Posthemorrhagic Hydrocephalus Of Prematurity Research Articles

Pathogenesis of posthemorrhagic hydrocephalus of prematurity: New horizons

Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a vexing problem for patients, their families, and the healthcare system. The complexity of the pathogenesis of PHHP also presents a unique challenge within the fields of neonatology, neurology and neurosurgery. Here we focus on pathogenesis of PHHP and its impact on the development of CSF dynamics including choroid plexus, ependymal motile cilia and glymphatic system. PHHP is contrasted with infantile hydrocephalus from other etiologies, and with other types of posthemorrhagic hydrocephalus that occur later in life. The important concept that distinguishing ventricular volume from brain health and function is highlighted. The influence of the pathogenesis of PHHP on current interventions is reviewed, with particular emphasis on how the unique pathogenesis of PHHP contributes to the high rate of failure of current existing interventions. Finally, we discuss emerging interventions. A thorough understanding of the pathogenesis of PHHP is essential to developing effective non-surgical therapeutics to prevent the transformation from severe IVH to PHHP

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity

BackgroundIntraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell–cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH.MethodsCSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons.ResultsCSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 − < 0.0001), LGIVH (p = 0.023 − < 0.0001), and HGIVH (p = 0.015 − 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 − 0.0008) in the whole cohort.ConclusionsCSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition.

Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity.

Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP.

Potential Risk Factors for Ventriculoperitoneal Shunt Implantation in Paediatric Patients with Posthemorrhagic Hydrocephalus of Prematurity Treated with Subcutaneous Reservoir: An Institutional Experience.

Posthemorrhagic hydrocephalus of prematurity (PHHP) is a result of intraventricular hemorrhage (IVH). IVH occurs in 6 to 23% of the preterms in countries with advanced medical health care. Most of these patients will eventually require the use of ventriculoperitoneal shunt (VPS). The purpose of this study is to assess the risk factors of VPS implantation in patients with PHHP who have been treated with ventricular catheter with subcutaneous reservoir (VCSR). The retrospective study was conducted evaluating 35 premature patients who suffered from severe IVH. Their mean gestational age was 28 weeks. The assessment included antenatal factors such as gestational age, birth weight, and intrauterine and perinatal infection. Postparturient period factors such as the IVH grade, time between diagnosis, and VCSR implantation and body weight on VCSR implantation were also considered in the study. Postprocedural complications, such as bacterial cerebrospinal fluid (CSF) infection, sepsis, and skin lesions, were evaluated. Data were calculated with R program, version 4.04. From among 35 evaluated patients, 23 (65.71%) required a VPS. Median of birth weight was 1,190 g. Infections were observed in 11 (31.43%) cases. Mean time between IVH diagnosis and VCSR implantation was 2.6 weeks. Postprocedural complications occurred in 19 (54.29%) patients. None of the evaluated factors has proven its statistical significance (p > 0.05) for being a potential risk factor for VPS implantation. External factors seem to not affect the necessity of VPS implantation in patients after the severe IVH. Ostensibly, there seems to be no difference between the grades III and the IV of Papile's IVH scale regarding VPS implantation necessity.

Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity.

ObjectiveEfforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH.Study designPreterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15–30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson’s partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores.ResultsCSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966).ConclusionCSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity.

Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae.

"Growing cerebellum" requiring operative decompression following perinatal ventriculoperitoneal shunting.

While cases of acquired Chiari I malformation following ventriculoperitoneal shunting for posthemorrhagic hydrocephalus have been reported, true disproportionate cerebellar growth is rare, with no previous cases requiring posterior fossa decompression reported. We present a premature neonate who underwent ventriculoperitoneal shunt placement for suspected posthemorrhagic hydrocephalus. He subsequently developed a symptomatic Chiari I malformation with volumetric measurements demonstrating disproportionate growth of the cerebellum. He did not demonstrate thickening of the supratentorial or posterior fossa cranium. The patient underwent an extradural posterior fossa decompression, with resolution of symptoms. We review the extant literature regarding the development of Chiari malformation type I as a manifestation of craniocerebral disproportion (CCD) following shunt placement for posthemorrhagic hydrocephalus of prematurity. Most previous reports reflect a mechanism that includes underdevelopment of the intracranial posterior fossa (or supratentorial) volume. The case presented in this report, as well as one additional case, indicates that there may exist a variant mechanism, characterized by rapid growth of the cerebellum itself, in the absence of one of the rare syndromes associated with primary macrocerebellum. While this case was effectively managed with extradural posterior fossa decompression, previous reports indicate that supratentorial cranial expansion procedures are preferable in some cases. As such, pediatric neurosurgeons should be able to distinguish the patterns of craniocerebral disproportion when considering treatment options for these patients. Further investigation regarding these uncommon patients may better describe the underlying mechanisms.

