Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia.

OBJECTIVE: Seizures are common among newborns with hypoxic-ischaemic encephalopathy (HIE) but the relationship between seizure burden and severity of brain injury among neonates receiving therapeutic hypothermia (TH) for HIE is unclear. We tested the hypothesis that seizure burden is associated with cerebral tissue injury independent of amplitude-integrated EEG (aEEG) background activity. STUDY DESIGN: Term neonates undergoing 72 h of TH at four centres were selected for study if they had continuous aEEG and MRI. The aEEG with corresponding 2-channel raw EEG (aEEG/EEG), was classified by severity of background and seizure burden; MR images were classified by the severity of tissue injury. RESULTS: Of 85 neonates, 52% had seizures on aEEG/EEG. Overall, 35% had high seizure burden, 49% had abnormal aEEG background in the first 24 h and 36% had severe injury on MRI. Seizures were most common on the first day, with significant recurrence during and after rewarming. Factors associated with severe injury on MRI were high seizure burden, poor aEEG background, 10 min Apgar and the need for more than one anticonvulsant. In multivariate logistic regression, high seizure burden was independently associated with greater injury on MRI (OR 5.00, 95% CI 1.47 to 17.05 p=0.01). Neither aEEG background, nor 10 min Apgar score were significant. CONCLUSIONS: Electrographic seizure burden is associated with severity of brain injury on MRI in newborns with HIE undergoing TH, independent of degree of abnormality on aEEG background. Seizures are common during cooling, particularly on day 1, with a significant rebound on day 4.

Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm.

Although language difficulties are common in children born prematurely, robust neuroanatomical correlates of these impairments remain to be established. This study investigated whether the greater prevalence of language problems in preterm (versus term-born) children might reflect injury to major intra- or interhemispheric white matter pathways connecting frontal and temporal language regions. To investigate this, we performed a comprehensive assessment of language and academic abilities in a group of adolescents born prematurely, some of whom had evidence of brain injury at birth (n = 50, mean age: 16 years, mean gestational age: 27 weeks) and compared them to a term-born control group (n = 30). Detailed structural magnetic resonance imaging and diffusion-tractography analyses of intrahemispheric and interhemispheric white matter bundles were performed. Analysis of intrahemispheric pathways included the arcuate fasciculus (dorsal language pathway) and uncinate fasciculus/extreme capsule (ventral language pathway). Analysis of interhemispheric pathways (in particular, connections between the temporal lobes) included the two major commissural bundles: the corpus callosum and anterior commissure. We found language impairment in 38% of adolescents born preterm. Language impairment was not related to abnormalities of the arcuate fasciculus (or its subsegments), but was associated with bilateral volume reductions in the ventral language pathway. However, the most significant volume reduction was detected in the posterior corpus callosum (splenium), which contains interhemispheric connections between the occipital, parietal and temporal lobes. Diffusion tractography showed that of the three groups of interhemispheric fibres within the splenium, only those connecting the temporal lobes were reduced. Crucially, we found that language impairment was only detectable if the anterior commissure (a second temporal lobe commissural pathway) was also small. Regression analyses showed that a combination of anatomical measures of temporal interhemispheric connectivity (through the splenium of the corpus callosum and anterior commissure) explained 57% of the variance in language abilities. This supports recent theories emphasizing the importance of interhemispheric connections for language, particularly in the developing brain.

Speech and oromotor outcome in adolescents born preterm: relationship to motor tract integrity.

