Perinatal Hypoxic-ischemic Injury Research Articles

Risk Factors and Outcomes for Cerebral Palsy With Hypoxic-Ischemic Brain Injury Patterns Without Documented Neonatal Encephalopathy.

Perinatal hypoxic-ischemic brain injury is a leading cause of term-born cerebral palsy, the most common lifelong physical disability. Diagnosis is commonly made in the neonatal period by the combination of neonatal encephalopathy (NE) and typical neuroimaging findings. However, children without a history of neonatal encephalopathy may present later in childhood with motor disability and neuroimaging findings consistent with perinatal hypoxic-ischemic injury. We sought to determine the prevalence of such presentations using the retrospective viewpoint of a large multiregional cerebral palsy registry. Patient cases were extracted from the Canadian Cerebral Palsy Registry with gestational age >36 weeks, an MRI pattern consistent with hypoxic-ischemic injury (HII, acute total, partial prolonged, or combined), and an absence of postnatal cause for HII. Documentation of NE was noted. Maternal-fetal risk factors, labor and delivery, neonatal course, and clinical outcome were extracted. Comparisons were performed using χ2 tests and multivariable logistic regression with multiple imputation. Propensity scores were used to assess for bias. Of the 170 children with MRI findings typical for HII, 140 (82.4%, 95% confidence interval [CI] 75.7%-87.7%) had documented NE and 29 (17.0%, 95% CI 11.7%-23.6%) did not. The group without NE had more abnormalities of amniotic fluid volume (odds ratio [OR] 15.8, 95% CI 1.2-835), had fetal growth restriction (OR 4.7, 95% CI 1.0-19.9), had less resuscitation (OR 0.03, 95% CI 0.007-0.08), had higher 5-minute Apgar scores (OR 2.2, 95% CI 1.6-3.0), were less likely to have neonatal seizures (OR 0.004, 95% CI 0.00009-0.03), and did not receive therapeutic hypothermia. MRI was performed at a median 1.1 months (interquartile range [IQR] 0.67-12.8 months) for those with NE and 12.2 months (IQR 6.6-25.9) for those without (p = 0.011). Patterns of injury on MRI were seen in similar proportions. Hemiplegia was more common in those without documented NE (OR 5.1, 95% CI 1.5-16.1); rates of preserved ambulatory function were similar. Approximately one-sixth of term-born children with an eventual diagnosis of cerebral palsy and MRI findings consistent with perinatal hypoxic-ischemic brain injury do not have documented neonatal encephalopathy, which was associated with abnormalities of fetal growth and amniotic fluid volume, and a less complex neonatal course. Long-term outcomes seem comparable with their peers with encephalopathy. The absence of documented neonatal encephalopathy does not exclude perinatal hypoxic-ischemic injury, which may have occurred antenatally and must be carefully evaluated with MRI.

Unequal Cerebral Magnetic Resonance Imaging Changes in Perinatal Hypoxic Ischemic Injury of Term Neonates.

Perinatal hypoxic ischemic injury (HII) has a higher prevalence in the developing world. One of the primary concepts for suggesting that an imaging pattern reflects a global insult to the brain is when the injury is noted to be bilateral and symmetric in distribution. In the context of HII in term neonates, this is either bilateral symmetric ( a ) peripheral/watershed (WS) injury or ( b ) bilateral symmetric basal-ganglia-thalamus (BGT) pattern, often with the peri-Rolandic and hippocampal injury. Unilateral, asymmetric, or unequal distribution of injury may therefore be misdiagnosed as perinatal arterial ischemic stroke. We aimed to determine the prevalence of unequal cerebral injury in HII, identify patterns, and determine their relationship with existing classification of HII. Review of brain magnetic resonance imaging from a database of children with HII. Reports with any unequal pattern of injury were included and further classified as a unilateral, bilateral asymmetric, or symmetric but unequal degree pattern of HII. A total of 1213 MRI scans in patients with a diagnosis of HII revealed 156 (13%) with unequal involvement of the hemispheres: unilateral in 2 of 1213 (0.2%) (involvement only in the WS), asymmetric in 48 of 1213 (4%) (WS in 6 [0.5%], BGT in 4 [0.3%], and combined BGT and WS in 38 [3.1%]), and bilateral symmetric but unequal degree in 106 of 1213 (8.7%) (WS in 20 [1.6%], BGT in 17 [1.4%], and combined BGT and WS in 69 [5.7%]). The majority of children with cerebral palsy due to HII demonstrate a characteristic bilateral symmetric pattern of injury. In our study, 13% demonstrated an unequal pattern. Differentiation from perinatal arterial ischemic stroke, which is mostly unilateral and distributed typically in the middle cerebral artery territory, should be possible and recognition of the typical BGT or WS magnetic resonance imaging patterns should add confidence to the diagnosis, in such scenarios.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p< .0001) in three cases and electrographic seizures (3.83/h to 0/h, p< .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

