key: cord-0773199-rw5vqdbh
authors: nan
title: Abstracts from Hydrocephalus 2021: The Thirteenth Meeting of the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders
date: 2021-12-21
journal: Fluids Barriers CNS
DOI: 10.1186/s12987-021-00293-w
sha: ec28189df2c546a1007ac5ccb48b0658132ba062
doc_id: 773199
cord_uid: rw5vqdbh

nan

Introduction: Congenital hydrocephalus (CH) is a disorder of ventricular expansion related to CSF physiology. CH has been linked to a number of genes including SMARCC1, a core SWI/ SNF complex subunit which regulates gene expression required for neural stem cell (NSC) proliferation during forebrain development. Recent whole exome sequencing studies have identified SMARCC1 as a high confidence pathogenic gene in CH. Methods: We collected a cohort of 12 CH patients with SMARCC1 variants and used a Xenopus model to investigate observed phenotypes with optical coherence tomography, single cell RNA sequencing, in situ hybridization and immunohistochemistry. Results: Aqueductal stenosis (AS) was present in all 12 patients, with cardiac and craniofacial defects each present in 3/12 patients. AS and ventriculomegaly were observed in the majority of Smarcc1 Xenopus morphants and CRISPR knockdowns in both F0 and F1 generations. Importantly, we demonstrated rescue of the AS phenotype with human WT SMARCC1 mRNA. Single cell RNA sequencing of human fetal tissue identified downregulation of NEUROD2, a gene related to NSC proliferation. In situ hybridization showed decreased expression of NEUROD2 in Xenopus morphants and knockdowns compared with WT in the prosencephalon. In contrast, surrounding the cerebral aqueduct, we found evidence of increased proliferation in Smarcc1 morphants. Conclusion: The clustering of phenotypes in SMARCC1 human variants with replication in our Xenopus model illustrates variable expressivity and pleiotropy, suggesting that SMARCC1 may define a novel Mendelian CH syndrome. Our results also provide mechanistic insight into pathogenesis of SMARCC1-related CH, which may enable identification of novel therapeutic targets. Introduction: MRI-volumetry is an interesting alternative to invasive tests of shunt function. In this study we aimed to assess ventricular volume (VV) before and after surgery and at different opening pressure (OP) of the shunt. Methods: The material consisted of 33 patients with a median (Md) age of 76 years with idiopathic normal pressure hydrocephalus who received a Strata ® shunt with OP 1.5. Participants underwent MRI with volumetric sequences before surgery and four times postoperatively; at one month before randomization to either OP 1.0 or 2.5, at two months before crossover to OP 2.5 or 1.0; at three months before lowering to OP 0.5 and finally at three months and one day after surgery before resetting OP to 1.5. VV was measured semiautomatically using SyMRI ® . Both the patient and the examiner were blinded to the OP. Results: Significant changes were seen in VV from before (Md 129 ml) to one month after shunt surgery (Md 121 ml) and between OP 1.0 (Md 116 ml), 1.5 (Md 121 ml) and 2.5 (Md 127 ml) (p < 0.001). A unidirectional change in VV was seen for all participants between OP 1.0 and OP 2.5, (Md 11.5 ml, range 2.1-40.7) (p < 0.001). No significant change was seen in VV after 24 hours at OP 0.5. Conclusion: The consistent decrease in VV after shunt surgery and between high and low OP of the shunt supports that MRI-volumetry could be a non-invasive method for evaluating shunt function, preventing unnecessary shunt revisions. Introduction: Posthemorrhagic hydrocephalus is the progressive dilation of the ventricular space following a hemorrhage within the brain. Exposure of the ventricular zone to blood is known to cause astrogliosis, microglial activation, cell junction dislocation, impairment of neural stem cell differentiation, and overall loss of ependymal cells, potentially leading to cerebrospinal fluid accumulation. In this study, the effect blood has on cellular response to a shunt catheter is evaluated. Methods: Development of a novel custom-built 3D resin printed chamber was used to model the placement of a catheter sample on the ventricular zone. Undifferentiated neural stem cells extracted from C57BL/6 mice lateral ventricle and ATCC C8-D30 astrocytes were used. Cell counts were obtained to compared between control and whole blood exposed samples. Results: Cells exposed to blood showed a significant increase (P < 0.0001) in astrocyte attachment when added concurrently with a catheter sample. The average total expression of DAPI on the sample exposed to blood was 392.0 ± 317.1 and 94.7 ± 44.5 for the control samples. Analysis of the GFAP stain expressed a total averages cell count of 174.3 ± 116.5 and 854.4 ± 450.7 for the sample not exposed to and exposed to blood, respectively. Conclusion: An increase in cell count and a simultaneous increase in GFAP expression after whole blood exposure may be indicative of enhanced neuroinflammation, astrocyte activation, cytoskeletal Objective: To assess the predictive value of the newly proposed Evans' Index cutoffs in patients presenting with suspected Normal Pressure Hydrocephalus. Methods: A retrospective chart review of 194 patients who underwent a cerebral spinal fluid tap test (CSF TT) at the Johns Hopkins Center for CSF Disorders was completed. Patients were divided into two groups: 130 patients were classified as having an EI above the ADNI cutoff (AC), and 64 patients were classified as having an EI below the ADNI cutoff (BC). Patients' gait was assessed before and after the CSF TT using the 10 Meter Walk Test, Timed Up & Go, Dual Timed Up & Go, 6-Minute Walk Test, Mini-Balance Evaluation Systems Test. To assess the normality of the measures the Shapiro-Wilk test was used. The Wilcoxon ranksum test and t-tests was used to assess between groups differences. The Wilcoxon matched-pairs signed-rank test and paired t-test were used assess within group differences. An ANCOVA controlled for age, sex, assistive device used, and past medical history effecting gait was used to assess the between groups response. Results: There was not a significant difference in response between the patients above the new cutoffs and below the cutoffs. The patients below the cutoffs improved on the timed up and go (TUG) by 13.30%, DualTUG: 14.36%, 10-meter Walk Test (10MWT): 12.52%, MiniBEST: 18.94%, and 6-minute Walk Test (6MWT): 14.84%, while the patients above the new cutoffs improved on the TUG by 16.24%, DualTUG: 17.70%, 10MWT: 16.68%, MiniBEST: 17.85%, and 6MWT: 16.96%. Conclusion: We recommend not adopting the newly proposed EI cutoffs for the differential diagnosis of NPH. The EI is primarily used as a screening tool to selecting patients for a CSF TT. Patients below the proposed cutoffs were shown to improve at the same levels as patients above below the cutoffs. Introduction: The aim of this exploratory observational study was to describe the relationship between static/pulsatile intracranial pressure(ICP) and radiological findings in patients with CMI. Methods: Single-centre retrospective observational study including a consecutive series of CMI patients investigated with elective 24-hour ICP monitoring. Night 24-hour ICP and pulse amplitude (PA) were retrieved from a prospectively built ICP monitoring database. Information on syringomyelia (present/absent), cerebellar tonsils descent(mm) and previous surgical treatments was collected. The association of ICP/ PA and syringomyelia, tonsillar descent, previous shunt or previous foramen magnum decompression (FMD) were tested(Mann-Whitney U test or linear regression model). Results: Thirty-six patients were included (33F, mean age was 36 ± 13 SD) years. Fourteen patients received previous treatment with foramen magnum decompression (n = 6), ventriculoperitoneal shunt (n = 1), or both (n = 7) before the time of ICP monitoring. Night ICP was not associated with any of the imaging findings investigated in this study. Night pulse amplitude had a significant association with tonsillar descent in patients without previous history of surgical treatment (β = 1.74, 95% CI 0.13 to 3.35, p = 0.03, adj. R2 = 0.16). In patients who did not improve despite previous ventriculoperitoneal shunt and foramen magnum decompression treatments (ultra-resistant CM I), there was a significant correlation of night pulse amplitude with syringomyelia length(in mm: β = 70, 95% CI 45 to 94, p = 0.001, and number of vertebral levels: β = 3.06, 95% CI 1.78 to 4.34, p = 0.002). Conclusion: This exploratory study found an association between intracranial compliance and imaging findings of CMI. The findings of this exploratory study provide suggestions on the pathophysiology of CMI and are relevant for the planning of further research in this field. Introduction: Cerebrospinal fluid (CSF) production rate in humans is not clearly defined but is thought to be 18-24ml/hour. We recorded CSF production rate (PRcsf ) in different pathological conditions using LiquoGuard, an automated CSF drainage machine. We analysed the data to see if CSF over-production is a feature of common neurosurgical conditions. Methods: We performed a prospective observational study in all patients in our hospital who required CSF drainage through lumbar drain or external ventricular drain as part of their ongoing treatment. The external drain was connected to a LiquoGuard7 (Möller-Medical, Germany) with the intracranial pressure (ICP) sensor at the level of the external auditory meatus. Patients were flat for 10 minutes during the measurement. The study was repeated for 3 consecutive days. Statistical analysis used SPSS (version 25.0, IBM) by unpaired t-test, comparing measured rates to 20ml/hour. Results: To date, we have calculated PRcsf in 37 patients. All patients suffering from a particular disease had similar results regardless of age, gender or co-morbidities. Conclusion: PRcsf is higher than expected in many conditions which may have implications for decisions on CSF diversion. More extensive studies are needed to validate this technique. Introduction: Extended lumbar drainage (ELD) is regarded by many as a reliable test for shunt-responsive idiopathic normal pressure hydrocephalus (iNPH). However, recent evidence has suggested its negative predictive value may be low. Methods: An institutional database of 741 consecutive new patients presenting to our service with possible/suspected NPH was interrogated to determine the diagnostic accuracy of extended lumbar drainage. Patients were excluded if < 60 or a potential secondary cause of NPH was identified. Gait and cognitive performance data were collected at baseline, pre-and post-ELD and at 3 and 12 months post-shunt insertion. The decision to shunt was not solely based on objective assessment of ELD outcome immediately after drain removal, but also on patient/carer reported improvement during a two-week diary exercise. Results: A clear relationship was found between improvement in Raftopoulos score at ELD and at 12 months post-shunt insertion (co-efficient 2.3, P < 0.01) and also between change in MMSE at ELD and at 12 months (co-efficient 0.5, P < 0.01). Using a composite of gait and cognitive improvement, ELD had a PPV of 81% and an NPV of 39%. ROC curve analysis suggested that ≥36% improvement in Raftopoulos score and ≥2 points on MMSE were the most discriminating thresholds for positivity. Conclusion: ELD, if using objective measures alone, has a relatively high PPV but a low NPV, suggesting it is most useful in demonstrating the degree of improvement a patient may experience and aiding decision-making in patients who are undecided, rather than as a 'rule out' test for shunt insertion. 

