RESUMEN
While the main neural networks are in place at term birth, intense changes in cortical microstructure occur during early infancy with the development of dendritic arborization, synaptogenesis and fiber myelination. These maturational processes are thought to relate to behavioral acquisitions and the development of cognitive abilities. Nevertheless, in vivo investigations of such relationships are still lacking in healthy infants. To bridge this gap, we aimed to study the cortical maturation using non-invasive Magnetic Resonance Imaging, over a largely unexplored period (1-5 post-natal months). In a first univariate step, we focused on different quantitative parameters: longitudinal relaxation time (T1), transverse relaxation time (T2), and axial diffusivity from diffusion tensor imaging (λ//) These individual maps, acquired with echo-planar imaging to limit the acquisition time, showed spatial distortions that were first corrected to reliably match the thin cortical ribbon identified on high-resolution T2-weighted images. Averaged maps were also computed over the infants group to summarize the parameter characteristics during early infancy. In a second step, we considered a multi-parametric approach that leverages parameters complementarity, avoids reliance on pre-defined regions of interest, and does not require spatial constraints. Our clustering strategy allowed us to group cortical voxels over all infants in 5 clusters with distinct microstructural T1 and λ// properties The cluster maps over individual cortical surfaces and over the group were in sound agreement with benchmark post mortem studies of sub-cortical white matter myelination, showing a progressive maturation of 1) primary sensori-motor areas, 2) adjacent unimodal associative cortices, and 3) higher-order associative regions. This study thus opens a consistent approach to study cortical maturation in vivo.
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Mapeo Encefálico/métodos , Encéfalo/crecimiento & desarrollo , Red Nerviosa/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Análisis por Conglomerados , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Lactante , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagenRESUMEN
Characteristic preterm EEG patterns of "Delta-brushes" (DBs) have been reported in the temporal cortex following auditory stimuli, but their spatio-temporal dynamics remains elusive. Using 32-electrode EEG recordings and co-registration of electrodes' position to 3D-MRI of age-matched neonates, we explored the cortical auditory-evoked responses (AERs) after 'click' stimuli in 30 healthy neonates aged 30-38 post-menstrual weeks (PMW). (1) We visually identified auditory-evoked DBs within AERs in all the babies between 30 and 33 PMW and a decreasing response rate afterwards. (2) The AERs showed an increase in EEG power from delta to gamma frequency bands over the middle and posterior temporal regions with higher values in quiet sleep and on the right. (3) Time-frequency and averaging analyses showed that the delta component of DBs, which negatively peaked around 550 and 750 ms over the middle and posterior temporal regions, respectively, was superimposed with fast (alpha-gamma) oscillations and corresponded to the late part of the cortical auditory-evoked potential (CAEP), a feature missed when using classical CAEP processing. As evoked DBs rate and AERs delta to alpha frequency power decreased until full term, auditory-evoked DBs are thus associated with the prenatal development of auditory processing and may suggest an early emerging hemispheric specialization.
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Audiometría de Respuesta Evocada , Corteza Cerebral/fisiología , Recien Nacido Prematuro/fisiología , Estimulación Acústica , Ritmo alfa/fisiología , Ritmo Delta/fisiología , Electroencefalografía , Potenciales Evocados Auditivos/fisiología , Femenino , Ritmo Gamma , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Sueño/fisiologíaRESUMEN
The strong positive-allometric relationship between brain size, cortical extension and gyrification complexity, recently highlighted in the general population, could be modified by brain developmental disorders. Indeed, in case of brain growth insufficiency, the pathophysiological relevance of the "simplified gyral pattern" phenotype is strongly disputed since almost no genotype-phenotype correlations have been found in primary microcephalies. Using surface scaling analysis and newly-developed spectral analysis of gyrification (Spangy), we tested whether the gyral simplification in groups of severe microcephalies related to ASPM, PQBP1 or fetal-alcohol-syndrome could be fully explained by brain size reduction according to the allometric scaling law established in typically-developing control groups, or whether an additional disease effect was to be suspected. We found the surface area reductions to be fully explained by scaling effect, leading to predictable folding intensities measured by gyrification indices. As for folding pattern assessed by spectral analysis, scaling effect also accounted for the majority of the variations, but an additional negative or positive disease effect was found in the case of ASPM and PQBP1-linked microcephalies, respectively. Our results point out the necessity of taking allometric scaling into account when studying the gyrification variability in pathological conditions. They also show that the quantitative analysis of gyrification complexity through spectral analysis can enable distinguishing between even (predictable, non-specific) and uneven (unpredictable, maybe disease-specific) gyral simplifications.
