Impact of persistent pulmonary hypertension and oxygenation on brain injury in neonates with neonatal encephalopathy treated with therapeutic hypothermia.

OBJECTIVE: To investigate the effects of persistent pulmonary hypertension (PPHN) and oxygenation on outcome of neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). STUDY DESIGN: We compared the outcome of neonates with NE treated with TH with or without PPHN. RESULTS: 384 neonates with NE were treated with TH; 24% had PPHN. The fraction of inspired oxygen was higher in the first 4 days of life (p < 0.001) in neonates with PPHN. They had a significantly lower arterial partial pressure of oxygen in the first 4 days of life (p = 0.005) and higher on days 3-4 of life (p < 0.001). They were more often intubated (p < 0.001) and more often had concomitant hypotension (p < 0.001). They had higher mortality (p = 0.009) and more often developed brain injury (p = 0.02). CONCLUSION: PPHN occurred frequently in neonates with NE treated with TH and was associated with a higher incidence of adverse outcome.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Distinctive Neuroimaging Pattern in Term Newborns With Neonatal Placental Encephalopathy: A Case Series.

BACKGROUND: Identifying antepartum versus intrapartum timing and the cause of neonatal encephalopathy (NE) often remains elusive owing to our limited understanding of the underlying pathophysiological processes and lack of appropriate biomarkers. OBJECTIVES: This retrospective observational study describes a case series of term newborns with NE who displayed a recognizable magnetic resonance imaging pattern of immediately postnatal brain abnormalities that rapidly evolved toward cavitation. Our aim is to (1) report this neuroimaging pattern, (2) look for placental determinants, and (3) depict the outcome. DESIGN/METHODS: This is a unicentric retrospective case series reporting the clinical, radiological, and laboratory findings of NE associated with a distinctive neuroimaging pattern, that is, immediately postnatal extensive corticosubcortical T2 hyperintensities, followed by rapid corticosubcortical cavitation that does not match the neuroimaging picture of intrapartum hypoxic-ischemic encephalopathy (HIE). RESULTS: Seven term newborns presented bilateral corticosubcortical hyperintensities that were detected on T2 between day of life (DOL) 1-4, which rapidly evolved toward cystic encephalomalacia, that is, between DOL9 and DOL12. All these newborns presented with moderate/severe NE. The outcome was either neonatal death or quadriplegic cerebral palsy and epilepsy. None of the reported patients fulfilled the criteria of a high likelihood of acute intrapartum hypoxic-ischemic or quadriplegic cerebral palsy. All these newborns were exposed to chronic and/or acute placental inflammation and/or hypoxic-ischemic. CONCLUSIONS: To further define the antepartum causes of NE, early neuroimaging and a placental examination are recommended. Brain T2 hyperintense injuries before DOL4 followed by rapid cavitation before DOL12 might be biomarkers of NE from an antepartum/placental origin.

The utility of arterial spin labeling in the presurgical evaluation of poorly defined focal epilepsy in children.

OBJECTIVE: The authors sought to assess the utility of arterial spin labeling (ASL) perfusion 3T-MRI for the presurgical evaluation of poorly defined focal epilepsy in pediatric patients. METHODS: Pseudocontinuous ASL perfusion 3T-MRI was performed in 25 consecutive children with poorly defined focal epilepsy. ASL perfusion abnormalities were detected qualitatively by visual inspection and quantitatively by calculating asymmetry index (AI) maps and significant z-score cluster maps based on successfully operated cases. ASL results were prospectively compared to scalp EEG, structural 3T-MRI, FDG-PET, ictal/interictal SPECT, magnetoencephalography (MEG), and intracranial recording results, as well as the final surgically proven epileptogenic zone (EZ) in operated patients who had at least 1 year of good (Engel class I/II) seizure outcome and positive histopathology results. RESULTS: Qualitative ASL perfusion abnormalities were found in 17/25 cases (68%), specifically in 17/20 MRI-positive cases (85.0%) and in none of the 5 MRI-negative cases. ASL was concordant with localizing scalp EEG findings in 66.7%, structural 3T-MRI in 90%, FDG-PET in 75%, ictal/interictal SPECT in 62.5%, and MEG in 75% of cases, and with intracranial recording results in 40% of cases. Eleven patients underwent surgery; in all 11 cases the EZ was surgically proven by positive histopathology results and the patient having at least 1 year of good seizure outcome. ASL results were concordant with this final surgically proven EZ in 10/11 cases (sensitivity 91%, specificity 50%). All 10 ASL-positive patients who underwent surgery had positive surgical pathology results and good long-term postsurgical seizure outcome at a mean follow-up of 39 months. Retrospective quantitative analysis based on significant z-score clusters found 1 true-positive result that was missed by qualitative analysis and 3 additional false-positive results (sensitivity 100%, specificity 23%). CONCLUSIONS: ASL supports the hypothesis regarding the EZ in poorly defined focal epilepsy cases in children. Due to its convenience and noninvasive nature, the authors recommend that ASL be added routinely to the presurgical MRI evaluation of epilepsy. Future optimized quantitative methods may improve the diagnostic yield of this technique.

