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Objectives: This study aims to assess the predictive capability of synthetic MRI in assessing neurodevelopmental outcomes for extremely preterm neonates with low-grade Germinal Matrix-Intraventricular Hemorrhage (GMH-IVH). The study also investigates the potential enhancement of predictive performance by combining relaxation times from different brain regions. Materials and methods: In this prospective study, 80 extremely preterm neonates with GMH-IVH underwent synthetic MRI around 38 weeks, between January 2020 and June 2022. Neurodevelopmental assessments at 18 months of corrected age categorized the infants into two groups: those without disability (n = 40) and those with disability (n = 40), with cognitive and motor outcome scores recorded. T1, T2 relaxation times, and Proton Density (PD) values were measured in different brain regions. Logistic regression analysis was utilized to correlate MRI values with neurodevelopmental outcome scores. Synthetic MRI metrics linked to disability were identified, and combined models with independent predictors were established. The predictability of synthetic MRI metrics in different brain regions and their combinations were evaluated and compared with internal validation using bootstrap resampling. Results: Elevated T1 and T2 relaxation times in the frontal white matter (FWM) and caudate were significantly associated with disability (p < 0.05). The T1- FWM, T1-Caudate, T2-FWM, and T2-Caudate models exhibited overall predictive performance with AUC values of 0.751, 0.695, 0.856, and 0.872, respectively. Combining these models into T1-FWM + T1-Caudate + T2-FWM + T2-Caudate resulted in an improved AUC of 0.955, surpassing individual models (p < 0.05). Bootstrap resampling confirmed the validity of the models. Conclusion: Synthetic MRI proves effective in early predicting adverse outcomes in extremely preterm infants with GMH-IVH. The combination of T1-FWM + T1- Caudate + T2-FWM + T2-Caudate further enhances predictive accuracy, offering valuable insights for early intervention strategies. [ABSTRACT FROM AUTHOR]

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a detrimental neurological complication that occurs in preterm infants, especially in babies born before 32 weeks of gestation and in those with a very low birth weight. GM-IVH is defined as a rupture of the immature and fragile capillaries located in the subependymal germinal matrix zone of the preterm infant brain, and it can lead to detrimental neurological sequelae such as posthemorrhagic hydrocephalus (PHH), cerebral palsy, and other cognitive impairments. PHH following GM-IVH is difficult to treat in the clinic, and no levelone strategies have been recommended to pediatric neurosurgeons. Several cellular and molecular mechanisms of PHH following GM-IVH have been studied in animal models, but no effective pharmacological strategies have been used in the clinic. Thus, a comprehensive understanding of molecular mechanisms, potential pharmacological strategies, and surgical management of PHH is urgently needed. The present review presents a synopsis of the pathogenesis, diagnosis, and cellular and molecular mechanisms of PHH following GM-IVH and explores pharmacological strategies and surgical management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: This study aims to assess the predictive capability of synthetic MRI in assessing neurodevelopmental outcomes for extremely preterm neonates with low-grade Germinal Matrix-Intraventricular Hemorrhage (GMH-IVH). The study also investigates the potential enhancement of predictive performance by combining relaxation times from different brain regions., Materials and Methods: In this prospective study, 80 extremely preterm neonates with GMH-IVH underwent synthetic MRI around 38 weeks, between January 2020 and June 2022. Neurodevelopmental assessments at 18 months of corrected age categorized the infants into two groups: those without disability ( n = 40) and those with disability ( n = 40), with cognitive and motor outcome scores recorded. T 1 , T 2 relaxation times, and Proton Density (PD) values were measured in different brain regions. Logistic regression analysis was utilized to correlate MRI values with neurodevelopmental outcome scores. Synthetic MRI metrics linked to disability were identified, and combined models with independent predictors were established. The predictability of synthetic MRI metrics in different brain regions and their combinations were evaluated and compared with internal validation using bootstrap resampling., Results: Elevated T 1 and T 2 relaxation times in the frontal white matter (FWM) and caudate were significantly associated with disability ( p  < 0.05). The T 1 -FWM, T 1 -Caudate, T 2 -FWM, and T 2 -Caudate models exhibited overall predictive performance with AUC values of 0.751, 0.695, 0.856, and 0.872, respectively. Combining these models into T 1 -FWM + T 1 -Caudate + T 2 -FWM + T 2 -Caudate resulted in an improved AUC of 0.955, surpassing individual models ( p  < 0.05). Bootstrap resampling confirmed the validity of the models., Conclusion: Synthetic MRI proves effective in early predicting adverse outcomes in extremely preterm infants with GMH-IVH. The combination of T 1 -FWM + T 1 -Caudate + T 2 -FWM + T 2 -Caudate further enhances predictive accuracy, offering valuable insights for early intervention strategies., Competing Interests: KW was an employee of GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zhu, Wang, Wang, Lu, Lu, Xing, Wang, Zhang and Zhao.)

