Germinal Matrix Hemorrhage Research Articles

Germinal Matrix Hemorrhage: Intraventricular Hemorrhage in Very-Low-Birth-Weight Infants

The etiology of germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is multifactorial and the role of genetic polymorphisms is unclear. The aim of this prospective study was to evaluate prothrombotic genetic mutations as independent risk factors for the development of all grades of GMH-IVH in very-low-birth-weight infants. The presence of both factor V Leiden and prothrombin gain-of-function gene mutations were prospectively assessed in 106 very-low-birth-weight infants. Infants with GMH-IVH were compared to those without GMH-IVH according to genetic and clinical characteristics. Twenty-two out of 106 infants had GMH-IVH develop (20.7%). Infants with GMH-IVH had significantly lower gestational ages and birth weights. In the multivariate Poisson regression model, the prevalence of GMH-IVH appeared to be inversely related to gestational age, with a risk ratio of 0.83 (95% CI, 0.72-0.97; P=0.02) per week. Risk ratio of GMH-IVH for carriers of either prothrombotic mutation was 2.65 (95% CI, 1.23-5.72; P=0.01), similar to the risk ratio associated with need for resuscitation at birth (2.30; 95% CI, 1.02-5.18; P=0.04). Very-low-birth-weight infants who are carriers for either prothrombotic mutations are at increased risk for development of GMH-IVH. Genetic factors act as independent risk factors of the same magnitude as other known risk factors.

Punctate white matter lesions in infants: new insights using susceptibility-weighted imaging

IntroductionPunctate white matter lesions (PWML) are recognized with magnetic resonance imaging (MRI) as hypersignal on T1-weighted imaging and hyposignal on T2-weighted imaging. Our aim was to assess how often a hemorrhagic component was present in PWML using susceptibility-weighted imaging (SWI).MethodsSeventeen preterm (gestational age, 25–34 weeks) and seven full-term infants (age at MRI, 37–42 weeks) with PWML were included. Seven preterm infants had sequential MRIs. PWML were diagnosed with conventional MRI and compared with SWI, where signal loss is suggestive of hemorrhage. The pattern of associated brain lesions was taken into account, and the percentage of lesions with signal loss on SWI was calculated for each infant.ResultsA significantly higher percentage of signal loss on SWI (median, 93.9%) was found among infants with germinal matrix and intraventricular hemorrhage as the primary diagnosis (n = 8) compared to those with a primary diagnosis of white matter injury (n = 14; median, 14.2%; p < 0.01). In the infants with serial MRIs, a reduction in the number of PWML and/or signal loss on SWI was noted at term equivalent age. In the patient who died, cystic lesions, associated with hemorrhage and gliosis, were demonstrated on histology.ConclusionsSWI can distinguish hemorrhagic and non-hemorrhagic PWML. Signal loss on SWI was more common when PWML were associated with an intraventricular hemorrhage. Longitudinal imaging showed a decrease in the number of PWML over time, with some PWML no longer showing signal loss on SWI, suggesting early gliosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00234-011-0872-0) contains supplementary material, which is available to authorized users.

Germinal matrix haemorrhage: destroying the brain's building blocks

The most skilled stonemasons cannot construct a cathedral without an ample supply of fine granite blocks. Likewise, the human brain cannot be built properly if stocks of neuroglial progenitors (the building blocks of the brain) are depleted by injury during the critical period of progenitor cell proliferation and migration, as occurs in germinal matrix haemorrhage in prematurity. The article by Prof. Marc Del Bigio (2011), representing the analysis of a career-spanning autopsy cohort of preterm infants with and without germinal matrix haemorrhage, he addresses a persistent clinical concern facing paediatric specialists caring for survivors of prematurity: what are the consequences of germinal matrix haemorrhage on normal brain development at the microanatomic level, and do they explain observed neurodevelopmental and neuroimaging outcome data? As a serious complication of prematurity, germinal matrix haemorrhage and its frequent accompaniment, intraventricular haemorrhage, have been recognized in the medical literature since the turn of the last century (Corvelaire, 1903). In the period from 1940 to 1970, population studies identified the maternal, obstetric and neonatal risk factors for development of germinal matrix haemorrhage, including vaginal delivery, low birth weight, low Apgar scores, hypoxia and hypercapnea (Bassan, 2009; Ballabh, 2010). Improvements since the 1970s in neonatal intensive care have reduced the incidence of cardiorespiratory complications and increased survival following preterm delivery; however, the overall incidence of intraventricular haemorrhage in very low birth weight infants has remained static over the last two decades (Jain et al. , 2009). Thus, intraventricular haemorrhage is still a significant problem affecting >12 000 infants per year in the USA …

