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INTRODUCTION: Literature lacks studies investigating the cortical generation of sleep spindles in drug-resistant epilepsy (DRE) and how they evolve after resection of the epileptogenic zone (EZ). Here, we examined sleep EEGs of children with focal DRE who became seizure-free after focal epilepsy surgery, and aimed to investigate the changes in the spindle generation before and after the surgery using low-density scalp EEG and electrical source imaging (ESI). METHODS: We analyzed N2-sleep EEGs from 19 children with DRE before and after surgery. We identified slow (8-12 Hz) and fast spindles (13-16 Hz), computed their spectral features and cortical generators through ESI and computed their distance from the EZ and irritative zone (IZ). We performed two-way ANOVA testing the effect of spindle type (slow vs. fast) and surgical phase (pre-surgery vs. post-surgery) on each feature. RESULTS: Power, frequency and cortical activation of slow spindles increased after surgery (p < 0.005), while this was not seen for fast spindles. Before surgery, the cortical generators of slow spindles were closer to the EZ (57.3 vs. 66.2 mm, p = 0.007) and IZ (41.3 vs. 55.5 mm, p = 0.02) than fast spindle generators. CONCLUSIONS: Our data indicate alterations in the EEG slow spindles after resective epilepsy surgery. Fast spindle generation on the contrary did not change after surgery. Although the study is limited by its retrospective nature, lack of healthy controls, and reduced cortical spatial sampling, our findings suggest a spatial relationship between the slow spindles and the epileptogenic generators.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Criança , Humanos , Estudos Retrospectivos , Epilepsia/diagnóstico por imagem , Epilepsia/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Sono/fisiologia , Eletroencefalografia/métodosRESUMO
Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.
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Recém-Nascido Prematuro , Leucomalácia Periventricular , Lactente , Recém-Nascido , Humanos , Leucomalácia Periventricular/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética , Idade GestacionalRESUMO
Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 ~ 5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward predicting prognosis, identifying high-risk patients, and evaluating treatment effects. It will lead to a more accurate estimation of prognosis, a better understanding of neurological symptoms, and a timely prediction of response to therapy. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of brain volume). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.
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Deep convolutional neural networks (CNNs) have been widely used for medical image segmentation. In most studies, only the output layer is exploited to compute the final segmentation results and the hidden representations of the deep learned features have not been well understood. In this paper, we propose a prototype segmentation (ProtoSeg) method to compute a binary segmentation map based on deep features. We measure the segmentation abilities of the features by computing the Dice between the feature segmentation map and ground-truth, named as the segmentation ability score (SA score for short). The corresponding SA score can quantify the segmentation abilities of deep features in different layers and units to understand the deep neural networks for segmentation. In addition, our method can provide a mean SA score which can give a performance estimation of the output on the test images without ground-truth. Finally, we use the proposed ProtoSeg method to compute the segmentation map directly on input images to further understand the segmentation ability of each input image. Results are presented on segmenting tumors in brain MRI, lesions in skin images, COVID-related abnormality in CT images, prostate segmentation in abdominal MRI, and pancreatic mass segmentation in CT images. Our method can provide new insights for interpreting and explainable AI systems for medical image segmentation. Our code is available on: https://github.com/shengfly/ProtoSeg.
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COVID-19 , Neoplasias , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de ComputaçãoRESUMO
OBJECTIVE: To evaluate the utility of the 1 Tesla (1 T) Embrace (Aspect Imaging) neonatal magnetic resonance imaging (MRI) scanner in a level III NICU. STUDY DESIGN: Embrace brain MRI findings for 207 infants were reviewed, including 32 scans directly compared within 5 days with imaging on a 3 T Siemens Trio. Clinical MRI scan abnormalities were also compared to cranial ultrasound findings. RESULT: Of the 207 Embrace brain MRIs, 146 (70.5%) were obtained for clinical indications and 61 (29.5%) were research cases. Abnormal findings were found in 80 scans, most commonly hemorrhage and white matter injury. Notable findings included a stroke, medullary brainstem tumor, and polymicrogyria. In the 1 T versus 3 T comparison cohort, results were discordant in only one infant with punctate foci of susceptibility noted only on the 3 T scan. CONCLUSION: The Embrace MRI scans detected clinically relevant brain abnormalities and in a subset were clinically comparable to 3 T scans.