Nutrition and Immunity in Perinatal Hypoxic-Ischemic Injury.

Perinatal hypoxia ischaemia (PHI), acute and chronic, may be associated with considerable adverse outcomes in the foetus and neonate. The molecular and cellular mechanisms of injury and repair associated with PHI in the perinate are not completely understood. Increasing evidence is mounting for the role of nutrients and bioactive food components in immune development, function and repair in PHI. In this review, we explore current concepts around the neonatal immune response to PHI with a specific emphasis on the impact of nutrition in the mother, foetus and neonate.

Microglia Activation in the Midbrain of the Human Neonate: The Effect of Perinatal Hypoxic-Ischemic Injury.

Perinatal hypoxia-ischemia (PHI) is a major risk factor for the development of neuropsychiatric deficits later in life. We previously reported that after prolonged PHI, the dopaminergic neurons of the human neonate showed a dramatic reduction of tyrosine hydroxylase (TH) in the substantia nigra, without important signs of neuronal degeneration despite the significant reduction in their cell size. Since microglia activation could precede neuronal death, we now investigated 2 microglia activation markers, ionized calcium-binding adapter molecule 1 (Iba1), and the phagocytosis marker Cd68. The highest Iba1 immunoreactivity was found in neonates with neuropathological lesions of severe/abrupt PHI, while the lowest in subjects with moderate/prolonged or older PHI. Subjects with very severe/prolonged or chronic PHI showed an increased Iba1 expression and very activated microglial morphology. Heavy attachment of microglia on TH neurons and remarkable expression of Cd68 were also observed indicating phagocytosis in this group. Females appear to express more Iba1 than males, suggesting a gender difference in microglia maturation and immune reactivity after PHI insult. PHI-induced microglial "priming" during the sensitive for brain development perinatal/neonatal period, in combination with genetic or other epigenetic factors, could predispose the survivors to neuropsychiatric disorders later in life, possibly through a sexually dimorphic way.

Hemodynamic optimization for neonates with neonatal encephalopathy caused by a hypoxic ischemic event: Physiological and therapeutic considerations

Neonatal encephalopathy due to a hypoxic-ischemic event is commonly associated with cardiac dysfunction and acute pulmonary hypertension; both therapeutic hypothermia and rewarming modify loading conditions and blood flow. The pathophysiological contributors to disease are complex with a high degree of clinical overlap and traditional bedside measures used to assess circulatory adequacy have multiple confounders. Comprehensive, quantitative echocardiography may be used to delineate the relative contribution of lung parenchymal, pulmonary vascular, and cardiac disease to hypotension and/or hypoxemic respiratory failure. In this review, we provide a detailed overview of the contributors to hemodynamic instability following perinatal hypoxic-ischemic injury. Our proposed approach to therapy focuses on physiopathological considerations with interventions individualized to this potentially complex condition and considers the pharmacological idiosyncrasies, which may occur among neonates with NE presenting with multiorgan dysfunction while undergoing therapeutic hypothermia.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

NEUROSONOGRAPHIC STUDY OF CHILDREN WITH HYPOXIC-ISCHEMIC BRAIN IJURY

The study is aimed at neurosonographic characteristics of brain injury in newborn patients with perinatal hypoxic-ischemic injury of central nervous system, complicated with inflectional process (meningitis, ventriculitis). It is settled that brain immaturity, hydrocephalic syndrome, ischemia of the brain tissue and intraventricular hemorrhages are found 2 times more often in infants with perinatal hypoxic-ischemic injury of central nervous system, complicated with inflectional process. This fact generally characterizes disorders of the hemato-encephalic barrier and the development of destructive processes in the tissue of the brain.

