Haemodynamics and oxygenation in the lower-limb muscles of young ambulatory adults with cerebral palsy.

AIM: To evaluate muscle haemodynamics and oxygen metabolism in adults with cerebral palsy (CP) at rest and during exercise. METHOD: This cross-sectional study included 12 adults with spastic CP (four females, eight males; mean age [SD] 29 years 6 months [7 years 10.8 months]) and 13 typically developing individuals (seven females, six males; mean age [SD] 26 years 6 months [1 year 1.9 months]). Near-infrared spectroscopy was used to assess changes in muscle blood flow (mBF), muscle oxygen consumption (mVO2 ), and muscle oxygen saturation in the vastus lateralis and rectus femoris muscles during three conditions: rest, low load at 20% maximum voluntary contraction (MVC), and high load at 80% MVC. RESULTS: MBF was lower in participants with CP than in typically developing participants at rest (p < 0.001) and at 20% MVC (p = 0.007) in both muscles. Increased load caused a reduction in mBF in typically developing participants and an increase in CP. MVO2 in typically developing participants increased from rest to 20% MVC and was reduced at 80% MVC compared with 20% MVC. In participants with CP, there was no change with load in the rectus femoris muscle; however, there was an increase in the vastus lateralis muscle from rest to 20% MVC, and 80% MVC had a similar value. Muscle saturation was higher in participants with CP across all conditions (vastus lateralis, p < 0.001; rectus femoris, p = 0.0518). INTERPRETATION: Oxidative metabolism in CP is not limited by oxygen delivery (mBF), because high muscle saturation suggests oxygen availability. Adults with CP demonstrate muscular responses to exercise that are inconsistent with typical high-workload activation, probably because of inefficient fibre recruitment and secondary anomalies.

Group versus individual occupational therapy for toddlers with autism as a means to improve access to public health-care services. Randomised controlled pilot study.

INTRODUCTION: In recent years, the increasing prevalence of autism-spectrum disorder has resulted in an increased demand for therapies including occupational therapy. In this pilot trial, we aimed to compare the efficacy of group versus individual occupational therapy among toddlers with autism as a means to improve accessibility to care. METHODS: Toddlers (2-4 years) undergoing autism evaluation in our public child developmental centre were recruited and randomised to receive 12 weekly sessions of group or individual occupational therapy based on the same mode of intervention: Developmental, Individual-Differences and Relationship-based (DIR). Primary outcomes related to intervention implementation included waiting days, nonattendance, intervention period, number of sessions attended and therapist satisfaction. Secondary outcomes were the Adaptive Behaviour Assessment System questionnaire, the Paediatric Quality of Life Inventory and the Peabody Developmental Motor Scale (PDMS-2). RESULTS: Twenty toddlers with autism were included, 10 in each occupational therapy mode of intervention. Children waited fewer days before beginning group occupational therapy compared to individual therapy (52.4 ± 28.1 vs. 108.8 ± 48.0 days p < 0.01). Mean numbers of nonattendance was similar for both interventions (3.2 ± 2.82 vs. 2 ± 1.76, p > 0.05). Worker satisfaction scores were similar at the beginning and end of the study (6.1 ± 0.4 vs. 6.07 ± 0.49, p > 0.05). There were no significant differences between the percentage changes in individual and group therapy outcomes for adaptive score (6.0 ± 16.0 vs. 4.5 ± 17.9, p > 0.05), quality of life (1.3 ± 20.9 vs. 18.8 ± 24.5, p > 0.05) and fine motor skills (13.7 ± 36.1 vs. 15.1 ± 41.5, p > 0.05). CONCLUSIONS: In this pilot study, the group DIR-based occupational therapy for toddlers with autism improved access to services and allowed earlier interventions, with no clinical inferiority to individual therapy. Further research is required to examine group clinical therapy benefit.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

Early Neonatal C-Reactive Protein Levels and Periventricular Leukomalacia.