OBJECTIVE: To assess speech abilities in adolescents born preterm and investigate whether there is an association between specific speech deficits and brain abnormalities. STUDY DESIGN: Fifty adolescents born prematurely (<33 weeks' gestation) with a spectrum of brain injuries were recruited (mean age, 16 years). Speech examination included tests of speech-sound processing and production and speech and oromotor control. Conventional magnetic resonance imaging and diffusion-weighted imaging was acquired in all adolescents born preterm and 30 term-born control subjects. Radiological ratings of brain injury were recorded and the integrity of the primary motor projections was measured (corticospinal tract and speech-motor corticobulbar tract [CST/CBT]). RESULTS: There were no clinical diagnoses of developmental dysarthria, dyspraxia, or a speech-sound disorder, but difficulties in speech and oromotor control were common. A regression analysis revealed that presence of a neurologic impairment, and diffusion-weighted imaging abnormalities in the left CST/CBT were significant independent predictors of poor speech and oromotor outcome. These left-lateralized abnormalities were most evident at the level of the posterior limb of the internal capsule. CONCLUSION: Difficulties in speech and oromotor control are common in adolescents born preterm, and adolescents with injury to the CST/CBT pathways in the left-hemisphere may be most at risk.

Total brain white matter is a major determinant of IQ in adolescents born preterm.

OBJECTIVE: In preterm infants, white matter (WM) abnormalities detected on magnetic resonance imaging (MRI) at term-age are associated with early developmental delay. We set out to study this association in adolescents born pre-term, by examining intellectual outcome in relation to markers of brain injury, focusing on the effects of WM reduction. METHODS: Seventy-nine participants were recruited and assessed at a mean age of 16 years: 49 adolescents born preterm (<32 weeks' gestation) with a wide spectrum of brain injuries (including 22 with no identifiable brain injury at birth) and 30 term-born controls. Data collected included: brain MRI scans, full-scale intelligence quotient (IQ) scores, educational attainments, and behavioral scores. Measures of WM reduction included total volume, cross-sectional area of the corpus callosum (CC), and ventricular dilatation. Cerebellar volumes and neuroradiological ratings were also included. RESULTS: WM volume and IQ were reduced in the preterm groups (both with and without brain injury). Total WM volume and CC area jointly explained 70% of IQ variance in the adolescents born preterm, irrespective of the presence or severity of brain abnormalities detected at birth or on follow-up MRI. This relationship was not seen in controls. Importantly, correlations were also found with real-world measures of academic achievement and behavioral difficulties. INTERPRETATION: Preterm birth has a long-term effect on cognition, behavior, and future academic success primarily as a consequence of global brain WM reduction. This emphasizes the need for early therapeutic efforts to prevent WM injury and promote or optimize its development in preterm neonates.

Ethics and hypothermia treatment.

Hypothermia is the first effective neuroprotective intervention for newborns who are critically ill following a life-threatening asphyxial insult. It is not surprising that it has raised complex and controversial ethical dilemmas for investigators and clinicians. Given the history of iatrogenic disasters in neonatology, there has been an understandable reluctance to incorporate hypothermia into routine clinical practice until there is persuasive evidence from high quality randomised trials. This article reviews ethical issues that arose during the design of the original clinical trials, the implications of accumulating evidence of safety and efficacy, and the problems of ensuring informed parental participation in treatment decisions.

Phosphorus magnetic resonance spectroscopy 2 h after perinatal cerebral hypoxia-ischemia prognosticates outcome in the newborn piglet.

Phosphorus magnetic resonance spectroscopy ((31)P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia-ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very-early, injury-severity biomarkers. Twenty-seven newborn piglets underwent cerebral HI: (31)P-MRS measures approximately 2 h after HI were compared between injury groups defined by secondary-energy-failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h. For severe and moderate injury versus baseline, [Pi]/[total exchangeable high-energy phosphate pool (EPP)] was increased (p < 0.001 and < 0.02, respectively), and [NTP]/[EPP] decreased (p < 0.03 and < 0.006, respectively): severe-injury [Pi]/[EPP] was also increased versus mild injury (p < 0.04). Mild-injury [phosphocreatine]/[EPP] was increased (p < 0.004). Severe-injury intracellular pH was alkaline versus baseline (p < 0.002). For severe and moderate injury [total Mg]/[ATP] (p < 0.0002 and < 0.02, respectively) and [free Mg] (p < 0.0001 and < 0.02, respectively) were increased versus baseline. [Pi]/[EPP], [phosphocreatine]/[Pi] and [NTP]/[EPP] correlated linearly with injury severity (p < 0.005, < 0.005 and < 0.02, respectively). Increased [Pi]/[EPP], intracellular pH and intracellular Mg approximately 2 h after intrapartum HI may prognosticate severe injury, whereas increased [phosphocreatine]/[EPP] may suggest mild damage. In vivo(31)P MRS may have potential to provide very-early prognosis in neonatal encephalopathy.