Cell proliferation in human ganglionic eminence and suppression after prematurity-associated haemorrhage

In premature infants, germinal matrix haemorrhage in the brain is a common occurrence. However, cell proliferation and fate determination in the normal human germinal matrix is poorly understood. Human ganglionic eminence samples were collected prospectively from autopsies of premature and term infants with no evidence of pathological process (n=78; dying at post-menstrual age 14-88 weeks). The ganglionic eminence was thickest at 20-26 weeks and involuted by 34-36 weeks. Proliferating cells, detected by Ki67 immunoreactivity, were abundant throughout the ganglionic eminence prior to 18 weeks, after which a sharp boundary between the dorsal and ventral ganglionic eminence appeared with reduced cell proliferation in the dorsal region. Ki67 immunoreactivity persisted in the majority of ventral cells until ∼28 weeks, after which time the proportion of proliferating cells dropped quickly. The expression of cell lineage markers (such as Olig2, SOX2, platelet-derived growth factor receptor alpha) showed partitioning at the microscopic level. The hypothesis that germinal matrix haemorrhage suppresses cell proliferation was then addressed. In comparison to controls, germinal matrix haemorrhage (n=47; born at post-menstrual age 18-34 weeks followed by survival of 0 h to 98 days) was associated with significantly decreased cell proliferation if survival was >12 h. The cell cycle arrest transcription factor p53 was transiently increased and the oligodendroglial lineage markers Olig2 and platelet-derived growth factor receptor alpha were decreased. Cell death was negligible. A low level of microglial activation was detected. Haemorrhage-associated suppression of cell proliferation in premature human infants could partially explain the reduced brain size and clinical effects in children who suffer germinal matrix haemorrhage after premature birth.

Posthemorrhagic hydrocephalus in very low birth weight infants—a new gentle surgical technique for external ventricular drainage

The germinal matrix hemorrhage in premature infants is related to the immaturity of the subependymal vascular bed. Posthemorrhagic ventricular dilation (PVD) in extremely low birth weight infants (ELBI) is a medical challenge and is associated with a high risk of long-term disability. Our aim was to find a safe and gentle surgical technique for external ventricular drainage implantation for this patient population. We implanted eight external ventricular drainages in ELBI with birth weights ranging from 479 to 884 g (24 to 27 weeks gestational age) and a grade III to IV hemorrhage, who developed a PVD soon after birth. A replacement of the drainage was required three times in one infant with a birth weight of 479 g. Due to the subcutaneous tunneling and drawing of the catheter through the sleeve, the skin contact remains slight, and thus, infections are avoided. There were no complications during the procedures which can also be carried out in the neonatal intensive care unit. Only in one case (479 g birth weight and severe concomitant diseases) was an infection observed, though the origin was most likely abdominal. In the same case, a temporary leakage was treated by suture. This patient died of non-neurological complications related to the patient's prematurity. Three of the five preterms were shunted over time. Although there is only a small number of extremely low birth weight infants with posthemorrhagic hydrocephalus who were treated with this technique, our findings suggest that this method is very safe and useful. It reduces the risk of infection and cerebrospinal fluid leaks and might be a better alternative to serial lumbar or transfontanel punctures in extremely low birth weight infants for bridging the first weeks of life.

Cerebral Oxygenation in Preterm Infants With Germinal Matrix–Intraventricular Hemorrhages