BACKGROUND: Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of publications on biomarkers of cPVL. OBJECTIVES: To determine C-reactive protein (CRP) levels during the first week of life of preterm infants who later developed cPVL and to identify the association between CRP levels with perinatal factors. METHODS: We retrospectively included infants ≤ 32 weeks gestation and/or birth weights ≤ 1500 grams; 17 with a cranial ultrasound diagnosis of cPVL and 54 with normal ultrasounds. Serum CRP levels were measured during days 1-7 (CRP1-7d) of life and subdivided into two timing groups: days 1-3 (CRP1-3d) and days 4-7 (CRP4-7d). RESULTS: The cPVL group had significantly higher mean CRP4-7d levels compared to controls (12.75 ± 21.2 vs. 2.23 ± 3.1, respectively, P = 0.03), while CRP1-3d levels were similar. CRP1-7d levels were significantly correlated with maximal fraction of inspired oxygen during the first 12 hours of life (FiO2-12h, r = 0.51, P < 0.001]. Additional risk factors were not associated with CRP levels. CONCLUSIONS: Our finding of elevated CRP4-7d levels and later development of cPVL supports earlier studies on the involvement of inflammation in the pathogenesis of cPVL. Whether CRP could serve as a biomarker of cPVL and its correlation with outcomes, awaits further trials. Furthermore, the correlation between FiO2-12h and CRP1-7d levels suggest that hypoxia and/or hyperoxia may serve as a trigger in the activation of inflammation during the first days of life of preterm infants.

Health-related quality of life after post-haemorrhagic hydrocephalus in children born preterm.

AIM: To determine the health-related quality of life (HRQoL) of children born preterm (gestational age <32wks) after post-haemorrhagic hydrocephalus requiring shunt (PHH-S), and to examine the impact of perinatal and neurological morbidity on their QoL. METHOD: Forty infants (18 females, 22 males; aged 2y 2mo-8y 4.5mo) born preterm with PHH-S were matched for gestational age, birthweight, and sex with infants born preterm with normal cranial ultrasonography. Pediatric QoL Inventory parent-proxy report was administered at a mean age of 5 years 8 months. RESULTS: Children with PHH-S exhibited significantly lower mean HRQoL compared with controls in motor (36 [SD 34.9] vs 96.2 [SD 6.6]), emotional (59.8 [SD 26.7] vs 80.6 [SD 18.8]), social (55.6 [SD 29.7] vs 89.6 [SD 16.6]), and school (40.5 [SD 22.9] vs 89.7 [SD 15.2]) domains (p<0.001). Multivariate regression incorporating neonatal risk factors revealed an independent effect of parenchymal brain involvement (ß=-0.6, p<0.01) and neonatal seizures (ß=-0.2, p<0.02) on total HRQoL. Low HRQoL of children with PHH-S was associated with neurodevelopmental morbidities: cerebral palsy (CP), epilepsy, vision and feeding problems, low cognitive, personal-social, and adaptive scores (p<0.05). Multivariate analysis indicated an independent contribution from severe CP (ß=-0.4, p<0.001) and low personal-social score (ß=0.5, p<0.001). INTERPRETATION: Children born preterm after PHH-S exhibit significantly lower HRQoL scores compared with preterm born peers. HRQoL is associated with neonatal cerebral complications and neurodevelopmental morbidities. WHAT THIS PAPER ADDS: Children born preterm, after post-haemorrhagic hydrocephalus requiring shunt, have low health-related quality of life (HRQoL). A low HRQoL is associated with parenchymal brain involvement and with neurological morbidity. Severe cerebral palsy and low personal-social developmental scores have independent contributions to HRQoL.

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

Maternal Sleep Disordered Breathing and Neonatal Outcome.

