MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.

Global cerebrospinal fluid circulation mapping using gold nanoparticle enhanced X-ray microtomography reveals region-specific brain and spinal cord CSF pathways

Cerebrospinal fluid (CSF) movement within the brain interstitium is essential for the development and functioning of the brain. However, the interstitium has largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with CSF. Here, we developed a novel technique for CSF tracking, gold nanoparticle enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF pathways during development. Using this method and subsequent histological analysis, we map global CSF pathways and present novel particle size-dependent circulation patterns through the CNS. We identify an intraparenchymal CSF circulation that targets stem cell-rich and cholinergic neuronal populations. CSF solute distribution to these areas is mediated by CSF flow along projections from the basal cisterns which is altered in posthemorrhagic hydrocephalus. Our study uncovers region-specific patterns in a biologically driven CSF circulation that has implications for normal brain development and the pathophysiology of hydrocephalus and neurodegenerative disorders.

The treatment of patients with posthemorrhagic hydrocephalus

The article discusses the possible causes of polycystic posthemorrhagic ventriculomegaly in infants, as well as predictors of this pathological process. When choosing a treatment method the doctor shall take into account not only the etiology of the disease, but also age parameters, concomitant pathology. An important aspect in the approach to the treatment of polycystic posthemorrhagic multilevel hydrocephalus includes the determination of the biomechanical properties of the craniospinal system, especially the compliance of the brain and resorption of cerebrospinal fluid. Particular attention is paid to the timely correction of complications, including the analysis of inflammatory changes markers in the craniospinal system, which serve as predictors of the outcome of cerebrospinal fluid resorption. The authors also noted that the violation of the cerebrospinal fluid outflow from the cranial cavity in children may depend on a large number of «extracerebral» factors. They consider the stages of neurosurgical care to patients in this group on a clinical example. This example and literature data demonstrate that children with age develop changes not only in the craniospinal segment, which is responsible for the transformation of free fluid, but also in the extracranial cavities. Thus, we are able to recommend an integrated approach for the management of newborns with intracranial hemorrhage, complicated by posthemorrhagic hyporesorbent and occlusive hydrocephalus, with the justification of the optimal neurosurgical tactics for managing drainage-dependent patients, the course of the disease in which is accompanied by a multicomponent inflammatory syndrome.

Does ventricle size contribute to cognitive outcomes in posthemorrhagic hydrocephalus? Role of early definitive intervention

OBJECTIVE Posthemorrhagic 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. METHODS Twenty-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. RESULTS The 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). CONCLUSIONS In 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.

Methods for increasing the efficiency of hydrocephalus treatment in neonatal practice

Posthemorrhagic hydrocephalus in newborns with ventricular occlusion leads to decompensation of CSF dynamics with a high risk of neurological disorders and child disability.Objective. To improve the effectiveness of treatment of hydrocephalus in newborns.Characteristics of children and research methods. The authors analyzed the treatment of hydrocephalus in 327 newborns in 2000– 2018. 184children (Group 1)underwent standard treatment with lumbar and ventricular punctures with 20-22G needles, and with progression of hydrocephalus – ventriculo-subgaleal drainage and ventriculo-peritoneal shunting. 143 children (Group 2) with ventricular occlusion underwentcomplex treatment with coronary-transluminal subarachnoventriculostomy (RF patent No. 2715535) and ventricular drainage with a ventriculo-subarachnoid stenting system (RF patent No. 2721455).Results. The effectiveness of treatment with the inclusion of the proposed options is improvedby eliminatingocclusion, restoring circulation and absorption of cerebrospinal fluid, prolonged sanitation of cerebrospinal fluid with isotonic sodium chloridesolution. A positive result with compensation for hydrocephalus was achievedin 75,4% of cases versus 28,2% with the «standard» protocol (p <0,001).Compensation of hydrocephalus was accompanied by regression of hypertensive symptoms, stabilization of the ventricular size. The authors demonstrate a decrease in the timethe child spent in the hospital after surgery to 3-6 weeks with dynamic observation after discharge in the follow-up room, neurovisual monitoring.>Conclusion. The data obtained allowus to consider the effectiveness of the inclusion of the proposed options in the modern algorithm for the treatment of hydrocephalus in newborns, to expand the possibilities for early rehabilitation and restorative treatment together with pediatricneurologists and doctors of related specialties.