Preterm infants are at risk of developing germinal matrix hemorrhages-intraventricular hemorrhages (GMH-IVH). Disturbances in cerebral perfusion are associated with GMH-IVH. Regional cerebral tissue oxygen saturation (r(c)SO₂), measured with near-infrared spectroscopy, and fractional tissue oxygen extraction (FTOE) were calculated to obtain an indication of cerebral perfusion. Our objective was to determine whether r(c)SO₂ and FTOE were associated with GMH-IVH in preterm infants. This case-control study included 17 preterm infants with Grade I to III GMH-IVH or periventricular hemorrhagic infarction (median gestational age, 29.4 weeks; range, 25.4 to 31.9 weeks; birth weight, 1260 g; range, 850 to 1840 g). Seventeen preterm infants without GMH-IVH, matched for gestational age and birth weight, served as control subjects (gestational age, 29.9 weeks; range, 26.0 to 31.6 weeks; birth weight, 1310 g; range, 730 to 1975 g). R(c)SO₂ and transcutaneous arterial oxygen saturation were measured during 2 hours on Days 1 to 5, 8, and 15 after birth. FTOE was calculated as FTOE=(transcutaneous arterial oxygen saturation-r(c)SO₂)/transcutaneous arterial oxygen saturation. Multilevel analyses showed that r(c)SO₂ was lower and FTOE higher in infants with GMH-IVH on Days 1, 2, 3, 4, 5, 8, and 15. The largest difference occurred on Day 5 with r(c)SO₂ median 64% in infants with GMH-IVH versus 77% in control subjects and FTOE median 0.30 versus 0.17. R(c)SO₂ and FTOE were not affected by the grade of GMH-IVH. Preterm infants with GMH-IVH had lower r(c)SO₂ and higher FTOE during the first 2 weeks after birth irrespective of the grade of GMH-IVH. This suggests that cerebral perfusion is decreased persistently for 2 weeks in infants with GMH-IVH, even in the presence of mild hemorrhages.

Germinal Matrix Hemorrhage in Zellweger Syndrome

A term male newborn was noted to have severe diffuse hypotonia, hyporeflexia, hepatosplenomegaly, and characteristic abnormal facies of Zellweger syndrome, the diagnosis of which was confirmed by identification of 2 mutations including Nt2098insT, a frameshift with premature stop codon in exon 13, as well as a novel second mutation at Nt3038G→A (Arg1013His) on skin fibroblast testing. His brain magnetic resonance imaging (MRI) demonstrated bilateral germinolytic cysts with unilateral hemorrhagic transformation. Germinolytic cysts are one of the characteristic radiographic features of Zellweger syndrome, but germinal matrix hemorrhage has never been reported. Germinal matrix hemorrhage is common in premature infants, but found in only 4% of normal term infants. Germinal matrix hemorrhage was seen in a case of Zellweger syndrome with a novel mutation.

Effect of Prenatal Glucocorticoids on Cerebral Vasculature of the Developing Brain

Prenatal glucocorticoids prevent germinal matrix hemorrhage in premature infants. The underlying mechanism, however, is elusive. Germinal matrix is enriched with angiogenic vessels exhibiting paucity of pericytes and glial fibrillary acidic protein-positive astrocyte end feet. Therefore, we asked whether glucocorticoid treatment would suppress angiogenesis and enhance periendothelial coverage by pericytes and glial fibrillary acidic protein-positive end feet in the germinal matrix microvasculature. We treated pregnant rabbits with intramuscular betamethasone and delivered pups prematurely by cesarean section at E29 (term=32 days). Endothelial turnover, vascular density, pericyte coverage, glial fibrillary acidic protein-positive end feet, cell death, and growth factors orchestrating angiogenesis, including vascular endothelial growth factor, angiopoietins, transforming growth factor-beta, and platelet-derived growth factor-B, were compared between betamethasone-treated and untreated pups. Similar comparisons were done between autopsy materials from premature infants exposed and unexposed to prenatal glucocorticoids. Antenatal glucocorticoid treatment reduced endothelial proliferation, vascular density, and vascular endothelial growth factor expression in the germinal matrix of both rabbits and humans. The pericyte coverage was greater in glucocorticoid-treated rabbit pups and human infants than in controls, but not the glial fibrillary acidic protein-positive end feet coverage. Transforming growth factor-beta, but not angiopoietins and platelet-derived growth factor-B, were elevated in glucocorticoid-treated rabbit pups compared with controls. Betamethasone treatment induced apoptosis, neuronal degeneration, and gliosis in rabbit pups. However, there was no evidence of increased cell death in glucocorticoid-exposed human infants. Prenatal glucocorticoid suppresses vascular endothelial growth factor and elevates transforming growth factor-beta levels, which results in angiogenic inhibition, trimming of neovasculature, and enhanced pericyte coverage. These changes contribute to stabilizing the germinal matrix vasculature, thereby reducing its propensity to hemorrhage. Prenatal glucocorticoid exposure does not induce neural cell death in humans, unlike rabbits.

