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Germinal Matrix-Intraventricular hemorrhage (GMH-IVH) remains a significant cause of adverse neurodevelopmental outcomes in preterm infants. Current management options for GMH-IVH rely on serial 2-dimensional cranial ultrasound (2D cUS) ventricular measurements and clinical signs. A need exists for reliable biomarkers to aid in the early detection of posthemorrhagic ventricular dilatation (PHVD) and cerebral palsy (CP). We incorporated 3-dimensional cranial US (3D cUS) and functional infrared spectroscopy (fNIRS) to monitor ventricle volumes (VV) and spontaneous functional connectivity (sFC) in preterm infants with GMH-IVH. Infants with severe GMH-IVH who underwent cerebrospinal fluid diversion showed larger VV, which correlated with decreased sFC. Our findings of increased ventricular volume in preterm neonates and reduced fNIRS-based functional connectivity suggest that regional disruptions of ventricular size may impact the development of the underlying grey matter. Findings suggest that 3D cUS and fNIRS are promising bedside tools for monitoring the progression of GMH-IVH in preterm infants.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

In infants with post-hemorrhagic ventricular dilatation (PHVD), earlier interventions to bring the intraventricular pressure, therefore the ventricular size, down based on ultrasonographic assessments result in smaller ventricular volumes and less brain injury at term-equivalent age. PHVD also causes impaired microstructure of the critical brain structures in extremely preterm infants. Thus, earlier interventions for PHVD based on ultrasonographic assessments also result in reduced composite outcome of mortality and neurodevelopmental disability at 2 years corrected age. In infants with PHVD, rapid reduction of the ventricular pressure and volume during the first week after the commencement of serial reservoir taps may result in intraparenchymal hemorrhage (IPH) in the periventricular and/or subcortical white matter tissues, and these IPHs can affect cognitive outcomes when multifocal. Therefore, it is essential to perform serial cUS scans to guide the amount of cerebrospinal fluid removal via reservoir taps. Neurosurgical interventions, especially reservoir insertions, can cause injury to the CC and subsequent thinning of the CC. However, this phenomenon does not appear to be related to impaired neurodevelopmental outcomes at 2 years of age. Periventricular hemorrhagic infarction (PVHI), a severe form of germinal matrix and intraventricular hemorrhage continues to be a significant complication in very preterm infants and is an independent risk factor for both cognitive and motor impairment at 2 years corrected age and cognitive and motor outcomes are within the normal range in two-thirds, and cerebral palsy (CP) is seen in around 40% of PVHI survivors at 2 years corrected age. The majority (81%) of infants with CP can walk independently. These neurodevelopmental findings appear more favorable when compared to previous studies conducted more than a decade ago.

In infants with post-hemorrhagic ventricular dilatation (PHVD), earlier interventions to bring the intraventricular pressure, therefore the ventricular size, down based on ultrasonographic assessments result in smaller ventricular volumes and less brain injury at term-equivalent age. PHVD also causes impaired microstructure of the critical brain structures in extremely preterm infants. Thus, earlier interventions for PHVD based on ultrasonographic assessments also result in reduced composite outcome of mortality and neurodevelopmental disability at 2 years corrected age. In infants with PHVD, rapid reduction of the ventricular pressure and volume during the first week after the commencement of serial reservoir taps may result in intraparenchymal hemorrhage (IPH) in the periventricular and/or subcortical white matter tissues, and these IPHs can affect cognitive outcomes when multifocal. Therefore, it is essential to perform serial cUS scans to guide the amount of cerebrospinal fluid removal via reservoir taps. Neurosurgical interventions, especially reservoir insertions, can cause injury to the CC and subsequent thinning of the CC. However, this phenomenon does not appear to be related to impaired neurodevelopmental outcomes at 2 years of age. Periventricular hemorrhagic infarction (PVHI), a severe form of germinal matrix and intraventricular hemorrhage continues to be a significant complication in very preterm infants and is an independent risk factor for both cognitive and motor impairment at 2 years corrected age and cognitive and motor outcomes are within the normal range in two-thirds, and cerebral palsy (CP) is seen in around 40% of PVHI survivors at 2 years corrected age. The majority (81%) of infants with CP can walk independently. These neurodevelopmental findings appear more favorable when compared to previous studies conducted more than a decade ago.