We used machine learning techniques to embed the entire PubMed corpus of over 33 million articles in a high dimensional vector space. We searched within the embedding for "hydrocephalus" and created a lower dimensional representation that allows interactive exploration of the results using cluster analysis, geo-temporal mapping and filtering by subtopic search terms. To evaluate utility, we compared our search results with those listed in published metaanalyses and reviews. In addition, we used geo-temporal mapping to identify trends in the hydrocephalus literature over time and space. Results: Through April 2021, a total of 35,320 published articles on the topic "hydrocephalus" were found. A surprising proportion of the retrieved literature related to secondary causes of hydrocephalus, including neoplasms, infections, vascular disease and metabolic causes. Emerging topics in the adult, pediatric and experimental hydrocephalus fields were readily identified. The number and relatedness of the retrieved articles compared favorably to those in several published hydrocephalus reviews. Introduction: According to Monro-Kellie doctrine, intracranial pressure (ICP) shares a unique relationship with the mean arterial pressure (MAP) and maintains the cerebral perfusion pressure (CPP) within normal limits. However, in this unique case, the patient needed subnormal ICP to maintain his GCS. Methods: A 48-year-old male, known case of hemophilia A on factor VIII transfusions. He had undergone decompressive hemicraniectomy followed later by mesh cranioplasty in 2014 for spontaneous right frontotemporoparietal acute SDH with temporal hematoma. In November 2019, he underwent insertion of a medium pressure ventriculoperitoneal shunt for spontaneous right cerebellar hemorrhage with intraventricular extension with hydrocephalus. In January 2021, he presented with features of acute hydrocephalus with meningitis. Despite appropriate antimicrobial therapy and a functioning shunt system, his sensorium remained poor. EVD was inserted and ICP monitoring showed pressures within 12-15mmHg. It was noted that patient's sensorium improved only at ICP levels of < 6mmHg.

The patient was entirely EVD dependent even with revision of VP shunt chamber to very low-pressure chamber, requiring subnormal intracranial pressures to maintain sensorium. To tide over this tricky situation with EVD being only a temporary measure, a permanent solution in the form of gravity dependent CSF drainage was established by removing the VP shunt chamber thereby establishing a direct communication of the ventricles with peritoneal cavity. This helped in improving the patient's sensorium while maintaining subnormal ICP levels.

Conclusion: This is a unique case where due to probable alteration in the cerebral compliance and autoregulation due to repeated insults to the brain, manifested as exponential reduction in CPP with minor changes in ICP though ICP and MAP were within physiological limits.

The authors declare that the patient has give written consent for the publication of this study. Figures and Charts: Introduction: Shunt-associated complications are extremely common. Computer-generated flow analysis reveals catheter limitations in terms of fluid dynamics, while in-vitro cell-attachment studies underline the importance of surface modifications to PDMS catheters. A high throughput rapid testing system is the combination of computergenerated flow analysis, experimental biomaterial analysis, protein adsorption and cell attachment and activation in vitro. Methods: A pulsating flow system with custom-built control and data-collection software was developed. 2D flow-optimized chambers were printed using DLP technique with 1:1 model of various catheters built into the catheter. The models were made by curing a thin membrane of PDMS on the tangent of a set of catheter holes. Metal needles were placed through PDMS based on the model catheter design to avoid PDMS from curing over the holes. 3D models were also created by placing commercial catheters into the flow-optimized chambers. Novel catheters were created by accurately punching holes onto surface modified PDMS tubes and adding caps prior to placement into the chambers. 2D and 3D models were seeded with A1 and A2 astrocytes and were incubated with pulsating flow running through the chambers for up to 4 weeks prior to confocal microscopy. Results: 2D and 3D models of novel ventricular catheters were connected to pulsating flow system. The flow system was able to induce controlled pulsation in the range of 40-230 bpm and 0.05-1 ml/min output.

Conclusion: This is a brief description of experimental catheter manufacturing and testing. 2D and 3D catheters allow rapid testing on novel catheter designs, surface modifications and biomaterials. 

To improve outcomes of current shunt treatments for hydrocephalus, a better understanding of cerebrospinal fluid (CSF) physiology is needed. Because malfunctions arise from posture changes, measurements of intracranial pressure (ICP) fluctuations and their relation to blood pressure during these changes shall provide valuable insights. Methods: ICP and femoral blood pressure (FBP) of five healthy rats were continuously measured in a chronic trial via radio telemetry implants and sampled at 1 kHz. While being awake and moving freely in an observation box, the rats were monitored with a camera system at 30 fps. Means and correlation coefficients of ICP and FBP during ten natural rear ups per rat were analyzed with t-tests. Results: Rear ups lasted on average 2.13 s. During these, FBP assessed as mean±SD (106.5 ± 17.4 mmHg) and ICP (1.4 ± 3.8 mmHg) were on average lower than FBP (118.9 ± 11.9 mmHg) and ICP (1.6 ± 4.0 mmHg) before rear ups. Changes of FBP were significant (p < 0.05) in all rats, whereas changes in ICP were significant (p < 0.05) in only two rats. In one of these two rats, correlation coefficients were significant (p < 0.01). ICP and FBP during these rear ups were on average moderately positively correlated (r = 0.24). Conclusion: Concurrent measurements of CSF related pressures in rats are inherently challenging due to the limited space for sensor implants and rapid movements leading to strong artefacts. However, statistically significant CSF dynamics due to posture changes could be observed using high resolution pressure and video recordings. Introduction: Abdominal pain is a common complication of peritoneal shunt catheters and can lead to revision surgery in some patients. We aimed to analyse the frequency of intra-abdominal pain following peritoneal shunt insertion relative to the various types of shunt tubing according to manufacturer.

We performed a retrospective comparative study looking at the incidence of abdominal pain relative to peritoneal shunt catheters during the period of 2012 to 2020 in our hospital. Clinical data from 649 patients was evaluated. Only patient records with documented information about shunt tubing manufacturer were included. Activity level was evaluated through Modified Rankin Scale. Statistical analysis was done using SPSS (version 25.0, IBM) by Chi-Square test. A p-value < 0.05 was considered significant. Results: After exclusion 426 patient records were examined. Ares abdominal catheter was found to be significantly associated with abdominal pain requiring revision surgery (p < 0.0001). Bactiseal shunt catheter had significantly low incidence of abdominal pain (p < 0.0001) in comparison to Ares. Modified Rankin Scale 0, 1 and 2 was associated with a higher incidence of abdominal pain. Conclusion: Ares shunt tubing is associated with a higher incidence of abdominal pain and revision surgery following peritoneal shunt insertion Introduction: Despite documented improvements of gait in iNPHpatients following shunt surgery, no effect on the magnitude of spontaneous daily physical activity has been proven. As a part of our previously reported rehabilitation study (iNPHys) this study aimed to evaluate the effects of a 12-weeks postoperative exercise program on physical activity, functional strength, endurance and sleep. Methods: Seventy-nine iNPH patients who had been randomized to either an exercise group (EG, n = 34) or a control group (CG, n = 45) with valid actigraphy recordings of physical activity and sleep were included in the study. Recordings were made during seven days preoperatively and three months and six months postoperatively. Endurance was evaluated with the 6-minute walk test and functional strength with the 30-second chair stand test. Results: Between group differences, all in favour of the EG, were seen in changes from baseline to three months regarding improvement in functional strength (p = 0.011) and endurance (p = 0.033) and a slight reduction in daytime sleep (p = 0.033). None of these differences remained after six months. The whole group (i.e., EG and CG together) improved in steps per day (p = 0.023), functional strength (p < 0.001) and endurance (p<0.001) and the proportion of sleep at night was increased (p = 0.024) after three months. These changes remained after six months. Conclusion: Shunt treatment of iNPH-patients improved spontaneous physical activity, functional strength and endurance. The proportion of sleep at night was increased. The effects remained after six months. Postsurgical participation in an exercise program had an additional short-term effect on functional strength and endurance. 

