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Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop.

ABSTRACT: The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood-brain and blood-CSF barriers. The goals of the workshop were to identify areas of opportunity in posthemorrhagic hydrocephalus research and encourage scientific collaboration across a diverse set of fields. This report details the major themes discussed during the workshop and research opportunities identified for posthemorrhagic hydrocephalus. The primary areas include (1) preventing intraventricular hemorrhage, (2) stopping primary and secondary brain damage, (3) preventing hydrocephalus, (4) repairing brain damage, and (5) improving neurodevelopment outcomes in posthemorrhagic hydrocephalus.

SUBMITTER: Koschnitzky JE

PROVIDER: S-EPMC5870202 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop.

Koschnitzky Jenna E JE Keep Richard F RF Limbrick David D DD McAllister James P JP Morris Jill A JA Strahle Jennifer J Yung Yun C YC

Fluids and barriers of the CNS 20180327 1

The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood-brain and blood-CSF barriers. The goals of the workshop were to identify areas of opportunity in posthe ...[more]

PMID: 29587767

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Project description:ObjectivePosthemorrhagic hydrocephalus (PHH) is associated with significant morbidity, smaller hippocampal volumes, and impaired neurodevelopment in preterm infants. The timing of temporary CSF (tCSF) diversion has been studied; however, the optimal time for permanent CSF (pCSF) diversion is unknown. The objective of this study was to determine whether cumulative ventricle size or timing of pCSF diversion is associated with neurodevelopmental outcome and hippocampal size in preterm infants with PHH.MethodsTwenty-five very preterm neonates (born at ≤ 32 weeks' gestational age) with high-grade intraventricular hemorrhage (IVH), subsequent PHH, and pCSF diversion with a ventriculoperitoneal shunt (n = 20) or endoscopic third ventriculostomy (n = 5) were followed until 2 years of age. Infants underwent serial cranial ultrasounds from birth until 1 year after pCSF diversion, brain MRI at term-equivalent age, and assessment based on the Bayley Scales of Infant and Toddler Development, Third Edition, at 2 years of age. Frontooccipital horn ratio (FOHR) measurements were derived from cranial ultrasounds and term-equivalent brain MRI. Hippocampal volumes were segmented and calculated from term-equivalent brain MRI. Cumulative ventricle size until the time of pCSF diversion was estimated using FOHR measurements from each cranial ultrasound performed prior to permanent intervention.ResultsThe average gestational ages at tCSF and pCSF diversion were 28.9 and 39.0 weeks, respectively. An earlier chronological age at the time of pCSF diversion was associated with larger right hippocampal volumes on term-equivalent MRI (Pearson's r = -0.403, p = 0.046) and improved cognitive (r = -0.554, p = 0.047), motor (r = -0.487, p = 0.048), and language (r = -0.414, p = 0.021) outcomes at 2 years of age. Additionally, a smaller cumulative ventricle size from birth to pCSF diversion was associated with larger right hippocampal volumes (r = -0.483, p = 0.014) and improved cognitive (r = -0.711, p = 0.001), motor (r = -0.675, p = 0.003), and language (r = -0.618, p = 0.011) outcomes. There was no relationship between time to tCSF diversion or cumulative ventricle size prior to tCSF diversion and neurodevelopmental outcome or hippocampal size. Finally, a smaller cumulative ventricular size prior to either tCSF diversion or pCSF diversion was associated with a smaller ventricular size 1 year after pCSF diversion (r = 0.422, p = 0.040, R2 = 0.178 and r = 0.519, p = 0.009, R2 = 0.269, respectively).ConclusionsIn infants with PHH, a smaller cumulative ventricular size and shorter time to pCSF diversion were associated with larger right hippocampal volumes, improved neurocognitive outcomes, and reduced long-term ventriculomegaly. Future prospective randomized studies are needed to confirm these findings.

Project description:ObjectiveIron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group.MethodsThis prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes.ResultsThirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively.InterpretationLongitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021;90:217-226.

Project description:IntroductionPosthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis.MethodsCSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions.ResultsThe rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions.ConclusionsCSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.

Project description:Neurological outcomes of preterm infants with posthemorrhagic hydrocephalus are among the worst in newborn medicine. There remains no consensus regarding the diagnosis or treatment of posthemorrhagic hydrocephalus, and the pathological pathways leading to the adverse neurological sequelae are poorly understood. In the current study, we developed an innovative approach to simultaneously identify potential diagnostic markers of posthemorrhagic hydrocephalus and investigate novel pathways of posthemorrhagic hydrocephalus-related neurological disability. Tandem multi-affinity fractionation for specific removal of plasma proteins from the hemorrhagic cerebrospinal fluid samples was combined with high resolution label-free quantitative proteomics. Analysis of cerebrospinal fluid obtained from infants with posthemorrhagic hydrocephalus demonstrated marked differences in the levels of 438 proteins when compared with cerebrospinal fluid from age-matched control infants. Amyloid precursor protein, neural cell adhesion molecule-L1, neural cell adhesion molecule-1, brevican and other proteins with important roles in neurodevelopment showed profound elevations in posthemorrhagic hydrocephalus cerebrospinal fluid compared with control. Initiation of neurosurgical treatment of posthemorrhagic hydrocephalus resulted in resolution of these elevations. The results from this foundational study demonstrate the significant promise of tandem multi-affinity fractionation-proteomics in the identification and quantitation of protein mediators of neurodevelopment and neurological injury. More specifically, our results suggest that cerebrospinal fluid levels of proteins such as amyloid precursor protein or neural cell adhesion molecule-L1 should be investigated as potential diagnostic markers of posthemorrhagic hydrocephalus. Notably, dysregulation of the levels these and other proteins may directly affect ongoing neurodevelopmental processes in these preterm infants, providing an entirely new hypothesis for the developmental disability associated with posthemorrhagic hydrocephalus.

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Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop.

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Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop.

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