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1.
Hum Brain Mapp ; 40(1): 53-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30136325

RESUMO

Clinical interpretation of cerebral positron emission tomography with 2-deoxy-2[F-18]fluoro-d-glucose (FDG-PET) images often relies on evaluation of regional asymmetries. This study was designed to establish age-related variations in regional cortical glucose metabolism asymmetries in the developing human brain. FDG-PET scans of 58 children (age: 1-18 years) were selected from a large single-center pediatric PET database. All children had a history of epilepsy, normal MRI, and normal pattern of glucose metabolism on visual evaluation. PET images were analyzed objectively by statistical parametric mapping with the use of age-specific FDG-PET templates. Regional FDG uptake was measured in 35 cortical regions in both hemispheres using an automated anatomical labeling atlas, and left/right ratios were correlated with age, gender, and epilepsy variables. Cortical glucose metabolism was mostly symmetric in young children and became increasingly asymmetric in older subjects. Specifically, several frontal cortical regions showed an age-related increase of left > right asymmetries (mean: up to 10%), while right > left asymmetries emerged in posterior cortex (including portions of the occipital, parietal, and temporal lobe) in older children (up to 9%). Similar trends were seen in a subgroup of 39 children with known right-handedness. Age-related correlations of regional metabolic asymmetries showed no robust gender differences and were not affected by epilepsy variables. These data demonstrate a region-specific emergence of cortical metabolic asymmetries between age 1-18 years, with left > right asymmetry in frontal and right > left asymmetry in posterior regions. The findings can facilitate correct interpretation of cortical regional asymmetries on pediatric FDG-PET images across a wide age range.


Assuntos
Córtex Cerebral , Epilepsia/metabolismo , Lateralidade Funcional/fisiologia , Glucose/metabolismo , Adolescente , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Epilepsia/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Lactente , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
2.
Inflamm Res ; 68(12): 993-998, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31511910

RESUMO

BACKGROUND: Neuroinflammation and toll-like receptors (TLR) of the innate immune system have been implicated in epilepsy. We previously reported high levels of microRNAs miR-142-3p and miR-223-3p in epileptogenic brain tissue resected for the treatment of intractable epilepsy in children with tuberous sclerosis complex (TSC). As miR-142-3p has recently been reported to be a ligand and activator of TLR7, a detector of exogenous and endogenous single-stranded RNA, we evaluated TLR7 expression and downstream IL23A activation in surgically resected TSC brain tissue. METHODS: Gene expression analysis was performed on cortical tissue obtained from surgery of TSC children with pharmacoresistent epilepsy. Expression of TLRs 2, 4 and 7 was measured using NanoString nCounter assays. Real-time quantitative PCR was used to confirm TLR7 expression and compare TLR7 activation, indicated by IL-23A levels, to levels of miR-142-3p. Protein markers characteristic for TLR7 activation were assessed using data from our existing quantitative proteomics dataset of TSC tissue. Capillary electrophoresis Western blots were used to confirm TLR7 protein expression in a subset of samples. RESULTS: TLR7 transcript expression was present in all TSC specimens. The signaling competent form of TLR7 protein was detected in the membrane fraction of each sample tested. Downstream activation of TLR7 was found in epileptogenic lesions having elevated neuroinflammation indicated by clinical neuroimaging. TLR7 activity was significantly associated with tissue levels of miR-142-3p. CONCLUSION: TLR7 activation by microRNAs may contribute to the neuroinflammatory cascade in epilepsy in TSC. Further characterization of this mechanism may enable the combined of use of neuroimaging and TLR7 inhibitors in a personalized approach towards the treatment of intractable epilepsy.