Therapeutic interventions for fetal inflammatory response syndrome (FIRS).

Fetal inflammatory response syndrome (FIRS) is a condition defined by systemic inflammation in the fetus, a rapid increase of pro-inflammatory cytokines into the fetal circulation (including interleukin-1 and interleukin-6), as well as a cellular response (such as increased neutrophils, monocyte/macrophages, and T cells) and the presence of funisitis. FIRS can lead to death and multisystem organ damage in the fetus and newborn. Brain injuries and subsequent risk of cerebral palsy and cognitive impairments are the most threatening long-term complications. This paper reviews the definition of FIRS, summarizes its associated complications, briefly describes the available methods to study FIRS, and discusses in more detail the potential therapeutic candidates that have been so far studied to protect the fetus/newborn from FIRS and to alleviate its associated complications and sequelae.

Predictors of Severe Neurologic Injury on Ultrasound Scan of the Head and Risk Factor-based Screening for Infants Born Preterm.

OBJECTIVE: To identify risk factors for severe neurologic injury (intraventricular hemorrhage grade 3 or greater and/or periventricular leukomalacia) diagnosed by ultrasound scan of the head among infants born at 300-326 weeks of gestation and compare different screening strategies. STUDY DESIGN: This was a retrospective cohort study of infants born at 300-326 weeks or >326 weeks of gestation with a birth weight <1500 g admitted to neonatal intensive care units in the Canadian Neonatal Network from 2011 to 2016. Stepwise logistic regression analysis was used to identify significant risk factors and calculate aORs and 95% CIs. Risk factor-based screening strategies were compared. RESULTS: The rate of severe neurologic injury was 3.1% among infants screened (285/9221). Significant risk factors included singleton birth (aOR 1.96, 95% CI 1.35-2.85), 5-minute Apgar <7 (aOR 1.81, 95% CI 1.30-2.50), mechanical ventilation on day 1 (aOR 2.65, 95% CI 1.88-3.71), and treatment with vasopressors on day 1 (aOR 3.23, 95% CI 2.19-4.75). Risk categories were low (no risk factor, 1.2%, 25/2137), moderate (singleton with no other risk factor: 1.8%, 68/3678), and high (≥1 risk factor among 5-minute Apgar <7, receipt of vasopressors or mechanical ventilation on day 1: 5.6%, 192/3408). Screening moderate- to high-risk infants identified 91% (260/285) of infants with severe neurologic injury and would require screening fewer infants (1647 infants per year) than screening all infants <33 weeks of gestation (2064 infants screened per year, 93% [265/285] of cases identified). CONCLUSIONS: Risk factor-based ultrasound scan of the head screening among infants born at 30-32 weeks of gestation could help optimize resources better than gestational age based screening.

Heavy Prenatal Alcohol Exposure is Related to Smaller Corpus Callosum in Newborn MRI Scans.

BACKGROUND: Magnetic resonance imaging (MRI) studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure (PAE) but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latter's incomplete myelination. This study is the first to use volumetric structural MRI to investigate PAE effects in newborns using manual tracing and to examine the cross-sectional area of the corpus callosum (CC). METHODS: Forty-three nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom-designed birdcage coil for infants, which increases signal-to-noise ratio almost 2-fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and fetal alcohol spectrum disorders diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi-echo FLASH protocol adapted for newborns, and a knowledge-based procedure was used to hand-segment the neonatal brains. RESULTS: CC was disproportionately smaller in alcohol-exposed neonates than controls after controlling for intracranial volume. By contrast, CC area was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. CONCLUSIONS: Given that midline craniofacial anomalies have been recognized as a hallmark of fetal alcohol syndrome in humans and animal models since this syndrome was first identified, the CC deficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CC during the newborn period may provide an early indicator of fetal alcohol-related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence.

Upregulation of cystathionine ß-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury.

Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia-ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine ß-synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long-Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho-p70S6K) and 40S ribosomal protein S6 (S6 and phospho-S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35-37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long-term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP-a still untreatable cause of autism, hyperactivity and cerebral palsy.

Impact of bronchopulmonary dysplasia on brain and retina.

Many premature newborns develop bronchopulmonary dysplasia (BPD), a chronic lung disease resulting from prolonged mechanical ventilation and hyperoxia. BPD survivors typically suffer long-term injuries not only to the lungs, but also to the brain and retina. However, currently it is not clear whether the brain and retinal injuries in these newborns are related only to their prematurity, or also to BPD. We investigated whether the hyperoxia known to cause histologic changes in the lungs similar to BPD in an animal model also causes brain and retinal injuries. Sprague Dawley rat pups were exposed to hyperoxia (95% O2, 'BPD' group) or room air (21% O2, 'control' group) from postnatal day 4-14 (P4-14); the rat pups were housed in room air between P14 and P28. At P28, they were sacrificed, and their lungs, brain, and eyes were extracted. Hematoxylin and eosin staining was performed on lung and brain sections; retinas were stained with Toluidine Blue. Hyperoxia exposure resulted in an increased mean linear intercept in the lungs (P<0.0001). This increase was associated with a decrease in some brain structures [especially the whole-brain surface (P=0.02)], as well as a decrease in the thickness of the retinal layers [especially the total retina (P=0.0008)], compared to the room air control group. In addition, a significant negative relationship was observed between the lung structures and the brain (r=-0.49,P=0.02) and retina (r=-0.70,P=0.0008) structures. In conclusion, hyperoxia exposure impaired lung, brain, and retina structures. More severe lung injuries correlated with more severe brain and retinal injuries. This result suggests that the same animal model of chronic neonatal hyperoxia can be used to simultaneously study lung, brain and retinal injuries related to hyperoxia.

Does angiogenesis play a role in the establishment of mesial temporal lobe epilepsy?

Mesial temporal lobe epilepsy (MTLE) is a focal epileptic disorder that is frequently associated with hippocampal sclerosis. This study investigated whether blocking angiogenesis prevents the development of seizures and hippocampal atrophy in the pilocarpine rat model of MTLE. To block angiogenesis, a subset of animals were given sunitinib orally. Continuous video recordings were performed to identify seizures. Brains were then extracted and sectioned, and hippocampal surfaces and angiogenesis were assessed. After a latent period of 6.6 ± 2.6 days, the sham-treated pilocarpine rats presented convulsive seizures, while the pilocarpine rats treated with sunitinib did not develop seizures. Sham-treated pilocarpine rats but not sunitinib-treated pilocarpine rats had significantly smaller hippocampi. Endothelial cell counts in sham-treated pilocarpine rats were significantly greater than in controls and sunitinib-treated pilocarpine rats. Blocking angiogenesis immediately following the initial insult in this animal model prevented thus angiogenesis and hippocampal atrophy and averted the development of clinical seizures.

Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?).

OBJECTIVE: The aim of this article was to describe the severity of brain injury and/or mortality in a cohort of newborns referred for therapeutic hypothermia, in relation to the degree of encephalopathy on admission, and to especially look at the ones with initial mild encephalopathy. STUDY DESIGN: Term newborns with perinatal depression referred to our neonatal intensive care unit for possible hypothermia treatment from 2008 to 2012 were enrolled prospectively. The modified Sarnat score on admission was correlated with severity of brain injury on brain imaging and/or autopsy. RESULTS: A total of 215 newborns were referred for possible cooling. Sixty percent (128/215) were cooled. Most of the not-cooled newborns with an available brain magnetic resonance imaging (85% = 50/59) had an initial mild encephalopathy, and 40% (20/50) developed brain injury. Some cooled newborns had an initial mild encephalopathy (12% = 13/108); only 31% (4/13) developed brain injury. CONCLUSION: Our results demonstrated that several newborns with an initial mild encephalopathy developed subsequent brain injury, especially when they were not cooled.

Brain Perfusion Is Increased at Term in the White Matter of Very Preterm Newborns and Newborns with Congenital Heart Disease: Does this Reflect Activated Angiogenesis?