Impaired autoregulation in preterm infants identified by using spatially resolved spectroscopy.

OBJECTIVE: The absence of cerebral autoregulation in preterm infants has been associated with adverse outcome, but its bedside assessment in the immature brain is problematic. We used spatially resolved spectroscopy to continuously measure cerebral oxygen saturation (expressed as a tissue-oxygenation index) and used the correlation of tissue-oxygenation index with spontaneous fluctuations in mean arterial blood pressure to assess cerebral autoregulation. PATIENTS AND METHODS: The tissue-oxygenation index and mean arterial blood pressure were continuously measured in very premature infants (n = 24) of mean (+/-SD) gestational age of 26 (+/-2.3) weeks at a mean postnatal age of 28 (+/-22) hours. The correlation between mean arterial blood pressure and tissue-oxygenation index in the frequency domain was assessed by using cross-spectral analysis techniques (coherence and transfer-function gain). Values of coherence reflect the strength of linear correlation, whereas transfer-function gain reflects the amplitude of tissue-oxygenation index changes relative to mean arterial blood pressure changes. RESULTS: High coherence (coherence > or = 0.5) values were found in 9 infants who were of lower gestational age, lower birth weight, and lower mean arterial blood pressure than infants with coherence of < 0.5; high-coherence infants also had higher median Clinical Risk Index for Babies scores and a higher rate of neonatal deaths. Coherence of > or = 0.5 predicted mortality with a positive predictive value of 67% and negative predictive value of 100%. In multifactorial analysis, coherence alone was the best predictor of mortality and Clinical Risk Index for Babies score alone was the best predictor of coherence. CONCLUSIONS: High coherence between mean arterial blood pressure and tissue-oxygenation index indicates impaired cerebral autoregulation in clinically sick preterm infants and is strongly associated with subsequent mortality. Cross-spectral analysis of mean arterial blood pressure and tissue-oxygenation index has the potential to provide continuous bedside assessment of cerebral autoregulation and to guide therapeutic interventions.

Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy.

OBJECTIVE: To evaluate whether therapeutic hypothermia alters the prognostic value of clinical grading of neonatal encephalopathy. STUDY DESIGN: This study was a secondary analysis of a multicenter study of 234 term infants with neonatal encephalopathy randomized to head cooling for 72 hours starting within 6 hours of birth, with rectal temperature maintained at 34.5 degrees C +/- 0.5 degrees C, followed by re-warming for 4 hours, or standard care at 37.0 degrees C +/- 0.5 degrees C. Severity of encephalopathy was measured pre-randomization and on day 4, after re-warming, in 177 infants; 31 infants died before day 4, and data were missing for 10 infants. The primary outcome was death or severe disability at 18 months of age. RESULTS: Milder pre-randomization encephalopathy, greater improvement in encephalopathy from randomization to day 4, and cooling were associated with favorable outcome in multivariate binary logistic regression. Hypothermia did not affect severity of encephalopathy at day 4, however, in infants with moderate encephalopathy at day 4, those treated with hypothermia had a significantly higher rate of favorable outcome (31/45 infants, 69%, P = .006) compared with standard care (12/33, 36%). CONCLUSION: Infants with moderate encephalopathy on day 4 may have a more favorable prognosis after hypothermia treatment than expected after standard care.

"Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets.

