Cerebrospinal Fluid Compartment Research Articles

Characterizing the Spatial Patterns and Determinants of Cerebrospinal Fluid Pseudorandom Flow in the Human Brain with Low b-value Diffusion MRI

Abstract The circulation of cerebrospinal fluid (CSF) is essential for maintaining brain homeostasis and clearance, and impairments in its flow can lead to various brain disorders. Recent studies have shown that CSF effective motility can be interrogated using low b-value diffusion magnetic resonance imaging (low-b dMRI). Nevertheless, the spatial organization of intracranial CSF flow dynamics remains largely elusive. Here, we developed a whole-brain voxel-based analysis framework, termed CSF pseudo-diffusion spatial statistics (CΨSS), to examine CSF mean pseudo-diffusivity (MΨ), a measure of CSF flow magnitude derived from low-b dMRI. We showed that intracranial CSF MΨ demonstrates characteristic covariance patterns by employing seed-based correlation analysis. Next, we applied non-negative matrix factorization analysis to further elucidate the covariance patterns of CSF MΨ in a hypothesis-free, data-driven way. We identified ten distinct CSF compartments with high reproducibility and reliability, reflected by a high mean adjusted Rand index with a low standard deviation (0.82 [SD: 0.018]) in split-half analyses of the discovery multimodal aging dataset (n = 187). The identified patterns displayed similar MΨ across three replication datasets. In discovery and replication multimodal aging cohorts (unique n = 264), our study revealed that age, sex, brain atrophy, ventricular anatomy, and cerebral perfusion differentially influence MΨ across these CSF spaces. Notably, of the 35 individuals exhibited anomalous CSF flow patterns, five displayed clinically consequential incidental findings on multimodal neuroradiological examinations, which were not observed in other participants (p = 3.04×10-5). Our work sets forth a new paradigm to study CSF flow, with potential applications in clinical settings.

A Hitchhiker's Guide Toward CSF Biomarkers for Neuro-Oncology.

Cerebrospinal fluid (CSF) has emerged as a valuable liquid biopsy source for glioma biomarker discovery and validation. CSF produced within the ventricles circulates through the subarachnoid space, where the composition of glioma-derived analytes is influenced by the proximity and anatomical location of sampling relative to tumor, in addition to underlying tumor biology. The substantial gradients observed between lumbar and intracranial CSF compartments for tumor-derived analytes underscore the importance of sampling site selection. Moreover, radiographic features, such as tumor-CSF contact and blood-brain barrier (BBB) disruption, are critical covariates that may affect biomarker detectability and the abundance of plasma-derived analytes in CSF, respectively. Longitudinal intracranial CSF sampling, enabled by access devices like Ommaya reservoirs, may offer a window into treatment response and disease progression, though variability in analyte yield, sample volumes, and the dynamic effects of surgical resection pose challenges. This review critically evaluates the anatomic, radiographic, and longitudinal factors that impact glioma CSF biomarker abundance. Practical considerations for longitudinal CSF biobanking, including access device placement and collection, are also reviewed. Key takeaways and recommendations for CSF glioma biomarker discovery and validation are provided based on our collective experience, along with resources for investigators aiming to develop CSF biobanking at their institutions.

Single-cell analysis of cerebrospinal fluid reveals common features of neuroinflammation.

Neuroinflammation is often characterized by immune cell infiltrates in the cerebrospinal fluid (CSF). Here, we apply single-cell RNA sequencing to explore the functional characteristics of these cells in patients with various inflammatory, infectious, and non-inflammatory neurological disorders. We show that CSF is distinct from the peripheral blood in terms of both cellular composition and gene expression. We report that the cellular and transcriptional landscape of CSF is altered in neuroinflammation but is strikingly similar across different neuroinflammatory disorders. We find clonal expansion of CSF lymphocytes in all disorders but most pronounced in inflammatory diseases, and we functionally characterize the transcriptional features of these cells. Finally, we explore the genetic control of gene expression in CSF lymphocytes. Our results highlight the common features of immune cells in the CSF compartment across diverse neurological diseases and may help to identify new targets for drug development or repurposing in multiple sclerosis (MS).