Germinal matrix-intraventricular brain hemorrhage is mostly found in preterm neonates, but may also occur in term neonates. The aim of this study was to analyze the prevalence and severity of this type of hemorrhage in moderate and late preterm and early term neonates with intrauterine growth restriction. In the prospective analysis, 100 newborns were examined, i.e. 70 with intrauterine growth restriction and 30 as a control group. Study subjects were neonates from 32 0/7 to 38 6/7 gestational weeks. Body weight, body length, head circumference and ponderal index at birth were analyzed. Hemorrhage was assessed by cranial ultrasound using Papile classification. Out of 70 neonates with intrauterine growth restriction, germinal matrix-intraventricular hemorrhage was not found in 36 (51.43%) neonates, 31 (44.29%) had hemorrhage grade 1, and three (4.29%) had hemorrhage grade 2, which was statistically significant (p, Periventrikulsko-intraventrikulsko krvarenje u mozgu uglavnom se nalazi u nedonoščadi, ali se također može pojaviti kod djece rođene u terminu. Cilj ovog istraživanja bio je analizirati učestalost i ozbiljnost ovog tipa krvarenja kod umjerene i kasne nedonoščadi i rane terminske novorođenčadi s intrauterinim zastojem u rastu. U prospektivnoj analizi ispitano je 100 novorođenčadi: 70 s intrauterinim zastojem u rastu i 30 kao kontrolna skupina. Ispitanici su bili novorođenčad od 32 0/7 do 38 6/7 tjedana gestacije. Analizirana je tjelesna težina, duljina tijela, opseg glave i ponderalni indeks pri rođenju. Krvarenje je određeno klasifikacijom Papile, uz pomoć ultrazvučne pretrage mozga. U 36 (51,43%) od 70 novorođenčadi s intrauterinim zastojem u rastu nije pronađeno periventrikulsko-intraventrikulsko krvarenje, 31 (44,29%) je imalo krvarenje 1. stupnja, dok ih je 3 (4,29%) imalo krvarenje 2. stupnja, što je bilo statistički značajno (p

The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most devastating complications of prematurity. The short- and long-term neurodevelopmental consequences after severe GM-IVH are a major concern for neonatologists. These kids are at high risk of psychomotor alterations and cerebral palsy; however, therapeutic approaches are limited. Erythropoietin (EPO) has been previously used to treat several central nervous system complications due to its role in angiogenesis, neurogenesis and as growth factor. In addition, EPO is regularly used to reduce the number of transfusions in the preterm infant. Moreover, EPO crosses the blood-brain barrier and EPO receptors are expressed in the human brain throughout development. To analyze the role of EPO in the GM-IVH, we have administered intraventricular collagenase (Col) to P7 mice, as a model of GM-IVH of the preterm infant. After EPO treatment, we have characterized our animals in the short (14 days) and the long (70 days) term. In our hands, EPO treatment significantly limited brain atrophy and ventricle enlargement. EPO also restored neuronal density and ameliorated dendritic spine loss. Likewise, inflammation and small vessel bleeding were also reduced, resulting in the preservation of learning and memory abilities. Moreover, plasma gelsolin levels, as a feasible peripheral marker of GM-IVH-induced damage, recovered after EPO treatment. Altogether, our data support the positive effect of EPO treatment in our preclinical model of GM-IVH, both in the short and the long term.

The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most important complications of the preterm newborn. Since these children are born at a critical time in brain development, they can develop short and long term neurological, sensory, cognitive and motor disabilities depending on the severity of the GM-IVH. In addition, hemorrhage triggers a microglia-mediated inflammatory response that damages the tissue adjacent to the injury. Nevertheless, a neuroprotective and neuroreparative role of the microglia has also been described, suggesting that neonatal microglia may have unique functions. While the implication of the inflammatory process in GM-IVH is well established, the difficulty to access a very delicate population has lead to the development of animal models that resemble the pathological features of GM-IVH. Genetically modified models and lesions induced by local administration of glycerol, collagenase or blood have been used to study associated inflammatory mechanisms as well as therapeutic targets. In the present study we review the GM-IVH complications, with special interest in inflammatory response and the role of microglia, both in patients and animal models, and we analyze specific proteins and cytokines that are currently under study as feasible predictors of GM-IVH evolution and prognosis.

Objective The purpose of this study is to identify the risk factors associated with the development of germinal matrix-intraventricular hemorrhage (GM-IVH) and the relationship of the severity of disease and prematurity. Methods A total of 168 premature neonates whose birth weight ≤1500 g or gestational age ≤34 weeks were examined by cranial ultrasound (CUS) for detection of GM-IVH among the babies admitted between January 2011 and December 2012 in our medical center neonatal intensive care unit. The babies were divided into two groups : GM-IVH and non-IVH. Clinical presentations, precipitating factors of the patients and maternal factors were analyzed. Results In univariate analysis, gestational age, birth weight, delivery method, presence of premature rupture of membrane (PROM) and level of sodium and glucose were statistically meaningful factors (p