BACKGROUND: It has been suggested that sleep disordered breathing (SDB) during pregnancy may adversely influence maternal as well as fetal well being. OBJECTIVES: To examine the effect of maternal SDB on neonatal neurological examination and perinatal complications. METHODS: Pregnant women of singleton uncomplicated pregnancies were prospectively recruited from a community and hospital low risk obstetric surveillance. All participants completed a sleep questionnaire in the second trimester and underwent ambulatory sleep evaluation (WatchPAT, Itamar Medical, Caesarea, Israel). They were categorized as SDB (apnea hypopnea index > 5) and non-SDB. Maternal and newborn records were reviewed and a neonatal neurologic examination was conducted during the first 48 hours. RESULTS: The study group included 44 women and full-term infants; 11 of the women (25%) had SDB. Mean maternal age of the SDB and non-SDB groups was 32.3 ± 2.8 and 32.5 ± 4.7 years, respectively (P = 0.86). Mean body mass index before the pregnancy in the SDB and non-SDB groups was 25.8 ± 4.7 and 22.0 ± 2.5 kg/m2, respectively (P = 0.028). No differences were found between infants born to mothers with SDB and non-SDB in birth weight (3353.8 ± 284.8 vs. 3379.1 ± 492.4 g), gestational age (39.5 ± 0.9 vs. 39.2 ± 1.5 weeks), 5 minute Apgar scores (9.8 ± 0.6 vs. 9.9 ± 0.3), and neurologic examination scores (95.2 ± 3.9 vs. 94.6 ± 4.1). P value for all was not significant. CONCLUSIONS: Our preliminary results suggest that maternal mild SDB during pregnancy has no adverse effect on neonatal neurologic examination or on perinatal complications.

Relationship Between Central Hypotonia and Motor Development in Infants Attending a High-Risk Neonatal Neurology Clinic.

PURPOSE: To study the relationship between central hypotonia and motor development, and to determine the relative contribution of nuchal, truncal, and appendicular hypotonia domains to motor development. METHODS: Appendicular, nuchal, and truncal tones of high-risk infants were assessed, as was their psychomotor developmental index (PDI). Infants with peripheral hypotonia were excluded. RESULTS: We included 164 infants (mean age 9.6 ± 4 months), 36 with normal tone in all 3 domains and 128 with central hypotonia. Twenty-six of the latter had hypotonia in 1 domain and 102 had multiple combinations of 3 domains. Hypotonia domains were distributed as follows: truncal (n = 115), appendicular (n = 93), and nuchal (n = 70). Each domain was significantly associated with PDI scores (P < .001) but not with a later diagnosis of cerebral palsy. On linear regression, nuchal hypotonia had the strongest contribution to PDI scores (ß = -0.6 [nuchal], -0.45 [appendicular], and -0.4 [truncal], P < .001). CONCLUSIONS: Central hypotonia, especially nuchal tone, is associated with lowered motor development scores.

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.

OBJECTIVE: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. METHODS: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. RESULTS: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. SIGNIFICANCE: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.

The effect of maternal sleep-disordered breathing on the infant's neurodevelopment.

OBJECTIVE: We sought to examine the effect of maternal sleep-disordered breathing (SDB) on infant general movements (GMs) and neurodevelopment. STUDY DESIGN: Pregnant women with uncomplicated full-term pregnancies and their offspring were prospectively recruited from a community and hospital low-risk obstetric surveillance. All participants completed a sleep questionnaire on second trimester and underwent ambulatory sleep evaluation (WatchPAT; Itamar Medical, Caesarea, Israel). They were categorized as SDB (apnea hypopnea index>5) and controls. Infant GMs were assessed in the first 48 hours and at 8-11 and 14-16 weeks of age. At 12 months of age the Infant Developmental Inventory and the Brief Infant Sleep Questionnaire were administered. RESULTS: In all, 74 women and their full-term infants were studied. Eighteen (24%) women had SDB. Mean birthweight was 3347.1±423.9 g. Median Apgar score at 5 minutes was 10 (range, 8-10). In adjusted comparisons, no differences were found between infants born to mothers with SDB and controls in GM scores in all 3 evaluations. Low social developmental score was detected at 12 months in 64% of infants born to SDB mothers compared to 25% of infants born to controls (adjusted P=.036; odds ratio, 16.7). Infant snoring was reported by 41.7% of mothers with SDB compared to 7.5% of controls (P=.004). CONCLUSION: Our preliminary results suggest that maternal SDB during pregnancy has no adverse effect on neonatal and infant neuromotor development but may affect social development at 1 year.