The impact of spinal stenosis on cerebrospinal fluid (CSF) dynamics is still unclear but can be observed in NPH patients. In particular, the correlation with the disease normal pressure hydrocephalus (NPH), respectively with its pathogenesis is vague. Therefore, the aim of this study was to experimentally investigate the influence of varying degrees of stenosis in the cervical region on CSF hydrodynamics with respect to NPH.

Methods: An in vitro model of the craniospinal CSF dynamics, developed in our lab, was used. The stenoses were located in the C6 region. The hydrodynamic cross-sectional area varied in seven measurements from 19.63 mm 2 (no stenosis) to 0 mm 2 (total blockage) to simulate different degrees of stenosis. Intracranial pressure (ICP), spinal flow and cranial and spinal compliance were measured.

The results show an increase of the ICP amplitude from 4.94 mmHg (physiological/ no stenosis) to 7.51 mmHg (total blockage), which is a rise of 52.02 % and furthermore an accompanying decrease in overall compliance of 56.15%. Conclusion: Increased ICP amplitudes and a decreased craniospinal compliance are typical characteristics of NPH patients. Nevertheless, it is not clear whether a spinal stenosis influences or favors the development of NPH. Therefore, clinical investigation should be performed to determine the prevalence and severity of spinal canal stenoses in NPH patients. Introduction: Balance and gait disorders (B&GDs) increase with ageing but often not adequately evaluated and largely underdiagnosed. We have therefore investigated the prevalence of B&GDs and the underlying diagnosis among patients with memory impairment. Methods: 410 consecutive patients enrolled between 2010 and 2014 from the Memory Disorders Clinic, Launceston, Tasmania. All patients had detailed history of memory, balance and gait symptoms including features suggesting dementia. A full examination included Mini-Mental State Examination (MMSE) and balance/gait functions by standing with eyes closed, on toes, and the tandem test. All patients had brain CT scan. Results: 218 women and 192 men participated in the study, median age 76.5 years (range 32.6-94.8) and mean MMSE score 23.3 (SD 4.9). 214 (53%) of patients had B&GDs. 214 (53%) had B&GIs of whom, 85 (40%) had mild cognitive impairment (MCI), 25 (12%) had Alzheimer's disease (AD), 62(29%) had INPH, 11 (5%) had mixed dementia (MD), 10 (5%) had vascular dementia (VD), 9 (4%) had Parkinson's disease dementia, 2(1%) had Lewy body disease (LBD). 196(48%) didn't have B&GIs, of whom, 97 (50%) had MCI, 66 (34%) had AD, 13(7%) had MD, 6(3%) had Gertsmann's syndrome, 4 (2%) had hypogonadism, and 4 (2%) had frontal lobe dementia (FLD). After excluding patients with MCI, patients with B&GIs (n = 129); 60 (48%) had INPH, 25 (20%) had AD, 11 (9%) had MD, 10 (8%) had VD, 2 (2%) had LBD. Patients without B&GDs (n = 100), 66% had AD, 13% had MD, 1% had VD and 4% had FLD.

The study shows that B&GDs are common among patients with memory impairment, and highlights the high prevalence of INPH, a condition that could be treated with shunt surgery with improvement of cognitive, balance and gait functioning. Introduction: While there have been decades of research dedicated to the mechanisms behind cerebrospinal fluid (CSF) dynamics, there are still knowledge gaps. The important pressure communications between spinal and intracranial compartments, including lag times, are sparsely studied and are invaluable to create more complete models. Methods: An in-vivo trial in sheep (n = 6) was conducted to quantify the intercompartmental communication existing within the CSF system. Standardized infusion testing was performed, including bolus and constant pressure infusions (CPI). Bolus infusions contained six lumbar infusions of 0.5 mL Ringer's solution. CPI were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Intracranial reaction lag times to infusions were calculated via crosscorrelation, pressure changes and the respective Rout calculated (1 kHz sampling frequency).

The study was successfully conducted on a novel CSF animal model. Four of six sheep reacted to the intrathecal pressure increase. The respective increase propagated across the CSF system cranially for the bolus infusion with a mean intracranial pressure change, lag, and Rout of 15.3 ± 1.3 mmHg, 131 ± 7 ms, and 46.5 ± 4.2 mmHg*mL -1 min, respectively, and for the CPI of 15.4 ± 1.5 mmHg, 122 ± 19 ms, and 77.8 ± 3.0 mmHg*mL -1 min respectively. Conclusion: Standardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal and intracranial compartments of the CSF system.

Interestingly we found no communication in two of six sheep, which needs to be further investigated. These results represent an important first step into improvements in current CSF modelling methodology. Introduction: Establishing site of obstruction and patency of bulk flow CSF pathways is important in evaluation of obstructive hydrocephalus. Re-establishing intracranial CSF flow is superior to extracranial CSF diversion. Methods: Case 1: A 13-year-old girl presented with 15 days history of mild headaches, occasional vomiting, diplopia, and ataxia, 7 years after successful ventriculo-peritoneal shunt (VPS) insertion for post-meningitic hydrocephalus. Magnetic resonance (MR) imaging and CT ventriculography with an iohexol (a water-soluble, non-ionic contrast) revealed a disproportionately enlarged, entrapped 4th ventricle. Patent basal cisterns were confirmed with basal cisternography. Case 2: A 72-year-old male presented with a 2-day history of altered sensorium and refusal to feed following a mechanical fall 7 years after successful VPS insertion for post-meningitic hydrocephalus. MR imaging revealed acute pan-ventricular hydrocephalus with ballooning of bilateral foramen of Luschka. Shunt series imaging revealed retro-auricular disconnection of the shunt tubing with complete migration into the pelvic peritoneal cavity. Basal cisternography confirmed patency of bulk flow CSF pathways. Both patients underwent diversion of CSF from 4 th ventricle into cisterna magna with a silastic catheter. Results: Both patients had instantaneous symptomatic relief and follow up imaging at 3 weeks revealed resolution of radiological abnormalities. Conclusion: Intracranial CSF diversion is superior as both ends of the catheter are subjected to the same pressure dynamics. Over-drainage, disconnection and infection are established complications of extracranial CSF diversion which can be avoided by this method. This is a safe, simple, low-cost and reasonably applicable technique which does not require any special equipment. Declarations: The authors declare that the patient has give written consent for the publication of this study. Here we present findings on ICP dynamics when moving from a sitting to standing posture. Methods: We recruited ambulatory patients either with (n = 4) or without a shunt (n = 7) who were undergoing ICP monitoring as part of their clinical work-up at the National Hospital for Neurology and Neurosurgery, London. Patients sat upright on a chair with their head in a neutral position and moved to and from a standing posture at 20 second intervals. ICP was recorded at 100Hz using a parenchymal ICP monitor (Neurovent P Raumedics). Postural data was acquired at 100Hz by inertial measurement units (MTw Awinda, Xsens, Netherlands) attached to the chest and thigh. We compared mean ICP when sitting and standing. Results: ICP increased significantly when moving from a sitting to standing posture (F(1,9) = 10.6; p = 0.01; β = 0.83; 95% confidence interval of mean difference: 0.6-3.5 mmHg). No differences in ICP dynamics were detected between shunted and non-shunted patients (group: F(1,9) = 0.3, p = 0.58; β = 0.06; group x posture: F(1,9) = 0.1, p = 0.74; β = 0.06), although at the time of submission the study is underpowered to detect any differences. Conclusion: Transitioning from a sitting to standing posture induces an increase in ICP. Future work should determine the effect of shunting on ICP dynamics during sit-to-stand transitions.

Introduction: Functional neurosurgery aims at modulating the function of neural networks involved in movement, spasticity, pain or behavior. Hydrocephalus shunting aims at restoring neurological function by improving brain fluid mechanics and intracranial pressure (ICP). We hypothesize that hydrocephalus shunting is functional neurosurgery. To validate this hypothesis, one must demonstrate the presence of i) an intracranial barosensitivity, ii) intracranial baroreceptors and integrating centers and iii) a shunt-induced neuromodulation with a pari passu clinical response. This work is designed to explore the first step. Methods: Modest ICP increase and decrease were achieved in mice and patients with intra-ventricular and lumbar fluid infusion. Sympathetic activity was gauged directly by microneurography, recording renal sympathetic nerve activity in mice and muscle sympathetic nerve activity in patients. Heart-rate variability analysis was also performed in both species. Results: In mice (n = 15), renal sympathetic activity increased from 29.9 ± 4.0 bursts.sec -1 (baseline ICP 6.6 ± 0.7 mmHg) to 45.7±6.4 bursts.sec -1 (plateau ICP 38.6 ± 1.0 mmHg) and decreased to 34.8 ± 5.6 bursts.sec -1 (post-infusion ICP 9.1 ± 0.8 mmHg). In patients (n = 10), muscle sympathetic activity increased from 51.2 ± 2.5 bursts.min -1 (baseline ICP 8.3 ± 1.0 mmHg) to 66.7 ± 2.9 bursts.min -1 (plateau ICP 25 ± 0.3 mmHg) and decreased to 58.8 ± 2.6 bursts.min -1 (post-infusion ICP 14.8±0.9 mmHg). Heart-rate variability analysis demonstrated a significant vagal withdrawal during the ICP rise, in accordance with the microneurography findings. Mice and human results are alike. Conclusion: We demonstrate in animal and human that ICP is a reversible determinant of neuronal efferent sympathetic outflow, even at relatively low ICP levels. Our work supports the presence of an intracranial barosensitivity. Introduction: Normal Pressure Hydrocephalus (NPH) patients can significantly benefit from treatment with Ventriculoperitoneal shunts (VPS). There is currently little data on long-term shunt survival in patients with NPH. Patients often ask how long is their shunt is likely to last? This information is important as NPH patients are elderly and can die of unrelated causes. This study describes the survival rates of VPS in NPH. Methods: This is a retrospective single-centre cohort study assessing the shunt survival rates in a consecutive series of NPH patients who had a VPS inserted >10 years ago. Data on shunt survival (months), shunt revisions, complications and mortality was collected from the patients' electronic records. Results: Forty-seven NPH patients were included (28 males). At the time of VPS insertion, the average age was 77 years (8 SD). Fourteen patients are alive, while 33 died of unrelated causes during the followup period after an average time of 77 months (34 SD) from the VPS insertion. Twelve patients required a shunt revision for suspected blockage or for the adjunct of an adjustable gravitational valve. The probability of shunt survival was 98% at 1 year, 89% at 2 years, 79% at 5 years and 40% at 10 years. Conclusion: Despite being elderly, NPH patients have a high probability of shunt survival compared with other hydrocephalic conditions. Introduction: Changes in the extracellular matrix (ECM) composition might be involved in the pathophysiology of idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery. Methods: Paired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays. Results: Brevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = -0.62, p < 0.0001).