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Lesões Encefálicas , Unidades de Terapia Intensiva Neonatal , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Lesões Encefálicas/patologia , Ecoencefalografia , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , NeuroimagemRESUMO
OBJECTIVE: Intracranial electroencephalographic (icEEG) studies show that interictal ripples propagate across the brain of children with medically refractory epilepsy (MRE), and the onset of this propagation (ripple onset zone [ROZ]) estimates the epileptogenic zone. It is still unknown whether we can map this propagation noninvasively. The goal of this study is to map ripples (ripple zone [RZ]) and their propagation onset (ROZ) using high-density EEG (HD-EEG) and magnetoencephalography (MEG), and to estimate their prognostic value in pediatric epilepsy surgery. METHODS: We retrospectively analyzed simultaneous HD-EEG and MEG data from 28 children with MRE who underwent icEEG and epilepsy surgery. Using electric and magnetic source imaging, we estimated virtual sensors (VSs) at brain locations that matched the icEEG implantation. We detected ripples on VSs, defined the virtual RZ and virtual ROZ, and estimated their distance from icEEG. We assessed the predictive value of resecting virtual RZ and virtual ROZ for postsurgical outcome. Interictal spike localization on HD-EEG and MEG was also performed and compared with ripples. RESULTS: We mapped ripple propagation in all patients with HD-EEG and in 27 (96%) patients with MEG. The distance from icEEG did not differ between HD-EEG and MEG when mapping the RZ (26-27mm, p = 0.6) or ROZ (22-24mm, p = 0.4). Resecting the virtual ROZ, but not virtual RZ or the sources of spikes, was associated with good outcome for HD-EEG (p = 0.016) and MEG (p = 0.047). INTERPRETATION: HD-EEG and MEG can map interictal ripples and their propagation onset (virtual ROZ). Noninvasively mapping the ripple onset may augment epilepsy surgery planning and improve surgical outcome of children with MRE. ANN NEUROL 2021;89:911-925.
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Mapeamento Encefálico/métodos , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Eletrocorticografia/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Magnetoencefalografia , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Resultado do TratamentoRESUMO
Background Children operated on for a simple congenital heart defect (CHD) are at risk of neurodevelopmental abnormalities. Abnormal cortical development and folding have been observed in fetuses with CHD. We examined whether sulcal folding patterns in adults operated on for simple CHD in childhood differ from those of healthy controls, and whether such differences are associated with neuropsychological outcomes. Methods and Results Patients (mean age, 24.5 years) who underwent childhood surgery for isolated atrial septal defect (ASD; n=33) or ventricular septal defect (VSD; n=30) and healthy controls (n=37) were enrolled. Sulcal pattern similarity to healthy controls was determined using magnetic resonance imaging and looking at features of sulcal folds, their intersulcal relationships, and sulcal graph topology. The sulcal pattern similarity values were tested for associations with comprehensive neuropsychological scores. Patients with both ASD and VSD had decreased sulcal pattern similarity in the left hemisphere compared with controls. The differences were found in the left temporal lobe in the ASD group and in the whole left hemisphere in the VSD group (P=0.033 and P=0.039, respectively). The extent of abnormal left hemispheric sulcal pattern similarity was associated with worse neuropsychological scores (intelligence, executive function, and visuospatial abilities) in the VSD group, and special educational support in the ASD group. Conclusions Adults who underwent surgery for simple CHD in childhood display altered left hemisphere sulcal folding patterns, commensurate with neuropsychological scores for patients with VSD and special educational support for ASD. This may indicate that simple CHD affects early brain development. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.
