Brain volumes and functional outcomes in children without cerebral palsy after therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

AIM: To investigate whether brain volumes were reduced in children aged 6 to 8 years without cerebral palsy, who underwent therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (patients), and matched controls, and to examine the relation between subcortical volumes and functional outcome. METHOD: We measured regional brain volumes in 31 patients and 32 controls (median age 7 years and 7 years 2 months respectively) from T1-weighted magnetic resonance imaging (MRI). We assessed cognition using the Wechsler Intelligence Scales for Children, Fourth Edition and motor ability using the Movement Assessment Battery for Children, Second Edition (MABC-2). RESULTS: Patients had lower volume of whole-brain grey matter, white matter, pallidi, hippocampi, and thalami than controls (false discovery rate-corrected p < 0.05). Differences in subcortical grey-matter volumes were not independent of total brain volume (TBV). In patients, hippocampal and thalamic volumes correlated with full-scale IQ (hippocampi, r = 0.477, p = 0.010; thalami, r = 0.452, p = 0.016) and MABC-2 total score (hippocampi, r = 0.526, p = 0.004; thalami, r = 0.505, p = 0.006) independent of age, sex, and TBV. No significant correlations were found in controls. In patients, cortical injury on neonatal MRI was associated with reduced volumes of hippocampi (p = 0.001), thalami (p = 0.002), grey matter (p = 0.015), and white matter (p = 0.013). INTERPRETATION: Children who underwent therapeutic hypothermia have reduced whole-brain grey and white-matter volumes, with associations between hippocampal and thalamic volumes and functional outcomes.

An Age-Specific Atlas for Delineation of White Matter Pathways in Children Aged 6-8 Years.

Introduction: Diffusion magnetic resonance imaging (MRI) allows noninvasive assessment of white matter connectivity in typical development and of changes due to brain injury or pathology. Probabilistic white matter atlases allow diffusion metrics to be measured in specific white matter pathways, and are a critical component in spatial normalization for group analysis. However, given the known developmental changes in white matter it may be suboptimal to use an adult template when assessing data acquired from children. Methods: By averaging subject-specific fiber bundles from 28 children aged from 6 to 8 years, we created an age-specific probabilistic white matter atlas for 12 major white matter tracts. Using both the newly developed and Johns Hopkins adult atlases, we compared the atlas with subject-specific fiber bundles in two independent validation cohorts, assessing accuracy in terms of volumetric overlap and measured diffusion metrics. Results: Our age-specific atlas gave better overall performance than the adult atlas, achieving higher volumetric overlap with subject-specific fiber tracking and higher correlation of fractional anisotropy (FA) measurements with those measured from subject-specific fiber bundles. Specifically, estimates of FA values for corticospinal tract, uncinate fasciculus, forceps minor, cingulate gyrus part of the cingulum, and anterior thalamic radiation were all significantly more accurate when estimated with an age-specific atlas. Discussion: The age-specific atlas allows delineation of white matter tracts in children aged 6-8 years, without the need for tractography, more accurately than when normalizing to an adult atlas. To our knowledge, this is the first publicly available probabilistic atlas of white matter tracts for this age group.

Motor function and white matter connectivity in children cooled for neonatal encephalopathy.

Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6-8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P < 0.05) were found in the anterior thalamic radiation bilaterally (left: r = 0.513; right: r = 0.488), the cingulate gyrus part of the left cingulum (r = 0.588), the hippocampal part of the left cingulum (r = 0.541), and the inferior fronto-occipital fasciculus bilaterally (left: r = 0.445; right: r = 0.494). No significant correlations were found in controls. We then constructed structural connectivity networks, for 22 cases and 32 controls, in which nodes represent brain regions and edges were determined by probabilistic tractography and weighted by fractional anisotropy. Analysis of whole-brain network metrics revealed correlations (FDR-corrected P < 0.05), in cases, between total motor scores and average node strength (r = 0.571), local efficiency (r = 0.664), global efficiency (r = 0.677), clustering coefficient (r = 0.608), and characteristic path length (r = -0.652). No significant correlations were found in controls. We then investigated edge-level association with motor function using the network-based statistic. This revealed subnetworks which exhibited group differences in the association between motor outcome and edge weights, for total motor scores (P = 0.0109) as well as for balance (P = 0.0245) and manual dexterity (P = 0.0233) domain scores. All three of these subnetworks comprised numerous frontal lobe regions known to be associated with motor function, including the superior frontal gyrus and middle frontal gyrus. The subnetwork associated with total motor scores was highly left-lateralised. These findings demonstrate an association between impaired motor function and brain organisation in school-age children treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

Disrupted brain connectivity in children treated with therapeutic hypothermia for neonatal encephalopathy.