Electroencephalographic characteristics in preterm infants born with intrauterine growth restriction.

OBJECTIVE: To determine the impact of fetal growth on postnatal amplitude-integrated electroencephalography (aEEG) and power spectrum electroencephalography (EEG) data in preterm infants born with intrauterine growth restriction (IUGR). STUDY DESIGN: We defined IUGR as birth weight <10th percentile, and control as birth weight appropriate for gestational age (GA). We performed single-channel (C3-C4) EEG during the first 48 hours of life and measured the upper and lower margins of the aEEG trace width. EEG readings were analyzed by spectral analysis, and the relative power of the frequency bands was calculated. The Lacey Assessment of the Preterm Infant was administered before discharge. RESULTS: We enrolled 14 infants with IUGR (mean GA, 34.3 ± 1.8 weeks; mean birth weight 1486 ± 304 g) and 16 appropriate for GA controls (mean GA, 33.7 ± 2 weeks; mean birth weight, 1978 ± 488 g). There were no significant between-group differences in perinatal complications. The mean aEEG trace width was 20.8 ± 1.4 µv in the infants with IUGR versus 17.3 ± 1.6 µv in controls (P < .001). The infants with IUGR also had significantly greater delta frequency activity and decreased theta, alpha, and beta frequency activities compared with controls. Delta frequency activity decreased with increasing GA (r = -0.8; P = .001 for infants with IUGR and r = -0.9; P < .001 for controls). The Lacey Assessment of the Preterm Infant developmental score was significantly lower in the infants with IUGR (P < .02) and was correlated with aEEG trace width (r = -0.6; P = .002) and with delta activity (r = -0.5; P = .02). CONCLUSION: Preterm infants with IUGR have delayed EEG maturation associated with delayed neuromotor development. The predictive value of these alterations regarding developmental deficits associated with IUGR remains undetermined, however.

Complex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy.

Mutations in the SCN8A gene, encoding the voltage-gated sodium channel NaV1.6, are associated with a range of neurodevelopmental syndromes. The p.(Gly1625Arg) (G1625R) mutation was identified in a patient diagnosed with developmental epileptic encephalopathy (DEE). While most of the characterized DEE-associated SCN8A mutations were shown to cause a gain-of-channel function, we show that the G1625R variant, positioned within the S4 segment of domain IV, results in complex effects. Voltage-clamp analyses of NaV1.6G1625R demonstrated a mixture of gain- and loss-of-function properties, including reduced current amplitudes, increased time constant of fast voltage-dependent inactivation, a depolarizing shift in the voltage dependence of activation and inactivation, and increased channel availability with high-frequency repeated depolarization. Current-clamp analyses in transfected cultured neurons revealed that these biophysical properties caused a marked reduction in the number of action potentials when firing was driven by the transfected mutant NaV1.6. Accordingly, computational modeling of mature cortical neurons demonstrated a mild decrease in neuronal firing when mimicking the patients' heterozygous SCN8A expression. Structural modeling of NaV1.6G1625R suggested the formation of a cation-π interaction between R1625 and F1588 within domain IV. Double-mutant cycle analysis revealed that this interaction affects the voltage dependence of inactivation in NaV1.6G1625R. Together, our studies demonstrate that the G1625R variant leads to a complex combination of gain and loss of function biophysical changes that result in an overall mild reduction in neuronal firing, related to the perturbed interaction network within the voltage sensor domain, necessitating personalized multi-tiered analysis for SCN8A mutations for optimal treatment selection.

Prolonged febrile seizures, clinical characteristics, and acute management.

