of the videos were made on parental initiative. The use of video has modified the first diagnosis hypothesis in 35% of cases. The physicians' feelings regarding the interest of the video used during the diagnostic phase were similar to those of the video used during follow-up. It appears that videos have become a part of the epilepsy clinic and are helpful for diagnosis as well as during follow-up. Unfortunately, one of the limitations of this study is the absence of private practitioner.


Assuntos
Epilepsia , Criança , Eletroencefalografia , Epilepsia/diagnóstico , Humanos , Estudos Prospectivos , Encaminhamento e Consulta , Convulsões/diagnóstico , Gravação em Vídeo
3.
Eur J Pediatr ; 180(9): 2959-2967, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33846821

RESUMO

Neurological morbidity is a growing concern in children with severe bronchiolitis. The aim of the study was to evaluate the frequency of occurrence and the factors associated with seizures in very young infants < 3 months of age, admitted to a pediatric intensive care unit (PICU) for severe bronchiolitis. We performed a single center retrospective cohort study evaluating occurrence of seizures in infants admitted to the PICU between 2010 and 2018 for severe bronchiolitis. We described characteristics of the patients, laboratory test, brain imaging, and electroencephalogram results, as well as the treatment used. We conducted a multivariable logistic regression to identify factors associated with the occurrence of seizures. A p value < 0.05 was considered significant. A total of 805 patients were included in the study; 722 (89.6%) were mechanically ventilated. Twenty-six infants (3.2%, 95% confidence interval, 95% CI [2.1%; 4.7%]) had seizures shortly prior to admission or during PICU stay. In the multivariable analysis, hyponatremia (odds ratio, OR: 4.6, 95%CI [1.86; 11.43], p = 0.001) and invasive ventilation (OR: 2.6, 95% CI [1.14; 5.9], p < 0.001) were associated with an increased likelihood of seizures occurrence.Conclusion: Seizures occur in at least 3% of very young infants with severe bronchiolitis, and the characteristics of these are different to those experienced by older infants, but they shared the same risk factors (hyponatremia and mechanical ventilation). This highlights the extrapulmonary morbidity associated with bronchiolitis in this population. What is Known: • Bronchiolitis is the leading cause of pediatric intensive care admission and use of mechanical ventilation in infants. • Neurological morbidities have to be investigated in this population at risk of neurological complications. What is New: • Seizure is a complication in at least 3% of very young infants with severe bronchiolitis. • Seizure characteristics are different, but the main risk factors are the same than in older infants (hyponatremia and mechanical ventilation).


Assuntos
Bronquiolite , Idoso , Bronquiolite/complicações , Bronquiolite/epidemiologia , Criança , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , Convulsões/epidemiologia , Convulsões/etiologia
4.
Epilepsia ; 61(2): 216-227, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31876960

RESUMO

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.


Assuntos
Epilepsia/cirurgia , Neurocirurgia/tendências , Procedimentos Neurocirúrgicos/tendências , Adolescente , Fatores Etários , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/epidemiologia , Epilepsia/patologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurocirurgia/estatística & dados numéricos , Procedimentos Neurocirúrgicos/estatística & dados numéricos , Estudos Retrospectivos , Convulsões/epidemiologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Resultado do Tratamento
5.
Arch Pediatr ; 31(1): 66-71, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37989656

RESUMO

BACKGROUND: Our study aimed to evaluate the prevalence and predictive factors of withholding life support for children suffering from severe neurological impairment before admission to the pediatric intensive care unit (PICU). METHOD: Children under 18 years of age with severe neurological impairment, who were hospitalized between January 2006 and December 2016, were included in this retrospective study. They were allocated to a withholding group or a control group, depending on whether life support was withheld or not, before admission to the PICU. RESULTS: Overall, 119 patients were included. At admission to the PICU, the rate of withholding life support was 10 % (n = 12). Predictive factors were: (1) a previous stay in the PICU (n = 11; 92 %, p<0.01, odds ratio [OR]: 14 [2-635], p = 0.001); (2) the need for respiratory support (n = 5; 42 %, p = 0.01, OR: 6 [1-27], p = 0.01); (3) the need for feeding support (n = 10; 83 %, p = 0.01, OR: 10 [2-100], p = 0.001); and (4) a higher functional status score (FSS: 16 [12.5-19] vs. 10 [8-13], p<0.01). CONCLUSION: The withholding of life support for children suffering from severe neurological impairment appeared limited in our pediatric department. The main predictor was at least one admission to the PICU, which raised the question of the pediatrician's role in the decision to withhold life support.