Therapeutic hypothermia following neonatal encephalopathy due to birth asphyxia reduces death and cerebral palsy. However, school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy still have reduced performance on cognitive and motor tests, attention difficulties, slower reaction times and reduced visuo-spatial processing abilities compared to typically developing controls. We acquired diffusion-weighted imaging data from school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy at birth, and a matched control group. Voxelwise analysis (33 cases, 36 controls) confirmed reduced fractional anisotropy in widespread areas of white matter in cases, particularly in the fornix, corpus callosum, anterior and posterior limbs of the internal capsule bilaterally and cingulum bilaterally. In structural brain networks constructed using probabilistic tractography (22 cases, 32 controls), graph-theoretic measures of strength, local and global efficiency, clustering coefficient and characteristic path length were found to correlate with IQ in cases but not controls. Network-based statistic analysis implicated brain regions involved in visuo-spatial processing and attention, aligning with previous behavioural findings. These included the precuneus, thalamus, left superior parietal gyrus and left inferior temporal gyrus. Our findings demonstrate that, despite the manifest successes of therapeutic hypothermia, brain development is impaired in these children.

Closed circuit xenon delivery for 72h in neonatal piglets following hypoxic insult using an ambient pressure automated control system: Development, technical evaluation and pulmonary effects.

BACKGROUND: Therapeutic hypothermia (TH) for 72h is the standard treatment following neonatal encephalopathy (NE). However, one-third do not benefit and adjunctive therapies are urgently needed. Xenon enhances neuroprotection with TH when administered at 50% concentration within 5hours of hypoxia in experimental studies. Delayed initiation (~10 hours of age) of 30% xenon for 24 hours during TH did not improve early adverse biomarkers in a clinical trial of Xenon+TH vs TH. After hypoxia-ischemia, excitotoxic injury via N-methyl-D-aspartate receptor overactivation lasts days. Since xenon partially inhibits this receptor, we hypothesised that giving 50% xenon throughout the entire 72h TH and rewarming periods would enhance neuroprotection. Xenon costs $30/litre, so a closed-circuit breathing system is desirable with automated fresh gas delivery. METHODS: Seven mechanically ventilated newborn pigs were randomized to receive 50% inhaled xenon for 72h during hypothermia (rectal-temperature 35°C) and subsequent rewarming following a global hypoxic-ischemic insult (XeHT, N = 4) or under normothermia for 72h (rectal-temperature 38.5°C) following sham insult (XeNT, N = 3). An automated fresh gas delivery system injected oxygen/air/xenon boluses into a closed-circuit based on measured gas concentrations. RESULTS AND DISCUSSION: Median (IQR) xenon consumption was 0.31 L/h (0.18, 0.50) and 0.34L/h (0.32, 0.49) for hypothermic and normothermic groups respectively, 0.34L/h (0.25, 0.53) overall. 92% of 9626 xenon and 69% of 9635 oxygen measurements were within 20% variation from targets. For xenon concentration, the median absolute performance errors for the XeHT and XeNT groups were 6.14% and 3.84% respectively and 4.31% overall. For oxygen these values were 13.42%, 15.05% and 12.4% respectively. There were no adverse pulmonary pathophysiology findings. Clinical problems over the total period included three related to sensors, seven breathing system leaks, ten partial and one complete tracheal tube occlusion episodes. CONCLUSION: The automated controller functioned as intended maintaining an inhaled xenon concentration close to the 50% target for 72-78h at a xenon cost of $11.1/h.

School-age outcomes of children without cerebral palsy cooled for neonatal hypoxic-ischaemic encephalopathy in 2008-2010.