PURPOSE: Prolonged febrile seizures (PFS) lasting ≥15 min have been associated with increased risk for epilepsy in later life. Initial treatment, mostly prehospital, aims to prevent its evolution to febrile status epilepticus (FSE) and reduce adverse outcome. Paucity of information is available on the immediate treatment before reaching a hospital facility. METHODS: We obtained data, prospectively, on all children who presented from January 2008 to March 2010 with PFS to the emergency rooms of four Israeli medical centers. Information related to seizure semiology, treatment, and medical history was collected into a predefined pro forma form and reviewed centrally. KEY FINDINGS: Sixty children, median age 18.3 months (interquartile range [IQR] 12-28) were included with a median seizure duration of 35 min (IQR 26-60), 43 (71.7%) lasting ≥30 min. Seizures had focal onset in 34 infants (57%). Fifty-four families (90%) activated the ambulance service; median ambulance arrival time was 8 min (IQR 5-10), 33 (61%) were medically treated by the ambulance paramedic, of whom 15 (45%) responded to treatment. Twelve children with active seizures did not receive medications. Initial treatment with rectal diazepam was more common in those with seizure duration >30 min. SIGNIFICANCE: Most children with PFS are treated with antiepileptic drugs early by the ambulance service. However, even timely treatment does not prevent status epilepticus in the majority of cases. These data highlight the need for effective early treatment of this common pediatric emergency.

Neonatal absolute nucleated red blood cell counts do not predict the development of cystic periventricular leukomalacia.

BACKGROUND: Infants with severe intraventricular-periventricular hemorrhage (IVH) have higher absolute nucleated red blood cell counts (aNRBC) at birth (a marker of intrauterine hypoxia) than controls. Periventricular leukomalacia (PVL) is known to be associated with prenatal and postnatal events. Whether PVL is also linked to intrauterine hypoxia is unknown. OBJECTIVES: To test the hypothesis that infants with PVL have higher aNRBC counts at birth than controls. METHODS: We studied 14 very low birth weight infants with PVL and compared them with 14 pair-matched controls without PVL. Head ultrasound scans were performed in all infants on days 3-5 and 21-25 of life. Paired tests, Fisher exact tests and stepwise logistic regression were performed for analysis. RESULTS: The groups were similar for gestational age (GA), birth weight (BW), prolonged rupture of membranes (PROM), Apgar scores, IVH, and aNRBC counts. PVL correlated significantly with low partial pressure of CO2 (PCO2) and IVH (P < 0.01). In logistic regression, when GA, gender, PROM, antenatal steroid therapy, 1 (or 5) minute Apgar scores, IVH grade, nosocomial sepsis, patent ductus arteriosus, necrotizing enterocolitis (NEC), need for pressors, aNRBC counts and lowest PCO2 were used as independent variables, PCO2 (P = 0.002), IVH grade (P= 0.001), GA (P = 0.038), NEC (P = 0.061) and use of dopamine (P = 0.010) remained in the analysis (total R2 = 68.2%). CONCLUSIONS: In contrast to severe IVH, aNRBC counts do not predict the development of PVL.

Blood pressure values in 8-12 year old children with a history of intrauterine growth retardation.

BACKGROUND: Epidemiological studies have found that intrauterine growth retardation (IUGR) is closely related to hypertension and is associated with a reduced number of nephrons that may be a predisposing factor for the development of hypertension. OBJECTIVES: To determine whether blood pressure levels of children with a history of IUGR are higher than those of children without IUGR. METHODS: Diastolic, systolic and mean arterial blood pressure levels were measured in 64 children aged 8-12 years old with a history of IUGR (mean birth weight 1780 +/- 422 g) and compared with 64 age and gender-matched controls who had a normal birth weight (mean 3134 +/- 594 g). RESULTS: Contrary to previous reports, systolic blood pressure values were significantly lower in the IUGR group compared to the controls (91.6 +/- 11.3 vs. 96.6 +/- 13.9, P = 0.027). There was no difference in diastolic blood pressure values. In the IUGR group, systolic blood pressure correlated significantly with current weight (P < 0.01) and body mass index (P < 0.05), and diastolic blood pressure with weight gain between age 2 and 4 years (P < 0.05). None of the blood pressure values correlated with birth weight. CONCLUSIONS: Children born with IUGR have lower systolic blood pressure levels than matched controls at age 8-12 years. These data indicate that postnatal weight gain in this group has a greater impact on systolic blood pressure than birth weight.

Therapeutic hypothermia for asphyxiated newborns: experience of an Israeli tertiary center.