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Corteza Cerebral/patología , Microcefalia/patología , Adolescente , Adulto , Mapeo Encefálico/métodos , Proteínas Portadoras/genética , Niño , Proteínas de Unión al ADN , Femenino , Trastornos del Espectro Alcohólico Fetal/patología , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Microcefalia/genética , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Análisis Espacial , Adulto JovenRESUMEN
In order to understand how genetic mutations might have favored language development in our species, we need a better description of the human brain at the beginning of life. As the linguistic network mainly involves the left perisylvian regions in adults, we used anatomical MRI to study the structural asymmetries of these regions in 14 preverbal infants. Our results show four significant asymmetries. First and foremost, they stress an important but little-known asymmetry: the larger depth of the right superior temporal sulcus (STS) at the base of Heschl's gyrus. Then, we characterized the early forward and upward shift of the posterior end of the right Sylvian fissure, the elongation of the left planum temporale as well as the thickening of the left Heschl's gyrus. The rightward bias of the STS is robust and large, and is not correlated with the leftward asymmetries of the planum and Heschl's gyrus, suggesting that different morphogenetic factors drive these asymmetries. As this sulcus is engaged in multiple high-level functions (e.g. language and theory of mind), and has been spotted as abnormal in several developmental disorders (e.g. schizophrenia, autism), this early rightward asymmetry should be further explored as a target for a genetic evolutionary pressure.
Asunto(s)
Encéfalo/anatomía & histología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Lactante , Recién Nacido , Imagen por Resonancia Magnética , MasculinoRESUMEN
Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.
Asunto(s)
Proteínas Portadoras/genética , Mutación , Proteínas Nucleares/genética , Fenotipo , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Parálisis Cerebral/complicaciones , Parálisis Cerebral/diagnóstico por imagen , Parálisis Cerebral/genética , Parálisis Cerebral/patología , Niño , Preescolar , Trastornos del Conocimiento/etiología , Proteínas de Unión al ADN , Femenino , Francia , Genotipo , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/complicaciones , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico por imagen , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/patología , Embarazo , Radiografía , Adulto JovenRESUMEN
BACKGROUND: Children who have been treated for a medulloblastoma often suffer long-term cognitive impairments that often negatively affect their academic performance and quality of life. In this article, we will review the neuropsychological consequences of childhood medulloblastoma and discuss the risk factors known to influence the presence and severity of these cognitive impairments and possible interventions to improve their quality of life. METHODS: This narrative review was based on electronic searches of PubMed to identify all relevant studies. RESULTS: Although many types of cognitive impairments often emerge during a child's subsequent development, the core cognitive domains that are most often affected in children treated for a medulloblastoma are processing speed, attention and working memory. The emergence and magnitude of these deficits varies greatly among patients. They are influenced by demographic (age at diagnosis, parental education), medical and treatment-related factors (perioperative complications, including posterior fossa syndrome, radiation therapy dose, etc.), and the quality of interventions such as school adaptations provided to the child or rehabilitation programs that focus on cognitive skills, behavior and psychosocial functioning. CONCLUSION: These patients require specialized and coordinated multidisciplinary rehabilitation follow-up that provides timely and adapted assessments and culminates in personalized intervention goals being set with the patient and the family. Follow-up should be continued until referral to adult services.