Autophagy in neurodegeneration: New insights underpinning therapy for neurological diseases.

In autophagy long-lived proteins, protein aggregates or damaged organelles are engulfed by vesicles called autophagosomes prior to lysosomal degradation. Autophagy dysfunction is a hallmark of several neurodegenerative diseases in which misfolded proteins or dysfunctional mitochondria accumulate. Excessive autophagy can also exacerbate brain injury under certain conditions. In this review, we provide specific examples to illustrate the critical role played by autophagy in pathological conditions affecting the brain and discuss potential therapeutic implications. We show how a singular type of autophagy-dependent cell death termed autosis has attracted attention as a promising target for improving outcomes in perinatal asphyxia and hypoxic-ischaemic injury to the immature brain. We provide evidence that autophagy inhibition may be protective against radiotherapy-induced damage to the young brain. We describe a specialized form of macroautophagy of therapeutic relevance for motoneuron and neuromuscular diseases, known as chaperone-assisted selective autophagy, in which heat shock protein B8 is used to deliver aberrant proteins to autophagosomes. We summarize studies pinpointing mitophagy mediated by the serine/threonine kinase PINK1 and the ubiquitin-protein ligase Parkin as a mechanism potentially relevant to Parkinson's disease, despite debate over the physiological conditions in which it is activated in organisms. Finally, with the example of the autophagy-inducing agent rilmenidine and its discrepant effects in cell culture and mouse models of motor neuron disorders, we illustrate the importance of considering aspects such a disease stage and aggressiveness, type of insult and load of damaged or toxic cellular components, when choosing the appropriate drug, timepoint and duration of treatment.

Dysregulation of Hyaluronan Homeostasis During White Matter Injury.

Although the extra cellular matrix (ECM) comprises a major proportion of the CNS parenchyma, new roles for the ECM in regeneration and repair responses to CNS injury have only recently been appreciated. The ECM undergoes extensive remodeling following injury to the developing or mature CNS in disorders that -include perinatal hypoxic-ischemic cerebral injury, multiple sclerosis and age-related vascular dementia. Here we focus on recently described mechanisms involving hyaluronan (HA), which negatively impact myelin repair after cerebral white matter injury. Injury induced depolymerization of hyaluronan (HA)-a component of the neural ECM-can inhibit myelin repair through the actions of specific sizes of HA fragments. These bioactive fragments selectively block the maturation of late oligodendrocyte progenitors via an immune tolerance-like pathway that suppresses pro-myelination signaling. We highlight emerging new pathophysiological roles of the neural ECM, particularly of those played by HA fragments (HAf) after injury and discuss strategies to promoter repair and regeneration of chronic myelination failure.

Dynamic TSPO-PET for assessing early effects of cerebral hypoxia and resuscitation in new born pigs