OBJECTIVE: Since therapeutic hypothermia became standard care for neonatal hypoxic-ischaemic encephalopathy (HIE), even fewer infants die or have disability at 18-month assessment than in the clinical trials. However, longer term follow-up of apparently unimpaired children is lacking. We investigated the cognitive, motor and behavioural performances of survivors without cerebral palsy (CP) cooled for HIE, in comparison with matched non-HIE control children at 6-8 years. DESIGN: Case-control study. PARTICIPANTS: 29 case children without CP, cooled in 2008-2010 and 20 age-matched, sex-matched and social class-matched term-born controls. MEASURES: Wechsler Intelligence Scales for Children, Fourth UK Edition, Movement Assessment Battery for Children, Second Edition (MABC-2) and Strengths and Difficulties Questionnaire. RESULTS: Cases compared with controls had significantly lower mean (SD) full-scale IQ (91 [10.37]vs105[13.41]; mean difference (MD): -13.62, 95% CI -20.53 to -6.71) and total MABC-2 scores (7.9 [3.26]vs10.2[2.86]; MD: -2.12, 95% CI -3.93 to -0.3). Mean differences were significant between cases and controls for verbal comprehension (-8.8, 95% CI -14.25 to -3.34), perceptual reasoning (-13.9, 95% CI-20.78 to -7.09), working memory (-8.2, 95% CI-16.29 to -0.17), processing speed (-11.6, 95% CI-20.69 to -2.47), aiming and catching (-1.6, 95% CI-3.26 to -0.10) and manual dexterity (-2.8, 95% CI-4.64 to -0.85). The case group reported significantly higher median (IQR) total (12 [6.5-13.5] vs 6 [2.25-10], p=0.005) and emotional behavioural difficulties (2 [1-4.5] vs 0.5 [0-2.75], p=0.03) and more case children needed extra support in school (34%vs5%, p=0.02) than the control group. CONCLUSIONS: School-age children without CP cooled for HIE still have reduced cognitive and motor performance and more emotional difficulties than their peers, strongly supporting the need for school-age assessments.

Attention and visuo-spatial function in children without cerebral palsy who were cooled for neonatal encephalopathy: a case-control study.

Objectives: Dorsal-stream functions are vulnerable to early brain injury associated with neonatal encephalopathy (NE) following perinatal asphyxia, even in children not developing cerebral palsy (CP). Since therapeutic hypothermia (TH) became the standard treatment for NE, the incidence of CP is reduced but the impact on dorsal-stream functions is unknown. We aimed to compare dorsal-stream functions in TH-treated survivors of NE, without CP, with those of matched controls. Methods: We administered tests of dorsal-stream function to 29 case children aged 6-to-8 years treated with TH for NE and without CP, and 20 age, sex and social class matched controls. We used the Conner's Continuous Performance Test (CPT) 2nd Edition to assess attentiveness, based upon Hit Reaction Time (HRT) percentile score and HRT standard error percentile, the CPT HRT block change measure to assess sustained attention and the NEPSY-II block construction and arrows tests to assess visuo-spatial performance and mental rotation. Results: Case children performed significantly worse than controls on measures of attention and visuo-spatial function. Conclusions: Children given TH treatment for NE can have subtle attention difficulties with slower reaction times and reduced visuo-spatial processing. These findings illustrate the continued vulnerability of dorsal-stream functions following NE despite the use of TH.

Fluoxetine overdose in a teenager resulting in serotonin syndrome, seizure and delayed onset rhabdomyolysis.

A 14-year-old young adult took an overdose of 1.2 g of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) that he had been prescribed for depression. He had a generalised tonic/clonic seizure at 6 hours postingestion.After the seizure, he developed signs consistent with serotonin syndrome: fine tremor, agitation, sweating and hyperreflexia. This was followed by severe muscle pain and rhabdomyolysis with peak creatine kinase (CK) of 33 941 at 74 hours. He was managed with intravenous fluids and analgesia and discharged after 4 days, having avoided renal injury. The use of SSRI's such as fluoxetine in teenagers has increased in recent years. While it is generally considered benign in overdose, this report illustrates the severe consequences of overdose at high quantities and discusses appropriate management in these cases. We note that in this case, there was a delayed onset of rhabdomyolysis with peak CK at 74 hours postingestion.

Children who abuse animals: when should you be concerned about child abuse? A review of the literature.

Animal abuse by children is common, with 3-44% of children being reported to abuse animals at some point during their childhood. Much of this behaviour may be regarded as an extension of exploratory behaviour in a younger child; however, the apparent link between child and animal abuse is an area of increasing interest; with children who abuse animals being 2-3 times more likely to be directly abused themselves. How concerned should a health professional be that a child who abuses animals could themselves be the victim of abuse? We reviewed the literature on the subject, finding that abuse to an animal that is perpetrated by an older child (>10 years) is more likely to be associated with child abuse. Animal abuse is less common in girls compared with boys and there is some suggestion that child abuse may be more likely in these cases. Some papers have reported a higher prevalence of animal abuse in children with attention deficit hyperactivity disorder, developmental delay and conduct disorder, but the relationship with child abuse in these cases is unknown. Information on both child and animal abuse needs to be shared between the veterinary, medical and social care teams in order to protect both children and animals who are vulnerable.