Sex Differences in Basal Cortisol Levels Across Body Fluid Compartments in a Cross-sectional Study of Healthy Adults

Abstract Context Many studies have moved toward saliva and peripheral blood sampling for studying cortisol, even in relation to disorders of the brain. However, the degree to which peripheral cortisol reflects central cortisol levels has yet to be comprehensively described. Data describing the effect that biological characteristics such as age and sex have on cortisol levels across compartments is also limited. Objective To assess the relationships of cortisol levels across cerebrospinal fluid (CSF), saliva, and plasma (total and free) compartments and describe the effects of age and sex on these relationships. Design Multisite cross-sectional observation study. Setting Samples collected in academic outpatient settings in 2001-2004. Patients or Other Participants Healthy community volunteers (n = 157) of both sexes, aged 20-85 years. Interventions None. Main Outcome Measures This study was a secondary analysis of data collected from a previously published study. Results CSF cortisol correlated more strongly with plasma (r = 0.49, P < .0001) than with saliva cortisol levels. Sex but not age was a significant modifier of these relationships. CSF cortisol levels trended higher with older age in men (R2 = 0.31, P < .001) but not women. Age-related cortisol binding globulin trends differed by sex but did not correlate with sex differences in cortisol levels in any compartment. Conclusion Variability in the correlations between central and peripheral cortisol discourages the use of peripheral cortisol as a direct surrogate for central cortisol measures. Further investigation of how mechanistic drivers interact with biological factors such as sex will be necessary to fully understand the dynamics of cortisol regulation across fluid compartments.

Differential Lipid Signatures of Lumbar and Cisternal Cerebrospinal Fluid.

The molecular composition of cerebrospinal fluid (CSF) is often used as a key indicator of biochemical alterations within distinct brain and spinal cord fluid compartments. The CSF protein content in lumbar CSF samples is widely employed as a biomarker matrix for diagnosing brain-related pathological conditions. CSF lipid profiles may serve as promising complementary diagnostics, but it remains unresolved if the lipid distribution is consistent along the neuroaxis. The lipid composition was determined with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in cisternal CSF obtained from healthy subjects undergoing preventive surgery of an unruptured aneurism (n = 11) and lumbar CSF obtained from individuals referred for the clinical evaluation of cognitive dysfunction but subsequently cleared and deemed healthy (n = 19). We reveal discernible variations in lipid composition along the neuroaxis, with a higher overall lipid concentration in cisternal CSF, although with different relative distributions of the various lipid classes in the two compartments. The cisternal CSF contained elevated levels of most lipid classes, e.g., sphingomyelins, lysophosphatidylcholines, plasmenylphosphatidylcholines, phosphatidic acids, and triacylglycerols, whereas a few select lipids from the classes of fatty acids, phosphatidylcholines, amides and plasmenylphosphatidylethanolamines were, oppositely, elevated in the lumbar CSF pool. The distinct lipid distribution along the neuroaxis illustrates that the molecular constituents in these two CSF compartments are not uniform. These findings emphasize the necessity of establishing a lumbar lipid index for the accurate interpretation of the cranial CSF lipid profile.

Cerebrospinal Fluid and Peripheral Blood Lymphomonocyte Single-Cell Transcriptomics in a Subject with Multiple Sclerosis Acutely Infected with HIV.

Signatures of neurodegeneration in clinical samples from a subject with multiple sclerosis (MS) acutely infected with HIV were investigated with single-cell transcriptomics using 10X Chromium technology. Sequencing was carried out on NovaSeq-TM, and the analysis was performed with Cell Ranger software (v 7.1.0) associated with a specifically established bioinformatic pipeline. A total of 1446 single-cell transcriptomes in cerebrospinal fluid (CSF) and 4647 in peripheral blood mononuclear cells (PBMCs) were obtained. In the CSF, many T-cell lymphocytes with an enriched amount of plasma cells and plasmacytoid dendritic (pDC) cells, as compared to the PBMCs, were detected. An unsupervised cluster analysis, putting together our patient transcriptomes with those of a publicly available MS scRNA-seq dataset, showed up-regulated microglial neurodegenerative gene expression in four clusters, two of which included our subject's transcriptomes. A few HIV-1 transcripts were found only in the CD4 central memory T-cells of the CSF compartment, mapping to the gag-pol, vpu, and env regions. Our data, which describe the signs of neurodegenerative gene expression in a very peculiar clinical situation, did not distinguish the cause between multiple sclerosis and HIV infection, but they can give a glimpse of the high degree of resolution that may be obtained by the single-cell transcriptomic approach.

