Germinal Matrix Hemorrhage Research Articles

Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

Radiologic, genetic, and endocrine findings in isolated congenital nasal pyriform aperture stenosis patients

BackgroundCongenital nasal pyriform aperture stenosis (CNPAS) is a rare cause of upper airway obstruction in neonates. It can occur either associated with a solitary median maxillary central incisor (SMMCI) in 40–75% of cases or as an isolated morphogenic variant. Brain MRI is routinely performed in patients with CNPAS with a SCMMI due to the concomitant risks of intracranial midline defects of the hypothalamic-pituitary axis (HPA), holoprosencephaly, or associated endocrine dysfunction. However, the role of routine brain imaging and endocrinologic evaluation in patients with isolated CNPAS is not frequently studied given the assumption that isolated CNPAS is unlikely to be associated with any intracranial findings. ObjectivesTo evaluate intracranial findings on dual brain MRI imaging in isolated CNPAS patients and to determine if any radiologic, endocrinologic, or genetic abnormalities existed in these patients. MethodsWe performed a single-institution retrospective review and case series of patients with isolated CNPAS from 2006 to 2019. Findings from dual brain MRI imaging, cytogenetic and karyotype testing, and formal endocrinologic testing were analyzed for each patient and compared to reported findings in isolated CNPAS patients within the literature. ResultsFrom 2006 to 2019, 16/29 patients were identified at our institution with isolated CNPAS. Inpatient otolaryngologic consultation, CT, and brain MRI imaging was obtained after a mean postnatal age of 3.21 days, 13.5 days, and 35.91 days, respectively. Dual brain MRI imaging was obtained in 12/16 (75%) patients. In our patients, abnormal MRI findings included hypothalamic hamartoma, pars intermedius cyst, and grades 1 and 4 germinal matrix hemorrhages. No holoprosencephaly was found in any patient. Genetic testing was performed on 10/16 (62.5%) patients. Karyotyping was normal in all patients and microarray testing was abnormal in 2/10 patients that represented a 2p16.3 deletion in one patient and a 7q36 deletion causing an unbalanced translocation mutation of the Sonic Hedgehog gene in the second patient. In the latter patient, a hypothalamic hamartoma and panhypopituitarism was found. Endocrine evaluation was performed in 5 patients and was normal in 3/5 patients. ConclusionsOur case series of isolated CNPAS patients identified multiple abnormalities on radiologic, genetic, and endocrine testing; one of which that involved a defect of the HPA with panhypopituitarism resulting from a hypothalamic hamartoma. Based upon our findings, dedicated brain MRI imaging, endocrinologic, and genetic testing, should likely be considered for any newly diagnosed, isolated CNPAS patient given the uncommon but potential risk for associated intracranial abnormalities.