Late Germinal Matrix Hemorrhage-Like Lesions in Very Preterm Infants

In preterm infants, the germinal matrix is a common origin of hemorrhages during the first 7 days of life. Sonographically, germinal matrix hemorrhages present as subventricular echodensities evolving into pseudocysts. Similar lesions have been reported as incidental findings also beyond 7 days of life. They may result from vasculitis and ischemic infarction, rather than hemorrhage. To assess the occurrence, time course, and significance for neurodevelopment of such late germinal matrix hemorrhage-like lesions, we reviewed serial cerebral ultrasound examinations obtained in 86 sequentially admitted infants (gestational age <32 weeks or birth weight <1500 g). Neurodevelopment was assessed at 3 years (Bayley Scales of Infant Development). Nine infants had late isolated germinal matrix hemorrhage-like lesions. Their Psychomotor Development Index scores were significantly lower than that in infants without hemorrhage. Our results suggest that late isolated germinal matrix hemorrhage-like lesions are of clinical significance because of their notable incidence and association with neurodevelopmental outcome.

Effect of hyperoxic resuscitation on propensity of germinal matrix haemorrhage and cerebral injury

Intraventricular haemorrhage (IVH) and cerebral injury are major neurological disorders of premature infants. The effect of hyperoxic resuscitation on the occurrence of IVH and cerebral injury is elusive. Therefore, we asked whether hyperoxia during neonatal resuscitation increased the incidence and severity of IVH and cerebral injury in premature newborns. Premature rabbit pups, delivered by C-section, were sequentially assigned to receive 100%, 40% or 21% oxygen for 15 or 60 min at birth. The pups were treated with intraperitoneal glycerol at 24-h postnatal age to determine the incidence and severity of glycerol-induced IVH. Vascular endothelial growth factor and angiopoietin-2 genes and protein expression, endothelial proliferation as well as free radical levels and antioxidants were assessed in the germinal matrix, white matter and cortex of pups exposed to 100% oxygen and to 21% oxygen. Exposure with 100% oxygen for 1 h did not adversely exacerbate the incidence of glycerol-induced IVH in premature rabbit pups. Compared with room air, 100% oxygen enhanced mRNA expression of both vascular endothelial growth factor and angiopoietin-2 as well as reactive oxygen species levels in the germinal matrix. Hyperoxia did not affect endothelial proliferation, apoptosis or neuronal degeneration in the forebrain. Our data suggest that 100% oxygen exposure for 1 h does not increase the risk of IVH or cerebral injury in premature rabbit pups. Although extrapolating rabbit neural developmental data into humans has obvious limitations, we speculate that hyperoxia of short duration at birth in premature infants may not result in major neurological adverse effects.

Delayed Etiologic Diagnosis of Meningitis in an Extremely Low Birth Weight Newborn

Delayed Etiologic Diagnosis of Meningitis in an Extremely Low Birth Weight Newborn

Ventriculosubgaleal shunt procedure and its long-term outcomes in premature infants with post-hemorrhagic hydrocephalus

ObjectiveIt is well known that 10–15% of hydrocephalus cases at childhood and 40–50% in premature infants, occur following Germinal matrix hemorrhage (GMH). Such hemorrhages are reported to arise due to the rupture of germinal matrix (GM) vessels as a result of cerebral blod flow changes among infants with <1500 g birth weight and <32 weeks old. Intraventricular hemorrhage (IVH) associated with GMH leads to a disruption in the cerebrospinal fluid (CSF) and ventricular dilatation. Ventriculosubgaleal shunt (VSGS) is preferred in those hydrocephalus cases because it is a simple and rapid method, precludes the need for repetitive aspiration for evacuation of CSF, establishes a permanent decompression without causing electrolyte and nutritional losses, and aims to protect the cerebral development of newborns with GMH.Material and methodThe present study comprises 25 premature cases, subjected to VSGS and diagnosed with post-hemorrhagic hydrocephalus (PHH) arising from IVH associated with GM, and low birth weight (LBW) in the Neurosurgery Department of the Medical Faculty of Erciyes University between July 2002 and September 2006. VSGS surgery was performed on those cases, and their clinical and radiological prognoses were monitored with regard to several parameters.ResultsMortality and morbidity results were found to be lower than those in PPH treatment methods. While prognosis of grade 4 GMHs was poor, grades 2 and 3 GMHs displayed a much better prognosis after VSGS along with complete recovery in some hydrocephalus cases.