Evaluation of cerebrospinal fluid (CSF) and interstitial fluid (ISF) mouse proteomes for the validation and description of Alzheimer’s disease biomarkers

BackgroundMass spectrometry (MS)-based cerebrospinal fluid (CSF) proteomics is an important method for discovering biomarkers of neurodegenerative diseases. CSF serves as a reservoir for interstitial fluid (ISF), and extensive communication between the two fluid compartments helps to remove waste products from the brain. New methodWe performed proteomic analyses of both CSF and ISF fluid compartments using intracerebral microdialysis to validate and detect novel biomarkers of Alzheimer's disease (AD) in APPtg and C57Bl/6J control mice. ResultsWe identified up to 625 proteins in ISF and 4483 proteins in CSF samples. By comparing the biofluid profiles of APPtg and C57Bl/6J mice, we detected 37 and 108 significantly up- and downregulated candidates, respectively. In ISF, 7 highly regulated proteins, such as Gfap, Aldh1l1, Gstm1, and Txn, have already been implicated in AD progression, whereas in CSF, 9 out of 14 highly regulated proteins, such as Apba2, Syt12, Pgs1 and Vsnl1, have also been validated to be involved in AD pathogenesis. In addition, we also detected new interesting regulated proteins related to the control of synapses and neurotransmission (Kcna2, Cacng3, and Clcn6) whose roles as AD biomarkers should be further investigated. Comparison with existing methodsThis newly established combined protocol provides better insight into the mutual communication between ISF and CSF as an analysis of tissue or CSF compartments alone. ConclusionsThe use of multiple fluid compartments, ISF and CSF, for the detection of their biological communication enables better detection of new promising AD biomarkers.

Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models.

Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) - an aging byproduct - in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.

Epstein-Barr Virus in the Cerebrospinal Fluid and Blood Compartments of Patients With Multiple Sclerosis and Controls.

Epstein-Barr virus (EBV) infection is a major risk factor of multiple sclerosis (MS). We examined the presence of EBV DNA in the CSF and blood of patients with MS and controls. We analyzed whether EBV DNA is more common in the CSF of patients with MS than in controls and estimated the proportions of EBV-positive B cells in the CSF and blood. CSF supernatants and cells were collected at diagnostic lumbar punctures from 45 patients with MS and 45 HLA-DR15 matched controls with other conditions, all participants were EBV seropositive. Cellular DNA was amplified by Phi polymerase targeting both host and viral DNA, and representative samples were obtained in 28 cases and 28 controls. Nonamplified DNA from CSF cells (14 cases, 14 controls) and blood B cells (10 cases, 10 controls) were analyzed in a subset of participants. Multiple droplet digital PCR (ddPCR) runs were performed per sample to assess the cumulative EBV positivity rate. To detect viral RNA as a sign of activation, RNA sequencing was performed in blood CD4-positive, CD8-positive, and CD19-positive cells from 21 patients with MS and 3 controls. One of the 45 patients with MS and none of the 45 controls were positive for EBV DNA in CSF supernatants (1 mL). CSF cellular DNA was analyzed in 8 independent ddPCRs: EBV DNA was detected at least once in 18 (64%) of the 28 patients with MS and in 15 (54%) of the 28 controls (p = 0.59, Fisher test). The cumulative EBV positivity increased steadily up to 59% in the successive ddPCRs, suggesting that all individuals would have reached EBV positivity in the CSF cells, if more DNA would have been analyzed. The estimated proportion of EBV-positive B cells was >1/10,000 in both the CSF and blood. We did not detect viral RNA, except from endogenous retroviruses, in the blood lymphocyte subpopulations. EBV-DNA is equally detectable in the CSF cells of both patients with MS and controls with ddPCR, and the probabilistic approach indicates that the true positivity rate approaches 100% in EBV-positive individuals. The proportion of EBV-positive B cells seems higher than previously estimated.

Modeling the impact of thoracic pressure on intracranial pressure

A potential contribution to the progression of Spaceflight Associated Neuro-ocular Syndrome is the thoracic-to-spinal dural sac transmural pressure relationship. In this study, we utilize a lumped-parameter computational model of human cerebrospinal fluid (CSF) systems to investigate mechanisms of CSF redistribution. We present two analyses to illustrate potential mechanisms for CSF pressure alterations similar to those observed in microgravity conditions. Our numerical evidence suggests that the compliant relationship between thoracic and CSF compartments is insufficient to solely explain the observed decrease in CSF pressure with respect to the supine position. Our analyses suggest that the interaction between thoracic pressure and the cardiovascular system, particularly the central veins, has greater influence on CSF pressure. These results indicate that future studies should focus on the holistic system, with the impact of cardiovascular changes to the CSF pressure emphasized over the sequestration of fluid in the spine.

Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies.

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management.