Case 2: Abdominal Distention in a Term Infant with Unilateral Ventriculomegaly

An early term female neonate is born at 37 weeks, 2 days of gestation with a birthweight of 3.1 kg. She is delivered vaginally by a 26-year-old woman after induction of labor for preeclampsia with severe features; magnesium sulfate was given during labor. Prenatal history is significant for late prenatal care (14 weeks) and fetal diagnosis of right-sided ventriculomegaly noted on serial ultrasonography, first at 20 weeks of gestation and confirmed on fetal magnetic resonance imaging (MRI) at 27 weeks. All prenatal serologic findings were negative, a 1-hour oral glucose tolerance test result was within normal limits, and cell-free fetal DNA was negative for trisomies 13, 18, and 21. Maternal-fetal medicine, neonatal-perinatal medicine, and pediatric neurosurgical physician teams were involved in the prenatal care, and a plan was developed to admit the infant to the level III NICU after birth for further brain imaging.At delivery, the infant is vigorous, with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Birthweight is at the 50th percentile, length is greater than the 97th percentile, and occipitofrontal circumference is at the 90th percentile. The remainder of the newborn examination is unremarkable, including a perforate anus, and the infant is admitted to the NICU for known right-sided ventriculomegaly. On the day of birth, postnatal MRI demonstrates asymmetric right-sided ventriculomegaly likely secondary to a prior germinal matrix and intraventricular hemorrhage. The infant feeds orally and voids normally but no stools are noted. At birth, a chromosomal microarray is obtained, which later reveals a likely benign duplication at 7q21.12-q21.13, with no known clinical significance associated.On the day after birth, the infant develops abdominal distention with decreased bowel sounds and lethargy. Oral feeding is discontinued and intravenous fluids are initiated. Vital signs are stable and examination findings are otherwise unremarkable, with no respiratory distress noted in room air. Voiding remains normal, but again, no stools are noted.A kidney, ureter, bladder (KUB) radiograph was obtained, which demonstrated mildly dilated loops of bowel throughout the abdomen. The infant was given nothing by mouth, and a Replogle tube was placed for abdominal decompression. Intravenous antibiotics (ampicillin and gentamicin) were started after performing a sepsis screen. The complete blood cell count and C-reactive protein levels were unremarkable. A repeat KUB radiograph remained concerning for a small bowel obstruction (Fig 1), and the infant developed bilious output from the appropriately positioned Replogle tube. A water-soluble contrast enema was performed on the third day, which revealed multiple intraluminal filling defects and meconium plugging (Fig 2). Shortly after the contrast enema, the infant began to pass stools, with 5 large-volume meconium stools noted in the following 24 hours. Abdominal distention and gastric output decreased, and a repeat KUB radiograph demonstrated decreased gaseous distention. Oral feedings were reinitiated 2 days after the enema and were advanced without difficulty. Daily occipitofrontal circumference measurements remained stable throughout the infant’s hospitalization. She was discharged from the hospital on the 7th day after birth, voiding and stooling appropriately, and with follow-up scheduled with the neurosurgical team to continue to monitor the stable ventriculomegaly.The differential diagnosis of abdominal distention in a newborn includes volvulus (with or without malrotation), necrotizing enterocolitis, sepsis, Hirschsprung disease, meconium syndromes (such as ileus or plug), intestinal webs or atresias, hypertrophic pyloric stenosis, congenital microcolon, spontaneous intestinal perforation, imperforate anus, peritoneal bands, internal hernias, and rarely, lactobezoars. (1)(2) Small left colon syndrome, first described in 1974, is thought to occur because of immaturity of the myenteric plexus ganglia (1) of the colon, which leads to a transient functional obstruction in newborns and carries a strong association with maternal diabetes mellitus, (3)(4) maternal preeclampsia treated with magnesium sulfate, (1) and prematurity. (1) Maternal diabetes mellitus, either gestational or pregestational, is the most common association, reported in 40% to 50% of the few published cases of small left colon syndrome. (3) Small left colon syndrome is the most common diagnosis in newborns who fail to pass meconium within the first 48 hours after birth. (1)(3)(4)(5)(6)Abdominal radiography will demonstrate lower bowel obstruction with or without air-fluid levels. Water-soluble contrast enema is frequently both diagnostic and therapeutic in these patients, demonstrating a significant change in colonic caliber. An abrupt transition occurs at the splenic flexure to a narrow distal colon, relieving the obstruction by flushing away any meconium present in the distal colon. Normal intestinal motility without long-term complications is expected in cases of neonatal small left colon syndrome.

Intraperitoneal cannabidiol attenuates neonatal germinal matrix hemorrhage-induced neuroinflamation and perilesional apoptosis

ABSTRACTBackground. As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage.Methods. 112 Wistar rat pups (P7) were submitted to an experimental collagenase induced model of GMH. Inflammatory response and neuronal death were analyzed both at the perilesional area as at the distant ipsilateral CA1 hippocampal area. Immunohistochemistry for GFAP and caspase 3 was used. The ipsilateral free water content was assessed for stimation of cerebral edema, and neurodevelopment and neurofunctional tests were conducted.Results. Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the Stratum oriens of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol.Conclusion. The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.

Reducing Germinal Matrix-Intraventricular Hemorrhage: Perinatal and Delivery Room Factors.