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.

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

Purpose: Brain functional connectivity (FC) changes and microstructural abnormalities are reported in infants born moderate and late preterm (MLPT). We evaluated the effect of low-grade (grades I, II) intraventricular hemorrhage (IVH) in MLPT babies on brain structural connectivity (SC) and FC. Methods: Babies born MLPT between January 2014 and May 2017 underwent brain ultrasound (US) at 72 h and 7 days after birth, and MRI at around term equivalent. The MRI protocol comprised T1- and T2-weighted sequences, diffusion tensor imaging (DTI), and resting-state functional MRI (fMRI). SC and FC were assessed using graph analysis. Results: Of 350 MLPT neonates, 15 showed low-grade IVH on US at 72 h, for which brain MRI was available in 10. These 10 infants, with mean gestational age (GA) 34.0 ± 0.8 weeks, comprised the study group, and 10 MLPT infants of mean GA 33.9 ± 1.1 weeks, with no abnormalities on brain US and MRI, were control subjects. All study subjects presented modularity, small world topology, and rich club organization for both SC and FC. The patients with low-grade IVH had lower FC rich club coefficient and lower SC betweenness centrality in the left frontoparietal operculum, and lower SC rich club coefficient in the right superior orbitofrontal cortex than the control subjects. Conclusions: Topological and functional properties of mature brain connectivity are present in MLPT infants. IVH in these infants was associated with structural and functional abnormalities in the left frontoparietal operculum and right orbitofrontal cortex, regions related to language and cognition. [ABSTRACT FROM AUTHOR]

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.

Background: Very preterm infants often show germinal matrix-intraventricular hemorrhage (GMH-IVH) on cranial ultrasound (cUS). Aim: To determine the impact of low-grade GMH-IVH on early neurodevelopmental outcome in very preterm infants. Methods: A retrospective case-control study in very preterm infants with and without low-grade GMH-IVH on cUS. Additional magnetic resonance imaging (MRI) was available in all infants with a gestational age (GA) <28 weeks and high-risk infants >28 weeks. Infants were seen at 2 years' corrected age to assess neurodevelopment. Results: In total, 136 infants (GA 24-32 weeks) with lowgrade GMH-IVH on cUS were matched with 255 controls. Outcome data was available for 342 (87%) infants. Adverse outcome (i.e., cerebral palsy [CP], neurodevelopmental delay) was present in 11 (9%) cases and 20 (9%) controls. No statistically significant differences in outcome were found between cases and controls. Additional MRI was performed in 165/391 infants (42%) and showed additional lesions in 73 (44%) infants that could explain subsequent development of CP in 2 out of 5 infants and epilepsy in 1 of 2 infants. Conclusion: Very preterm infants with low-grade GMH-IVH on cUS have a similar early neurodevelopmental outcome compared with controls. Additional MRI showed mostly subtle abnormalities that were missed with cUS, but these could not explain subsequent development of CP and developmental delay in all infants. [ABSTRACT FROM AUTHOR]

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<0.05). But only two factors, gestational age and presence of patent ductus arteriosus (PDA) were statistically meaningful in multivariate logistic regression (p<0.05). Delivery method [normal vaginal delivery (NVD) to Caeserean section] was borderline significant (p<0.10). Conclusion : Presence of PDA and gestational age were the important risk factors associated with development of GM-IVH. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alves-Martinez, Atienza-Navarro, Vargas-Soria, Carranza-Naval, Infante-Garcia, Benavente-Fernandez, Del Marco, Lubian-Lopez and Garcia-Alloza.)

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The two principal brain lesions that underlie the neurologic manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. This article emphasizes the neurology, neuropathology, and pathogenesis of these two lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be preventable by prevention of germinal matrix-intraventricular hemorrhage, and periventricular leukomalacia may be preventable by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow, and interruption of the cascade to oligodendroglial cell death by such agents as free radical scavengers. MRDD Research Reviews 3:3–12, 1997. © 1997 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2020 Hierro-Bujalance, Infante-Garcia, Sanchez-Sotano, del Marco, Casado-Revuelta, Mengual-Gonzalez, Lucena-Porras, Bernal-Martin, Benavente-Fernandez, Lubian-Lopez and Garcia-Alloza.)

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<0.05). But only two factors, gestational age and presence of patent ductus arteriosus (PDA) were statistically meaningful in multivariate logistic regression (p<0.05). Delivery method [normal vaginal delivery (NVD) to Caeserean section] was borderline significant (p<0.10)., Conclusion: Presence of PDA and gestational age were the important risk factors associated with development of GM-IVH.