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Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Córtex Cerebral/diagnóstico por imagem , Função Executiva/fisiologia , Comunicação Interatrial/cirurgia , Comunicação Interventricular/cirurgia , Inteligência/fisiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Previsões , Cardiopatias Congênitas/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Complicações Pós-Operatórias , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: To assess the ability of high-density Electroencephalography (HD-EEG) and magnetoencephalography (MEG) to localize interictal ripples, distinguish between ripples co-occurring with spikes (ripples-on-spike) and independent from spikes (ripples-alone), and evaluate their localizing value as biomarkers of epileptogenicity in children with medically refractory epilepsy. METHODS: We retrospectively studied 20 children who underwent epilepsy surgery. We identified ripples on HD-EEG and MEG data, localized their generators, and compared them with intracranial EEG (icEEG) ripples. When ripples and spikes co-occurred, we performed source imaging distinctly on the data above 80 Hz (to localize ripples) and below 70 Hz (to localize spikes). We assessed whether missed resection of ripple sources predicted poor outcome, separately for ripples-on-spikes and ripples-alone. Similarly, predictive value of spikes was calculated. RESULTS: We observed scalp ripples in 16 patients (10 good outcome). Ripple sources were highly concordant to the icEEG ripples (HD-EEG concordance: 79%; MEG: 83%). When ripples and spikes co-occurred, their sources were spatially distinct in 83-84% of the cases. Removing the sources of ripples-on-spikes predicted good outcome with 90% accuracy for HD-EEG (P = 0.008) and 86% for MEG (P = 0.044). Conversely, removing ripples-alone did not predict outcome. Resection of spike sources (generated at the same time as ripples) predicted good outcome for HD-EEG (P = 0.036; accuracy = 87%), while did not reach significance for MEG (P = 0.1; accuracy = 80%). INTERPRETATION: HD-EEG and MEG localize interictal ripples with high precision in children with refractory epilepsy. Scalp ripples-on-spikes are prognostic, noninvasive biomarkers of epileptogenicity, since removing their cortical generators predicts good outcome. Conversely, scalp ripples-alone are most likely generated by non-epileptogenic areas.
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Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia/normas , Magnetoencefalografia/normas , Procedimentos Neurocirúrgicos/normas , Avaliação de Resultados em Cuidados de Saúde/normas , Adolescente , Biomarcadores , Ondas Encefálicas/fisiologia , Criança , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocorticografia/normas , Feminino , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Couro CabeludoRESUMO
OBJECTIVE: To localize the seizure onset zone (SOZ) and irritative zone (IZ) using electric source imaging (ESI) on intracranial EEG (iEEG) and assess their clinical value in predicting epilepsy surgery outcome in children with focal cortical dysplasia (FCD). METHODS: We analyzed iEEG data from 25 children with FCD-associated medically refractory epilepsy (MRE) who underwent surgery. We performed ESI on ictal onset to localize SOZ (ESI-SOZ) and on interictal discharges to localize IZ (ESI-IZ). We tested whether resection of ESI-SOZ and ESI-IZ predicted good surgical outcome (Engel 1). We further compared the prediction performance of ESI-SOZ and ESI-IZ to those of SOZ and IZ defined using conventional methods, i.e. by identifying iEEG-contacts showing ictal onsets (conventional-SOZ) or being the most interictally active (conventional-IZ). RESULTS: The proximity of ESI-SOZ (p = 0.043, odds-ratio = 3.9) and ESI-IZ (p = 0.011, odds-ratio = 7.04) to resection has higher effect on patients' outcome than proximity of conventional-SOZ (p = 0.17, odds-ratio = 1.7) and conventional-IZ (p = 0.038, odds-ratio = 2.6). Resection of ESI-SOZ and ESI-IZ presented higher discriminative power in predicting outcome (68% and 60%) than conventional-SOZ and conventional-IZ (48% and 53%). CONCLUSIONS: Localizing SOZ and IZ via ESI on iEEG offers higher predictive value compared to conventional-iEEG interpretation. SIGNIFICANCE: iEEG-ESI may help surgical planning and facilitate prognostic assessment of children with FCD-associated MRE.