Germinal matrix hemorrhage-intraventricular hemorrhage (IVH) is the most common form of brain injury in preterm infants. Although severe IVH has declined over the years, it still affects approximately 6% of infants born before 32 weeks of gestation. Most IVH cases are detectable by the first 24 hours after birth; therefore interventions to prevent IVH should focus on antenatal management for pregnant women and delivery room management. Obstetrical interventions, including antenatal corticosteroids, maternal rather than infant transport, and possibly elective cesarean delivery have been associated with a decreased risk of IVH. Neonatal interventions in the delivery room, including delayed cord clamping or umbilical cord milking, maintaining normothermia, avoiding fluctuations in cerebral blood flow, and optimal ventilation management are associated with a decreased risk of IVH. Multiple clinical trials are under way to further identify IVH risk factors, ability to monitor or predict IVH, and ideally prevent IVH altogether. This discussion will focus on reviewing current obstetric and neonatal management practices and their associations with germinal matrix hemorrhage-IVH.

Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage

Germinal matrix hemorrhage (GMH) results from the rupture of the immature thin-walled blood vessels and consequent bleeding into the subependymal germinal matrix and possible lateral ventricles. The purpose of this study is to investigate how astrogliosis impacts the glymphatic-meningeal lymphatic system in cerebrospinal fluid (CSF) reabsorption after GMH and how the anti-scarring agent olomoucine attenuates post-hemorrhagic hydrocephalus. GMH was induced by stereotaxic collagenase infusion into P7 Sprague-Dawley rats of both sexes. Western blot and immunofluorescence were used to assess astrogliosis and how astrogliosis affects glymphatic function by measuring Aquaporin-4 expression. Intracisternal injection of fluorescence tracer was used to measure CSF diffusion throughout the brain, its dispersion in the paravascular area and CSF drainage into the deep cervical lymph nodes at 28 days after GMH. Both short-term and long-term behavioral tests were used to assess the neurological outcomes. Nissl staining was used to assess the morphological changes at 28 days after hemorrhage. GMH elicited astrogliotic scarring and reduced the exchange between CSF and interstitial fluid, as well as CSF reabsorption through the meningeal lymphatic vessels. This might be associated with redistribution of Aquaporin-4. Olomoucine ameliorated scar tissue formation and attenuated post-hemorrhagic hydrocephalus. These findings of this study suggested that the glymphatic system might play a role in CSF reabsorption in neonates following GMH. Scar tissue formation impairs this CSF clearance route, and therefore astrogliosis inhibition might be a potential therapeutic strategy for neonatal post-hemorrhagic hydrocephalus.

Secukinumab attenuates reactive astrogliosis via IL-17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage.

AimsReactive astrogliosis plays a critical role in neurological deficits after germinal matrix hemorrhage (GMH). It has been reported that interleukin‐17A and IL‐17A receptor IL‐17RA/(C/EBPβ)/SIRT1 signaling pathway enhances reactive astrogliosis after brain injuries. We evaluated the effects of secukinumab on reactive astrogliosis in a rat pup model of GMH.MethodsA total of 146 Sprague Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of collagenase. Secukinumab was administered intranasally 1 hour post‐GMH. C/EBPβ CRISPR or SIRT1 antagonist EX527 was administrated intracerebroventricularly (icv) 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, histology, and immunohistochemistry were used to assess treatment regiments in the short term and long term.ResultsThe endogenous IL‐17A, IL‐17RA, C/EBPβ, and GFAP and proliferation marker CyclinD1 were increased, while SIRT1 expression was decreased after GMH. Secukinumab treatment improved neurological deficits, reduced ventriculomegaly, and increased cortical thickness. Additionally, treatment increased SIRT1 expression and lowered proliferation proteins PCNA and CyclinD1 as well as GFAP expression. C/EBPβ CRISPR activation plasmid and EX527 reversed the antireactive astrogliosis effects of secukinumab.ConclusionSecukinumab attenuated reactive astrogliosis and reduced neurological deficits after GMH, partly by regulating IL‐17RA/(C/EBPβ)/SIRT1 pathways. Secukinumab may provide a promising therapeutic strategy for GMH patients.