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Neoplasias Cerebelosas/psicología , Disfunción Cognitiva/psicología , Meduloblastoma/psicología , Pruebas Neuropsicológicas , Adulto , Atención/fisiología , Neoplasias Cerebelosas/complicaciones , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Cognición/fisiología , Terapia Cognitivo-Conductual/tendencias , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Femenino , Humanos , Masculino , Meduloblastoma/complicaciones , Meduloblastoma/terapia , Calidad de Vida/psicologíaRESUMEN
Both language capacity and strongly lateralized hand preference are among the most intriguing particularities of the human species. They are associated in the adult brain with functional and anatomical hemispheric asymmetries in the speech perception-production network and in the sensori-motor system. Only studies in early life can help us to understand how such asymmetries arise during brain development, and to which point structural left-right differences are the source or the consequence of functional lateralization. In this study, we aimed to provide new in vivo structural markers of hemispheric asymmetries in infants from 1 to 4 months of age, with diffusion tensor imaging. We used 3 complementary analysis methods based on local diffusion indices and spatial localizations of tracts. After a prospective approach over the whole brain, we demonstrated early leftward asymmetries in the arcuate fasciculus and in the cortico-spinal tract. These results suggest that the early macroscopic geometry, microscopic organization, and maturation of these white matter bundles are related to the development of later functional lateralization.
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Lactante , Lenguaje , Red Nerviosa/anatomía & histología , Envejecimiento/fisiología , Núcleo Arqueado del Hipotálamo/anatomía & histología , Núcleo Arqueado del Hipotálamo/fisiología , Interpretación Estadística de Datos , Imagen de Difusión por Resonancia Magnética , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Red Nerviosa/fisiología , Tractos Piramidales/anatomía & histología , Tractos Piramidales/fisiologíaRESUMEN
OBJECTIVE: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations. RESULTS: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia. CONCLUSIONS: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.
Asunto(s)
Lisencefalia/genética , Tubulina (Proteína)/genética , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Lactante , Lisencefalia/patología , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Fenotipo , Tubulina (Proteína)/químicaRESUMEN
Surgery of partial epilepsies in childhood has largely benefited from the recent advances of imaging techniques, which carry a triple goal: (1) to contribute to the localization of the epilepsy onset zone, (2) to detect and delineate an underlying lesion, and (3) to study the spatial relationship between the epileptogenic zone and the neighboring functional cortex, in order to select patients and plan the resection. This noninvasive presurgical imaging workup must be compared to clinical and electrical data to estimate the postoperative prognosis, while invasive techniques such as SEEG, cortical stimulations, and IAT often remain indispensable in difficult cases, i.e., in cryptogenic epilepsies. As in adults, advances in MRI allow us to detect more and more subtle underlying lesions, but this requires repeating MR studies during early childhood and using adapted sequence parameters to account for ongoing myelination. Ictal SPECT and PET imaging prove especially useful in planning depth electrode placement when video-EEG is not contributive, when MRI looks normal or shows multiple abnormalities, or in cases of discrepant findings. Multimodal imaging greatly enhances the sensitivity of all of these techniques. Finally, functional MRI of motor and language functions provide noninvasive cortical mapping of essential functions, using age-adapted paradigms, in cooperating children from age five to six and from IQs around 60.
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Epilepsia/diagnóstico , Imagen por Resonancia Magnética , Niño , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/patología , Epilepsia/cirugía , Humanos , Procedimientos Neuroquirúrgicos , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Robust spatial alignment of post mortem data and in vivo MRI acquisitions from different ages, especially from the early developmental stages, into standard spaces is still a bottleneck hampering easy comparison with the mainstream neuroimaging results. In this paper, we test a landmark-based spatial normalization strategy as a framework for the seamless integration of any macroscopic dataset in the context of the Human Brain Project (HBP). This strategy stems from an approach called DISCO embedding sulcal constraints in a registration framework used to initialize DARTEL, the widely used spatial normalization approach proposed in the SPM software. We show that this strategy is efficient with a heterogeneous dataset including challenging data as preterm newborns, infants, post mortem histological data and a synthetic atlas computed from averaging the ICBM database, as well as more commonly studied data acquired in vivo in adults. We then describe some perspectives for a research program aiming at improving folding pattern matching for atlas inference in the context of the future HBP's portal.