Endoscopic third ventriculostomy inpatient failure rates compared with shunting in post-hemorrhagic hydrocephalus of prematurity.

Endoscopic third ventriculostomy (ETV) has gained traction as a method for treating post-hemorrhagic hydrocephalus of prematurity (PHHP) in an effort to obviate lifelong shunt dependence in neonates. However, data remains limited regarding inpatient failures. A retrospective analysis of the NIS between 1998 and 2014 was performed. Discharges with age < 1year and ICD-9-CM codes indicating intraventricular hemorrhage of prematurity (772.1x) and ETV/shunt (02.22 and 02.3x) were included. Patients with ICD-9-CM codes for ventricular drain/reservoir (02.21) were excluded to prevent confounding. Time trend series plots were created. Yearly trends were quantified using logarithmic regression analysis. Kaplan-Meier curves were utilized to analyze time to treatment failure. Time to failure for each treatment was compared using log-rank. A total of 11,017 discharges were identified. ETV was more likely to be utilized at < 29weeks gestational age (p = 0.0039) and birth weight < 1000g (p = 0.0039). Shunts were less likely to fail in older and heavier newborns (OR 0.836 p = 0.00456, OR 0.828 p = 0.0001, respectively). Those initially shunted had lower failure rates compared with ETV (OR 0.44, p < 0.0001) but time to failure was longer with ETV (p = 0.04562). 79.5% of ETVs that failed were shunted after the first failure. Shunts were much less likely to undergo ETV if they failed (OR 0.21, p < 0.0001). Higher grade IVH was predictive of shunt failure but not ETV (OR 2.36, p = 0.0129). Although ETV can be effective in PHHP, it has a much higher initial failure rate than shunting and should thus be chosen based on a multifactorial approach.

MR diffusion changes in the perimeter of the lateral ventricles demonstrate periventricular injury in post-hemorrhagic hydrocephalus of prematurity.

Injury to the preterm lateral ventricular perimeter (LVP), which contains the neural stem cells responsible for brain development, may contribute to the neurological sequelae of intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus of prematurity (PHH). This study utilizes diffusion MRI (dMRI) to characterize the microstructural effects of IVH/PHH on the LVP and segmented frontal-occipital horn perimeters (FOHP). Prospective study of 56 full-term infants, 72 very preterm infants without brain injury (VPT), 17 VPT infants with high-grade IVH without hydrocephalus (HG-IVH), and 13 VPT infants with PHH who underwent dMRI at term equivalent. LVP and FOHP dMRI measures and ventricular size-dMRI correlations were assessed. In the LVP, PHH had consistently lower FA and higher MD and RD than FT and VPT (p<.050). However, while PHH FA was lower, and PHH RD was higher than their respective HG-IVH measures (p<.050), the MD and AD values did not differ. In the FOHP, PHH infants had lower FA and higher RD than FT and VPT (p<.010), and a lower FA than the HG-IVH group (p<.001). While the magnitude of AD in both the LVP and FOHP were consistently less in the PHH group on pairwise comparisons to the other groups, the differences were not significant (p>.050). Ventricular size correlated negatively with FA, and positively with MD and RD (p<.001) in both the LVP and FOHP. In the PHH group, FA was lower in the FOHP than in the LVP, which was contrary to the observed findings in the healthy infants (p<.001). Nevertheless, there were no regional differences in AD, MD, and RD in the PHH group. HG-IVH and PHH results in aberrant LVP/FOHP microstructure, with prominent abnormalities among the PHH group, most notably in the FOHP. Larger ventricular size was associated with greater magnitude of abnormality. LVP/FOHP dMRI measures may provide valuable biomarkers for future studies directed at improving the management and neurological outcomes of IVH/PHH.

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats.

Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a global challenge. Early preterm infants (<32 weeks gestation), particularly those exposed to chorioamnionitis (CAM), are prone to intraventricular hemorrhage (IVH) and PHHP. We established an age-appropriate, preclinical model of PHHP with progressive macrocephaly and ventriculomegaly to test whether non-surgical neonatal treatment could modulate PHHP. We combined prenatal CAM and postnatal day 1 (P1, equivalent to 30 weeks human gestation) IVH in rats, and administered systemic erythropoietin (EPO) plus melatonin (MLT), or vehicle, from P2 to P10. CAM-IVH rats developed progressive macrocephaly through P21. Macrocephaly was accompanied by ventriculomegaly at P5 (histology), and P21 (ex vivo MRI). CAM-IVH rats showed impaired performance of cliff aversion, a neonatal neurodevelopmental test. Neonatal EPO+MLT treatment prevented macrocephaly and cliff aversion impairment, and significantly reduced ventriculomegaly. EPO+MLT treatment prevented matted or missing ependymal motile cilia observed in vehicle-treated CAM-IVH rats. EPO+MLT treatment also normalized ependymal yes-associated protein (YAP) mRNA levels, and reduced ependymal GFAP-immunolabeling. Vehicle-treated CAM-IVH rats exhibited loss of microstructural integrity on diffusion tensor imaging, which was normalized in EPO+MLT-treated CAM-IVH rats. In summary, combined prenatal systemic inflammation plus early postnatal IVH caused progressive macrocephaly, ventriculomegaly and delayed development of cliff aversion reminiscent of PHHP. Neonatal systemic EPO+MLT treatment prevented multiple hallmarks of PHHP, consistent with a clinically viable, non-surgical treatment strategy.