OBJECTIVE: For optimal neuroprotection following transient perinatal hypoxia-ischaemia (HI), therapy should start before overt secondary energy failure and its irreversible neurotoxic cascade. Hypothermia is a promising neuroprotective intervention that also prolongs the therapeutic time window ("latent-phase"; the period between re-establishment of apparently normal cerebral metabolism after HI, and the start of secondary energy failure). The influences of HI severity on latent-phase duration and regional neuroprotection are unclear. Under normothermia and delayed whole-body cooling to 35 and 33 degrees C we aimed to assess relationships between HI severity and: (i) latent-phase duration; (ii) secondary-energy-failure severity; and (iii) neuronal injury 48 h following HI. METHODS: Newborn piglets were randomized to: (i) HI-normothermia (n=12), (ii) HI-35 degrees C (n=7), and (iii) HI-33 degrees C (n=10). HI-35 degrees C and HI-33 degrees C piglets were cooled between 2 and 26 h after HI. Insult and secondary-energy-failure severity and latent-phase duration were evaluated using phosphorus magnetic resonance spectroscopy and compared with neuronal death in cortical-grey and deep-grey matter. RESULTS: More severe HI was associated with shorter latent-phase (p=0.002), worse secondary energy failure (p=0.023) and more cortical-grey-matter neuronal death (p=0.016). CONCLUSIONS: Latent-phase duration is inversely related to insult severity; latent-phase brevity may explain the apparently less effective neuroprotection following severe cerebral HI.

Determinants of outcomes after head cooling for neonatal encephalopathy.

OBJECTIVE: The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS: A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 +/- 0.5 degrees C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS: Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as > or =25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (> or =38 degrees C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS: Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

Magnetic resonance imaging of neonatal encephalopathy at 4.7 tesla: initial experiences.

OBJECTIVES: The goals were to develop safe 4.7-T MRI examination protocols for newborn infants and to explore the advantages of this field strength in neonatal encephalopathy. METHODS: Nine ventilated newborn infants with moderate or severe encephalopathy were studied at 4.7 T, with ethical approval and informed parental consent. The custom-made, 4.7-T-compatible, neonatal patient management system included acoustic noise protection and physiologic monitoring. An adult head coil was used. Acquisition parameters for T2-weighted fast spin echo MRI and a variety of T1-weighted methods were adapted for MRI of neonatal brain at 4.7 T. The pulse sequences used had a radiofrequency specific absorption rate of <2 W/kg. RESULTS: Physiologic measures were normal throughout each scan. T2-weighted fast spin echo imaging provided better anatomic resolution and gray/white matter contrast than typically obtained at 1.5 T; T1-weighted images were less impressive. CONCLUSIONS: With appropriate safety precautions, MRI of newborn infants undergoing intensive care is as feasible at 4.7 T as it is at 1.5 T; our initial studies produced T2-weighted fast spin echo images with more detail than commonly obtained at 1.5 T. Although T1-weighted images were not adequately informative, additional pulse sequence optimization may be advantageous. A smaller neonatal head coil should also permit greater flexibility in acquisition parameters and even more anatomic resolution and tissue contrast. In neonatal encephalopathy, interpretation of the T2-weighted pathologic detail in combination with comprehensive neurodevelopmental follow-up should improve prognostic accuracy and enable more patient-specific therapeutic interventions. In addition, more precise relationships between structural changes and functional impairment may be defined.

Superficial brain is cooler in small piglets: neonatal hypothermia implications.