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Encéfalo/anatomía & histología , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Atlas como Asunto , Bases de Datos Factuales , Humanos , Recién Nacido , Recien Nacido Prematuro , Persona de Mediana Edad , Programas InformáticosRESUMEN
Neuroimaging is critical for the diagnosis of neonatal arterial ischemic stroke (NAIS) and for prognosis estimation. The purpose of this work is to define guidelines of clinical neuroimaging for the diagnosis of NAIS, for the optimization of the imaging timing and for the assessment of the prognostic value of each imaging technique. A systematic search of electronic databases (Medline via Pubmed) for studies whose title and abstract were focused on NAIS has been conducted. One hundred and ten articles were selected and their results were analyzed by three Senior Practitioners of pediatric radiology using common methodology for guidelines elaboration within the group of experts gathered by Scientific Societies in the field. MRI with a diffu si on-weighted sequence (DWI) and T1, T2, and T2*-weighted sequences must be performed in the case of suspected NAIS (no sedation is required). In the first hours after the injury, an acute ischemic lesion is characterized by a hypersignal on the diffusion-weighted sequence, with a decrease of the apparent coefficient of diffusion (ADC). The best time to evaluate the extent of the ischemic lesion is between day 2 and day 4 after injury, when the ADC decrease reaches its nadir. In the acute phase, US may be useful as first imaging at the bedside to exclude other pathologies like large space-occupying hemorrhages, but its specific added value on NAIS diagnosis or prognosis assessment is very low. CT scan has no added value in NAIS, compared to MRI. Motor outcome is correlated with the extent of the lesion and with the presence of a definite injury of the corticospinal tract, which is well seen on the diffusion sequence at the acute stage. A secondary atrophy within the mesencephalon (cerebral peduncles) is tied in with a high risk of hemiplegia. Visual outcome is more often compromised in the case of lesions of the posterior cerebral artery territory.
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Isquemia Encefálica/diagnóstico por imagen , Neuroimagen/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Humanos , Recién Nacido , Guías de Práctica Clínica como AsuntoRESUMEN
Neonatal arterial ischemic stroke (NAIS) is a rare event that occurs in approximately one in 5000 term or close-to-term infants. Most affected infants will present with seizures. Although a well-recognized clinical entity, many questions remain regarding diagnosis, risk factors, treatment, and follow-up modalities. In the absence of a known pathophysiological mechanism and lack of evidence-based guidelines, only supportive care is currently provided. To address these issues, a French national committee set up by the French Neonatal Society (Société française de néonatologie) and the national referral center (Centre national de référence) for arterial ischemic stroke in children drew up guidelines based on an HAS (Haute Autorité de santé [HAS]; French national authority for health) methodology. The main findings and recommendations established by the study group are: (1) among the risk factors, male sex, primiparity, caesarean section, perinatal hypoxia, and fetal/neonatal infection (mainly bacterial meningitis) seem to be the most frequent. As for guidelines, the study group recommends the following: (1) the transfer of neonates with suspected NAIS to a neonatal intensive care unit with available equipment to establish a reliable diagnosis with MRI imaging and neurophysiological monitoring, preferably by continuous video EEG; (2) acute treatment of suspected infection or other life-threatening processes should be addressed immediately by the primary medical team. Persistent seizures should be treated with a loading dose of phenobarbital 20mg/kg i.v.; (3) MRI of the brain is considered optimal for the diagnosis of NAIS. Diffusion-weighted imaging with apparent diffusion coefficient is considered the most sensitive measure for identifying infarct in the neonatal brain. The location and extent of the lesions are best assessed between 2 and 4 days after the onset of stroke; (4) routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocysteinemia, the Lp(a) test, the MTHFR thermolabile variant should not be considered in neonates with NAIS. Testing for FV Leiden can be performed only in case of a documented family history of venous thromboembolic disease. Testing neonates for the presence of antiphospholipid antibodies should be considered only in case of clinical events arguing in favor of antiphospholipid syndrome in the mother; (5) unlike childhood arterial ischemic stroke, NAIS has a low 5-year recurrence rate (approximately 1 %), except in those children with congenital heart disease or multiple genetic thrombophilia. Therefore, initiation of anticoagulation or antithrombotic agents, including heparin products, is not recommended in the newborn without identifiable risk factors; (6) the study group recommends that in case of delayed motor milestones or early handedness, multidisciplinary rehabilitation is recommended as early as possible. Newborns should have physical therapy evaluation and ongoing outpatient follow-up. Given the risk of later-onset cognitive, language, and behavioral disabilities, neuropsychological testing in preschool and at school age is highly recommended.