Levels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics. Introduction: If a patient is presenting with clinical deterioration after shunt surgery, several diagnostic tools are available to detect the failure and the side of the shunt dysfunction. One possible tool is manual non-invasive shunt pumping, although controversially discussed. Shunt pumping differs technically very much by the valve design and shunt configuration. The technical description, feasibility, indications as well as evaluations will be demonstrated. Methods: Shunt pumping, particularities of different shunt configurations and requirement for successful testing are technically explained and video demonstrated. Also, clinical evaluations are shown. Results: Depending on the hydrocephalus shunt design, evaluation of the shunt function can be more or less easily be done by pumping a reservoir or flushing chamber with simultaneous catheter occlusion by manual compression. With this procedure the detection of occluded catheters (ventricular, peritoneal or the valve itself ) is non-invasively possible in a completely outpatients setting. Depending on the shunt design through pumping it is possible to drain a special quantity of CSF -so performing a non-invasive tap-test as well. Discussion: Noninvasive evaluation of shunt failure via pumping is non-invasively with less risks (no infections) and is fast to perform in an outpatient setting. So, pumping can substitute many invasive tests with less risks for the patients (no infections!) and with less time consuming for the medical staff. If the pumping-result will not be conclusive, of course further investigations as imaging and invasive tests with ICP measurement, infusion tests, and others can be added.

Mathematically designed ventricular catheter, optimized to reduce astrocyte activation through shear reduction and flow Introduction: Shunt-associated complications are extremely common with 40% failure within two years of placement. Shunt obstruction accounts for 70% of revisions in the United States. Recent analysis of astrocyte cytokine secretion under shear stress reveal a statistically significant increase in pro-inflammatory IL-6 cytokine secretion. Flow analysis reveals the presence of a shear gradient, inherent to the geometry of commercial catheters, supporting the hypothesis that the catheters need to be optimized to reduce shear.

Methods: A CAD model of a ventricular catheter was generated using confocal microscopy for accurate measurements. Computational fluid dynamic modeling was simulated using Ansys Fluent. Using a coupled pressure method, velocity and pressure profiles were extracted into Fluent Post Processing for imaging, revealing increased flow through holes furthest from the catheter tip and localized high shear hotspots. Results: We hypothesized that the observed gradient is the result of uneven fluid velocity inside the lumen, forming a pressure gradient that results in preferential flow through the catheter holes adjacent to regions of high velocity luminal flow. A cone-shaped catheter was generated by applying the ANSYS results to Bernoulli principles. The modified catheter is intentionally identical to control catheters except for its optimized geometry. Ansys analysis of the modified catheter demonstrate uniform flow, pressure, and shear rate throughout the catheter with equal flow through all catheter holes and the elimination of hotspots and shear distribution throughout the catheter. Conclusion: A truly optimized catheter is the implementation of various modifications to current catheters. This is a brief description of catheter geometry optimization. Introduction: We present three adult patients with a meningoencephalocele in the anterior skull base and rhinorrhea. Secondary and idiopathic increased intracranial pressure (ICP) can cause thinning of cortical bone and can lead to a protrusion of meninges and brain tissue. We present the imaging and surgical treatment in these patients and try to explain the pathophysiology and reflect on the relationship between defects in the skull base and chronic increased ICP in adult patients. Material and methods: Three adult patients presented with rhinorrhea. CT imaging showed bone defects of anterior skull base. MRI revealed a meningoencephalocele and signs of chronic increased ICP (empty sella, narrowing of the aqueduct and disruption of the septum pellucidum). Patients had different causes of the hydrocephalus. The location of the meningoencephalocele was in patient 1 in the ethmoid sinus and lamina cribrosa, in patient 2 in the frontal sinus and lamina cribrosa and in patient 3 in the sphenoid sinus. Results: Patients underwent dual-staged surgery. Endoscopic closure of the fistula was feasible and safe, but turned out not to be enough. The post-operative evolution (recurrence of leakage or symptoms of ICP) shows how these patients require solution of the CSF resorption problem to prevent new leakage. Conclusion: Meningoencephaloceles are probably the consequence of an underlying CSF resorption problem. Chronic increased ICH leads to thinning of the cortical bone. This can lead to a protrusion of brain and meninges. The combination of surgical closure of the leakage and CSF shunting can cure these patients with good outcome on the long term. Introduction: Frequently, ventricular tumours causing the obstruction of cerebrospinal flow (CSF) pathways, by neuroimaging are documented. Neuroendoscopic procedures enable fenestration of cystic lesions or tumours resection, in addition with third ventriculostomy or septostomy to restore CSF pathways. Methods: In 96 patients, affected by tumours arising by the wall of the third or lateral ventricle, hydrocephalus or obstruction of CSF flow was present. By endoscopic technique, septostomy, cystostomy, third ventriculostomy (ETV) or tumour resection were alone or simultaneously performed to control intracranial hypertension. The (thulium) ™ laser for tumours shrinkage and haemostasis of high vascularized tumours was used. Results: In 68 patients with non-communicating hydrocephalus the ETV was realized. In 6 LG astrocytoma the ETV was the only surgical treatment, definitely. In 20 cystic tumours cystostomy and marsupialization into the ventricle solved the mass effect and intracranial hypertension syndrome. In 12 patients neuroendoscopic relief of CSF pathways by septostomy associated to Ommaya reservoir or one catheter shunt was possible. In 6 colloid cysts and 5 cystic craniopharyngiomas removal was possible, by restoring CSF flow without other procedures. After intracranial hypertension control, in 28 malignant gliomas, 18 metastasis or leptomeningeal carcinomatosis and 6 lymphomas tumour adjuvant therapy was performed. In 6 cystic central neurocytomas and 12 ependymomas subsequent microsurgical removal was achieved. Conclusion: In ventricular tumours neuroendoscopy is a challenge but by the Tm laser complications can be reduced. Neuroendoscopy is safe and effective to restore CSF pathways, avoiding major surgical approaches and without any relevant post-operative morbidity. Introduction: Neuropathology in hydrocephalus comprises ventriculomegaly, white matter injury, inflammation, edema, and gliosis in both humans and experimental models. Our group has developed a large animal model of acquired hydrocephalus in juvenile pigs to evaluate the current treatments for the disease. We hypothesized that this pig model mimics the neuropathology found in the periventricular parenchyma described in human hydrocephalic infants. Methods: Hydrocephalus was induced by percutaneous intracisternal kaolin injections in 35-day old pigs (n = 7). Age-matched sham controls received saline injections (n = 6). After 30 days, MRI, immunohistochemistry and cerebrospinal fluid (CSF) protein analyses were performed. Results: The expansion of the ventricles was especially pronounced in the atrium, where ependymal disruption occurred. In this area, the periventricular white matter showed a 44% increase in cell death (p < 0.05) and a 67% reduction of oligodendrocytes (p < 0.01). In the subventricular zone (SVZ), the number of proliferative cells and oligodendrocyte progenitors decreased by 75% and 57% respectively (p < 0.01), suggesting possible neurodevelopment impairment. The decrease of the SVZ area correlated significantly to the ventricular volume increase (p < 0.03). Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the white matter (p < 0.02), and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF (p < 0.01). Conclusion: The induction of acquired hydrocephalus produced damage in the periventricular white matter, reduced cell proliferation in the SVZ, and neuroinflammation. These findings mimic those found in human hydrocephalus, demonstrating that the pig model can be a useful tool for preclinical studies of the pathophysiology of hydrocephalus. Conclusion: Using a standardized assessment and treatment protocol for patients with suspected iNPH allows identification of patients with a high probability of significant improvement in gait and cognitive outcomes assessed 3 months after surgery.