BACKGROUND: Major advances in the treatment of perinatal asphyxial-hypoxic ischemic encephalopathy (PA-HIE) followed the translation of hypothermia animal studies into successful randomized controlled clinical trials that substantially influenced the current standard of care. OBJECTIVES: To present our preliminary experience with the first cases of clinical application of therapeutic hypothermia for PA-HIE in what we believe is the first report on nonexperimental hypothermia for PA-HIE from Israel. METHODS: We reviewed the medical records, imaging scans, electroencephalograms and outcome data of the six identified asphyxiated newborns who were managed with hypothermia in our services in 2008-2009. RESULTS: All asphyxiated newborns required resuscitation and were encephalopathic. Systemic hypothermia (33.5 degrees C) was begun at a median age of 4.2 hours of life (range 2.5-6 hours) and continued for 3 days. All six infants showed a significantly depressed amplitude integrated electroencephalography background, and five had electrographic seizures. One infant died (16%) after 3.5 days. Major complications included fat necrosis and hypercalcemia (n=1), pneumothorax (n=1), and meconium aspiration syndrome (n=2). None of the infants developed major bleeding. Neurodevelopmental followup of the five surviving infants at median age 7.2 months (4.1-18.5 months) revealed developmental delays (Battelle screening), with their motor scores ranging from -1 to +1 standard deviation (Bayley scale). None developed feeding problems, oculomotor abnormalities, spasticity or seizures. CONCLUSIONS: Our preliminary experience with this novel modality in a large Tel Aviv neonatal service is consistent with the clinical findings of published trials.

Metabolic biomarkers of small and large for gestational age newborns.

BACKGROUND: Small for gestational age (SGA) and large for gestational age (LGA) newborns are at increased risk for developmental, metabolic and cardiovascular morbidities. AIMS: To compare the metabolic biomarkers of SGA and LGA infants with those of appropriate for gestational age (AGA) newborns in order to shed more light on a possible pathogenesis of those morbidities. STUDY DESIGN: An observational retrospective study. SUBJECTS: 70,809 term newborns divided into AGA, SGA, LGA, and severe subcategories (<3rd percentile or ≥97th percentile). OUTCOME MEASURES: 18 metabolites were measured by dried blood tandem mass spectrometry and compared in between groups in univariate and multivariate logistic regression. RESULTS: SGA newborns had a significant likelihood for elevated methionine, proline, free carnitine, and reduced valine levels compared to AGA newborns (P < .0001). Severe SGA showed more apparent trends including elevated leucine. LGA newborns had a significant likelihood for low citrulline, glutamine, proline, tyrosine, and elevated leucine levels (P ≤ .0033). Severe LGA newborns showed the same trends, with the exception of citrulline and glutamine. CONCLUSIONS: SGA and LGA newborns demonstrate distinct metabolic biomarkers in newborn screening. Most of the altered metabolites in the SGA group were elevated while those in the LGA group were decreased in comparison to AGA newborns. These trends were more apparent in the severe SGA subgroup while they mostly remained the same in the severe LGA subgroup. Whether these metabolic changes are involved with or can predict long-term outcome awaits further trials.

Novel perspectives of super-high dose sulfonylurea and high-dose oral prednisolone in an infant with DEND syndrome due to V64M heterozygote KCNJ11 mutation.

AIMS: To report a novel mutation associated with developmental delay, epilepsy, and neonatal diabetes-DEND Syndrome, responsive to a novel management combination. METHODS: We describe the investigation, treatment, and genetic diagnosis of a newborn diagnosed with DEND syndrome. RESULTS: The patient was found to be de-novo heterozygous for pathogenic KCNJ11 missense variant: c.190G > A, p. (Val64Met), associated with DEND syndrome, responsive to a combination of super high doses of sulfonylurea (SU) and oral high-dose steroids. A single case was reported so far due to this mutation, presenting with severe DEND syndrome, treated by insulin only. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. CONCLUSIONS: We have identified a heterozygous missense mutation as the etiology for severe DEND syndrome in a one-day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.