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Infarto Cerebral/terapia , Adhesión a Directriz , Infarto Cerebral/diagnóstico , Infarto Cerebral/etiología , Diagnóstico Diferencial , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Comunicación Interdisciplinaria , Colaboración Intersectorial , Recurrencia , Factores de RiesgoRESUMEN
PURPOSE: To describe the characteristics of a previously overlooked devastating epileptic encephalopathy that presents as intractable bilateral perisylvian epilepsy starting with prolonged status epilepticus (SE) in normally developing school-aged children. METHODS: Retrospective study over 7 years of all normally developing children admitted in our institution for a prolonged SE following non-specific febrile illness with at least one seizure recorded on EEG. RESULTS: Fourteen children were included at a median age of 7.5 years (4-11) (median follow-up of 4 years (1-7)). Intractable SE lasted 4-60 days (median 30). CSF cell count was normal in five cases and moderately increased in the others. During SE, seizures were recorded in 11 patients and involved temporal lobes in 7; the other 4 patients exhibited perisylvian clinical features with secondary generalization. Intractable epilepsy followed SE in all cases without any latent period. Persisting seizures were recorded in 10 patients and involved temporo-perisylvian regions in 8, frontal regions in 2; 3 others had perisylvian ictal semiology. Spiking was bilateral in 10 cases. MRI showed bilateral hippocampal hypersignal and/or atrophy in 10 cases (extended to the neocortex in 3). All children had major cognitive sequelae. When feasible (six patients), detailed neuropsychology suggested fronto-temporal impairment. CONCLUSIONS: Among so called grey matter encephalitis patients, we identified a recognizable pattern we propose to call Devastating Epileptic encephalopathy in School-age Children (DESC) that begins with prolonged SE triggered by fever of unknown cause, and persists as intractable perisylvian epilepsy with severe cognitive deterioration.
Asunto(s)
Cognición/fisiología , Encefalitis/etiología , Epilepsia/etiología , Estado Epiléptico/complicaciones , Anticonvulsivantes/uso terapéutico , Proteínas del Líquido Cefalorraquídeo/análisis , Niño , Preescolar , Resistencia a Medicamentos , Electroencefalografía , Encefalitis/líquido cefalorraquídeo , Encefalitis/fisiopatología , Epilepsia/tratamiento farmacológico , Fiebre de Origen Desconocido/complicaciones , Humanos , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Pronóstico , Estudios RetrospectivosRESUMEN
CONTEXT: CHARGE (coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities, and/or hearing loss defect) syndrome consists of a combination of congenital malformations including genital hypoplasia and retarded growth. OBJECTIVE: The objective of the study was to study gonadotropic axis function and growth parameters in CHARGE syndrome. DESIGN: This was a retrospective study. PATIENTS: The study included 32 children with CHARGE syndrome. RESULTS: Nineteen of 20 affected boys had micropenis and/or cryptorchidism, consistent with hypogonadotropic hypogonadism during fetal life. None of the boys was of pubertal age. Seven of nine boys tested before the age of 5 months during the neonatal peak period had extremely low testosterone levels. LH response to GnRH stimulation was variable during the first year of life and not correlated with existing clinical abnormalities. None of the girls over the age of 12 yr (n = 7) had begun puberty spontaneously, and a lack of response to GnRH stimulation was documented in five of them. Olfactory evaluation (n = 10) and magnetic resonance imaging (n = 18) of the forebrain revealed defective sense of smell and abnormal olfactory bulbs in all cases. Cardiorespiratory and nutritional problems were corrected, but the mean height of the 25 children who had reached 5 yr of age was -2 +/- 0.2 sd score. Height was not correlated with birth length or body mass index. GH deficiency was diagnosed in only three children. CONCLUSION: These findings suggest that CHARGE syndrome includes the main features of Kallmann syndrome, which is defined by hypogonadotropic hypogonadism combined with a defective sense of smell and abnormal olfactory bulb development. This forebrain abnormality, if confirmed in a larger group of patients, could serve as a major new criterion for the diagnosis of CHARGE syndrome.
