Age related changes and sex related differences of functional brain networks in childhood: A high-density EEG study.

OBJECTIVE: The aim of this study was to explore functional network age-related changes and sex-related differences during the early lifespan with a high-density resting state electroencephalography (rs-EEG). METHODS: We analyzed two data sets of high-density rs-EEG in healthy children and adolescents. We recorded a 64-channel EEG and calculated functional connectomes in 27 participants aged 5-18 years. To validate our results, we used publicly available data and calculated functional connectomes in another 86 participants aged 6-18 years from a 128-channel rs-EEG. We were primarily interested in alpha frequency band, but we also analyzed theta and beta frequency bands. RESULTS: We observed age-related increase of characteristic path, clustering coefficient and interhemispheric strength in the alpha frequency band of both data sets and in the beta frequency band of the larger validation data set. Age-related increase of global efficiency was seen in the theta band of the validation data set and in the alpha band of the test data set. Increase in small worldness was observed only in the alpha frequency band of the test data set. We also observed an increase of individual peak alpha frequency with age in both data sets. Sex-related differences were only observed in the beta frequency band of the larger validation data set, with females having higher values than same aged males. CONCLUSIONS: Functional brain networks show indices of higher segregation, but also increasing global integration with maturation. Age-related changes are most prominent in the alpha frequency band. SIGNIFICANCE: To the best of our knowledge, our study was the first to analyze maturation related changes and sex-related differences of functional brain networks with a high-density EEG and to compare functional connectomes generated from two diverse high-density EEG data sets. Understanding the age-related changes and sex-related differences of functional brain networks in healthy children and adolescents is crucial for identifying network abnormalities in different neurologic and psychiatric conditions, with the aim to identify possible markers for prognosis and treatment.

The influence of maternal levels of vitamin D and adiponectin on offspring's health.

BACKGROUND: From the very beginning of life, biological events in the intrauterine environment influence the developing child, its growth, maturation and adaptation. The aim of this study was to assess the impact of maternal vitamin D and adiponectin status on offspring growth, general and bone health. METHODS: 162 healthy pregnant women were included in the study, with their vitaminD and adiponectin levels measured in the 32 nd week of pregnancy. Body weight and bone mineral density measurements of their offspring were performed at birth and at the age of three, six, nine and twelve months. Information on children's infectious, allergic and chronic disease was collected from their medical records. RESULTS: Vitamin D insufficiency/deficiency was present in 44% of pregnant women. There was no significant association between maternal vitamin D during pregnancy and offspring body weight at birth or later, as well as between maternal vitamin D and newborn bone mineral density. Additionally, there was no significant association between maternal vitamin D and infectious, allergic or other chronic diseases in offspring. A negative correlation between maternal adiponectin and offspring's body weight at birth was observed (r = - 0.37, p = 0.002), while association with bone mineral density in newborns was not significant. CONCLUSION: Despite the significant prevalence of vitamin D insufficiency among pregnant women, it did not influence growth or health of their offspring in this study. Maternal adiponectin levels showed an inverse relationship with birth weight of the infants, which may highlight the important link between maternal health and the offspring's growth.

Case report: Pneumocystis jirovecii pneumonia in a severe case of Aicardi-Goutières syndrome with an IFIH1 gain-of-function mutation mimicking combined immunodeficiency.

Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset progressive encephalopathy caused by mutations leading to overexpression of type I interferon (IFN) and resulting in various clinical phenotypes. A gain-of-function (GOF) mutation in the IFIH1 gene is associated with robust production of type I IFN and activation of the Janus kinase (JAK) signal transducer and activator of the transcription (STAT) pathway, which can cause AGS type 7. We detail the clinical case of an infant who initially presented with Pneumocystis jirovecii pneumonia (PCP), had recurrent respiratory infections, and was later treated with a JAK inhibitor, baricitinib, because of a genetically confirmed GOF mutation in the IFIH1 gene. This spectrum of IFIH1 GOF mutations with overlapping features of hyperinflammation and severe opportunistic infection, which mimics combined immunodeficiency (CID), has not been described before. In this case, therapy with baricitinib effectively blocked IFN-α activation and reduced STAT1 signaling but had no effect on the progression of the neurological disease.

Genetic Polymorphisms, Gene-Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia.