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Encéfalo/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia/fisiopatologia , Malformações do Desenvolvimento Cortical do Grupo I/fisiopatologia , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Mapeamento Encefálico , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico por imagem , Malformações do Desenvolvimento Cortical do Grupo I/cirurgia , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To use novel optical techniques to measure perioperative cerebral hemodynamics of diverse congenital heart disease (CHD) groups (two-ventricle, d-transposition of the great arteries [TGA], and single ventricle [SV]) and (1) compare CHD groups with healthy controls preoperatively and (2) compare preoperative and postoperative values within each CHD group. METHODS: Frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy were used to measure cerebral oxygen saturation, cerebral blood volume, cerebral blood flow index, cerebral oxygen extraction fraction (OEF, calculated using arterial oxygen saturation and cerebral oxygen saturation), and an index of cerebral metabolic rate of oxygen consumption in control and CHD neonates. Preoperative CHD measures were compared with controls. Preoperative and postoperative measures were compared within each CHD group. RESULTS: In total, 31 CHD neonates (7 two-ventricle, 11 TGA, 13 SV) and 13 controls were included. Only neonates with SV CHD displayed significantly lower preoperative cerebral blood flow index (P < .04) than controls. TGA and SV groups displayed greater OEF (P < .05) during the preoperative period compared with controls. Compared with the preoperative state, postoperative neonates with TGA had a greater arterial oxygen saturation with lower OEF. CONCLUSIONS: Differences in cerebral hemodynamics and oxygen metabolism were observed in diverse CHD groups compared with controls. Increased OEF appears to be a compensatory mechanism in neonates with TGA and SV. Studies are needed to understand the relationship of these metrics to outcome and their potential to guide interventions to improve outcome.
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Circulação Cerebrovascular/fisiologia , Cardiopatias Congênitas/fisiopatologia , Hemodinâmica/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/cirurgia , Humanos , Recém-Nascido , Masculino , Oxigênio/sangue , Assistência Perioperatória , Estudos ProspectivosRESUMO
BACKGROUND: To investigate dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) MRI as a means to non-invasively image glucose transport in the human placenta. METHODS: Continuous wave (CW) CEST MRI was performed at 3.0 Tesla. The glucose contrast enhancement (GCE) was calculated based on the magnetization transfer asymmetry (MTRasym), and the DGE was calculated with the positive side of Z-spectra in reference to the first time point. The glucose CEST (GlucoCEST) was optimized using a glucose solution phantom. Glucose solution perfused ex vivo placenta tissue was used to demonstrate GlucoCEST MRI effect. The vascular density of ex vivo placental tissue was evaluated with yellow dye after MRI scans. Finally, we preliminarily demonstrated GlucoCEST MRI in five pregnant subjects who received a glucose tolerance test. For human studies, the dynamic R2* change was captured with T2*-weighted echo planar imaging (EPI). RESULTS: The GCE effect peaks at a saturation B1 field of about 2 µT, and the GlucoCEST effect increases linearly with the glucose concentration between 4-20 mM. In ex vivo tissue, the GlucoCEST MRI was sensitive to the glucose perfusate and the placenta vascular density. Although the in vivo GCE baseline was sensitive to field inhomogeneity and motion artifacts, the temporal evolution of the GlucoCEST effect showed a consistent and positive response after oral glucose tolerance drink. CONCLUSIONS: Despite the challenges of placental motion and field inhomogeneity, our study demonstrated the feasibility of DGE placenta MRI at 3.0 Tesla.
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Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).
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Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do GenomaRESUMO
OBJECTIVE: To evaluate the accuracy and clinical utility of conventional 21-channel EEG (conv-EEG), 72-channel high-density EEG (HD-EEG) and 306-channel MEG in localizing interictal epileptiform discharges (IEDs). METHODS: Twenty-four children who underwent epilepsy surgery were studied. IEDs on conv-EEG, HD-EEG, MEG and intracranial EEG (iEEG) were localized using equivalent current dipoles and dynamical statistical parametric mapping (dSPM). We compared the localization error (ELoc) with respect to the ground-truth Irritative Zone (IZ), defined by iEEG sources, between non-invasive modalities and the distance from resection (Dres) between good- (Engel 1) and poor-outcomes. For each patient, we estimated the resection percentage of IED sources and tested whether it predicted outcome. RESULTS: MEG presented lower ELoc than HD-EEG and conv-EEG. For all modalities, Dres was shorter in good-outcome than poor-outcome patients, but only the resection percentage of the ground-truth IZ and MEG-IZ predicted surgical outcome. CONCLUSIONS: MEG localizes the IZ more accurately than conv-EEG and HD-EEG. MSI may help the presurgical evaluation in terms of patient's outcome prediction. The promising clinical value of ESI for both conv-EEG and HD-EEG prompts the use of higher-density EEG-systems to possibly achieve MEG performance. SIGNIFICANCE: Localizing the IZ non-invasively with MSI/ESI facilitates presurgical evaluation and surgical prognosis assessment.