OBJECTIVE: Hypothermia was not neuroprotective in low body weight (BW) infants on subgroup analysis in a recent clinical trial of selective head cooling (SHC) in neonatal encephalopathy (CoolCap Trial). METHODS: The BW dependence of regional cerebral temperature was investigated in 14 newborn piglets under normothermia (38.5 degrees C), whole-body cooling (WBC; 36.5, 34.5, 32.5, and 30.5 degrees C), or SHC (20, 15, and 10 degrees C). RESULTS: Normothermia: Lower BW led to lower superficial brain temperature (p < 0.01). Deep to superficial brain and rectal to superficial brain temperature gradients increased with decreasing BW (both p < 0.05). WBC: Lower BW led to lower superficial brain temperature and higher rectal to superficial brain temperature gradient (p < 0.05 and p < 0.01, respectively). SHC: For lower BW, superficial and deep brain temperatures decreased (p < 0.01 and p < 0.05, respectively), whereas rectal to deep, rectal to superficial, and deep to superficial brain temperature gradients increased (p < 0.05, p < 0.01, and p < 0.05, respectively). Compared with SHC alone, superimposition of WBC (34.5 degrees C) reduced all regional temperatures (all p < 0.001); gradients were unaffected. INTERPRETATION: Brain cooling (under normothermia, WBC, or SHC) was more efficient with lower BW due to greater head surface area-to-volume ratios. In the CoolCap Trial, low BW infants might have been excessively cooled. WBC and SHC may require BW adjustment to accomplish consistent regional temperatures and optimal neuroprotection.

Comparative prognostic utilities of early quantitative magnetic resonance imaging spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy.

OBJECTIVE: We sought to compare the prognostic utilities of early MRI spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy. METHODS: Twenty-one term infants with neonatal encephalopathy were studied at a mean age of 3.1 days (range: 1-5). Basal ganglia, thalamic and frontal, parietal, and occipital white matter spin-spin relaxation times were determined from images with echo times of 25 and 200 milliseconds. Metabolite ratios were determined from an 8-mL thalamic-region magnetic resonance spectroscopy voxel (1H point-resolved spectroscopy; echo time 270 milliseconds). Outcomes were assigned at age 1 year as follows: (1) normal, (2) moderate (neuromotor signs or Griffiths developmental quotient of 75-84), (3) severe (functional neuromotor deficit or developmental quotient <75 or died). Predictive efficacies for differentiation between normal and adverse (combined moderate and severe) outcomes were compared by receiver operating characteristic curve analysis and logistic regression. RESULTS: Thalamic and basal ganglia spin-spin relaxation times correlated positively with outcome and predicted adversity. Although thalamic and basal ganglia spin-spin relaxation times were prognostic of adversity, magnetic resonance spectroscopy metabolite ratios were better predictors, and, of these, lactate/N-acetylaspartate was most accurate. CONCLUSIONS: Deep gray matter spin-spin relaxation time was increased in the first few days after birth in infants with an adverse outcome. Proton magnetic resonance spectroscopy was more prognostic than spin-spin relaxation time, with lactate/N-acetylaspartate the best measure. Nevertheless, both techniques were useful for early prognosis, and the potential superior spatial resolution of spin-spin relaxometry may define better the precise anatomic pattern of injury in the early days after birth.

Brain and cognitive-behavioural development after asphyxia at term birth.

Perinatal asphyxia occurs in approximately 1-6 per 1000 live full-term births. Different patterns of brain damage can result, though the relation of these patterns to long-term cognitive-behavioural outcome remains under investigation. The hippocampus is one brain region that can be damaged (typically not in isolation), and this site of damage has been implicated in two different long-term outcomes, cognitive memory impairment and the psychiatric disorder schizophrenia. Factors in addition to the acute episode of asphyxia likely contribute to these specific outcomes, making prediction difficult. Future studies that better document long-term cognitive-behavioural outcome, quantitatively identify patterns of brain injury over development and consider additional variables that may modulate the impact of asphyxia on cognitive and behavioural function will forward the goals of predicting long-term outcome and understanding the mechanisms by which it unfolds.

Delayed whole-body cooling to 33 or 35 degrees C and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet.