Posthemorrhagic hydrocephalus development after germinal matrix hemorrhage: Established mechanisms and proposed pathways

In addition to being the leading cause of morbidity and mortality in premature infants, germinal matrix hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model

Neuroinflammation occurs after germinal matrix hemorrhage (GMH) and induces secondary brain injury. Interferon-α (IFN-α) has been shown to exert anti-inflammatory effects in infectious diseases via activating IFNAR and its downstream signaling. We aimed to investigate the anti-inflammatory effects of Recombinant human IFN-α (rh-IFN-α) and the underlying mechanisms in a rat GMH model. Two hundred and eighteen P7 rat pups of both sexes were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Rh-IFN-α was administered intraperitoneally. Small interfering RNA (siRNA) of IFNAR, and siRNA of tumor necrosis factor receptor associated factor 3 (TRAF3) were administered through intracerebroventricular (i.c.v.) injections. JAK1 inhibitor ruxolitinib was given by oral lavage. Post-GMH evaluation included neurobehavioral function, Nissl staining, Western blot analysis, and immunofluorescence. Our results showed that endogenous IFN-α and phosphorylated IFNAR levels were increased after GMH. Administration of rh-IFN-α improved neurological functions, attenuated neuroinflammation, inhibited microglial activation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These observations were concomitant with IFNAR activation, increased expression of phosphorylated JAK1, phosphorylated STAT1 and TRAF3, and decreased levels of phosphorylated NF-κB, IL-6 and TNF-α. Specifically, knockdown of IFNAR, JAK1 and TRAF3 abolished the protective effects of rh-IFN-α. In conclusion, our findings demonstrated that rh-IFN-α treatment attenuated neuroinflammation, neurological deficits and hydrocephalus formation through inhibiting microglial activation after GMH, which might be mediated by IFNAR/JAK1-STAT1/TRAF3/NF-κB signaling pathway. Rh-IFN-α may be a promising therapeutic agent to attenuate brain injury via its anti-inflammatory effect.

A comprehensive review of therapeutic targets that induce microglia/macrophage-mediated hematoma resolution after germinal matrix hemorrhage.

Currently, there is no effective treatment for germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the germinal matrix, grade II includes intraventricular hemorrhage, grade III includes intraventricular hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.

ABSTRACTGerminal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.

Chapter 8 - Preterm brain injury: Germinal matrix–intraventricular hemorrhage and post-hemorrhagic ventricular dilatation

Germinal matrix hemorrhage and intraventricular hemorrhages (GMH-IVH) remain a common and clinically significant problem in preterm infants, particularly extremely preterm infants. A large GMH-IVH is often complicated by posthemorrhagic ventricular dilation (PHVD) or parenchymal hemorrhagic infarction and is associated with an increased risk of adverse neurologic sequelae. The widespread use of cranial ultrasonography since the early 1980s has shown a gradual decrease in the incidence of GMH-IVH and has helped with the identification of antenatal and perinatal risk factors and timing of the lesion. The increased use of magnetic resonance imaging (MRI) has contributed to more detailed visualization of the site and extent of the GMH-IVH. In addition, MRI has contributed to the awareness of associated white matter changes as well as associated cerebellar hemorrhages. Although GMH-IVH and PHVD still cannot be prevented, cerebrospinal fluid drainage initiated in the early stage of PHVD development seems to be associated with a better neurodevelopmental outcome. Further studies are underway to improve treatment strategies for PHVD and to potentially prevent and repair GMH-IVH and PHVD and associated brain injury. This chapter discusses the pathogenesis, incidence, risk factors, and management, including preventive measures, of GHM-IVH and PHVD.

Research Advances of Germinal Matrix Hemorrhage: An Update Review.