Ultrasound and MRI features of connatal cysts: clinicoradiological differentiation from other supratentorial periventricular cystic lesions

A 2-week-old neonate, born at 39 weeks via an uncomplicated vaginal delivery following a normal pregnancy, presented with a febrile illness suspected to be meningitis. A cranial ultrasound scan was performed (Figure 1). Figure 1 Coronal ultrasound image. As the patient had a persistent febrile illness, MRI was performed for investigation of suspected meningoencephalitis (Figure 2). Figure 2 Axial FLAIR (a) coronal T2-weighted (b) and coronal FLAIR (c) MR images performed to investigate suspected meningoencephalitis. What is your diagnosis?

Cerebellar Loss and Brain-Stem Atrophy Associated with Neonatal Alloimmune Thrombocytopenia in a Discordant Twin

Neonatal alloimmune thrombocytopenia (NAIT) is due to an immune-mediated maternal-fetal platelet antigen incompatibility. Central nervous system abnormalities have been reported in infants with NAIT and include intracranial hemorrhage, ventriculomegaly, porencephalic cysts, neuronal migrational disorders, and, rarely, cerebellar lesions. We present the clinical and neuropathological findings from a case of a 3-day-old diamniotic/dichorionic female twin with known bilateral ventriculomegaly born prematurely at 33-1/7 weeks in gestational age. The pregnancy was further complicated by discordant intrauterine growth, intraventricular hemorrhage in the co-twin, and NAIT. At birth, the infant was noted to have diffuse body ecchymoses and petechiae and arthrogryposis. She subsequently developed multisystem organ failure and disseminated intravascular coagulopathy and died on the 3rd day of life. Neuropathological findings at autopsy included a posterior fossa cyst with no gross anatomic evidence of a cerebellum, atrophic pons and medulla with prominent pyramidal tracts and absent olivary nuclei, thinned corpus callosum, and symmetrical dilation of bilateral lateral ventricles. Microscopic examination confirmed the gross findings and revealed no histological evidence of cerebellar tissue, absence of superior and inferior cerebellar peduncles, and acute and chronic germinal matrix hemorrhages. Immunohistochemical studies revealed a focus of reactive gliosis at the base of the posterior fossa cyst with no evidence of cerebellar Purkinje or granule cells. To our knowledge, this is the 1st report with well-characterized neuropathological examination detailing complete cerebellar loss and brain-stem atrophy in a neonate with NAIT.

Oxidative-Nitrosative Stress in a Rabbit Pup Model of Germinal Matrix Hemorrhage

Germinal matrix hemorrhage-intraventricular hemorrhage is the most common neurological problem of premature infants. Despite this, mechanisms of brain injury from intraventricular hemorrhage are elusive. We hypothesized that germinal matrix hemorrhage-intraventricular hemorrhage, by induction of NAD(P)H oxidases, might cause oxidative/nitrosative stress contributing to brain injuries and that NAD(P)H oxidase inhibition could offer neuroprotection. To test this hypothesis, we exploited our rabbit pup model of glycerol-induced germinal matrix hemorrhage-intraventricular hemorrhage. We delivered rabbit pups prematurely (E29) by cesarean section and administered intraperitoneal glycerol at 2 hours postnatal age. Free-radical adducts, including nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine as well as O(2)(.-) and H(2)O(2) levels were measured in the forebrain. To determine the source of free-radical generation, we used inhibitors for NAD(P)H oxidase (apocynin), xanthine oxidase (allopurinol), cyclo-oxygenase-2 (indomethacin), or nitric oxide synthases (L-NAME). Intraventricular hemorrhage pups were treated with apocynin and cell death was compared between apocynin-treated and vehicle-treated pups. Nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine levels were higher in pups with intraventricular hemorrhage than controls. Likewise, O(2)(.-) and H(2)O(2) levels were significantly greater in both the periventricular area and cerebral cortex of pups with intraventricular hemorrhage than controls. In pups with intraventricular hemorrhage, reactive oxygen species production was more in the periventricular area than in the cortex. Apocynin, but not allopurinol, indomethacin, or nitric oxide synthases, inhibited reactive oxygen species generation. Importantly, apocynin reduced cell death in pups with intraventricular hemorrhage. Activation of NAD(P)H oxidase was the predominant mechanism of free-radical generation in pups with intraventricular hemorrhage. NAD(P)H oxidase inhibition by apocynin might suppress reactive oxygen species production and confer neuroprotection in premature infants with intraventricular hemorrhage.