We identified 11 cases of PaVM. All underwent ELD and 73% showed improvement. Eight patients underwent permanent CSF diversion (VP shunt) and 75% were improved at 12 months. Compared to the iNPH group (N = 498), PaVM patients had a larger Evans index (0.45 vs. 0.39, P < 0.01) and larger temporal horns (8.4mm vs. 6.6mm, P = 0.02). No difference was seen in callosal angle or convexity tightness, however, narrow Sylvian fissures were more prevalent (55% vs. 1%), as was depressed floor of the third ventricle (50% vs. 0%). None of the nonshunted PaVM patients had a depressed floor of third ventricle. There was a high degree of concordance between tight Sylvian fissures and depressed floor of the third. All those with a depressed floor of third ventricle improved with a shunt. Conclusion: A depressed floor of the third ventricle with a patent aqueduct should prompt consideration of PaVM in patients presenting with NPH. If the floor of third ventricle is depressed, a straight-to-shunt approach is recommended. Improvement with lumbar drainage supports the presence of an intracisternal block as the point of obstruction. Introduction: Parkinsonism is a frequent feature in iNPH patients, but the descriptions are scarce. We used mUPDRS (part III) and classical tools (TUG test, 10MWT, Tinetti, MMSE and FAB) to describe the extrapiramidal features of a prospective cohort of suspected iNPH patients. Methods: 139 consecutive patients suspected having NPH according to International Guidelines were enrolled. Each patient completed a neurological visit before and 24 hours after a lumbar infusion test with tap test (TT). On the basis of shunt effectiveness, clinical and radiological criteria, patients were classified as iNPH, LOVA, NOT-NPH and Probable-NPH. Results: 88% of iNPH, 75% of NOT-NPH, 80% of Probable-NPH and 25% of LOVA have significant (mUPDRS>10 points) extrapyramidal signs; the burden of symptoms is skewed versus the lower body in iNPH (76% have higher scores in lower body) but is present also in the upper limbs (upper bradykinesia score in iNPH equal to NOT-NPH and Probable-NPH). Severity of mUPDRS correlates with TUG, 10MWT and FAB score at baselines. Overall mUPDRS doesn't correlate with Rout neither with age but with duration of symptoms. After TT mUPDRS improves significantly in all except NOT-NPH group. The change (mean 3.3±2.9 points) was higher for iNPH and Probable-NPH and significant versus LOVA and NOT-NPH. Tremor scores didn't change at all as well as score of postural instability. The main contributors to mUPDRS improvement were bradykinesia and some gait scores. Conclusion: extrapyramidal signs are frequent in iNPH patients and they change accordingly to diagnosis after TT; LOVA patients represent a clinical distinct entity. 

The classic presentation of hydrocephalus involves elevated intracranial pressure which manifests with clinical symptoms. The underlying cause of hydrocephalus is not fully understood in many hydrocephalus patients, and recent studies indicate that idiopathic normal pressure hydrocephalus might be more common than it was previously supposed. Therefore, it is imperative to study the CSF production, reabsorption, and its interactions with the cardiovascular system and autonomic nervous system. Methods: A photo-electric pulse monitor and electrocardiography module with a portable data logging device was developed to record patient heart activity in 24-hour cycles. The patient data was transferred to custom-built software for reading raw patient data and generating appropriate output signals for controlling the motors of reciprocating pumps to replicate the pulsations as a function of time. The pump flow rate was set at a constant physiological 0.3 ml/min. The pump output was recorded using a flow sensor. Results: The data logger registered heart rate variability and momentary changes in heart rate. The pump was able to replicate the exact number of recorded pulses, the time interval between two subsequent pulses, while maintaining the constant output volume. Using this setup, an experimental algorithm was also tested to automatically adjust the pump output rate based on the correlations between patient heart output and CSF production rate. The calculated CSF production rate was within the expected physiologic range. Conclusion: A recording and simulation in-vitro setup was developed to study the impact of pulsating flow on immune cells and shunt system. Introduction: Intra-ventricular haemorrhage (IVH) is common in premature neonates. An estimated 15% of neonates who suffer IVH will develop post-haemorrhagic hydrocephalus (PHH) requiring permanent CSF diversion. Management of perinatal PHH may begin with temporising measures (e.g. with a ventricular access device) to reduce ventricular CSF volume. Definitive CSF diversion is often delayed until the infant is older -but there is no consensus or guideline on timing. It has been suggested that the delayed insertion of a permanent shunt is associated with fewer infections and shunt failures. The aim of this study was to identify factors associated with shunt success in this cohort. Methods: Single-centre retrospective review of operative records between 2015-2019, to identify patients undergoing primary shunt insertion for PHH. Clinical characteristics (including gestational age at birth and shunt, Papile grade of IVH, weight, occipital-frontal circumference) and causes for any shunt failure were extracted from electronic patient records. A generalised linear model was constructed to fit the dichotomised outcome of shunt success or failure at 12 months. Results: 26 patients (16 male) underwent ventriculo-peritoneal shunt insertion for PHH in this period. 10 patients suffered from shunt failure within the first 12 months. The most common causes of failure were migration of the proximal catheter (n = 4), infection (n = 2), and obstruction (n = 2). Weight at the time of shunt insertion was highly predictive for shunt success (F = 6.6, p = 0.02), with no other characteristic significantly correlated. Conclusion: Careful stratification by weight may improve outcomes for shunting in infants with PHH. Larger cohort studies are planned to confirm this finding and we intend to use these to derive a multi-factorial PHH shunt success score.

H Sabir 1 , A Jeppsson 1 , K Andrén 1 , K Laurell 2 , H Zetterberg 3,4 , K Blennow 3 , C Wikkelsø 1 , P Hellstrom 1 , M Tullberg 1 Introduction: In modern studies, around 80% of treated patients with idiopathic normal pressure hydrocephalus, iNPH, improve in their symptoms. To date there is no test that can reliably predict which patients will benefit from shunt surgery. This study aims to explore the predictive value of symptoms and signs in the clinical picture of iNPH. Methods: A prospective dual-centre study, with inclusion of all patients diagnosed with iNPH October 2014 to June 2016, who underwent shunt surgery and in whom postoperative assessment of iNPH symptoms were possible, n = 143. Clinical data were collected pre-and median 5 months postoperatively. Logistic regression analyses were used to assess outcome defined as improvement or not (by ≥5 points) in the iNPH scale. Results: After surgery, 73% of the patients were improved. Each of the symptom domains as well as the total iNPH scale score improved significantly (median 53 to 69, p < 0.001). The proportions of patients with the following clinical signs decreased significantly: shuffling gait, broad-based gait, paratonic rigidity and retropulsion. A range of gait, mobility and balance tests were all significantly improved, and patients slept significantly shorter postoperatively. Univariable logistic regression analyses of all baseline clinical variables, did not yield any predictors of beneficial outcome with a significance level of <0.10.

The study confirms that the recorded clinical signs, symptoms, and impairments in the adopted clinical tests are characteristic findings in iNPH, as they all improved after shunt surgery. However, these clinical data cannot predict which patients will benefit from shunt surgery. Introduction: Bladder dysfunction is one of the main symptoms of NPH beside gait disturbance and cognitive decline forming the Hakim Triad. Fecal urgency and incontinence is often described as an additional symptom, however, no exact numbers are found in the literature. The aim of this study was to investigate the prevalence of fecal urgency and incontinence in NPH patients. Methods and patients: All patients who presented to our outpatient department or presented to shunt surgery since Jan. 2021 with confirmed diagnosis of NPH were interviewed about fecal function. Additionally, the extent of gait disturbance, cognitive decline, ventriculomegaly (Evans-Index), DESH presence, age, gender and length of history were documented to investigate if there might be any interrelated dependence. Results: 50 patients were evaluated (35 men, 15 females, medium age 77.1 years, median length of history of NPH: 3,26 years, median Evans Index: 0,37, 43 with positive DESH pattern). 48 patients showed gait disturbance, 41 a cognitive decline and 39 bladder dysfunctions. 34 (68%) patients showed the complete Hakim triad. 19 (38%) patients complained about fecal incontinence (14 with urge incontinence, 5 with complete incontinence). There was no clear dependence between fecal disturbance and sex, age, length of history, but with dementia. Discussion/conclusion: Fecal urgency and incontinence is a frequent finding in NPH (38%) and is essential for the quality of live. In the general population, fecal incontinence in elderly is found up to 15%. The more than twofold higher prevalence in NPH patients suggests that NPH causes directly fecal disturbance in a larger percentage.

Introduction: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a syndrome described by the symptomatic triad of dysfunction, cognitive impairment, gait and urinary incontinence. The diagnosis is based on ventricular dilation and clinical symptoms with normal intracranial pressure. The role of clinical interpretation in iNPH remains crucial, as multiple comorbidities may affect iNPH patients, which is typical of elderly people. In this context, Geriatrician may represent an equally important role to the neurosurgeon in the evaluation of complex and frail patients which may affect surgical options, timeliness and effectiveness. Methods: Comprehensive Geriatric Assessment (CGA) will be applied to iNPH patients. The evaluation of social, functional, clinical and cognitive domains will be performed using various screening scores described in the literature. Focus will be on global assessment of frailty and mortality risk. The disease impact on caregivers will be investigated by Caregiver Burden Inventory (CBI). Patients will be followed at 6-and 12-months. Results: CGA will guide treatment pathways, because suspected iNPH patients will be screened and risk stratified. This way, we expect a better selection of patients for surgical procedure with decreased intraand post-operative complications. And at the same time, we also expect better surgical outcomes at follow-up months 6 and 12.