OBJECTIVE: This study aims to evaluate brain perfusion at term in very preterm newborns and newborns with congenital heart disease before their corrective surgery, and to search for histopathological indicators of whether the brain perfusion abnormalities of these newborns may be related to an activated angiogenesis. MATERIALS AND METHODS: Using magnetic resonance imaging and arterial spin labeling, regional cerebral blood flow was measured at a term-equivalent age for three very preterm newborns (born at < 32 weeks), one newborn with congenital heart disease before his corrective surgery and three healthy newborns. In addition, a histopathological analysis was performed on a newborn with congenital heart disease. RESULTS: The very preterm newborns and the newborn with congenital heart disease included in this study all displayed an increased signal in their white matter on T2-weighted imaging. The cerebral blood flow of these newborns was increased in their white matter, compared with the healthy term newborns. The vascular endothelial growth factor was overexpressed in the injured white matter of the newborn with congenital heart disease. CONCLUSION: Brain perfusion may be increased at term in the white matter, in very preterm newborns, and newborns with congenital heart disease, and it correlates with white matter abnormalities on conventional imaging.

Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns.

Bronchopulmonary dysplasia (BPD) is a common long-term complication in premature newborns requiring ventilatory support and is the most common cause of chronic diffuse lung disease in this population. We present the clinical course of a premature newborn with a complicated neonatal respiratory course that was initially thought to be related to BPD, but it did not respond to the typical therapies for this condition. Due to the findings of periventricular nodular heterotopia, the diagnosis of a filamin A gene mutation was eventually made, which explained the respiratory pathology of this patient. When time of onset and clinical course do not correlate with typical BPD, one should consider alternative diagnoses in premature infants, including neonatal diffuse lung disease.

Perfusion Imaging of Focal Cortical Dysplasia Using Arterial Spin Labeling: Correlation With Histopathological Vascular Density.

Focal cortical dysplasia is the most common malformation of cortical development, causing intractable epilepsy. This study investigated the relationship between brain perfusion and microvessel density in 7 children with focal cortical dysplasia. The authors analyzed brain perfusion measurements obtained by magnetic resonance imaging of 2 of the children and the microvessel density of brain tissue specimens obtained by epilepsy surgery on all of the children. Brain perfusion was approximately 2 times higher in the area of focal cortical dysplasia compared to the contralateral side. The microvessel density was nearly double in the area of focal cortical dysplasia compared to the surrounding cortex that did not have morphological abnormalities. These findings suggest that hyperperfusion can be related to increased microvessel density in focal cortical dysplasia rather than only to seizures. Further investigations are needed to determine the relationship between brain perfusion, microvessel density, and seizure activity.

Neonatal enteroviral sepsis/meningoencephalitis and hemophagocytic lymphohistiocytosis: diagnostic challenges.

We present the clinical course of three neonates with proven enteroviral infection and an initial clinical picture suggestive of hemophagocytic lymphohistiocytosis (HLH). After a complete workup, only one was treated for HLH. Of particular interest, the first newborn presented with hemophagocytic cells in the cerebrospinal fluid (CSF) and proved to have enteroviral meningoencephalitis but was ultimately not diagnosed with HLH. A fourth infant, who fulfilled the diagnostic criteria for HLH but did not have enteroviral infection, is included for comparison. We suggest that severe neonatal enteroviral infection and HLH are difficult to distinguish. Careful assessment is recommended, as prognosis and treatment differ between these two entities. Literature regarding neonatal enteroviral infection and HLH is reviewed, to demonstrate the continuum between the inflammation triggered by enteroviral infection and the occurrence of HLH, as well as their comparable CSF findings.

Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia.

OBJECTIVE: We sought to describe placental findings in asphyxiated term newborns meeting therapeutic hypothermia criteria and to assess whether histopathologic correlation exists between these placental lesions and the severity of later brain injury. STUDY DESIGN: We conducted a prospective cohort study of the placentas of asphyxiated newborns, in whom later brain injury was defined by magnetic resonance imaging. RESULTS: A total of 23 newborns were enrolled. Eighty-seven percent of their placentas had an abnormality on the fetal side of the placenta, including umbilical cord lesions (39%), chorioamnionitis (35%) with fetal vasculitis (22%), chorionic plate meconium (30%), and fetal thrombotic vasculopathy (26%). A total of 48% displayed placental growth restriction. Chorioamnionitis with fetal vasculitis and chorionic plate meconium were significantly associated with brain injury (P = .03). Placental growth restriction appears to significantly offer protection against the development of these injuries (P = .03). CONCLUSION: Therapeutic hypothermia may not be effective in asphyxiated newborns whose placentas show evidence of chorioamnionitis with fetal vasculitis and chorionic plate meconium.