External ventricular drainage for posthemorrhagic ventricular dilatation in preterm infants: insights on efficacy and failure

OBJECTIVE The objective of this study was to describe the clinical and neuroradiological characteristics of a cohort of preterm infants who had undergone external ventricular drain insertion as a temporary measure to treat posthemorrhagic ventricular dilatation. In addition, the authors investigated the factors predicting permanent shunt dependency. METHODS The authors retrospectively reviewed the medical records of a cohort of preterm infants who had undergone external ventricular drain insertion at Gaslini Children’s Hospital (Genoa, Italy) between March 2012 and February 2018. They also analyzed clinical characteristics and magnetic resonance imaging data, including diffusion- and susceptibility-weighted imaging studies, which were obtained before both catheter insertion and removal. RESULTS Twenty-eight infants were included in the study. The mean gestational age was 28.2 ± 2.7 weeks, and the mean birth weight was 1209 ± 476 g. A permanent ventriculoperitoneal shunt was inserted in 15/28 (53.6%) infants because of the failure of external ventricular drainage as a temporary treatment option. Compared with the shunt-free group, the shunt-dependent group had a significantly lower gestational age (29.3 ± 2.3 vs 27.2 ± 2.7 weeks, p = 0.035) and tended toward a lower birth weight (p = 0.056). None of the clinical and neuroradiological characteristics significantly differed between the shunt-free and shunt-dependent groups at the time of catheter insertion. As expected, ventricular parameters as well as the intraventricular extension of intracerebral hemorrhage, as assessed using the intraventricular hemorrhage score, were reportedly higher in the shunt-dependent group than in the shunt-free group before catheter removal. CONCLUSIONS External ventricular drainage is a reliable first-line treatment for posthemorrhagic hydrocephalus. However, predicting its efficacy as a unique treatment remains challenging. A lower gestational age is associated with a higher risk of posthemorrhagic hydrocephalus progression, suggesting that the more undeveloped the mechanisms for the clearance of blood degradation products, the greater the risk of requiring permanent cerebrospinal fluid diversion, although sophisticated MRI investigations are currently unable to corroborate this hypothesis.

Global Surgery Indicators and Pediatric Hydrocephalus: A Multicenter Cross-Country Comparative Study Building the Case for Health System Strengthening

Objective: The aim of this study is to compare specific three-institution, cross-country data that are relevant to the Global Surgery indicators and the functioning of health systems.Methods: We retrospectively reviewed the clinical and socioeconomic characteristics of pediatric patients who underwent cerebrospinal fluid (CSF) diversion surgery for hydrocephalus in three different centers: the University of Tsukuba Hospital in Ibaraki, Japan (HIC), the Jose R. Reyes Memorial Medical Center in Manila, Philippines [low-to-middle-income country (LMIC)], and the Federal Neurosurgical Center in Novosibirsk, Russia (UMIC). The outcomes of interest were the timing of CSF diversion surgery and mortality. Statistical tests included descriptive statistics, Cox proportional hazards model, and logistic regression. Nation-level data were also obtained to provide the relevant socioeconomic contexts in discussing the results.Results: In total, 159 children were included, where 13 are from Japan, 99 are from the Philippines, and 47 are from the Russian Federation. The median time to surgery at the specific neurosurgical centers was 6 days in the Philippines and 1 day in both Japan and Russia. For the cohort from the Philippines, non-poor patients were more likely to receive CSF diversion surgery at an earlier time (HR = 4.74, 95% CI 2.34–9.61, p &lt;0.001). In the same center, those with infantile or posthemorrhagic hydrocephalus (HR = 3.72, 95% CI 1.70–8.15, p = 0.001) were more likely to receive CSF diversion earlier compared to those with congenital hydrocephalus, and those with postinfectious (HR = 0.39, 95% CI 0.22–0.70, p = 0.002) or myelomeningocele-associated hydrocephalus (HR = 0.46, 95% CI 0.22–0.95, p = 0.037) were less likely to undergo surgery at an earlier time. For Russia, older patients were more likely to receive or require early CSF diversion (HR = 1.07, 95% CI 1.01–1.14, p = 0.035). External ventricular drain (EVD) insertion was found to be associated with mortality (cOR 14.45, 95% CI 1.28–162.97, p = 0.031).Conclusion: In this study, Filipino children underwent late time-interval of CSF diversion surgery and had mortality differences compared to their Japanese and Russian counterparts. These disparities may reflect on the functioning of the health systems of respective countries.

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.

Survey of Quaternary Neonatal Management of Posthemorrhagic Hydrocephalus

Objective This study aimed to determine clinical care practices for infants at risk for posthemorrhagic hydrocephalus (PHH) across level IV neonatal intensive care units (NICUs). Study Design Cross-sectional survey that addressed center-specific surveillance, neurosurgical intervention, and follow-up practices within the Children's Hospitals Neonatal Consortium. Results We had a 59% (20/34 sites) response rate, with 10 sites having at least two participants. Respondents included neonatologists (53%) and neurosurgeons (35%). Most participants stated having a standard guideline for PHH (79%). Despite this, 42% of respondents perceive inconsistencies in management. Eight same-center pairs of neonatologists and neurosurgeons were used to determine response agreement. Half of these pairs disagreed on nearly all aspects of care. The greatest agreement pertained to a willingness to adopt a consensus-based protocol. Conclusion Practice variation in the management of infants at risk of PHH in level IV NICUs exists despite the perception that a common practice is available and used. Key Points

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

Background 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). Methods 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. Results 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. Conclusion 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.