Shunt revision requirements after posthemorrhagic hydrocephalus of prematurity: insight into the time course of shunt dependency.

Intraventricular hemorrhage (IVH) is a common affliction of preterm infants and often results in posthemorrhagic hydrocephalus (PHH). These patients typically eventually require permanent CSF diversion and are presumed to be indefinitely shunt-dependent. To date, however, there has been no study of long-term shunt revision requirements in patients with PHH. We analyzed retrospectively collected data for 89 preterm patients diagnosed with grades III and IV IVH and PHH at our institution from 1998 to 2011. Sixty-nine out of 89 patients (77.5%) underwent ventriculoperitoneal (VP) shunt placement, and 33 (47.8%) required at least one shunt revision and 18 (26.1%) required multiple revisions. The mean ± standard deviation follow-up time for shunted patients was 5.0 ± 3.3 years. The majority of early failures were due to proximal catheter malfunction, while later failures were mostly due to distal catheter problems. There was a significant difference in the number of patients requiring revisions in the first 3 years following initial VP shunt insertion compared after 3 years, with 28 revisions versus 10 (p < 0.004). In 8 out of 10 patients who underwent shunt revisions after 3 years, evidence of obstructive hydrocephalus was found on imaging either in the form of an isolated fourth ventricular cyst or aqueductal stenosis. Our results suggest that in a distinct subset of patients with PHH, obstructive hydrocephalus may develop, resulting in long-term dependence on CSF diversion. Further study on the factors associated with long-term shunt dependence and revision requirements within the PHH group is warranted.

Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity.

BackgroundNeurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment.ObjectiveThe objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH.MethodsCSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses.ResultsCSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95).ConclusionsHerein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.

Analysis of the potential risk of central intravenous lines and/or total parenteral nutrition with ventriculoatrial shunts.

The distal catheter of a ventriculoatrial (VA) cerebrospinal fluid shunt is potentially exposed to bacterial seeding from a subclavian central line. The risk of blood stream infections (BSIs) from central lines increases with administration of total parenteral nutrition (TPN). The potential risks of shunt malfunction or infection in patients with a VA shunt and a concurrent subclavian central line and/or TPN administration have not been studied. A retrospective review of 49 pediatric patients with placement of a VA shunt was performed. Three outcome measures were studied: shunt malfunction, shunt infection, and bacteremia/fungemia requiring shunt removal. All outcomes were measured by 1 year after shunt insertion. We analyzed the following potential risk factors: age at shunt insertion, prior ventriculoperitoneal (VP) shunt, prior shunt infection, abdominal infection/necrotizing enterocolitis (NEC), concurrent subclavian central line, and administration of TPN. The association between each risk factor and outcome was evaluated using Fisher's exact test to generate the relative risk. Additionally, a logistic regression analysis was performed to evaluate the odds ratio of the outcomes to risk factors considering age as a covariate. The average age at shunt insertion was 6.3 ± 7.6 years. The most common diagnosis was posthemorrhagic hydrocephalus of prematurity (53.1 %). Fifteen patients (30.1 %) had a shunt malfunction within 1 year, 6 (12.2 %) had a shunt infection, and 3 (6.1 %) required removal of the shunt due to bacteremia/fungemia. The age at shunt insertion was not a statistically significant independent risk factor for any of the three outcomes. Prior shunt infection predicted an increased risk for both future shunt malfunction and infection in both the associative relative risk analysis and the age-dependent logistic regression analysis, although the correlation did not reach statistical significance. The presence of a subclavian central line or TPN administration did not statistically increase the risk over baseline for any of the outcomes in either analysis. The relatively small number of patients limits the power of the study. Considering this limitation, the data suggests that the presence of a concurrent subclavian central line or administration of TPN does not increase the risk of shunt malfunction or infection over the baseline of this high-risk cohort.