Assuntos
Epilepsia/genética , MicroRNAs/genética , Receptor 7 Toll-Like/genética , Esclerose Tuberosa/genética , Criança , Pré-Escolar , Feminino , Expressão Gênica , Humanos , Lactente , Masculino , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
3.
Childs Nerv Syst ; 35(8): 1341-1349, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31243582

RESUMO

PURPOSE: To evaluate microsurgical trans-sylvian trans-ventricular anatomical hemispherectomy with regard to seizure outcome, risk of hydrocephalus, blood loss, and risk of chronic hemosiderosis in patients with intractable seizures selected for surgery using current preoperative assessment techniques. METHODS: Out of 86 patients who underwent hemispherectomy between February 2000 and April 2019, by a single surgeon, at a tertiary care referral center, 77 patients (ages 0.2-20 years; 40 females) who had an anatomical hemispherectomy were analyzed. Five of these were 'palliative' surgeries. One-stage anatomical hemispherectomy was performed in 55 children, two-stage anatomical hemispherectomy after extraoperative intracranial monitoring in 16, and six hemispherectomies were done following failed previous resection. Mean follow-up duration was 5.7 years (range 1-16.84 years). Forty-six patients had postoperative MRI scans. RESULTS: Ninety percent of children with non-palliative hemispherectomy achieved ILAE Class-1 outcome. Twenty-seven patients were no longer taking anticonvulsant medications. Surgical failures (n = 4) included one patient with previous meningoencephalitis, one with anti-GAD antibody encephalitis, one with idiopathic neonatal thalamic hemorrhage, and one with extensive tuberous sclerosis. There were no failures among patients with malformations of cortical development. Estimated average blood loss during surgery was 387 ml. Ten (21%) children developed hydrocephalus and required a shunt following one-stage hemispherectomy, whereas 10 (50%) patients developed hydrocephalus among those who had extraoperative intracranial monitoring. Only 20% of the shunts malfunctioned in the first year. Early malfunctions were related to the valve and later to fracture disconnection of the shunt. One patent had a traumatic subdural hematoma. None of the patients developed clinical signs of chronic 'superficial cerebral hemosiderosis' nor was there evidence of radiologically persistent chronic hemosiderosis in patients who had postoperative MRI imaging. CONCLUSION: Surgical results of anatomical hemispherectomy are excellent in carefully selected cases. Post-operative complications of hydrocephalus and intraoperative blood loss are comparable to those reported for hemispheric disconnective surgery (hemispherotomy). The rate of shunt malfunction was less than that reported for patients with hydrocephalus of other etiologies Absence of chronic 'superficial hemosiderosis', even on long-term follow-up, suggests that anatomical hemispherectomy should be revisited as a viable option in patients with intractable seizures and altered anatomy such as in malformations of cortical development, a group that has a reported high rate of seizure recurrence related to incomplete disconnection following hemispheric disconnective surgery.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Hemisferectomia/efeitos adversos , Hemisferectomia/métodos , Complicações Pós-Operatórias/etiologia , Adolescente , Perda Sanguínea Cirúrgica , Criança , Pré-Escolar , Feminino , Hemossiderose/epidemiologia , Hemossiderose/etiologia , Humanos , Hidrocefalia/epidemiologia , Hidrocefalia/etiologia , Lactente , Masculino , Complicações Pós-Operatórias/epidemiologia , Adulto Jovem
4.
Neurobiol Dis ; 109(Pt A): 76-87, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28993242

RESUMO

Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[11C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.


Assuntos
MicroRNAs/metabolismo , Tomografia por Emissão de Pósitrons , Convulsões/metabolismo , Triptofano/metabolismo , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/metabolismo , Criança , Pré-Escolar , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Convulsões/complicações , Convulsões/diagnóstico por imagem , Convulsões/genética , Simportadores/metabolismo , Triptofano/análogos & derivados , Triptofano/análise , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética
5.
Hum Brain Mapp ; 39(4): 1596-1606, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29274110