OBJECTIVES: Fundamental questions remain about the precise temperature providing optimal neuroprotection after perinatal hypoxia-ischemia (HI). Furthermore, if hypothermia delays the onset of the neurotoxic cascade and the secondary impairment in cerebral energy generation, the "latent phase" may be prolonged, thus extending the period when additional treatments may be effective. The aims of this study were to investigate the effects of delayed systemic cooling at either 33 degrees C or 35 degrees C on the following: (1) latent-phase duration, and (2) cerebral metabolism during secondary energy failure itself, in the 48-hour period after transient HI. METHODS: Piglets were randomly assigned to the following: (1) HI-normothermic (HI-n) rectal temperature (Trectal; n = 12), (2) HI-Trectal 35 degrees C (HI-35; n = 7), and (3) HI-Trectal 33 degrees C (HI-33; n = 10). Groups were cooled to the target Trectal between 2 and 26 hours after HI. Serial magnetic resonance spectroscopy was performed over 48 hours. The effect of cooling on secondary energy failure severity (indexed by the nucleotide triphosphate/exchangeable phosphate pool [NTP/EPP] and phosphocreatine/inorganic phosphate [PCr/Pi] ratios) was assessed. RESULTS: Compared with HI-n, HI-35 and HI-33 had a longer NTP/EPP latent phase and during the entire study duration had higher mean NTP/EPP and PCr/Pi. The latent phase (both PCr/Pi and NTP/EPP) and the whole-brain cerebral energetics were similar for HI-35 and HI-33. During the hypothermic period, compared with HI-n, PCr/Pi was preserved in the cooled groups, but this advantage was not maintained after rewarming. Compared with HI-n, HI-35 and HI-33 had higher NTP/EPP after rewarming. CONCLUSIONS: Whole-body hypothermia for 24 hours at either 35 or 33 degrees C, commenced 2 hours after resuscitation, prolonged the NTP/EPP latent phase and reduced the overall secondary falls in mean PCr/Pi and NTP/EPP during 48 hours after HI. Reducing the temperature from 35 to 33 degrees C neither increased mean PCr/Pi and NTP/EPP nor further lengthened the latent phase.

Neurodevelopmental outcome of preterm infants with ventricular dilatation with and without associated haemorrhage.

This study investigated whether in preterm children who had ventricular dilatation (VD) on neonatal cranial ultrasound outcome at age 8 years was influenced by the additional presence of germinal matrix haemorrhage--intraventricular haemorrhage (GMH-IVH). Six-hundred and ninety-nine preterm infants (<33 wks' gestation, mean 29.6 wks [SD 2.1]) with either normal cranial ultrasound (n=616; 286 females, 330 males), or with VD with (n=66; 32 females, 34 males) or without (n=17; 4 females, 13 males) GMH-IVH were enrolled in the study. At age 8 years outcome was assessed in 567 (81%) of the 699 children by neurological examination, the Test of Motor Impairment (TOMI), the test of Visuo-Motor Integration (VMI), and the Wechsler Intelligence Scales for Children. Results showed that the proportion of children with disabling impairments was higher in the group with VD and GMH-IVH. Performance on TOMI and VMI (even in those without disabling impairments) was poorer in those with VD and GMH-IVH than in children with normal scans or those with VD only. Children with VD and GMH-IVH had significantly lower performance IQ than children with normal ultrasound, whereas those with VD only were not different from those with normal scans. Results suggest the presence of subtle white matter injury that has not been identified by neonatal cranial ultrasound. Although this study did not investigate biochemical markers of haemorrhage, we hypothesize that non-protein-bound iron is likely to be a contributing factor to white matter damage in preterm infants.

Long-term neurodevelopmental outcome of preterm children with unilateral cerebral lesions diagnosed by neonatal ultrasound.