Assuntos
Hospitalização , Unidades de Terapia Intensiva Pediátrica , Criança , Humanos , Lactente , Adolescente , Estudos Retrospectivos , Prevalência
7.
Eur J Paediatr Neurol ; 33: 121-124, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34174751

RESUMO

BACKGROUND: Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. METHODS AND RESULTS: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. CONCLUSION: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.1/genética , Epilepsias Mioclônicas/genética , Síndromes Epilépticas , Humanos , Mutação , Fenótipo , Convulsões Febris/genética
8.
Neurol Genet ; 5(6): e373, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32042906

RESUMO

OBJECTIVE: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy. METHODS: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding. RESULTS: Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype. CONCLUSIONS: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

9.
Sleep Med Rev ; 42: 220-228, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30293919

RESUMO

The vestibular system encodes linear and angular head motion supporting numerous functions from gaze stabilization and postural control, to high-level cortical functions involving spatial cognition, including self-body perception, verticality perception, orientation, navigation and spatial memory. At the brainstem and mesencephalic levels, the vestibular organs also influence postural blood pressure regulation, bone density and muscle composition via specific vestibulo-sympathetic efferences and have been shown to act as a powerful synchronizer of circadian rhythms. Here, we review the evidence that sleep deprivation and sleep apnea syndrome alter vestibular-related oculo-motor and postural control, and that, in turn, vestibular pathologies induce sleep disturbances. We suggest that sleep-related neuroplasticity might serve the adaptation and compensation processes following vestibular lesions in patients. Interestingly, a reciprocal neuroanatomical route between the vestibular nuclei and the orexinergic neurons has been reported. While orexinergic modulation of the vestibular nuclei related to postural control has been suggested, we postulate that vestibular inputs might in turn influence the sleep-wake state switch, informing the brain about the daily quantity of motion.


Assuntos
Síndromes da Apneia do Sono/fisiopatologia , Sono/fisiologia , Vestíbulo do Labirinto , Encéfalo , Humanos , Plasticidade Neuronal
10.
Neurosci Lett ; 683: 43-47, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29936267

RESUMO

There is substantial evidence that loss of vestibular function impairs spatial learning and memory related to hippocampal (HPC) function, as well as increasing evidence that striatal (Str) plasticity is also implicated. Since the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor is considered essential to spatial memory, previous studies have investigated whether the expression of HPC NMDA receptors changes following vestibular loss; however, the results have been contradictory. Here we used a novel flow cytometric method to quantify the number of neurons expressing NMDA receptors in the HPC and Str following bilateral vestibular loss (BVL) in rats. At 7 and 30 days post-op., there was a significant increase in the number of HPC neurons expressing NMDA receptors in the BVL animals, compared to sham controls (P ≤ 0.004 and P ≤ 0.0001, respectively). By contrast, in the Str, at 7 days there was a significant reduction in the number of neurons expressing NMDA receptors in the BVL group (P ≤ 0.05); however, this difference had disappeared by 30 days post-op. These results suggest that BVL causes differential changes in the number of neurons expressing NMDA receptors in the HPC and Str, which may be related to its long-term impairment of spatial memory.


Assuntos
Corpo Estriado/metabolismo , Citometria de Fluxo/métodos , Hipocampo/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Vestíbulo do Labirinto/metabolismo , Animais , Corpo Estriado/citologia , Orelha Interna/citologia , Orelha Interna/metabolismo , Orelha Interna/cirurgia , Expressão Gênica , Hipocampo/citologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Vestíbulo do Labirinto/citologia , Vestíbulo do Labirinto/cirurgia
11.
Neurol Genet ; 4(6): e281, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30533527

RESUMO

OBJECTIVE: To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. METHODS: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. RESULTS: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. CONCLUSIONS: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

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