RESUMO

To evaluate metabolic changes in the ipsi- and contralateral hemisphere in children showing a cognitive profile consistent with early reorganization of cognitive function, we evaluated the regional glucose uptake, interhemispheric metabolic connectivity, and cognitive function in children with unilateral SWS. Interictal 2-deoxy-2[18 F]fluoro-D-glucose (FDG)-PET scans of 27 children with unilateral SWS and mild epilepsy and 27 age-matched control (non-SWS children with epilepsy and normal FDG-PET) were compared using statistical parametric mapping (SPM). Regional FDG-PET abnormalities calculated as SPM(t) scores in the SWS group were correlated with cognitive function (IQ) in left- and right-hemispheric subgroups. Interhemispheric metabolic connectivity between homotopic cortical regions was also calculated. Verbal IQ was substantially (≥10 points difference) higher than non-verbal IQ in 61% of the right- and 71% of the left-hemispheric SWS group. FDG SPM(t) scores in the affected hemisphere showed strong positive correlations with IQ in the left-hemispheric, but not in right-hemispheric SWS group in several frontal, parietal, and temporal cortical regions. Significant positive interhemispheric metabolic connectivity, present in controls, was diminished in the SWS group. In addition, the left-hemispheric SWS group showed inverse metabolic interhemispheric correlations in specific parietal, temporal, and occipital regions. FDG SPM(t) scores in the same regions of the right (unaffected) hemisphere showed inverse correlations with IQ. These findings suggest that left-hemispheric lesions in SWS often result in early reorganization of verbal functions while interfering with ("crowding") their non-verbal cognitive abilities. These cognitive changes are associated with specific metabolic abnormalities in the contralateral hemisphere not directly affected by SWS.


Assuntos
Encéfalo/metabolismo , Cognição/fisiologia , Síndrome de Sturge-Weber/metabolismo , Síndrome de Sturge-Weber/psicologia , Adolescente , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Fluordesoxiglucose F18 , Lateralidade Funcional , Glucose , Humanos , Inteligência/fisiologia , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Síndrome de Sturge-Weber/diagnóstico por imagem , Síndrome de Sturge-Weber/tratamento farmacológico
6.
Epilepsia ; 59(7): 1307-1315, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29786852

RESUMO

OBJECTIVE: We analyzed long-term changes of lobar glucose metabolic abnormalities in relation to clinical seizure variables and development in a large group of children with medically refractory epilepsy. METHODS: Forty-one children (25 males) with drug-resistant epilepsy had a baseline positron emission tomography (PET) scan at a median age of 4.7 years; the scans were repeated after a median of 4.3 years. Children with progressive neurological disorders or space-occupying lesion-related epilepsy and those who had undergone epilepsy surgery were excluded. The number of affected lobes on 2-deoxy-2(18 F)-fluoro-D-glucose-PET at baseline and follow-up was correlated with epilepsy variables and developmental outcome. RESULTS: On the initial PET scan, 24 children had unilateral and 13 had bilateral glucose hypometabolism, whereas 4 children had normal scans. On the follow-up scan, 63% of the children showed an interval expansion of the hypometabolic region, and this progression was associated with persistent seizures. In contrast, 27% showed less extensive glucose hypometabolism at follow-up; most of these subjects manifested a major interval decrease in seizure frequency. Delayed development was observed in 21 children (51%) at baseline and 28 (68%) at follow-up. The extent of glucose hypometabolism at baseline correlated with developmental levels at the time of both baseline (r = .31, P = .05) and follow-up scans (r = .27, P = .09). SIGNIFICANCE: In this PET study of unoperated children with focal epilepsy, the lobar pattern of glucose hypometabolism changed over time in 90% of the cases. The results support the notion of an expansion of metabolic dysfunction in children with persistent frequent seizures and its association with developmental delay, and support that optimized medical treatment to control seizures may contribute to better neurocognitive outcome if no surgery can be offered.


Assuntos
Glicemia/metabolismo , Encéfalo/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Metabolismo Energético/fisiologia , Adolescente , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Dominância Cerebral/efeitos dos fármacos , Dominância Cerebral/fisiologia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Eletroencefalografia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Fluordesoxiglucose F18 , Seguimentos , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos
7.
Epilepsy Behav ; 80: 202-207, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29414553