The presence of Geriatricians in multidisciplinary teams dedicated to surgical patients is well established in the current literature. Still, collaborative work between neurosurgery and geriatric is just recently arising. The geriatric assessment in iNPH patients could be beneficial and innovative for the co-management of frail and complex patients. Objectives: There are only a limited number of reports on self-rated quality of life and symptoms of depression in idiopathic normal pressure hydrocephalus, especially from a population-based perspective. The objective was to compare health related quality of life (HRQoL) and depressive symptoms between individuals with and without idiopathic normal pressure hydrocephalus (iNPH). Methods: A total of 122 individuals from the general population (30 with iNPH), median age 75 years, 67 females, underwent neurological examinations and computed tomography of the brain with standardised rating of imaging findings and clinical symptoms. The participants completed the Geriatric Depression Scale (GDS-15) and the HRQoL instrument EQ5D-5L. The sample derived from the general population, which diminish the risk of inclusion bias. Results: Participants with iNPH reported a higher median score on GDS-15 (Md = 3) than those with unlikely iNPH (Md = 1) (p < 0.05). Further, those with iNPH rated their HRQoL lower (VAS-scale = 70, EQ5D-5L index = 0.79) than those without (VAS-scale = 80, EQ5D-5L index = 0.86) (p < 0.05). Conclusion: Individuals with iNPH reported more depressive symptoms and a lower HRQoL than those without the condition, underlining the need for shunt surgery as this treatment has been reported to improve HRQoL in previous studies. We sought to use this technology to measure shunt flow in real-time during normal position changes. Methods: CSF flow through implanted shunts was monitored using a non-invasive, wearable flow sensor placed on the skin overlying the distal shunt catheter just above the clavicle. Patients started in a supine position and were then transitioned to a sitting position during monitoring. Shunt flow was assessed both qualitatively and quantitatively. Basic patient demographics (age, hydrocephalus etiology, shunt valve and setting) were also recorded. Results: Real-time CSF flow measurements were performed in 15 adult patients. Mean age was 57.3 years (range 18-80 years). Hydrocephalus etiology included normal pressure hydrocephalus (8 patients), tumor (2), idiopathic intracranial hypertension (2), trauma (1), hemorrhage (1), and congenital (1). All patients had programmable shunt valves. Shunt flow was demonstrated in all cases and increased from supine to sitting in all but one patient (p < 0.0001). Conclusion: Real-time non-invasive measurement of CSF flow through an implanted shunt shows that flow changes in a significant and measurable way when patients transition from a supine to a sitting position. Further studies demonstrating real-time shunt flow will allow for a better understanding of the hydrodynamics of shunted hydrocephalus. Introduction: Normal Pressure Hydrocephalus (NPH) remains a diagnostic and therapeutic dilemma. Accurate and timely surgical management can lead to considerable improvement in disease course and quality of life. However, identification of patients with NPH who are likely to respond to surgical treatment is challenging, particularly in the elderly who may have multiple concurrent co-morbidities. Furthermore, there are no consensus guidelines to date for optimal NPH management. Methods: The 'REVERsible dementia projecT (REVERT) aims to improve clinical diagnosis and management of NPH in the UK-French cross-border region through a combined approach of establishing a common clinical network of excellence to transform the current management pathway, clinical informatics, and the parallel development of novel diagnostic tools based on CSF Infusion test and PC MRI pulse-flow morphology analysis. REVERT is a collaboration involving a consortium of clinicians, physicists, mathematicians and software specialists. Results: REVERT was approved by the European Regional Development Fund via the Interreg France (Channel) England Programme in October 2020 and is currently underway. Conclusion: The ultimate objective of REVERT is to work towards a unique solution consisting of a combined diagnostics approach including analysis and interpretation of PCMRI images (pulse morphology analysis) and CSF Infusion tests, with an underlying AI model to guide diagnosis based on both flow and pressure measurements and Web portal for streamlining referrals, patient management, diagnostic/clinical results and including audit tools of standard of care evaluation (also linked to the national shunt registry and the shunt evaluation registry).

Squire: a novel multi-dye in vivo system for testing real-time neuroinflammation during shunting Jeffrey Horbatiuk 1 , Carolyn A Harris

Department of Chemical Engineering

O54 O60 Pilot study of a multi-center, randomized controlled trial of shunt surgery in iNPH Adult Hydrocephalus Clinical Research Network

malm@umu.se) Fluids Barriers CNS 2021

Introduction: iNPH is characterized by Hakim triad. Unclear pathogenesis leads to abnormal dynamics of CSF and secondary neurodegeneration that can be co-existing and participate secondary or primarily in the genesis of ventricular enlargement. The aim of our work was to assess whether there was a subgroup not susceptible to shunt, with clinical and liquor biomarkers, indices of progressive dementia: T-tau, P-tau181, Abeta42, Abeta42/P-tau181 ratio. Methods: 52 patients with suspected iNPH were assessed for TAP test; MMSE and walking test, prior and after 2/72 hours CSF removal. CT/ MRI showed dilated ventricles, Evans' ratio>0.3. We removed 30mL of CSF. We analyzed CFS concentration (ng/L) of Abeta42, P-tau181, T-tau, ratio P-tau181/Abeta42 (ELISA) to address surgical treatment. Results: Mean age 76 years. All with Hakim triad. Mean MMSE 23; 31 patient had prevalence walking disorder (group A), 21 increased cognitive difficulties (group B). In group A, T-tau 224, P-tau181 32.8, Abeta42 599, ratio 21. In group B, T-tau 360 rises, Abeta42 489 decreases, P-tau181 38.4, ratio 14.7 up to 17.7, cut-off for progression to Alzheimer (Hansson). 24 patients (> with gait disturbance) improved at the TAP test, were shunted.

Recent post hoc studies have shown shunt obstruction is caused by a predominately astrocytic ingrowth, with a small percent of catheters obstructed with choroid plexus. However, the catalysts remain a mystery. Currently, real time in vivo studies exist but do not study more than two cell types at a time. To develop better treatments, multifactorial models need to be a priority. Here, we present a new model system showing cell interplay as a function of shunt insertion speed. Methods: Cell-permanent dyes staining for astrocytes (Sulforhodamine 101), microglia (Lycopersicon esculentum tomato lectin), neurons (4-Chlorobenzenesulfonate Salt), bloodborne macrophages (F4/80), and calcium (Cal-520) were either injected into the venous system or directly into the cortex of adult Sprague-Dawley rats. These dyes were chosen to validate the system because they are part of the well documented tripartite synapse. 1, 5, and 10 mm/s. 10x confocal microscope images recorded at speeds up to 25 frames per second, were stitched together could track the cell's movement and communication. Results: This model shows that live simultaneous labeling can be assayed and suggests that different insertion speeds lead to different immune responses. Future work will create a repeated measures in vivo system during which changes in cellular response can be documented. Conclusion: By looking at the initial neuroinflammation response, better shunt coatings can be designed using time release technologies. While some studies have investigated these propositions in pieces, this is among the first models to simultaneously test each mechanism in addition as a function of shunting speed. Introduction: A new cerebrospinal fluid (CSF) shunt device (CereVasc eShunt) has been developed for insertion by a percutaneous transvenous endovascular approach. A clinical trial in patients with post-subarachnoid hemorrhage (SAH) hydrocephalus is underway. We present here our clinical experience with the first patient treated with this device. Methods: An 84-year-old woman with SAH underwent aneurysm coiling. An external ventricular drain (EVD) was placed for communicating hydrocephalus. An EVD clamp trial on day 9 showed intracranial pressure (ICP) of 44 cmH2O. On day 10 she underwent endovascular placement of the eShunt device from the cerebello-pontine angle (CPA) cistern to the jugular vein. Results: The patient's EVD was closed eight hours prior to the procedure. ICP immediately prior to implant deployment was 38 cmH2O. Following implant placement, the ICP reached normal levels (< 20 cmH2O) within 90 minutes. A post-implant CT scan showed no blood in the CPA cistern. The patient's ICP was monitored through the EVD for 39 hours post-procedure at which point the EVD was safely removed. An MRI six days postprocedure showed reduction in the size of the lateral and third ventricles. Discussion: We describe the first patient treated for communicating hydrocephalus using the novel eShunt endovascular CSF diversion implant. Following device deployment, the patient experienced a rapid reduction of ICP to normal levels (< 20 cmH 2 O), coupled with a reduction in ventricular size. No bleeding or adverse effects occurred during the three-week follow-up period. This is the first patient treated for communicating hydrocephalus by an endovascular approach without the need for a burr hole, brain penetration or multiple skin incisions. Declarations: The authors declare that the patient has give written consent for the publication of this study.