IntroductionInflammation associated with microglial activation may be an early prognostic indicator of perinatal hypoxic ischemic injury, where translocator protein (TSPO) is a known inflammatory biomarker. This piglet study used dynamic TSPO-PET with [18F]GE180 to evaluate if microglial activation after global perinatal hypoxic injury could be detected. MethodsNew born anesthetized pigs (n = 14) underwent hypoxia with fraction of inspired oxygen (FiO2)0.08 until base excess −20 mmol/L and/or a mean arterial blood pressure decrease to 20 mm Hg, followed by resuscitation with FiO2 0.21 or 1.0. Three piglets served as controls and one had intracranial injection of lipopolysaccharide (LPS). Whole body [18F]GE180 Positron emission tomography-computed tomography (PET-CT) was performed repeatedly up to 32 h after hypoxia and resuscitation. Volumes of interest were traced in the basal ganglia, cerebellum and liver using MRI as anatomic correlation. Standardized uptake values (SUVs) were measured at baseline and four time-points, quantifying microglial activity over time. Statistical analysis used Mann Whitney- and Wilcoxon rank test with significance value set to p < 0.05. ResultsAt baseline (n = 5), mean SUVs ±1 standard deviation were 0.43 ± 0.10 and 1.71 ± 0.62 in brain and liver respectively without significant increase after hypoxia at the four time-points (n = 5–13/time point). Succeeding LPS injection, SUV increased 80% from baseline values. ConclusionsCerebral inflammatory response caused by severe asphyxia was not possible to detect with [18F]GE180 PET CT the first 32 h after hypoxia and only sparse hepatic uptake was revealed. Advances in knowledgeEarly microglial activation as indicator of perinatal hypoxic ischemic injury was not detectable by TSPO-PET with [18F]GE180. Implications for patient careTSPO-PET with [18F]GE180 might not be suitable for early detection of perinatal hypoxic ischemic brain injury.

Systemic 7,8-Dihydroxyflavone Treatment Protects Immature Retinas Against Hypoxic-Ischemic Injury via Müller Glia Regeneration and MAPK/ERK Activation.

Perinatal hypoxic-ischemic (HI) injury causes significant damages in the immature retina. The brain-derived neurotrophic factor is well known for its neuroprotective role but has limited clinical applications. A selective agonist of tyrosine kinase receptor B, 7,8-dihydroxyflavone (DHF), is a powerful therapeutic tool, when administered systemically. However, it remains unclear whether DHF treatment can protect the immature retinas against HI injury. Postnatal (P) day 7 rat pups were intraperitoneally injected with DHF or vehicle 2 hours before and 18 hours after being subjected to HI injury. The outcomes were assessed at various timepoints after injury by electroretinography and histologic examinations. Neurogenesis was assessed by double-labeling of retinal sections with 5-bromo-2'-deoxyuridine and different neuronal markers. At P8, 24-hours postinjury, brain-derived neurotrophic factor mRNA levels in the retina decreased significantly. DHF treatment partially protected immature retinas at both histologic and functional levels between P14 and P30 but did not prevent apoptosis, inflammation, or damage of the blood-retinal barrier (BRB) at P8. On the other hand, DHF treatment promoted the survival of proliferating inner retinal cells, including Müller glia, and enhanced their transdifferentiation to bipolar cells at P17. Moreover, DHF treatment rescued the levels of extracellular signal-regulated kinase (ERK) phosphorylation, which were significantly decreased after injury. The neuroprotective effects of DHF were markedly eliminated by inhibition of ERK phosphorylation. Early systemic DHF treatment has neuroprotective effects against HI injury in immature retinas, possibly via promoting neurogenesis through the tyrosine kinase receptor B/ERK signaling pathway.

Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury

There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury.

Behavioral and neuroanatomical outcomes in a rat model of preterm hypoxic-ischemic brain Injury: Effects of caffeine and hypothermia