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Coloboma/patología , Gonadotropinas/deficiencia , Trastornos del Crecimiento/patología , Cardiopatías Congénitas/patología , Hipogonadismo/patología , Bulbo Olfatorio/anomalías , Bulbo Olfatorio/crecimiento & desarrollo , Índice de Masa Corporal , Niño , Preescolar , Coloboma/metabolismo , Femenino , Genitales/anomalías , Crecimiento/fisiología , Trastornos del Crecimiento/congénito , Trastornos del Crecimiento/metabolismo , Cardiopatías Congénitas/metabolismo , Hormonas/sangre , Humanos , Hipogonadismo/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/patología , Lactante , Imagen por Resonancia Magnética , Masculino , Estado Nutricional , Bulbo Olfatorio/patología , Olfato/fisiología , SíndromeRESUMEN
Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.
Asunto(s)
ADN Mitocondrial/genética , Complejo I de Transporte de Electrón/genética , Mutación , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Enfermedad de Leigh/genética , MasculinoRESUMEN
Leigh syndrome is a subacute necrotising encephalomyopathy frequently ascribed to mitochondrial respiratory chain deficiency. This condition is genetically heterogeneous, as mutations in both mitochondrial (mt) and nuclear genes have been reported. Here, we report the G13513A transition in the ND5 mtDNA gene in three unrelated children with complex I deficiency and a peculiar MRI aspect distinct from typical Leigh syndrome. Brain MRI consistently showed a specific involvement of the substantia nigra and medulla oblongata sparing the basal ganglia. Variable degrees of heteroplasmy were found in all tissues tested and a high percentage of mutant mtDNA was observed in muscle. The asymptomatic mothers presented low levels of mutant mtDNA in blood leucocytes. This mutation, which affects an evolutionary conserved amino acid (D393N), has been previously reported in adult patients with MELAS or LHON/MELAS syndromes, emphasising the clinical heterogeneity of mitochondrial DNA mutations. Since the G13513A mutation was found in 21% of our patients with Leigh syndrome and complex I deficiency (3/14), it appears that this mutation represents a frequent cause of Leigh-like syndrome, which should be systematically tested for molecular diagnosis in affected children and for genetic counselling in their maternal relatives.
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ADN Mitocondrial/genética , Enfermedad de Leigh/genética , Síndrome MELAS/genética , NADH Deshidrogenasa/genética , NADH NADPH Oxidorreductasas/deficiencia , Encéfalo/patología , Preescolar , ADN Mitocondrial/metabolismo , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Complejo I de Transporte de Electrón , Humanos , Lactante , Enfermedad de Leigh/enzimología , Enfermedad de Leigh/patología , Síndrome MELAS/enzimología , Imagen por Resonancia Magnética , Masculino , NADH NADPH Oxidorreductasas/genética , Mutación PuntualRESUMEN
Rasmussen's encephalitis (RE) is a rare inflammatory brain disease mainly affecting children and characterised by intractable epilepsy involving a single hemisphere that undergoes progressive atrophy. RE is characterized by refractory focal seizures, often associated with epilepsia partialis continua, progressive unilateral motor defect, slow EEG activity over the entire contralateral hemisphere, with focal white matter hyperintensity and insular cortical atrophy on neuroimaging. Surgical exclusion of the affected hemisphere is the only treatment that interrupts progression of the disease. Pathogenic concepts have considered viruses, autoimmune antibodies and autoimmune cytotoxic T lymphocytes that might contribute to the initiating or perpetuating events in the central nervous system. Based on these concepts, different therapeutic strategies have been pursued, such as antiviral agents, plasmapheresis, immuno-adsorption, immunosuppression or immunomodulation with intravenous immunoglobulins. However, due to the lack of large studies, to date there is no established therapeutic strategy for this devastating condition. In this review, we give an overview of the current state of immunopathogenic concepts for Rasmussen's encephalitis and discuss the different therapeutic options for future perspectives.