OBJECTIVE: Little information is available on long-term neurodevelopmental outcome of preterm infants with unilateral cerebral lesions detected by neonatal cranial ultrasound. This study aims to investigate the long-term outcome in a cohort of very preterm infants with unilateral cerebral lesions acquired in the perinatal period. METHODS: A prospective cohort study of 668 preterm infants (<33 weeks gestation; birth years 1985-1991) at a single tertiary perinatal centre in the UK. All infants had serial cranial ultrasound examination in the neonatal period. Outcome was assessed at age 8 years with the Wechsler Intelligence Scales for Children (WISC-R), Test of Visuo-motor Integration (VMI) and the Test of Motor Impairment (TOMI). RESULTS: Of the 668 infants, 369 infants had normal ultrasound scans. Two hundred and ninety nine children had bilateral parenchymal or non-parenchymal lesions (57 left-sided, 41 right-sided, 201 bilateral). Five hundred and thirty four (79%) children attended follow-up at age 8 years. Mean Full Scale IQ (FSIQ) was 101 (SD+/-16), 93 (SD+/-17), 102 (SD+/-17) and 91 (SD+/-21) for normal, left-sided, right-sided and bilateral lesion groups respectively. In all groups verbal IQ (VIQ) was higher than performance IQ (PIQ). Scores of FSIQ, VIQ and PIQ, VMI and TOMI were significantly different between the groups. After exclusion of children with parenchymal lesions, however, the difference was only significant for the TOMI scores. In all tests, children with left-sided lesions performed poorer than children with right-sided lesions. CONCLUSIONS: In this cohort of preterm infants with unilateral cerebral lesions, verbal function was preserved over non-verbal function independently of the side of lesion. Furthermore, the results suggest that the neurodevelopmental outcome of children with left-sided lesions is less favourable than that of children with right-sided lesions.

Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia.

Hypothermia after perinatal hypoxia-ischemia (HI) is neuroprotective; the precise brain temperature that provides optimal protection is unknown. To assess the pattern of brain injury with 3 different rectal temperatures, we randomized 42 newborn piglets: (Group i) sham-normothermia (38.5-39 degrees C); (Group ii) sham-33 degrees C; (Group iii) HI-normothermia; (Group iv) HI-35 degrees C; and (Group v) HI-33 degrees C. Groups iii through v were subjected to transient HI insult. Groups ii, iv, and v were cooled to their target rectal temperatures between 2 and 26 hours after resuscitation. Experiments were terminated at 48 hours. Compared with normothermia, hypothermia at 35 degrees C led to 25 and 39% increases in neuronal viability in cortical gray matter (GM) and deep GM, respectively (both p < 0.05); hypothermia at 33 degrees C resulted in a 55% increase in neuronal viability in cortical GM (p < 0.01) but no significant increase in neuronal viability in deep GM. Comparing hypothermia at 35 and 33 degrees C, 35 degrees C resulted in more viable neurons in deep GM, whereas 33 degrees C resulted in more viable neurons in cortical GM (both p < 0.05). These results suggest that optimal neuroprotection by delayed hypothermia may occur at different temperatures in the cortical and deep GM. To obtain maximum benefit, you may need to design patient-specific hypothermia protocols by combining systemic and selective cooling.

Time for a cool head-neuroprotection becomes a reality.

Studies in encephalopathic infants have demonstrated a brief phase of normal cerebral energetics following hypoxia-ischaemia prior to development of delayed energy failure. In experimental models, mild hypothermia has shown a consistent neuroprotective action, although its efficacy is critically dependent on the severity of the primary insult, the delay in initiating cooling, and the duration and depth of hypothermia. Early electroencephalographic assessment of encephalopathic infants has the potential to provide objective information about the preceding insult, aiding the selection of infants for enrollment to clinical trials. Preliminary results from a large randomised trial of selective head cooling suggest that early intervention can lead to significantly improved outcome in a subgroup of encephalopathic infants with intermediate electroencephalographic abnormalities. Further research in established experimental models is essential to improve the identification of suitable infants for treatment, to investigate the importance of variations in regional brain temperature, and to examine the therapeutic potential of hypothermia combined with other neuroprotective agents.