Shunt revision requirements after posthemorrhagic hydrocephalus of prematurity: insight into the time course of shunt dependency

Results 69 out of 89 patients (77.5%) underwent VP shunt placement, and 33 (47.8%) required at least one shunt revision and 18 (26.1%) required multiple revisions. The mean ± standard deviation follow-up time for shunted patients was 5.0 ± 3.3 years. The majority of early failures are due to proximal catheter malfunction, while later failures were mostly due to distal catheter problems. There was a significant difference in the number of patients requiring revisions in the first three years following initial VP shunt insertion compared after three years, with 28 revisions versus 10 (p<0.004). In the 10 patients who underwent shunt revisions after three years, evidence of obstructive hydrocephalus was found on imaging either in the form of an isolated fourth ventricular cyst or aqueductal stenosis. Conclusions Our results suggest that in a distinct subset of patients with PHH, obstructive hydrocephalus may develop, resulting in long-term dependence on CSF diversion. Further study on the factors associated with long-term shunt dependence and revision requirements within the PHH group is warranted.

Endoscopic third ventriculostomy and choroid plexus cauterization in posthemorrhagic hydrocephalus of prematurity

The aim of this study was to determine the role of endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) in the management of posthemorrhagic hydrocephalus of prematurity (PHHP) and to analyze which factors affect patient outcomes. This study retrospectively reviewed medical records of 27 premature infants with intraventricular hemorrhage (IVH) and hydrocephalus treated with ETV and CPC from 2008 to 2011. All patients were evaluated using MRI before the procedure to verify the anatomical feasibility of ETV/CPC. Endoscopic treatment included third ventriculostomy, septostomy, and bilateral CPC. After ETV/CPC, all patients underwent follow-up for a period of 6-40 months (mean 16.2 months). The procedure was considered a failure if the patient subsequently required a shunt. The following factors were analyzed to determine a relationship to patient outcomes: gestational age at birth, corrected age and weight at surgery, timing of surgery after birth, grade of IVH, the status of the prepontine cistern and cerebral aqueduct on MRI, need for a ventricular access device prior to the endoscopic procedure, and scarring of the prepontine cistern noted at surgery. Seventeen (63%) of 27 patients required a shunt after ETV/CPC, and 10 patients did not require further CSF diversion. Several factors studied were associated with a higher rate of ETV/CPC failure: Grade IV hemorrhage, weight 3 kg or less and age younger than 3 months at the time of surgery, need for reservoir placement, and presence of a normal cerebral aqueduct. Two factors were found to be statistically significant: the patient's corrected gestational age of less than 0 weeks at surgery and a narrow prepontine cistern on MRI. The majority (83%) of ETV/CPC failures occurred in the first 3 months after the procedure. None of the patients had a complication directly related to the procedure. Endoscopic third ventriculostomy/CPC is a safe initial procedure for hydrocephalus in premature infants with IVH and hydrocephalus, obviating the need for a shunt in selected patients. Even though the success rate is low (37%), the lower rate of complications in comparison with shunt treatment may justify this procedure in the initial management of hydrocephalus. As several of the studied factors have shown influence on the outcome, patient selection based on these observations might increase the success rate.

Alterations in Protein Regulators of Neurodevelopment in the Cerebrospinal Fluid of Infants with Posthemorrhagic Hydrocephalus of Prematurity

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.

Initial experience with combined endoscopic third ventriculostomy and choroid plexus cauterization for post-hemorrhagic hydrocephalus of prematurity: the importance of prepontine cistern status and the predictive value of FIESTA MRI imaging

Post-hemorrhagic hydrocephalus of prematurity (PHHP) is among the most common causes of infant hydrocephalus in developed nations. This population has a high incidence of shunt failure, infection, and slit ventricle syndrome. Although effective for other etiologies of infant hydrocephalus, the efficacy of combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) in PHHP has not been investigated. This pilot study reports the initial experience. Ten patients (four grade III and six grade IV intraventricular hemorrhage) requiring definitive treatment for PHHP underwent ETV/CPC within 6 months of birth. Seven had a prior ventriculo-subgaleal shunt. Mean age at birth was -12.8 weeks, or 25.2 weeks gestation (24-28 weeks), and at surgery was -1.6 weeks (-11 to +11 weeks). Mean weight at surgery was 3.3 (1.0-5.5 kg). Each patient had preoperative magnetic resonance imaging (MRI) with fast imaging employing steady-state acquisition (FIESTA). Four of ten (40%) required no further operations related to hydrocephalus (mean follow-up, 29.7 months). Six required another procedure (five ultimately shunted). Prepontine cistern status correlated with outcome (p = 0.033). Procedures in all infants with unobstructed cisterns were successful but failed in six of seven with cisternal obstruction, with the one success having an alternative lamina terminalis endoscopic third ventriculostomy. Preoperative MRI FIESTA images correlated well with intraoperative assessment of the cistern. Results from this small homogenous cohort suggest cistern status is an important determinant of outcome. FIESTA imaging correlated with endoscopic observation. Preliminary analysis suggests ETV/CPC as an effective treatment for PHHP, but only when the cistern is unscarred. This information should guide patient selection for future study protocols.