Repeated lumbar or ventricular punctures in newborns with intraventricular haemorrhage.

BACKGROUND: Although in recent years the percentage of preterm infants who suffer intraventricular haemorrhage (IVH) has reduced, posthaemorrhagic hydrocephalus (PHH) remains a serious problem with a high rate of cerebral palsy and no evidence-based treatment. Survivors often have to undergo ventriculoperitoneal shunt (VPS) surgery, which makes the child permanently dependent on a valve and catheter system. This carries a significant risk of infection and the need for surgical revision of the shunt. Repeated removal of cerebrospinal fluid (CSF) by either lumbar puncture, ventricular puncture, or from a ventricular reservoir in preterm babies with IVH has been suggested as a treatment to reduce the risk of PHH development. OBJECTIVES: To determine the effect of repeated cerebrospinal fluid (CSF) removal (by lumbar/ventricular puncture or removal from a ventricular reservoir) compared to conservative management, where removal is limited to when there are signs of raised intracranial pressure (ICP), on reduction in the risk of permanent shunt dependence, neurodevelopmental disability, and death in neonates with or at risk of developing posthaemorrhagic hydrocephalus (PHH). SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3), MEDLINE via PubMed (1966 to 24 March 2016), Embase (1980 to 24 March 2016), and CINAHL (1982 to 24 March 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: RCTs and quasi-RCTs that compared serial removal of CSF (via lumbar puncture, ventricular puncture, or from a ventricular reservoir) with conservative management (removing CSF only when there were symptoms of raised ICP). Trials also had to report on at least one of the specified outcomes of death, disability, or shunt insertion. DATA COLLECTION AND ANALYSIS: We extracted details of the participant selection, participant allocation and the interventions. We assessed the following outcomes: VPS, death, death or shunt, disability, multiple disability, death or disability, and CSF infection. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Four trials (five articles) met the inclusion criteria of this review; three were RCTs and one was a quasi-RCT; and included a total of 280 participants treated in neonatal intensive care units in the UK. The trials were published between 1980 and 1990. The studies were sufficiently similar regarding the research question they asked and the interventions that we could combine the trials to assess the effect of the intervention.Meta-analysis showed that the intervention produced no significant difference when compared to conservative management for the outcomes of: placement of hydrocephalus shunt (typical risk ratio (RR) 0.96, 95% confidence interval (CI) 0.73 to 1.26; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), death (RR 0.88, 95% CI 0.53 to 1.44; 4 trials, 280 infants; I² statistic = 0%; low quality evidence), major disability in survivors (RR 0.98, 95% CI 0.81 to 1.18; 2 trials, 141 infants; I² statistic = 11%; high quality evidence), multiple disability in survivors (RR 0.9, 95% CI 0.66 to 1.24; 2 trials, 141 infants; I² statistic = 0%; high quality evidence), death or disability (RR 0.99, 95% CI 0.86 to 1.14; 2 trials, 180 infants; I² statistic = 0%; high quality evidence), death or shunt (RR 0.91, 95% CI 0.75 to 1.11; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), and infection of CSF presurgery (RR 1.73, 95% CI 0.53 to 5.67; 2 trials, 195 infants; low quality evidence).We assessed the quality of the evidence as high for the outcomes of major disability, multiple disability, and disability or death. We rated the evidence for the outcomes of shunt insertion, and death or shunt insertion as of moderate quality as one included trial used an alternation method of randomisation. For the outcomes of death and infection of CSF presurgery, the quality of the evidence was low as one trial used an alternation method, the number of participants was too low to assess the objectives with sufficient precision, and there was inconsistency regarding the findings in the included trials regarding the outcome of infection of CSF presurgery. AUTHORS' CONCLUSIONS: There was no evidence that repeated removal of CSF via lumbar puncture, ventricular puncture or from a ventricular reservoir produces any benefit over conservative management in neonates with or at risk for developing PHH in terms of reduction of disability, death, or need for placement of a permanent shunt.