The value of pre-shunt CSF biomarkers in idiopathic normal pressure hydrocephalus: does it matter? R. Gambin 1 , A. Musumeci 1 , M. Testa, G. Zanusso 2 , F. Cozzi, F. Sala 1 , G. Pinna 1 Conclusion: iNPH is a neurodegenerative condition reversible with surgery. CFS biomarkers analysis helps to better identify tap test no responders. The rate of group B for T-tau and Abeta42, Hazard ratio 14.7 can be index of risk of progression to dementia. We believe that liquor biomarkers in iNPH can be useful for better selection of patients who can be shunted for long-term improvement. Introduction: Optic nerve sheath diameter (ONSD) can be used to estimate intracranial pressure in a non-invasive way. The aim of our study was to evaluate the changing of ONSD during lumbar infusion test and tap test as a tool to guide the effectiveness of the CSF withdraw and the induced decrease of in intracranial pressure. We continuously measured the sub-arachnoid pressure during the procedure correlating with ONSD. Methods: we enrolled a series of patients clinically affected by possible IIH. We performed a lumbar CSF pressure monitoring, infusion test and tap test with continuous ultrasound measurement of ONSD with a 7,5 Mhz linear probe. We performed a CSF tap according to real-time OSND reduction. We measured lumbar subarachnoid pressures in all the patients with LiquoGuard 7 ® device. Results: we studied 6 patients with IIH. After the tap test we obtained a significant reduction of ONSD of 0,875 mm (range 0,6-1 mm) in all patients. All the patients performed a pre and post-test ophtalmological evaluation with OCT. A case of asymmetric papilledema was reported. All patient except one showed improvement of symptoms after the procedure. Conclusion: continuous ultrasound measurement of ONSD can became an important bed-side instrument to guide the correct execution of lumbar CSF pressure monitoring, infusion test and tap test in IIH. Moreover, transorbital ultrasound can be easily used as a follow up tool in IIH. Introduction: Idiopathic normal pressure hydrocephalus (iNPH) is an elderly-onset syndrome characterised by progressive cognitive impairment, gait apraxia and urinary incontinence. The diagnosis is based on chronic ventricular dilation associated with normal cerebrospinal fluid pressure. Despite gait alterations are broadly studied in literature, a lack of emphasis is commonly placed on possible impairment involving other motor functions, such as those related to the upper limb. The aim of the study was to investigate and describe upper limb motor alterations in iNPH. Methods: A cohort of iNPH's patients and a control group of healthy subjects, underwent upper limb evaluation of ideomotor apraxia (Spinner-Tognoni's Test), executive functions (Luria's Test), bradykinesia and tremor, manual dexterity (Nine Holes Peg's test). A descriptive statistics was conducted; Fisher Yates-Test was used to analyse statistically significative difference between groups. Results: A total of 49 subjects were recruited (30 iNPH patients, 19 controls). Groups were homogeneous in terms of demographic characteristics and sex. Data analysis showed a significative alteration of upper limb motor function in iNPH in terms of motor sequences organisation (Luria's Test, p value < 0.0001), bradykinesia and impaired dexterity. Ideomotor apraxia was not present (Spinner-Tognoni's Test, p value = 1). Conclusion: Apraxic and extrapyramidal features may involve upper limb's function and ability in daily activities. In particular, impairment of executive functions in terms of organisation and production of motor sequences, may affect the ability to perform complex motor tasks as postural transitions or walking with aids. Introduction: The intracranial arachnoid cysts are 1% of expanding lesions in pediatric age, but very rare in adults. Especially, in the ventricular system the cerebrospinal flow (CSF) can be obstructed, by developing hydrocephalus. The endoscopic treatment with cystostomy and combined septostomy or ETV can restore the CSF pathways. Methods: Seven adult patients (age 27 -67 yrs.) were affected by ventricular arachnoid cysts. The site was: occipital horn, septum pellucidum, 3° and 4° ventricle, mesencephalic cistern, vermis of cerebellum. At admission, all patients complained with gait imbalance and signs of chronic intracranial hypertension, as the NPH syndrome. A flexible or rigid endoscope and in 4 cases the Tm laser (LISA) were used. Results: In 6 cases the cystostomy was performed, while in 1 only the ETV. In 2 cases combined cystostomy and ETV or septostomy were achieved. In 2 cases by Tm laser the cyst's wall was almost completely vaporized to get a full communication with the CSF pathways. The surgical median time was 65 minutes. After endoscopic procedure, all patients improved with complete recovery. No postoperative morbidity or mortality. At follow-up (from 2 to 7 years) all patients have still a good quality of life and normal social activity. Conclusion: The endoscopic treatment of intracranial arachnoid cysts is a safe and mininvasive surgical procedure without complicances and long follow-up good results. In adults mimicking NPH syndrome, neuroendoscopy restores CSF pathways achieving quick recovery. The Tm laser was helpful to remove the cyst's wall for wide communication into the ventricular system.

To describe preliminary results of a multi-center, randomized, blinded, placebo-controlled, pilot trial of shunt surgery in INPH. Methods: Five sites randomized 18 patients scheduled for ventriculoperitoneal shunting based on CSF-drainage response. Patients were randomized to a Codman ® Certas ® Plus valve with SiphonGuard at either setting 4 (Active, N = 9) or setting 8/"virtual off" (Placebo, N = 9). Patients and assessors were blinded to the shunt setting. Outcomes included 10-meter gait velocity, cognitive function, and bladder activity scores. The prespecified primary analysis compared changes in 4-month gait velocity in the Active versus Placebo groups. After the 4 months follow up, all shunts were opened, i.e., adjusted to setting 4 whereafter patients underwent 8 and 12-month post-surgical assessment. At the 8-month follow-up, the Placebo group had had an open shunt for 4 months and the Active group for 8 months. Results: At 4-months, gait velocity increased by 0.28±0.28m/s in the Active Group and 0.04±0.17m/s in the Placebo Group (p = 0.071). Overactive Bladder (OAB-q) scores improved in the Active versus Placebo groups (p = 0.007). At 8 months, Placebo gait velocity increased by 0.36±0.27m/s and was comparable to the Active Group (0.40±0.20m/s; p = 0.56). Conclusions: This study shows a trend suggesting gait velocity improves more at an Active shunt setting than a Placebo shunt setting and demonstrates the feasibility of a placebo-controlled trial in iNPH. Introduction: This study evaluates changes in the use of cognitive assessment in routine practice over 15 years in the NPH diagnostic pathway. In particular, it evaluates the impact of developing a joint multidisciplinary clinic, including Neuropsychology, and examines the impact on the demand for cognitive assessment. Methods: Assessment and appointment data were collected via a retrospective review of electronic records of all patients with suspected NPH. Data collected included; cognitive tests undertaken, length of assessment and administrator qualifications. Data were collected at three time points spanning 15 years to allow a review of change in practice. Results: A total of 148 patients (M = 91, F = 57) were seen. An increase in NPH activity was seen over the decade (T1 N = 30, T3 N = 88) with more patients having a formal cognitive assessment as part of their NPH evaluation upon commencement of the joint multidisciplinary clinic (T2 N = 10, T3 N = 49). Cost implications for an increased demand for Consultant Neuropsychologist time was mediated by a significantly increased Assistant Psychologist role. Conclusion: The demand for neuropsychological involvement within the NPH pathway has increased over time. The main change has been in the proportion of patients having formal cognitive assessment as part of their evaluation. With the creation of an NPH multidisciplinary team patients are now routinely assessed at all stages of the pathway including at initial assessment, pre and postsurgical procedures and following shunt adjustment. We discuss the clinical capacity required to deliver this work ongoing and a model that is a cost-efficient use of the Consultant Neuropsychologist's time.