RESUMO

PURPOSE: Most children with Sturge-Weber syndrome (SWS) develop seizures that may contribute to neurocognitive status. In this study, we tested the hypothesis that very early seizure onset has a particularly detrimental effect on the cognitive and/or motor outcomes of children with unilateral SWS. We also tested whether side of SWS brain involvement modulates the effect of seizure variables on the pattern of cognitive abnormalities. METHODS: Thirty-four children (22 girls; mean age 6.1years) with unilateral SWS and history of epilepsy in a longitudinal cohort underwent neurological and cognitive evaluations. Global intelligent quotient (GIQ), verbal intelligent quotient (VIQ), nonverbal intelligent quotient (IQ), and motor function were correlated with epilepsy variables, side and extent of brain involvement on magnetic resonance imaging (MRI). RESULTS: Mean age at seizure onset was 1.3years (0.1-6years) and mean IQ at follow-up was 86 (45-118). Age at seizure onset showed a logarithmic association with IQ, with maximum impact of seizures starting before age 1year, both in uni- and multivariate regression analyses. In the left SWS group (N=20), age at seizure onset was a strong predictor of nonverbal IQ (p=0.001); while early seizure onset in the right-hemispheric group had a more global effect on cognitive functions (p=0.02). High seizure frequency and long epilepsy duration also contributed to poor outcome IQ independently in multivariate correlations. Children with motor involvement started to have seizures at/before 7months of age, while frontal lobe involvement was the strongest predictor of motor deficit in a multivariate analysis (p=0.017). CONCLUSION: These findings suggest that seizure onset prior to age 1year has a profound effect on severity of cognitive and motor dysfunction in children with SWS; however, the effect of seizures on the type of cognitive deficit is influenced by laterality of brain involvement.


Assuntos
Idade de Início , Encéfalo/diagnóstico por imagem , Cognição , Inteligência , Imageamento por Ressonância Magnética/métodos , Síndrome de Sturge-Weber/diagnóstico , Síndrome de Sturge-Weber/psicologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Transtornos Cognitivos/complicações , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Lobo Frontal/fisiopatologia , Lateralidade Funcional , Humanos , Lactente , Testes de Inteligência , Estudos Longitudinais , Masculino , Análise Multivariada , Estudos Prospectivos , Convulsões/complicações , Convulsões/etiologia , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/fisiopatologia
8.
Hum Brain Mapp ; 38(6): 3098-3112, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28322026

RESUMO

To determine the spatial relationship between 2-deoxy-2[18 F]fluoro-D-glucose (FDG) metabolic and intracranial electrophysiological abnormalities in children undergoing two-stage epilepsy surgery, statistical parametric mapping (SPM) was used to correlate hypo- and hypermetabolic cortical regions with ictal and interictal electrocorticography (ECoG) changes mapped onto the brain surface. Preoperative FDG-PET scans of 37 children with intractable epilepsy (31 with non-localizing MRI) were compared with age-matched pseudo-normal pediatric control PET data. Hypo-/hypermetabolic maps were transformed to 3D-MRI brain surface to compare the locations of metabolic changes with electrode coordinates of the ECoG-defined seizure onset zone (SOZ) and interictal spiking. While hypometabolic clusters showed a good agreement with the SOZ on the lobar level (sensitivity/specificity = 0.74/0.64), detailed surface-distance analysis demonstrated that large portions of ECoG-defined SOZ and interictal spiking area were located at least 3 cm beyond hypometabolic regions with the same statistical threshold (sensitivity/specificity = 0.18-0.25/0.94-0.90 for overlap 3-cm distance); for a lower threshold, sensitivity for SOZ at 3 cm increased to 0.39 with a modest compromise of specificity. Performance of FDG-PET SPM was slightly better in children with smaller as compared with widespread SOZ. The results demonstrate that SPM utilizing age-matched pseudocontrols can reliably detect the lobe of seizure onset. However, the spatial mismatch between metabolic and EEG epileptiform abnormalities indicates that a more complete SOZ detection could be achieved by extending intracranial electrode coverage at least 3 cm beyond the metabolic abnormality. Considering that the extent of feasible electrode coverage is limited, localization information from other modalities is particularly important to optimize grid coverage in cases of large hypometabolic cortex. Hum Brain Mapp 38:3098-3112, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Mapeamento Encefálico , Encéfalo , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/fisiopatologia , Glucose/metabolismo , Imageamento Tridimensional/métodos , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsias Parciais/cirurgia , Potenciais Evocados/fisiologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Lactente , Masculino , Tomografia por Emissão de Pósitrons , Estatísticas não Paramétricas
9.
Dev Med Child Neurol ; 59(9): 952-958, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28397986