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Eletroencefalografia/métodos , Epilepsia/diagnóstico , Magnetoencefalografia/métodos , Adolescente , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Excitabilidade Cortical , Eletroencefalografia/normas , Epilepsia/fisiopatologia , Epilepsia/cirurgia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Magnetoencefalografia/normas , Masculino , Reprodutibilidade dos TestesRESUMO
Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.
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Transtorno do Espectro Autista/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Tubulina (Proteína)/genética , Substância Branca/diagnóstico por imagem , Adulto , Fatores Etários , Anisotropia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Casos e Controles , Córtex Cerebral/patologia , Criança , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Endofenótipos , Feminino , Fibrose/diagnóstico por imagem , Fibrose/genética , Fibrose/patologia , Fibrose/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Síndrome de Kallmann/diagnóstico por imagem , Síndrome de Kallmann/genética , Síndrome de Kallmann/patologia , Síndrome de Kallmann/fisiopatologia , Masculino , Mutação , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Testes Neuropsicológicos , Oftalmoplegia/diagnóstico por imagem , Oftalmoplegia/genética , Oftalmoplegia/patologia , Oftalmoplegia/fisiopatologia , Tamanho do Órgão , Tratos Piramidais/patologia , Síndrome , Substância Branca/patologia , Adulto JovemRESUMO
INTRODUCTION: Patients with medically refractory epilepsy (MRE) need surgical resection of the epileptogenic zone (EZ) to gain seizure-freedom. High-frequency oscillations (HFOs, > 80 Hz) are promising biomarkers of the EZ that are typically localized using intracranial electroencephalography (icEEG). The goal of this study was to localize the cortical generators of HFOs non-invasively using high-density (HD) EEG and magnetoencephalography (MEG) and validate the localization against the gold-standard given by the icEEGdefined HFO-zone. METHODS: We analyzed simultaneous HDEEG and MEG data from six children with MRE who underwent icEEG and surgery. We detected interictal HFOs (80-160 Hz) on HD-EEG and MEG separately, using an inhouse automatic detector followed by visual human review, and distinguished between HFOs with and without spikes. We localized the cortical generators of each HFO on HD-EEG or MEG using the wavelet Maximum Entropy on the Mean (wMEM). For the HFOs localized in the brain area covered by icEEG, we estimated the localization error (Eloc) with respect to the gold-standard, and classified them as either concordant (Eloc≤15mm) or not. RESULTS: We found that: (i) HD-EEG presented a higher rate of HFOs than MEG (1 vs 0.5 HFOs/min, p=0.031); (ii) HFOs without spikes were more likely to be localized outside the brain regions of interest (i.e. covered by icEEG) than HFOs with spikes; and (iii) both HD-EEG and MEG showed high precision to the gold-standard (92% and 96%). CONCLUSION: We reported quantitative evidence that HDEEG and MEG can localize the HFO cortical generators with high precision to the icEEG gold-standard in children with MRE, suggesting that they may possibly limit the need for icEEG prior to surgery. We also showed that HFOs with spikes on HD-EEG/MEG are more likely to be epileptogenic than those independent from spikes, which may represent physiological events from normal brain.
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Eletroencefalografia , Epilepsia , Magnetoencefalografia , Criança , Eletrocorticografia , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , HumanosRESUMO
The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.
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OBJECTIVE: In patients with medically refractory epilepsy (MRE), interictal ripples (80-250Hz) are observed in large brain areas whose resection may be unnecessary for seizure freedom. This limits their utility as epilepsy biomarkers for surgery. We assessed the spatiotemporal propagation of interictal ripples on intracranial electroencephalography (iEEG) in children with MRE, compared it with the propagation of spikes, identified ripples that initiated propagation (onset-ripples), and evaluated their clinical value as epilepsy biomarkers. METHODS: Twenty-seven children who underwent epilepsy surgery were studied. We identified propagation sequences of ripples and spikes across multiple iEEG contacts and calculated each ripple or spike latency from the propagation onset. We classified ripples and spikes into categories (ie, onset, spread, and isolated) based on their spatiotemporal characteristics and correlated their mean rate inside and outside resection with outcome (good outcome, Engel 1 versus poor outcome, Engel≥2). We determined, as onset-zone, spread-zone, and isolated-zone, the areas generating the corresponding ripple or spike category and evaluated the predictive value of their resection. RESULTS: We observed ripple propagation in all patients and spike propagation in 25 patients. Mean rate of onset-ripples inside resection predicted the outcome (odds ratio = 5.37; p = 0.02) and correlated with Engel class (rho = -0.55; p = 0.003). Resection of the onset-ripple-zone was associated with good outcome (p = 0.047). No association was found for the spread-ripple-zone, isolated-ripple-zone, or any spike-zone. INTERPRETATION: Interictal ripples propagate across iEEG contacts in children with MRE. The association between the onset-ripple-zone resection and good outcome indicates that onset-ripples are promising epilepsy biomarkers, which estimate the epileptogenic tissue better than spread-ripples or onset-spikes. Ann Neurol 2018;84:331-346.