The current study investigated behavioral and post mortem neuroanatomical outcomes in Wistar rats with a neonatal hypoxic-ischemic (HI) brain injury induced on postnatal day 6 (P6; Rice-Vannucci HI method; Rice et al., 1981). This preparation models brain injury seen in premature infants (gestational age (GA) 32–35 weeks) based on shared neurodevelopmental markers at time of insult, coupled with similar neuropathologic sequelae (Rice et al., 1981; Workman et al., 2013). Clinically, HI insult during this window is associated with poor outcomes that include attention deficit hyperactivity disorder (ADHD), motor coordination deficits, spatial memory deficits, and language/learning disabilities. To assess therapies that might offer translational potential for improved outcomes, we used a P6 HI rat model to measure the behavioral and neuroanatomical effects of two prospective preterm neuroprotective treatments – hypothermia and caffeine. Hypothermia (aka “cooling”) is an approved and moderately efficacious intervention therapy for fullterm infants with perinatal hypoxic-ischemic (HI) injury, but is not currently approved for preterm use. Caffeine is a respiratory stimulant used during removal of infants from ventilation but has shown surprising long-term benefits, leading to consideration as a therapy for HI of prematurity. Current findings support caffeine as a preterm neuroprotectant; treatment significantly improved some behavioral outcomes in a P6 HI rat model and partially rescued neuropathology. Hypothermia treatment (involving core temperature reduction by 4 °C for 5 h), conversely, was found to be largely ineffective and even deleterious for some measures in both HI and sham rats. These results have important implications for therapeutic intervention in at-risk preterm populations, and promote caution in the application of hypothermia protocols to at-risk premature infants without further research.

Pentoxifylline Alleviates Perinatal Hypoxic-Ischemia-Induced Short-term Memory Impairment by Suppressing Apoptosis in the Hippocampus of Rat Pups

Purpose:Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurologic morbidity in infants and children. We investigated the effects of pentoxifylline, a methylxanthine derivative and type-4 phosphodiesterase inhibitor, on short-term memory and apoptotic neuronal cell death in the hippocampus following perinatal hypoxic-ischemia in newborn rats.Methods:We used a step-down avoidance task to evaluate short-term memory and 3ʹ-5ʹ-cyclic adenosine monophosphate (cAMP) assay to detect cAMP levels. We evaluated apoptosis using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for evidence of DNA fragmentation, immunohistochemistry for caspase-3 levels, and western blot for Bcl-2 and Bax.Results:Perinatal hypoxic-ischemic injury increased apoptotic cell death in the hippocampus, resulting in impaired short-term memory with decreased cAMP levels. Pentoxifylline treatment improved short-term memory by suppressing apoptotic cell death in the hippocampus with elevated cAMP levels.Conclusions:Pentoxifylline ameliorated perinatal hypoxic-ischemia in rat pups. This alleviating effect could be ascribed to the inhibition apoptosis due to increased cAMP production by pentoxifylline.

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death.

Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed protein kinase, which regulates cell fate in numerous injury conditions. Therefore, ASK1 may be a promising novel therapeutic target for injury. However, the expression and distribution of ASK1 in the perinatal brain following hypoxia-ischemia (HI) remains to be elucidated. In the present study, western blotting and immunofluorescence were used to determine the expression and distribution of ASK1 and any associated downstream targets in the perinatal rat brain following HI. NQDI-1, a specific inhibitor of ASK1 was intracerebroventricularly injected following neonatal rats brain insult for neuroprotection. The results revealed an increased expression of ASK1 and this expression was localized to the neurons and astrocytes, compared with the sham controls. Additionally, it was demonstrated that the ASK1/c-Jun N-terminal kinases (JNK) pathway was involved in the brain damage following HI in neonatal rats. Notably, NQDI-1 significantly inhibited the in vivo expression levels of ASK1, phosphorylated (p-)JNK, p-c-Jun, p53 and caspase 3. Reduced acute hypoxic-ischemic cerebral injury and cell apoptosis was observed following the injection of NQDI-1. Collectively, NQDI-1 attenuated acute perinatal hypoxic-ischemic cerebral injury by inhibiting the expression of ASK1 and cell apoptosis. This may be a promising novel neuroprotective inhibitor for perinatal cerebra injury.

Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia

Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main contributor to enhanced recovery of motor ability after neonatal HI.