Germinal matrix hemorrhage (GMH) refers to bleeding that derives from the subependymal (or periventricular) germinal region of the premature brain. GMH can induce severe and irreversible damage attributing to the vulnerable structure of germinal matrix and deleterious circumstances. Molecular mechanisms remain obscure so far. In this review, we summarized the newest preclinical discoveries recent years about GMH to distill a deeper understanding of the neuropathology, and then discuss the potential diagnostic or therapeutic targets among these pathways. GMH studies mostly in recent 5years were sorted out and the authors generalized the newest discoveries and ideas into four parts of this essay. Intrinsic fragile structure of preterm germinal matrix is the fundamental cause leading to GMH. Many molecules have been found effective in the pathophysiological courses. Some of these molecules like minocycline are suggested active to reduce the damage in animal GMH model. However, researchers are still trying to find efficient diagnostic methods and remedies that are available in preterm infants to rehabilitate or cure the sequent injury. Merits have been obtained in the last several years on molecular pathways of GMH, but more work is required to further unravel the whole pathophysiology.

Predictive Value of Cranial Ultrasound for Neurodevelopmental Outcomes of Very Preterm Infants with Brain Injury.

Background:Compared with full-term infants, very preterm infants are more vulnerable to injury and long-term disability and are at high risk of death. The predictive value of ultrasound and imaging on the neurodevelopment is one of the hot topics. This study aimed to investigate the relationship between cranial ultrasound (cUS) variables and neurodevelopmental outcomes of very preterm infants.Methods:Totally 129 very preterm infants (gestational age ≤28 weeks) in neonatal intensive care unit of Hunan Children's Hospital between January 2012 and November 2014 were included in this retrospective study. Serial cUS (weekly before discharge and monthly after discharge) was performed on the infants until 6 months or older. Magnetic resonance imaging (MRI) was performed on the infants at approximately the term-equivalent age. The mental developmental index (MDI) and psychomotor developmental index (PDI) were followed up until the infants were 24 months or older. The relationship between brain injury and MDI/PDI scores was analyzed.Results:The consistency rate between cUS and MRI was 88%. At the first cUS, germinal matrix hemorrhage (GMH) Grades 3 and 4, hospitalization duration, and weight are significantly correlated with MDI/PDI and prognosis (MDI: odds ratio [OR] = 8.415, 0.982, and 0.042, P = 0.016, 0.000, and 0.004; PDI: OR = 7.149, 0.978, and 0.012, P = 0.025, 0.000, and 0.000, respectively). At the last cUS, gestational age, extensive cystic periventricular leukomalacia (c-PVL), and moderate and severe hydrocephaly are significantly correlated with MDI (OR = 0.292, 60.220, and 170.375, P = 0.004, 0.003, and 0.000, respectively). Extensive c-PVL and moderate and severe hydrocephaly are significantly correlated with PDI (OR = 76.861 and 116.746, P = 0.003 and 0.000, respectively).Conclusions:Very premature infants with GMH Grades 3 and 4, short hospitalization duration, and low weight have low survival rates and poorly developed brain nerves. Cerebral palsy can result from severe cerebral hemorrhage, moderate and severe hydrocephaly, and extensive c-PVL. The sustained, inhomogeneous echogenicity of white matter may suggest subtle brain injury.