Asunto(s)
Encefalitis/etiología , Encefalitis/terapia , Diagnóstico Precoz , Encefalitis/diagnóstico , HumanosRESUMEN
In vivo evaluation of the brain white matter maturation is still a challenging task with no existing gold standards. In this article we propose an original approach to evaluate the early maturation of the white matter bundles, which is based on comparison of infant and adult groups using the Mahalanobis distance computed from four complementary MRI parameters: quantitative qT1 and qT2 relaxation times, longitudinal λâ and transverse λ⥠diffusivities from diffusion tensor imaging. Such multi-parametric approach is expected to better describe maturational asynchrony than conventional univariate approaches because it takes into account complementary dependencies of the parameters on different maturational processes, notably the decrease in water content and the myelination. Our approach was tested on 17 healthy infants (aged 3- to 21-week old) for 18 different bundles. It finely confirmed maturational asynchrony across the bundles: the spino-thalamic tract, the optic radiations, the cortico-spinal tract and the fornix have the most advanced maturation, while the superior longitudinal and arcuate fasciculi, the anterior limb of the internal capsule and the external capsule have the most delayed maturation. Furthermore, this approach was more reliable than univariate approaches as it revealed more maturational relationships between the bundles and did not violate a priori assumptions on the temporal order of the bundle maturation. Mahalanobis distances decreased exponentially with age in all bundles, with the only difference between them explained by different onsets of maturation. Estimation of these relative delays confirmed that the most dramatic changes occur during the first post-natal year.
Asunto(s)
Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , Imagen de Difusión Tensora/métodos , Sustancia Blanca/anatomía & histología , Sustancia Blanca/crecimiento & desarrollo , Adulto , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Lactante , Recién Nacido , Masculino , Procesamiento de Señales Asistido por Computador , Adulto JovenRESUMEN
OBJECTIVE: To identify age-dependent activation patterns of verbal fluency with functional MRI (fMRI). BACKGROUND: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. METHODS: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Signa MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. RESULTS: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca's area) and left middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. CONCLUSIONS: In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity.
Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Encéfalo/anatomía & histología , Encéfalo/fisiología , Cognición/fisiología , Imagen por Resonancia Magnética , Adolescente , Adulto , Encéfalo/crecimiento & desarrollo , Niño , Femenino , Humanos , Masculino , Aprendizaje Verbal/fisiologíaRESUMEN
OBJECTIVE: To evaluate the reliability of temporal and frontal functional MRI (fMRI) activation for the assessment of language dominance, as compared with the Wada test. PATIENTS AND METHODS: Ten patients with temporal lobe epilepsy were studied using blood oxygen level dependent fMRI and echoplanar imaging (1.5-T). Three tasks were used: semantic verbal fluency, covert sentence repetition, and story listening. Data were analyzed using pixel by pixel autocorrelation and cross-correlation. fMRI laterality indices were defined for several regions of interest as the ratio (L - R)/(L + R), L being the number of activated voxels in the left hemisphere and R in the right hemisphere. Wada laterality indices were defined as the difference in the percentages of errors in language tests between left and right carotid injections. RESULTS: Semantic verbal fluency: The asymmetry of frontal activation was correlated with Wada laterality indices. The strongest correlation was observed in the precentral/middle frontal gyrus/inferior frontal sulcus area. Story listening: The asymmetry of frontal, but not temporal, activation was correlated with Wada laterality indices. Covert sentence repetition: No correlation was observed. CONCLUSIONS: There was a good congruence between hemispheric dominance for language as assessed with the Wada test and fMRI laterality indices in the frontal but not in the temporal lobes. The story listening and the covert sentence repetition tasks increased the sensitivity of detection of posterior language sites that may be useful for brain lesion surgery.