Germinal Matrix Hemorrhage of Prematurity: Treatment Approaches and Outcomes in a Single Institutional Review in the Ukraine

Objective: To review the treatment outcome of germinal matrix hemorrhage (GMH) in premature infants in a single Ukrainian institution in an effort to determine optimal diagnostic and therapeutic approaches. Materials and Methods: Eight hundred and thirty-five premature newborns (gestational age 33.0 ± 2.50 weeks, birth weight 2,124.81 ± 282.54 g; mean ± SD) were examined for the development of perinatal hypoxic-ischemia injury and asphyxia condition. This research focuses on various types of massive intracranial hemorrhage (ICH) and posthemorrhagic hydrocephalus (PHH). The diagnostic methods were based on intracranial imaging studies and clinical features that are present at birth. The therapeutic and preventive strategies consist of parental counseling, supportive and rehabilitative care for affected infants. Surgical intervention was indicated for the prevention and treatment of severe PHH. Thirty-four preterm infants were treated by ventricular-peritoneal/subgaleal shunting with close monitoring of intracerebral pressure. Results: Massive GMH took place at 32–35 gestational weeks as a result of increased periventricular anastomosis. GMH was unusual in full-term newborns, whereas cerebral hypoxic-ischemic injuries were more common in full-term neonates. Approximately 98% of premature infants with low birth weight survived and 2% died due to respiratory distress syndrome and other complications. ICH which occurs in neonates at 24–28 gestational weeks was mainly due to immature vascular walls and insufficiency of vascular anastomosis at the germinal matrix. Conclusions: ICH occurring in the germinal matrix of premature newborns is closely related to the development of the brain vasculature. Evacuation of the hematoma is more detrimental than beneficial, despite the rapid strides being taken to keep low-birth weight premature infants alive. Therefore, the treatment of ICH and PHH requires a fundamental understanding of pathogenetic changes, which is necessary for the neurorehabilitation and immediate elimination of cerebral compression and its complications.

From Fossil to Fetus: Nonhemorrhagic Germinal Matrix Echodensity Caused by Mineralizing Vasculitis—Hypothesis of Fossilizing Germinolysis and Gliosis

Subventricular echodensities medioventral to the caudate nucleus near the caudothalamic groove are regular ultrasonographic findings in preterm infants with germinal matrix hemorrhages. The transformation into pseudocysts is termed germinolysis. Interestingly, identical ultrasonographic findings are rarely even reported for near-term infants. We examined 5 cases of near-term infants presenting with various localized subventricular echodensities after various noncerebral infections (intra-amniotic infection, gastroenteritis of unidentified pathogens, septic wound, and a twin pair with rotavirus gastroenteritis), suggesting an inflammatory or ischemic rather than a hemorrhagic etiology. With high-resolution ultrasonography, these lesions showed similar characteristics: all were space-occupying, homogeneous, echodense, and ultimately transformed into pseudocysts. Additionally, Doppler ultrasonography showed linear perivascular echodensities in the basal ganglia of one infant. All infants were also examined by cerebral magnetic resonance imaging (MRI) including T2*-weighted gradient-echo sequences so that subventricular hemorrhages could be excluded in 4 infants. One of these 4 infants died unexpectedly at home. Brain autopsy revealed nonhemorrhagic germinal matrix pseudocysts with gliotic walls. Based on our findings and the original literature, we favored an ischemic infarction of the strongly vascularized and highly metabolic germinal matrix as cause of this germinolysis and gliosis. We postulated that the infarction was the result of an obstructive and possibly mineralizing, or even fossilizing vasculopathy due to an inflammatory response. The precise pathogenesis of the suspected immune-mediated vasculitis remains unknown. We concluded that cerebral ultrasonography should be performed in infants with noncerebral infection and that it should be complemented by MRI in cases of subventricular echodensities to prove or to exclude a germinal matrix hemorrhage.