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

Hypoxic-ischemic brain lesions in children are the main environmental (non-genetic) factor in forming severe neurological pathology with subsequent disability. Scientists see the improvement of therapeutic approaches in acute phase of the disease as a main way to reduce the severity of neurologic complications. Due to the achievements in neuroscience in the field of perinatal hypoxicischemic injury mechanisms, three energy phases of pathologic events deployment were identified: primary (up to 6 hours from the lesion), secondary (6 to 24–48 h after the lesion) and distal tertiary (during few weeks, months). At the same time, necrosis, apoptosis, glutamate excitotoxicity, oxidative stress, inflammation, angiogenesis and neurogenesis make up separate links of destruction process. On the basis of new data on the pathogenesis of the disease, scientists from different countries have already offered modern treatment methods for perinatal hypoxic-ischemic injury with erythropoietin, allopurinol, melatonin, N-acetylcysteine, magnesium sulphate, albumin, -interferon, as well as with the help of controlled hypothermia, xenon, the use of stem cells, etc. This article presents a review of new data on pathogenesis and promising treatment methods for perinatal hypoxic-ischemic injuries.

Apparent diffusion coefficient scalars correlate with near-infrared spectroscopy markers of cerebrovascular autoregulation in neonates cooled for perinatal hypoxic-ischemic injury.

Neurologic morbidity remains high in neonates with perinatal hypoxic-ischemic injury despite therapeutic hypothermia. DTI provides qualitative and quantitative information about the microstructure of the brain, and a near-infrared spectroscopy index can assess cerebrovascular autoregulation. We hypothesized that lower ADC values would correlate with worse autoregulatory function. Thirty-one neonates with hypoxic-ischemic injury were enrolled. ADC scalars were measured in 27 neonates (age range, 4-15 days) in the anterior and posterior centrum semiovale, basal ganglia, thalamus, posterior limb of the internal capsule, pons, and middle cerebellar peduncle on MRI obtained after completion of therapeutic hypothermia. The blood pressure range of each neonate with the most robust autoregulation was identified by using a near-infrared spectroscopy index. Autoregulatory function was measured by blood pressure deviation below the range with optimal autoregulation. In neonates who had MRI on day of life ≥10, lower ADC scalars in the posterior centrum semiovale (r = -0.87, P = .003, n = 9) and the posterior limb of the internal capsule (r = -0.68, P = .04, n = 9) correlated with blood pressure deviation below the range with optimal autoregulation during hypothermia. Lower ADC scalars in the basal ganglia correlated with worse autoregulation during rewarming (r = -0.71, P = .05, n = 8). Blood pressure deviation from the optimal autoregulatory range may be an early biomarker of injury in the posterior centrum semiovale, posterior limb of the internal capsule, and basal ganglia. Optimizing blood pressure to support autoregulation may decrease the risk of brain injury in cooled neonates with hypoxic-ischemic injury.

Validation of a neuropathology score using quantitative methods to evaluate brain injury in a pig model of hypoxia ischaemia.

Neuropathological examination is the classic outcome measure in experimental studies of newborn brain injury to evaluate novel therapies. We have used a graded neuropathology score in an established global model of perinatal hypoxic-ischaemic (HI) injury. We wished to validate the score using cell counting in our model. 32 newborn pigs underwent a 45 min global HI insult then maintained at normothermia (NT, rectal temperature, Trectal 38.5 °C) for 72 h or mild total body hypothermia (HT, Trectal 37.0 °C) combined with selective head cooling for 48 h and subsequently maintained at NT for 24h before brain perfusion fixation. A perinatal pathologist scored haematoxylin and eosin stained 6 μm histological sections for injury in the hippocampus and basal ganglia on a 9-step scale (0.0=no injury, 4.0=>75% injury). We counted the number of healthy neurons in the hippocampus CA1 region and putamen using morphological criteria in eight random, non-overlapping fields from representative sections. Healthy neuronal cell density correlated with neuropathology score in the hippocampus CA1 (r = -0.74) and in the putamen (r = -0.75) and both measures detected a difference between groups. The correlation coefficients were better for the NT compared to the HT group in both the hippocampus (r = -0.87 vs. -0.53) and putamen (r = -0.77 vs. -0.54). We have validated a histological neuropathological scoring system in our model of perinatal HI by showing correlation between neuronal cell count and estimated injury. Our neuropathology score is a valid method to assess brain injury with good reproducibility and sensitivity.