Inflammation and oxidative stress after hypoxic-ischemic brain injury may be modified by genetic variability in addition to therapeutic hypothermia. The aim of our study was to evaluate the association between the polymorphisms in genes of antioxidant and inflammatory pathways in newborns treated with therapeutic hypothermia and the development of epilepsy or CP at two years follow-up. The DNA of 55 subjects was isolated from buccal swabs. Genotyping using competitive allele-specific PCR was performed for polymorphisms in antioxidant (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) and inflammatory (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs10716 76, TNF rs1800629) pathways. Polymorphic CARD8 rs2043211 T allele was less frequent in patients with epilepsy, but the association was not statistically significant. The interaction between CARD8 rs2043211 and IL1B rs16944 was associated with epilepsy after HIE: CARD8 rs2043211 was associated with lower epilepsy risk, but only in carriers of two normal IL1B rs16944 alleles (ORadj = 0.03 95% CI = 0.00-0.55; padj = 0.019). Additionally, IL1B rs16944 was associated with higher epilepsy risk only in carriers of at least one polymorphic CARD8 rs2043211 (ORadj = 13.33 95% CI = 1.07-166.37; padj = 0.044). Our results suggest that gene-gene interaction in inflammation pathways might contribute to the severity of brain injury in newborns with HIE treated with therapeutic hypothermia.

CARD8 and IL1B Polymorphisms Influence MRI Brain Patterns in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia.

Inflammation and oxidative stress are recognized as important contributors of brain injury in newborns due to a perinatal hypoxic-ischemic (HI) insult. Genetic variability in these pathways could influence the response to HI and the outcome of brain injury. The aim of our study was to evaluate the impact of common single-nucleotide polymorphisms in the genes involved in inflammation and response to oxidative stress on brain injury in newborns after perinatal HI insult based on the severity and pattern of magnetic resonance imaging (MRI) findings. The DNA of 44 subjects was isolated from buccal swabs. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1B rs16944, IL1B rs1143623, IL1B rs1071676, TNF rs1800629, CAT rs1001179, SOD2 rs4880, and GPX1 rs1050450. Polymorphism in CARD8 was found to be protective against HI brain injury detected by MRI overall findings. Polymorphisms in IL1B were associated with posterior limb of internal capsule, basal ganglia, and white matter brain patterns determined by MRI. Our results suggest a possible association between genetic variability in inflammation- and antioxidant-related pathways and the severity of brain injury after HI insult in newborns.

Clinical presentation and spectrum of neuroimaging findings in newborn infants with incontinentia pigmenti.

AIM: To report on the neurological presentation and neuroimaging findings in newborn infants with incontinentia pigmenti. METHOD: The clinical and neurological course including neuroimaging and follow-up data of eight newborn infants with the neurological phenotype of incontinentia pigmenti were retrospectively reviewed. RESULTS: While the clinical picture was polymorphic, the neurological manifestations were defined as encephalopathic and comprised lethargy and seizures in all but one of the infants. Magnetic resonance imaging (MRI) abnormalities were predominantly in the white matter. Diffusion-weighted imaging (DWI) was obtained during the acute phase in seven of the eight infants, showing restricted diffusion in the deep and subcortical white matter but also in the corpus callosum, basal ganglia, thalami, cerebellum, and cerebral peduncles. Susceptibility-weighted imaging (SWI), performed in five infants, showed a variable amount of signal loss, mainly in the white matter, within areas of restricted diffusion. Extensive MRI abnormalities in newborn infants were followed by abnormal neurodevelopment, with significant motor, cognitive, and/or visual problems. INTERPRETATION: To assess the extent of central nervous system involvement, MRI is recommended in the clinical evaluation of infants with incontinentia pigmenti. They have a characteristic pattern of brain lesions seen on MRI, best recognized using DWI and SWI in the acute neonatal phase, which allow the identification of and distinction between ischaemic and haemorrhagic lesions.

Vitamin D Status and Its Determinants in Healthy Slovenian Pregnant Women.

BACKGROUND/AIMS: Vitamin D deficiency is a common underdiagnosed condition. The aim of this was to analyze the status of vitamin D and its determinants in healthy Slovenian pregnant women. METHODS: A total of 132 volunteer pregnant women completed a questionnaire including baseline demographics, food frequency, physical activities; anthropometrical measurements, body mass index and levels of 25-(OH)D in serum were performed during the third trimester, and dietary intakes were assessed during the 27-28th week of gestation. RESULTS: Vitamin D deficiency was present in 14% while insufficiency was present in 41% of women. The risk for inadequacy was higher in women older than 30 years (p = 0.01), in those with less frequent outdoor physical activity (p = 0.01) and in pregnancies during the low sun exposure season (p = 0.04). Insufficiency was not significantly more frequent in less educated women, unemployed and in those living in urban area. The median value of vitamin D from habitual dietary intake was 1.5 µg/day (range 0.1-13.4) and did not influence 25-hydroxyvitamin D level (p = 0.91). CONCLUSIONS: The prevalence of vitamin D inadequacy was 55% and was dependent on age, season and outdoor physical activities. The results suggest a discrepancy between vitamin D intake through habitual diet and the reference needs.