RESUMO

AIM: To evaluate clinical and metabolic correlates of cerebral calcifications in children with Sturge-Weber syndrome (SWS). METHOD: Fifteen children (11 females, four males; age range 7mo-9y, mean 4y 1mo) with unilateral SWS underwent baseline and follow-up magnetic resonance imaging (MRI) with susceptibility weighted imaging (SWI), glucose metabolism positron emission tomography (PET), and neurocognitive assessment (mean follow-up 1y 8mo). Calcified brain volumes measured on SWI were correlated with areas of abnormal glucose metabolism, seizure variables, and cognitive function (IQ). RESULTS: Ten children had brain calcification at baseline and 11 at follow-up. Mean calcified brain volume increased from 1.69 to 2.47cm3 (p=0.003) in these children; the rate of interval calcified volume increase was associated with early onset of epilepsy (Spearman's rho [rs ]=-0.63, p=0.036). Calcified brain regions showed a variable degree of glucose hypometabolism with the metabolic abnormalities often extending to non-calcified cerebral lobes. Larger calcified brain volumes at baseline were associated with longer duration of epilepsy (rs =0.69, p=0.004) and lower outcome IQ (rs =-0.53, p=0.042). INTERPRETATION: Brain calcifications are common and progress faster in children with SWS with early epilepsy onset, and are associated with a variable degree of hypometabolism, which is typically more extensive than the calcified area. Higher calcified brain volumes may indicate a risk for poorer neurocognitive outcome.


Assuntos
Encefalopatias/fisiopatologia , Encéfalo/diagnóstico por imagem , Calcinose/fisiopatologia , Síndrome de Sturge-Weber/fisiopatologia , Encefalopatias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Pré-Escolar , Cognição , Progressão da Doença , Feminino , Seguimentos , Glucose/metabolismo , Humanos , Lactente , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Síndrome de Sturge-Weber/diagnóstico por imagem , Fatores de Tempo
10.
Cereb Cortex ; 26(3): 1059-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25452577

RESUMO

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a.


Assuntos
Encéfalo/metabolismo , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/metabolismo , MicroRNAs/metabolismo , Esclerose Tuberosa/metabolismo , Encéfalo/cirurgia , Criança , Pré-Escolar , Cromatografia Líquida , Epilepsia Resistente a Medicamentos/epidemiologia , Epilepsia Resistente a Medicamentos/cirurgia , Feminino , Humanos , Masculino , Análise em Microsséries , NF-kappa B/metabolismo , Proteoma , Reação em Cadeia da Polimerase em Tempo Real , Risco , Sinapses/metabolismo , Espectrometria de Massas em Tandem , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/cirurgia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo
11.
Proc Natl Acad Sci U S A ; 111(36): 13010-5, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25157149

RESUMO

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.


Assuntos
Metabolismo Basal , Evolução Biológica , Encéfalo/embriologia , Encéfalo/metabolismo , Adulto , Envelhecimento/metabolismo , Peso Corporal , Feminino , Glucose/metabolismo , Humanos , Masculino , Adulto Jovem
12.
Hum Brain Mapp ; 37(11): 3946-3956, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27312605

RESUMO

To determine brain plasticity changes due to resective epilepsy surgery in children, we performed a longitudinal connectome analysis on the pattern of axonal connectivity in the contralateral hemisphere. Pre- and postoperative diffusion tensor imaging (DTI) data were acquired from 35 children with intractable focal epilepsy. A total of 54 brain regions of interest (ROIs) were generated in the hemisphere contralateral to the resection. Within a 54 × 54 connectivity matrix, a pairwise connectivity score was calculated for each connection between two ROIs, based on the DTI fiber streamline number in each connection. A permuted Spearman's ρ-rank analysis was used to identify specific inter-regional connections showing a significant association between the postoperative change of connectivity score and clinical variables. Nineteen connections in the contralateral hemisphere showed postoperative increases in the strength of connectivity. Postoperative increase in connectivity between insular-inferior frontal operculum regions as well as that between superior frontal orbital and mid frontal orbital regions were both significantly associated with a larger surgical resection volume (ρ > +0.40) and a younger patient age (ρ > -0.34). These increases were more robust in patients with frontal resection and in those achieving seizure freedom. Neuropsychological evaluation on subsets of patients revealed that such increases in connectivity were associated with preserved or improved cognitive functions such as visual memory and planning. Resective epilepsy surgery may lead to increased contralateral axonal connectivity in children with focal epilepsy. Our data lead to a hypothesis that such increased connectivity may be an imaging marker of postoperative brain plasticity to compensate for cognitive function. Hum Brain Mapp 37:3946-3956, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/cirurgia , Adolescente , Axônios , Criança , Pré-Escolar , Conectoma , Imagem de Tensor de Difusão , Epilepsia Resistente a Medicamentos/parasitologia , Epilepsias Parciais/parasitologia , Feminino , Lateralidade Funcional , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/cirurgia , Testes Neuropsicológicos , Resultado do Tratamento , Adulto Jovem
13.
J Pediatr ; 174: 264-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27156180