Intracranial hemorrhage in term neonates

BackgroundIntracranial hemorrhage (ICH) is an uncommon but important cause of morbidity and mortality in term neonates; currently, ICH is more frequently diagnosed because of improved neuroimaging techniques.PurposeThe study aims to evaluate the clinical characteristics and neuroimaging data (pattern, size, distribution) of neonatal ICH.MethodsWe reviewed MRI data from July 2004 to June 2015 for 42 term neonates with ICH who were less than 1 month old. We recorded clinical data and manifestations, mode of delivery, Apgar score at 1 and 5 min, associated hypoxic insult, birth trauma, neurological symptoms, EEG results, extent and site of hemorrhage, neurosurgical intervention, and developmental outcomes. The clinical outcome was determined for 27 neonates. Risk factors were assessed in relation to ICH.ResultsA total of 42 neonates who presented with ICH underwent MR imaging 2 to 22 days postnatally (mean age 9.3 days). The majority of clinical symptoms were present in patients within the first 24 h of life (n = 31), but symptoms appeared until day 10 postnatally (mean 4.9 days, n = 11). Seizure or seizure-like activity was the most common presenting symptom (17/42, 40.5%), with apnea seen in another seven infants (7/42, 16.7%). The majority of infants had a normal prenatal course. Two patients had antenatally detected hydrocephalus. Ten had infratentorial hemorrhage, and two had supratentorial hemorrhage. A total of 30 infants had a combination of infratentorial and supratentorial hemorrhage. Subdural hemorrhage (SDH) was the most common type of hemorrhage (40/42, 95.2%), followed by nine cases of parenchymal hemorrhage, seven of subarachnoid hemorrhage, three of germinal matrix hemorrhage (GMH), and one of epidural hemorrhage (EDH). A total of 16 infants had two or more types of hemorrhage. SDH was identified along the tentorium (n = 38) as well as over the cerebellar hemispheres (n = 39), along the interhemispheric fissure (n = 10), and over the occipital (n = 13) or parietooccipital (n = 11) lobes. Intraparenchymal hemorrhage involved either the frontal (n = 4), parietal (n = 3), or cerebellar (n = 2) lobes. Traumatic delivery was suspected in 20 patients (47.6%), and perinatal asphyxia was present in 21 patients (50.0%). A low Apgar score at 5 min and a history of perinatal asphyxia were the factors that most predicted poor clinical outcomes (n = 12/27). Logistic regression analysis revealed that a history of perinatal asphyxia resulted in poor outcomes. No patients died. One infant required burr hole drainage of a right parietal EDH, one infant needed a subcutaneous reservoir, and three infants required a ventriculoperitoneal shunt for obstructive hydrocephalus.ConclusionSDH was the most common type of ICH in term infants. Combined supratentorial and infratentorial hemorrhage was more common than isolated infratentorial hemorrhage in these infants. A total of 44.4% of patients had poor outcomes, with perinatal asphyxia the most common statistically significant cause.

Neonatal hyperinsulinemic hypoglycemia in a patient with 9p deletion syndrome

We report the clinical and neuroradiological findings in a young boy harboring the 9p deletion syndrome including the novel findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. Both the hypoglycemic events and the ventriculomegaly found in this patient have previously only been reported in two patients, while the thalamic infarction and germinal matrix haemorrhage are novel features.

Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats

Chemerin, an adipokine, has been reported to reduce the production of pro-inflammatory cytokines and neutrophil infiltration. This study investigated the role of Chemerin and its natural receptor, ChemR23, as well as its downstream mediator calmodulin-dependent protein kinase kinase 2 (CAMKK2)/adenosine monophosphate-activated protein kinase (AMPK) /Nuclear factor erythroid 2-related factor 2 (Nrf2) following germinal matrix hemorrhage (GMH) in neonatal rats, with a specific focus on inflammation. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. The results demonstrated that human recombinant Chemerin (rh-Chemerin) improved neurological and morphological outcomes after GMH. Rh-Chemerin promoted accumulation and proliferation of M2 microglia in periventricular regions at 72 h. Rh-Chemerin increased phosphorylation of CAMKK2, AMPK and expression of Nrf2, and decreased IL-1beta, IL-6 and TNF-alpha levels. Selective inhibition of ChemR23/CAMKK2/AMPK signaling in microglia via intracerebroventricular delivery of liposome-encapsulated specific ChemR23 (Lipo-alpha-NETA), CAMKK2 (Lipo-STO-609) and AMPK (Lipo-Dorsomorphin) inhibitor increased the expression levels of IL-1beta, IL-6 and TNF- alpha, demonstrating that ChemR23/CAMKK2/AMPK signaling in microglia suppressed inflammatory response after GMH. Cumulatively, these data showed that rh-Chemerin ameliorated GMH-induced inflammatory response by promoting ChemR23/CAMKK2/AMPK/Nrf2 pathway, and M2 microglia may be a major mediator of this effect. Thus, rh-Chemerin can serve as a potential agent to reduce the inflammatory response following GMH.

Evaluation of symmetrical increased echogenicity of bilateral caudothalamic grooves detected on cranial ultrasonography by comparing with susceptibility-weighted imaging.