Neuroimaging and neurodevelopmental outcome of preterm infants with a periventricular haemorrhagic infarction located in the temporal or frontal lobe.

AIM: The aim of the study was to compare clinical and neuroimaging characteristics and neurodevelopmental outcome in preterm infants with a periventricular haemorrhagic infarction (PVHI) located in the temporal or frontal periventricular white matter. METHOD: The study was a retrospective hospital-based study of preterm infants with a frontal PVHI (n=21; 11 males, 10 females; mean birthweight 1527g; mean gestational age 30.3wks) or temporal PVHI (n=13; five males, eight females; mean birthweight 1205g; mean gestational age 30.2wks) admitted to the neonatal intensive care unit between 1990 and 2012. The clinical course, results of neuroimaging studies, and neurodevelopmental outcomes of preterm infants with a gestational age less than 34 weeks with a confirmed PVHI on early cranial ultrasonography and/or magnetic resonance imaging were reviewed. For assessment of neurodevelopmental outcome we used the Griffiths Mental Development Scales, the Movement Assessment Battery for Children, the Gross Motor Function Classification System, the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and ophthalmological assessment. An unfavourable neurodevelopmental outcome was defined as moderately or severely atypical neurological examination during the last visit: presence of cerebral palsy, epilepsy, a hearing or visual impairment, and/or atypical cognitive development (Griffiths Mental Development Scales developmental quotient or Wechsler Preschool and Primary Scale of Intelligence <85). RESULTS: Unfavourable outcome was observed in 12 out of 13 children with a temporal PVHI compared with six out of 21 children with a frontal PVHI (p=0.002). Only one of the included infants with a PVHI in the temporal white matter developed cerebral palsy, which was due to a parietal PVHI in the contralateral hemisphere. Cognitive impairment was noted in seven infants with a frontal PVHI and five with a temporal PVHI. There were more infants with a temporal PVHI who developed visual impairment (n=5) or behavioural problems (n=7) compared with those with a frontal PVHI (visual impairment (n=2), behavioural problems (n=3). INTERPRETATION: PVHI located in the temporal or frontal lobe is almost invariably related to a typical motor outcome, but carries a risk of cognitive, behavioural, and visual problems, especially in infants with a PVHI located in the temporal lobe.

Risk factors and scoring system as a prognostic tool for epilepsy after neonatal seizures.

BACKGROUND: Neonatal seizures may cause irreversible changes to the immature brain and. A scoring system for early prognostic information could be a useful clinical tool. The aim of the study was to analyze risk factors for epilepsy after neonatal seizures, to validate Garfinkle's scoring system, and to analyze whether a new scoring system is feasible. METHODS: A retrospective study of 176 newborns (59.1% boys, 40.9% girls, 70.5% term, 29.5% preterm; mean birth weight 2820 g), admitted to the Department of Neonatology, Division of Pediatrics, University Medical Centre, Ljubljana, because of neonatal seizures (clinical and/or neurophysiological), was performed. Epilepsy rate between 2 and 12 years of follow-up was 18.1%. Five independent predictors from Garfinkle's study and other known predictors were entered into hierarchical binary logistic regression models and analyzed through four steps to identify independent predictors of epilepsy. We tested whether any of the predictors was an effect modifier. RESULTS: Of five potential predictors from Garfinkle's score, electroencephalograph background findings and etiology were predictive. Etiologies, gestation, mode of delivery, duration of seizures, and other risk factors at birth were found to be independent predictors. Duration of seizures has a different effect on prognosis depending on the gestational age. CONCLUSION: Gestational age determines the association between duration of seizures and epilepsy. Scoring systems to predict development of epilepsy after neonatal seizures need to limit interaction between important predictor variables.

Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case.

Benign familial neonatal convulsions (BFNC) is a rare, clinically and genetically heterogenous epileptic disorder. Two voltage gated potassium genes, KCNQ2 and KCNQ3, have been identified as genes responsible for BFNC1 and BFNC2 respectively. While as many as 73 mutations of KCNQ2 have been described up to date, only 4 mutations in KCNQ3, 3 of them appearing in exon 5, have been identified. Mutation in exon 6 was found for the first time in a Chinese family, and here we report the same missense mutation of KCNQ3 within exon 6 in a Caucasian family, whose history and clinical picture were in accordance with BFNC.