RESUMO

The use of gonadotropin-releasing hormone analogs has been reported in the treatment of gelastic seizures and precocious puberty associated with hypothalamic hamartomas, but not in other seizure types without hypothalamic hamartoma. We describe a 7.5 year-old girl whose seizures subsided after gonadotropin-releasing hormone analog implant, administered for precocious puberty.


Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Puberdade Precoce/tratamento farmacológico , Convulsões/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Criança , Feminino , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Puberdade Precoce/complicações , Convulsões/complicações , Convulsões/diagnóstico por imagem
14.
J Pediatr ; 170: 45-53.e1-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26746121

RESUMO

OBJECTIVES: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). STUDY DESIGN: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. RESULTS: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. CONCLUSIONS: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00873509.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Buspirona/administração & dosagem , Desenvolvimento Infantil/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem , Buspirona/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Serotonina/sangue , Agonistas do Receptor de Serotonina/uso terapêutico , Resultado do Tratamento
15.
J Magn Reson Imaging ; 44(6): 1504-1512, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27251476

RESUMO

PURPOSE: To investigate whether different genetic mutations observed in children with global developmental delay (GD) are associated with unique patterns of the arcuate fasciculus dysmorphology. MATERIALS AND METHODS: Six children with GD (age: 36.8 ± 14.1 months, 5 boys) having mutations in MID1, CDK4, SFRP1, EN2, RXRG-GLRB, or MECP2, and five children with typical development (TD, age: 38.5 ± 20.5 months, 4 boys) underwent a 3 Tesla MRI including diffusion weighted imaging (DWI). Five language pathway segments in the left hemisphere, "C1 : Broca's to Wernicke's area," "C2 : Broca's to premotor area," "C3 : premotor to Wernicke's area," "C4 : Wernicke's to inferior parietal area," and "C5 : premotor to inferior parietal area" were objectively identified using the DWI "maximum a posteriori probability" classifier. RESULTS: Affinity propagation clustering analysis found that three arcuate pathway segments, C1,2,4 , of MID1, CDK4, EN2, and MECP2 had a similar pattern of volume ratio while those of SFRP1 and RXRG-GLRB had a heterogeneous pattern of volume ratio (net similarity = -0.01). Using receiver operating characteristic curve analysis, the fiber ratios of C1,2,4 showed a high probability to discriminate between GD and TD, yielding an accuracy of 0.91, 0.91, 1.00, respectively. The fiber volumes of C1 and C4 showed a strong correlation with expressive language (R2 = 0.6019; P-value = 0.033) and receptive language (R2 = 0.6379; P-value = 0.028), respectively. CONCLUSION: The findings of the present study provide preliminary evidence to suggest that different segments of the arcuate fasciculus are formed under the regulation of different genes which, when mutated, may result in developmental delay. J. Magn. Reson. Imaging 2016;44:1504-1512.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Imagem de Tensor de Difusão/métodos , Vias Neurais/patologia , Lobo Parietal/patologia , Lobo Temporal/patologia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia
16.
J Magn Reson Imaging ; 41(2): 431-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24391057