Sulfonylurea Receptor 1 in the Germinal Matrix of Premature Infants

Germinal matrix (GM) hemorrhage (GMH) is a major cause of mortality and of life-long morbidity from cerebral palsy. GMH is typically preceded by hypoxic/ischemic events and is believed to arise from rupture of weakened veins in the GM. In the CNS, hypoxia/ischemia up-regulate sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in microvascular endothelium, with channel activation by depletion of ATP being responsible for progressive secondary hemorrhage. We hypothesized that this channel might be up-regulated in the GM of preterm infants at risk for GMH. Here, we studied expression of the regulatory subunit of the channel, SUR1, and its transcriptional antecedent, hypoxia inducible factor 1 (HIF1), in postmortem tissues of premature infants who either were at risk for or who sustained GMH. We found regionally specific up-regulation of HIF1 and of SUR1 protein and mRNA in GM tissues, compared with remote cortical tissues. Up-regulation was prominent in most progenitor cells, whereas in veins, SUR1 was found predominantly in infants who had sustained GMH compared with those without hemorrhage. Our data suggest that the SUR1-regulated NCCa-ATP channel may be associated with GMH, and that pharmacological block of these channels could potentially reduce the incidence of this devastating complication of prematurity.

Characterization of Acute Brain Injuries and Neurobehavioral Profiles in a Rabbit Model of Germinal Matrix Hemorrhage

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is the most common neurological problem of premature infants and has enormous financial and social impact. Despite this, there is no standardized animal model of IVH depicting acute brain injuries. We delivered rabbit-pups prematurely at 29-day gestation by C-section, administered intraperitoneal glycerol to the pups at 3-hour postnatal age to induce IVH, and evaluated the brain for evidence of injuries. About 80% of glycerol-treated pups developed gross IVH. We found greater neutrophil and microglia infiltration around the ventricles (periventricular zone) in pups with IVH than in controls. We noted more apoptosis and neuronal degeneration in the periventricular zone than in the neocortex in pups with IVH, but not in controls. There was evidence of axonal damage revealed by beta-amyloid precursor protein and neurofilament immunolabeling. Neurobehavioral testing showed that pups with IVH were more wobbly with lesser capability to walk on inclination than pups without IVH. There was no evidence of acute systemic toxicity in the glycerol-treated pups. An evaluation of autopsy materials from premature infants revealed similar evidence of apoptosis and cellular infiltration in the periventricular zone in cases with IVH, but not in cases without IVH-suggesting clinical relevance of the model. The study provides an instructive animal model of IVH with evidence of acute brain injuries that can be used to evaluate strategies in prevention of IVH and acute posthemorrhagic complications.

Risk Factors for Adverse Outcome in Preterm Infants With Periventricular Hemorrhagic Infarction

Our objective was to identify risk factors that were associated with mortality and adverse neurologic outcome at 18 months of age in preterm infants with periventricular hemorrhagic infarction. This was a retrospective cohort study of all preterm infants who were <37 weeks' gestation, had periventricular hemorrhagic infarction, and were admitted between 1995 and 2006. Ultrasound scans were reviewed for grading of germinal matrix hemorrhage, localization and extension of the infarction, and other abnormalities. Several clinical factors were scored. Outcome measures were mortality, cerebral palsy, and Gross Motor Function Classification System level. Odds ratios were calculated by univariate and multivariate logistic regression analyses. Of 54 infants, 16 (30%) died. Twenty-five (66%) of 38 survivors developed cerebral palsy: 21 mild (Gross Motor Function Classification System levels 1 and 2) and 4 moderate to severe (levels 3 and 4). Several perinatal and neonatal risk factors were associated with mortality. After multivariate logistic regression, only use of inotropic drugs and maternal intrauterine infection were predictors of mortality. In survivors, only the most extended form of periventricular hemorrhagic infarction was associated with the development of cerebral palsy but not with severity of cerebral palsy. Cystic periventricular leukomalacia and concurrent grade 3 germinal matrix hemorrhage were associated with more severe cerebral palsy. In preterm infants with periventricular hemorrhagic infarction, mortality occurred despite optimal treatment and was associated with circulatory failure and maternal intrauterine infection. In survivors, motor development was abnormal in 66%, but functional abilities were good in the majority. Extension and localization of the periventricular hemorrhagic infarction were not related to functional outcome.