To assess symmetrical increased echogenicity of bilateral caudothalamic grooves (SIEBCG) detected on newborn cranial ultrasonography (CUS) using magnetic resonance susceptibility-weighted imaging (SWI). A total of 14 newborns (8 girls; 12 premature with mean gestational age of 30weeks and 5days, 2 mature) who were detected to have SIEBCG on routine serial CUS and underwent cranial magnetic resonance imaging (MRI) were recruited for the study. The cranial MRI examinations including SWI acquired on the same day of SIEBCG detection and serial CUS to assess the progress of SIEBCG lesions in the following 6month period were retrospectively evaluated and compared for the presence of germinal matrix hemorrhage. On SWI, solely one patient (7, 1%) had signal alteration on caudothalamic groove compatible with grade 1 germinal matrix hemorrhage. Two patients (14, 2%) had parenchymal (on cerebellar and parietal white matter) millimetric hemorrhagic foci. Seven patients (50%) had signs of presumptive hypoxic insult including hyperintense dots on centrum semiovale and periventricular white matter in five, and increased signal intensity on the globus pallidi in two, on T1-weighted images. Four patients (28, 6%) had normal findings. Of these, 10 patients became normal on follow-up CUS at postterm-equivalent age, whereas four were missing. Symmetrical increased echogenicity of bilateral caudothalamic grooves seen on newborn CUS may be the indicator of other pathologies as ischemic insult or focal parenchymal hemorrhage. In the presence of SIEBCG, further examination with SWI should be performed.

Utility of Various Ultrafast Magnetic Resonance Sequences in the Detection of Fetal Intracranial Hemorrhage.

Objective:The aim of this study is to compare the images obtained from standard ultrafast magnetic resonance (MR) imaging sequences with gradient (GRE) sequence images in identifying fetal intracranial hemorrhage (ICH).Materials and Methods:MR images of fetal brains with ICH done between October 2012 and September 2015 were reviewed. The images obtained from four ultrafast MR sequences– Turbo Fast Low Angle Shot (Turbo FLASH) T1-weighted images, Half Fourier Acquisition single-shot turbo spin echo (HASTE) T2-weighted images, b0 images of diffusion-weighted imaging (DWI) and b800 images of DWI were compared with images obtained from GRE sequence in depicting fetal ICH.Results:Out of the 212 fetuses during the study period, 15 fetuses had ICH. In the 15 fetuses with ICH as detected on GRE, Grade1 germinal matrix hemorrhage was seen in 5 fetuses, Grade 2 in 4 fetuses, Grade 3 in 3 fetuses, and Grade 4 in two fetuses. Subdural hemorrhage was seen in 1 fetus. In comparison to GRE sequence, b0 of DWI sequence was almost equal in the depiction of ICH. T2 HASTE sequence also delineated hemorrhage, although not as effectively as GRE and b0 images of images DWI. T1 Turbo FLASH and b800 images of DWI were less reliable in the depiction of fetal ICH but were useful in predicting the stage of hemorrhage.Conclusion:As compared to GRE sequence, b0 images of DWI followed by HASTE are the two preferred ultrafast sequences in the diagnosis of fetal ICH.

Bliverdin reductase-A improves neurological function in a germinal matrix hemorrhage rat model

Germinal matrix hemorrhage is induced by stereotaxic injection of collagenase into the germinal matrix of P7 Sprague-Dawley rats. Hemoglobin assay, western blot, immunofluorescence and neurobehavioral tests were used to test the effects of BLVRA on hematoma resolution and anti-inflammatory response. We showed that BLVRA triggered a signaling cascade that ameliorated post-hemorrhagic neurological deficits in both short-term and long-term neurobehavioral tests in a GMH rat model. Specifically, BLVRA inhibited toll-like receptor 4 (TLR4) expression by translocating to the nucleus in an endothelial nitric oxide (eNOS)/nitric oxide (NO)-dependent manner. BLVRA also induced the upregulation of CD36 scavenger receptor level in microglia/microphages, of which the prominent role is to enhance hematoma resolution. However, the beneficial effects of BLVRA were abolished with the knockdown of eNOS, indicating that the eNOS/NO system is an important downstream factor of BLVRA. Our results demonstrate a mechanism of BLVRA modulating hematoma resolution and suppressing inflammation through eNOS/NO/TLR4 pathway in the GMH rat model.