RESUMO

PURPOSE: To determine the relation between glucose metabolic changes of the primary visual cortex, structural abnormalities of the corresponding visual tracts, and visual symptoms in children with Sturge-Weber syndrome (SWS). MATERIALS AND METHODS: In 10 children with unilateral SWS (ages 1.5-5.5 years), a region-of-interest analysis was applied in the bilateral medial occipital cortex on positron emission tomography (PET) and used to track diffusion-weighted imaging (DWI) streamlines corresponding to the central visual pathway. Normalized streamline volumes of individual SWS patients were compared with values from age-matched control groups as well as correlated with normalized glucose uptakes and visual field deficit. RESULTS: Lower glucose uptake and lower corresponding streamline volumes were detected in the affected occipital lobe in 9/10 patients, as compared to the contralateral side. Seven of these 9 patients had visual field deficit and normal or decreased streamline volumes on the unaffected side. The two other children had no visual symptoms and showed high contralateral visual streamline volumes. There was a positive correlation between the normalized ratios on DWI and PET, indicating that lower glucose metabolism was associated with lower streamline volume in the affected hemisphere (R = 0.70, P = 0.024). CONCLUSION: We demonstrated that 18F-flurodeoxyglucose (FDG)-PET combined with DWI tractography can detect both brain damage on the side of the lesion and contralateral plasticity in children with early occipital lesions.


Assuntos
Imagem de Tensor de Difusão/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Síndrome de Sturge-Weber/patologia , Córtex Visual/patologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18 , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Compostos Radiofarmacêuticos
17.
Epilepsia ; 56(1): 49-57, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25489639

RESUMO

OBJECTIVE: To examine whether diffusion-weighted imaging (DWI) tractography can detect multiple white matter pathways connected to language cortices, we employed a maximum a posteriori probability (MAP) classification method, which has been recently validated for the corticospinal tract. METHODS: DWI was performed in 12 normally developing children and 17 children with intractable focal epilepsy who underwent subsequent two-stage epilepsy surgery with intracranial functional mapping. First, whole-brain DWI tractography was performed to identify unique pathways originating from Broca's area, premotor area, and Wernicke's area on functional magnetic resonance imaging (fMRI) of normal children and intracranial electrical stimulation mapping (ESM) of children with epilepsy. Group averaging of these pathways based on fMRI was performed to construct the probability maps of language areas in standard MRI space. These maps were finally used to design a DWI-MAP classifier, which can automatically sort individual fibers originating from fMRI language areas as well as ESM language areas. RESULTS: In normally developing children, the DWI-MAP classifier predicted language-activation areas on fMRI with up to 77% accuracy. In children with focal epilepsy, the DWI-MAP classifier also showed high accuracy (up to 82%) for the fibers terminating in proximity to essential language areas determined by ESM. Decreased volumes in DWI-MAP-defined pathways after epilepsy surgery were associated with postoperative language deficits. SIGNIFICANCE: This study encourages further investigations to determine if DWI-MAP analysis can serve as a noninvasive diagnostic tool during pediatric presurgical planning by estimating not only the location of essential language cortices, but also the underlying fibers connecting these cortical areas.


Assuntos
Epilepsias Parciais/cirurgia , Idioma , Vias Neurais/fisiologia , Cirurgia Assistida por Computador/métodos , Área de Wernicke/fisiologia , Substância Branca/fisiologia , Adolescente , Mapeamento Encefálico/métodos , Estudos de Casos e Controles , Criança , Pré-Escolar , Imagem de Tensor de Difusão , Estimulação Elétrica/métodos , Feminino , Neuroimagem Funcional , Humanos , Monitorização Neurofisiológica Intraoperatória , Imageamento por Ressonância Magnética , Masculino , Probabilidade
18.
Epilepsia ; 56(12): 1941-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26522016