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Encéfalo/cirurgia , Epilepsia/cirurgia , Convulsões/cirurgia , Adolescente , Encéfalo/fisiopatologia , Ondas Encefálicas/fisiologia , Criança , Eletrocorticografia/métodos , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Feminino , Humanos , Masculino , Convulsões/diagnóstico , Resultado do TratamentoRESUMO
BACKGROUND: Sturge-Weber syndrome (SWS) is often accompanied by seizures, stroke-like episodes, hemiparesis, and visual field deficits. This study aimed to identify early pathophysiologic changes that exist before the development of clinical symptoms and to evaluate if the apparent diffusion coefficient (ADC) map is a candidate early biomarker of seizure risk in patients with SWS. METHODS: This is a prospective cross-sectional study using quantitative ADC analysis to predict onset of epilepsy. Inclusion criteria were presence of the port wine birthmark, brain MRI with abnormal leptomeningeal capillary malformation (LCM) and enlarged deep medullary veins, and absence of seizures or other neurological symptoms. We used our recently developed normative, age-specific ADC atlases to quantitatively identify ADC abnormalities, and correlated presymptomatic ADC abnormalities with risks for seizures. RESULTS: We identified eight patients (three girls) with SWS, age range of 40 days to nine months. One patient had predominantly LCM, deep venous anomaly, and normal ADC values. This patient did not develop seizures. The remaining seven patients had large regions of abnormal ADC values, and all developed seizures; one of seven patients had late onset seizures. CONCLUSIONS: Larger regions of decreased ADC values in the affected hemisphere, quantitatively identified by comparison with age-matched normative ADC atlases, are common in young children with SWS and were associated with later onset of seizures in this small study. Our findings suggest that quantitative ADC maps may identify patients at high risk of seizures in SWS, but larger prospective studies are needed to determine sensitivity and specificity.
Assuntos
Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Convulsões/diagnóstico , Convulsões/etiologia , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Prognóstico , Estudos ProspectivosRESUMO
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
Assuntos
Encéfalo/anormalidades , Neoplasias Colorretais/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Perda de Heterozigosidade/genética , Mutação/genética , Sistema Nervoso Central/anormalidades , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Neurônios/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genéticaRESUMO
The neonatal brain is extremely vulnerable to injury during periods of hypoxia and/or ischemia. Risk of brain injury is increased during neonatal cardiac surgery, where pre-existing hemodynamic instability and metabolic abnormalities are combined with long periods of low cerebral blood flow and/or circulatory arrest. Our understanding of events associated with cerebral hypoxia-ischemia during cardiopulmonary bypass (CPB) remains limited, largely due to inadequate tools to quantify cerebral oxygen delivery and consumption non-invasively and in real-time. This pilot study aims to evaluate cerebral blood flow (CBF) and oxygen metabolism (CMRO2) intraoperatively in neonates by combining two novel non-invasive optical techniques: frequency-domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS). CBF and CMRO2 were quantified before, during and after deep hypothermic cardiopulmonary bypass (CPB) in nine neonates. Our results show significantly decreased CBF and CMRO2 during hypothermic CPB. More interestingly, a change of coupling between both variables is observed during deep hypothermic CPB in all subjects. Our results are consistent with previous studies using invasive techniques, supporting the concept of FD-NIRS/DCS as a promising technology to monitor cerebral physiology in neonates providing the potential for individual optimization of surgical management.