Adult external hydrocephalus presenting as subdural haematoma following sinus venous thrombosis L. Darie 1 , S.M. Toescu 1 , S. Khawari 1 , P. J. Grover 1 , A. K. Toma 1 1 Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospital, London, UK Correspondence: Lucia Darie (darielucia@yahoo.com) Fluids Barriers CNS 2021, 18(2): P02 Introduction: Hydrocephalus caused by venous sinus thrombosis in adults is exceedingly rare, with only a few existing case reports. Benign subdural frontal collections, as a form of external hydrocephalus, in infants can be associated with venous sinus stenosis. In adults, venous sinus thrombosis and bilateral hygromas can be seen in the context of intracranial hypotension and suspected cerebrospinal fluid leak. Case description: A 49-year-old male with a background of metastatic prostate cancer was admitted following multiple falls whilst on anticoagulants (Tinzaparin) for pulmonary emboli. He complained of progressively worsening headaches, nausea and diplopia. The initial CT head showed bilateral subdural hygromas, which progressed after 8 days, with significant mass effect on the right hemisphere. He underwent burr hole drainage and evacuation of what appeared to be radiologically a right sided chronic subdural haematoma. Intraoperatively, the fluid appeared similar to CSF and was under high pressure. Fundoscopy revealed bilateral acute haemorrhagic papilloedema, and supranuclear vertical gaze palsy with Collier's sign. Post-contrast MRI head and CT venogram revealed filling defects in the right transverse and sigmoid sinus as well as multiple stenoses and irregularities throughout the superior sagittal sinus, indicative of venous sinus thrombosis. The patient subsequently underwent image-guided insertion of ventriculo-peritoneal shunt. The CSF opening pressure was high. Conclusion: We would like to point out the importance of the cerebral venous system in cerebrospinal fluid disturbances. Declarations: The authors declare that the patient has give written consent for the publication of this study. Introduction: Increased recognition of communicating or normal pressure hydrocephalus (NPH) in an aging population and technological improvements in ventriculoperitoneal shunts (VPS), specifically programmable valves, has resulted in an increase in diagnosis and treatment. Shunt malfunction is considered when a patient initially does not respond to VPS or has symptom recurrence. Malfunction may be evaluated with a shunt series for catheter disconnection or breaks and with a shunt patency study (SPS) for obstruction. SPS is invasive with risk of infection and incurs significant cost. Thermal transcutaneous flow (TTF) is a noninvasive alternative to evaluate for obstruction. While TTF is useful in evaluating flow in non-communicating hydrocephalus where there is high cerebrospinal fluid (CSF) pressure there is no data for communicating hydrocephalus with low or normal CSF pressure. This study assesses the performance characteristics of CSF flow using TTF in asymptomatic NPH (aNPH) . Methods: 27 consecutive patients with aNPH and VPS at a single center prospectively underwent 2 tests in the sitting position. Specificity was calculated for one versus two tests.The manufacturer's recommended threshold of 0.2 degree C temperature decrease was used to confirm flow. Results: One test demonstrated 48 % and two tests demonstrated 59% specificity. Lowering the threshold to 0.15 increased the 2 test specificity to 78%.Conclusion: TTF is a useful noninvasive screening tool to evaluate CSF flow in NPH;, however, cannot definitively rule in obstruction as there may be intermittent flow. 2 tests improve the specificity. Consideration is given to lowering the manufacture's temperature threshold to confirm flow. Introduction : Premature newborn lntraventricular hemorrhages (IVH) is often associated with ventricular dilatation. Classical MRI protocol investigate morphology of the brain without CSF and cerebral blood flows (CBF) quantification. Phase contrast MRI (PC-MRI) can quantify CSF and (CBF) in adults. The objective was to quantify potential alterations of these cerebral flows in IVH newborns. Material and methods: 12 premature newborn between 22 and 39 weeks whom presented active IVH were investigated by a 1.5 T MRI. PC-MRI acquisitions were added to the morphological acquisition to quantify CSF and CBF. These flows dynamics curves were reconstructed during the cardiac cycle to calculate CSF and blood volume displacement through the cranio spinal compartments.Results: CBF was well correlated with mass of the patients (R 2 = 0. 87; p < 10 -6 ) and also between intracranial and cervical level (R 2 = 0.79; p = 0.0.37). In response of intracranial blood volume expansion during cardiac cycle CSF flush in the spinal canal was very small in 8 subjects and hyper dynamic in one. The CSF flow in the aqueduct was null in 4; pseudo-normal in 6 and hyper dynamics in 2 patients. Conclusion: PCMRI can quantify CBF and CSF in newborn to show that IVH not only impact the brain morphology but also CSF dynamics at different locations of the cranio spinal compartments. Impact can result as a blockage or by an hyper dynamic CSF flow. PC MRI bring complementary informations to the morphological analysis that could be helpful for the understanding of physiopathology and in the different surgical technics to treat hydrocephalus. Introduction: Intracranial pressure (ICP) monitoring is a valuable tool to diagnose and treat disorders of cerebrospinal fluid (CSF) dynamics, hydrocephalus and head injuries. ICP monitoring probes can be inserted with local anaesthetics or/and sedation. The reliability of ICP measurements taken under the effect of sedative agents is unclear. Methods: A retrospective study includes patients who underwent 48 hours of ICP monitoring with ICP probes inserted with local anaesthetic or sedation to investigate CSF dynamics disturbances. Local anaesthetic used was 1% lignocaine. General anaesthetic ranged from midazolam, propofol or fentanyl. The median 24-hour ICP results of the first and second day of ICP monitoring were compared (Wilcoxon signed-rank test). The comparison was stratified by type of anaesthetic (local versus sedation). Results: Twenty patients undergoing 48-hour ICP monitoring were identified (14 females, mean age 42 years). Ten patients had ICP probes inserted with local anaesthetic and 10 with sedation. The baseline characteristics of the two groups were similar. The mean difference between the second day of ICP data recording and the first day was -1.7 (3.6 SD) mmHg for the local anaesthetic and +1.9 (3.1 SD) in the sedation group, and the difference between these two means was statistically significant (Wilcoxon signed-rank test p = 0.019).

The results of this study suggest that sedation may affect ICP measurements; this factor should be taken into account when interpreting the results of ICP monitoring. More extensive studies will be needed to confirm this finding and investigate the duration of sedation on ICP monitoring results and the effect of different anaesthetic agents. Introduction: Isolated fourth ventricle is a rare and late complication insertion of lateral ventricular shunt for hydrocephalus in children and adults. A history of prematurity, hydrocephalus secondary to intraventricular hemorrhage or infection is common in this rare entity. Isolated fourth ventricle is reported at around 2.5% of some series, with an interval from ventriculoperitoneal shunt (VPS) insertion of 1-7 years. Methods: Treatment strategies for this pathology go from the colocation of a free tube or connected to a valve and endoscopic management with aqueductoplasty with or without stenting of the Sylvius aqueduct. Previously reported complications with the shunting of the fourth ventricle are cranial nerve palsies and injuries to the floor of the fourth ventricle. Here we present a case of a 6 years old girl with a post hemorrhagic hydrocephalus with a VPS that went through a suboccipital endoscopic aqueductoplasty with stent of an isolated fourth ventricle. Because of neurological deterioration and increased size of the isolated ventricle, she required a free tube to the fourth ventricle. Control magnetic resonances showed a normal size of the fourth ventricle and a transtentorial herniation of the occipital horn of the left lateral ventricle and a thinning of the pons. Results conclusion: After the implantation of an adjustable valve, the transtentorial herniation, the slendering of the pons and the neurological status improved but the size of the fourth increased to nearly normal size. Case report: 20 year old lady with hydrocephalus, latest clinical procedure was insertion of a lumbo-peritoneal shunt (LPS). She presented with two week history of abdominal pain, radiating towards the neck and tip of left shoulder, associated with constipation. Examination revealed tenderness in left hypochondriac region, no surgical site leaks nor discharge. Neurologically, Glasgow Coma Score was 15/15, normal visual findings. Fluoroscopy revealed dilated loops of bowel compressing distal catheter against peritoneum, abdominopelvic ultrasound, ECG, CRP and urinalysis were normal, Beta hCG was negative. Diagnosis of referred pain secondary to distal shunt catheter peritoneal irritation was made. Patient was conservatively managed, improved and discharged. Discussion: Few literatures have reported referred pain as complication of peritoneal shunts; similarly this case presents and explores the need for more reported cases if noted. It can be seen that it's still important to rule out possible red flag diagnoses as potential differentials. General surgical input and advice was required in this case, of which recommendation was conservative management of constipation being culprit of distended bowel loops, mechanically pressing against distal catheter of the shunt. Conclusion: Referred pain in peritoneal shunts is a rare complication or perhaps under-reported, therefore necessary to be includmyped when obtaining consents from patients ahead of shunting procedures. This case emphasizes need for consideration of referred shoulder tip pain as recognized complication of ventriculo-peritoneal or Lumboperitoneal shunts.

The variation of optic nerve sheath diameter (ONSD) measured by ultrasound before and after the surgery for hydrocephalus Mindaugas Urbonas 1,2 , Algimantas Matukevicius 1 , Arimantas Tamasauskas Objectives/aim: Little is known about the value of the change in optic nerve sheath diameter (ONSD) during the treatment and follow up of hydrocephalus. The aim of this report was to investigate the variation of ONSD measured by ultrasound before the surgical treatment of hydrocephalus and 4 -5 days after the operation. Methods: 20 adult patients (mean age 56.8 ± 15.98 (SD) years) were operated for hydrocephalus (7 endoscopic third ventriculostomies and 13 ventriculoperitoneal shunt insertions). ONSD was measured 3 mm behind the papilla in each eye by ultrasound in two positionsstanding and supine. The variation of ONSD was calculated as follows: ((ONSD supine position-ONSD standing position)/ONSD supine position) x 100%. Also MRI scans were done for the patients before and 4-5 days after the operation. Results: Preoperatively, ONSD variation was 3.74% in the right eye and 5.7% in the left eye. 4-5 days after operation, ONSD variation was 5.74% in the right eye and 6.88% in the left eye. There was a strong correlation between ONSD in supine position measured by ultrasound and ONSD measured from MRI scans (preoperatively and after the operation). Conclusion: We observed that ONSD measured by ultrasound changes significantly after the surgical treatment for hydrocephalus. We propose that lower intracranial pressure after the operation could be related with the greater narrowing of ONSD especially in standing position. The variation of ONSD is directly related with the changes of intracranial pressure and could be used for the evaluation and follow up of the patients with hydrocepalus. Larger studies, in a wider ranging population, are required to establish how widely these data apply. Introduction: The development of vascular stiffening (VS) is a risk factor of normal pressure hydrocephalus (NPH). The mechanism of VS remains ambiguous, and there is currently no prevention for this pathological condition. Methods: Here, we studied whether phospholipase A2 group 6 (PLA2g6)/Ca 2+ signaling was involved in arterial stiffness induced by aging. Aortic stiffness was measured in vivo by pulse wave velocity (PWV) in wild type (WT) mice and animals in which PLA2g6/Ca 2+ function was constitutively impaired. Results: We found that aging significantly increased PWV in WT, but not in PLA2g6ex2 KO mice. In vitro analysis of vascular smooth muscle cells (SMCs) from PLA2g6ex2 KO animals showed a significant impairment of PLA2g6-dependent Ca 2+ signaling and reduced proliferation. Histology revealed that the thickness of aortic media was decreased in aged PLA2g6ex2 KO mice. Analyses of SMC layer of thoracic aorta from the aged (24 months old) mice revealed a significant elevation of BCL11B whose deficiency is known to stiffen arteries. Furthermore, RT-PCR of human postmortem caudate nucleus of patients with NPH showed differential gene expressions of transmembrane proteins (TMEMs), which mediate hydrocephalus. Conclusion: Our results demonstrate that aortic stiffening caused by aging can be prevented by inhibition of PLA2g6/Ca 2+ signaling. This effect is associated with reduced SMC proliferation and increased BCL11B in the vasculature. Discovery of the previously unknown role of PLA2g6/Ca 2+ in age-related VS revealed a new molecular mechanism that can promote BCL11B in aged individuals and may offer a novel target for prevention of pathological VS and NPH.

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