RESUMO

OBJECTIVE: We reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms. METHODS: Data were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded. RESULTS: Mean age at surgery was 5.1 (range 0.2-19) years, with mean postsurgical follow-up of 45.3 (6-120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2-8), which decreased to 1.2 (0-4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome. Thirty-seven (79%) of 47 patients with lesional MRI had class-I outcome, whereas 9 (50%) of 18 with normal MRI had class I outcome. Positron emission tomography (PET) scan was abnormal in almost all patients [61 (97%) of 63 with lateralizing/localizing findings in 56 (92%) of 61 patients, thus helping in surgical decision making and guiding subdural grid placements, particularly in patients with nonlesional MRI. Fifteen patients had postoperative complications, mostly minor. SIGNIFICANCE: Curative epilepsy surgery in ES patients, with or without history of infantile spasms, is best accomplished at an early age and in those patients with lesional abnormalities on MRI with electroencephalography (EEG) concordance. Good outcomes can be achieved even when there is no MRI lesion but positive PET localization.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Hemisferectomia/métodos , Espasmos Infantis/cirurgia , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/patologia , Eletrocorticografia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Complicações Pós-Operatórias/etiologia , Espasmos Infantis/patologia , Resultado do Tratamento , Adulto Jovem
19.
Cereb Cortex ; 24(6): 1451-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23377288

RESUMO

The human neocortex is characterized by protracted developmental intervals of synaptogenesis and myelination, which allow for an extended period of learning. The molecular basis of these and other postnatal developmental changes in the human cerebral cortex remain incompletely understood. Recently, a new large class of mammalian genes, encoding nonmessenger, long nonprotein-coding ribonucleic acid (lncRNA) molecules has been discovered. Although their function remains uncertain, numerous lncRNAs have primate-specific sequences and/or show evidence of rapid, lineage-specific evolution, making them potentially relevant to the evolution of unique human neural properties. To examine the hypothesis that lncRNA expression varies with age, potentially paralleling known developmental trends in synaptogenesis, myelination, and energetics, we quantified levels of nearly 6000 lncRNAs in 36 surgically resected human neocortical samples (primarily derived from temporal cortex) spanning infancy to adulthood. Our analysis identified 8 lncRNA genes with distinct developmental expression patterns. These lncRNA genes contained anthropoid-specific exons, as well as splice sites and polyadenylation signals that resided in primate-specific sequences. To our knowledge, our study is the first to describe developmental expression profiles of lncRNA in surgically resected in vivo human brain tissue. Future analysis of the functional relevance of these transcripts to neural development and energy metabolism is warranted.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , RNA Longo não Codificante/metabolismo , Transcriptoma/fisiologia , Adolescente , Adulto , Córtex Cerebral/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
20.
Hum Brain Mapp ; 35(7): 3216-26, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24142581

RESUMO

As a new tool to quantify primary motor pathways and predict postoperative motor deficits in children with focal epilepsy, the present study utilized a maximum a posteriori probability (MAP) classification of diffusion weighted imaging (DWI) tractography combined with Kalman filter. DWI was performed in 31 children with intractable focal epilepsy who underwent epilepsy surgery. Three primary motor pathways associated with "finger," "leg," and "face" were classified using DWI-MAP classifier and compared with the results of invasive electrical stimulation mapping (ESM) via receiver operating characteristic (ROC) curve analysis. The Kalman filter analysis was performed to generate a model to determine the probability of postoperative motor deficits as a function of the proximity between the resection margin and the finger motor pathway. The ROC curve analysis showed that the DWI-MAP achieves high accuracy up to 89% (finger), 88% (leg), 89% (face), in detecting the three motor areas within 20 mm, compared with ESM. Moreover, postoperative reduction of the fiber count of finger pathway was associated with postoperative motor deficits involving the hand. The prediction model revealed an accuracy of 92% in avoiding postoperative deficits if the distance between the resection margin and the finger motor pathway seen on preoperative DWI tractography was 19.5 mm. This study provides evidence that the DWI-MAP combined with Kalman filter can effectively identify the locations of cortical motor areas even in patients whose motor areas are difficult to identify using ESM, and also can serve as a reliable predictor for motor deficits following epilepsy surgery.


Assuntos
Mapeamento Encefálico , Imagem de Difusão por Ressonância Magnética , Vias Eferentes/patologia , Epilepsias Parciais/complicações , Córtex Motor/patologia , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/patologia , Adolescente , Criança , Pré-Escolar , Imagem de Tensor de Difusão , Estimulação Elétrica , Eletroencefalografia , Epilepsias Parciais/cirurgia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Masculino , Transtornos dos Movimentos/cirurgia , Probabilidade , Curva ROC
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