Reply to Wostyn, P. Targeting the Cerebrospinal Fluid Compartment in Glaucoma: Still the Dark Side of the Moon? Comment on "Passaro et al. Glaucoma as a Tauopathy-Is It the Missing Piece in the Glaucoma Puzzle? J. Clin. Med. 2023, 12, 6900".

We are grateful to the author of the comment [...].

Temporal Changes in CSF Cell Parameters After SAH: Comparison of Ventricular and Spinal Drain Samples

BackgroundForty percent of patients with aneurysmatic subarachnoid hemorrhage (aSAH) develop acute hydrocephalus requiring treatment with cerebrospinal fluid (CSF) drainage. CSF cell parameters are used in the diagnosis of nosocomial infections but also reflect sterile inflammation after aSAH. We aimed to study the temporal changes in CSF parameters and compare external ventricular drain (EVD)–derived and lumbar spinal drain–derived samples.MethodsWe retrospectively identified consecutive patients with aSAH treated at our neurointensive care unit between January 2014 and May 2019. We mapped the temporal changes in CSF leucocyte count, erythrocyte count, cell ratio, and cell index during the first 19 days after aSAH separately for EVD-derived and spinal drain–derived samples. We compared the sample sources using a linear mixed model, controlling for repeated sampling.ResultsWe included 1360 CSF samples from 197 patients in the analyses. In EVD-derived samples, the CSF leucocyte count peaked at days 4–5 after aSAH, reaching a median of 225 × 106 (interquartile range [IQR] 64–618 × 106). The cell ratio and index peaked at 8–9 days (0.90% [IQR 0.35–1.98%] and 2.71 [IQR 1.25–6.73], respectively). In spinal drain–derived samples, the leucocyte count peaked at days 6–7, reaching a median of 238 × 106 (IQR 60–396 × 106). The cell ratio and index peaked at 14–15 days (4.12% [IQR 0.63–10.61%]) and 12–13 days after aSAH (8.84 [IQR 3.73–18.84]), respectively. Compared to EVD-derived samples, the leucocyte count was significantly higher in spinal drain–derived samples at days 6–17, and the cell ratio as well as the cell index was significantly higher in spinal drain–derived samples compared to EVD samples at days 10–15.ConclusionsCSF cell parameters undergo dynamic temporal changes after aSAH. CSF samples from different CSF compartments are not comparable.

Spinal ependymal tumors.

Spinal ependymomas are strictly to be subdivided into intramedullary lesions and extramedullary lesions as they are histologically and genetically distinct. Whereas the intramedullary lesions (SPE) are assigned to the WHO grade 2 and very rarely grade 3, the extramedullary lesions or myxopapilary tumors (MPE) are only as recently also assigned to WHO grade 2. The major difference is that in general, an intramedullary lesion of grade 2 remains confined to the local site of origin, even when rarely recurring after complete resection. In contrast, the MPEs have the capacity to spread throughout the cerebrospinal fluid compartment but can also be controlled by cautious complete resection. We here review the clinical features of spinal ependymomas, contrasting the entities, and describe the treatment found best from the literature to manage these lesions including interdisciplinary approaches.

Targeting the Cerebrospinal Fluid Compartment in Glaucoma: Still the Dark Side of the Moon? Comment on Passaro et al. Glaucoma as a Tauopathy—Is It the Missing Piece in the Glaucoma Puzzle? J. Clin. Med. 2023, 12, 6900

I read with great interest the article by Passaro et al [...]

Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.

The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma. Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Fixel based analysis of white matter alterations in Mild cognitive impairment and Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia, and is associated with altered white matter (WM) microstructures in the brain (Clerx et al., 2012; Jack Jr et al., 2013). Diffusion weighted imaging (DWI) is a non‐invasive method of examining white matter alterations in AD and Mild cognitive Impairment (MCI). DWI based Fixel‐based analysis (FBA) is a novel method that enables the investigation of fibre specific WM alterations at the microscopic level. In this study, we investigated fibre tract‐specific changes in the whole‐brain WM, in individuals with MCI and AD using DWI based FBA.MethodN = 102 participants (>70 years) from the University of California Davis Alzheimer’s Disease Research Center were included in this study, including 34 individuals with AD, 34 with MCI, and 34 control subjects. DWI data were obtained on a 3T Siemens TimTrio scanner (resolution = 2mm, 60 directions, at b = 1000s/mm2) and pre‐processed using MRtrix3 (Tournier et al., 2019). Single‐Shell 3‐tissue CSD (SS3T‐CSD) was performed to obtain Fibre Orientation Distributions (FODs) related to WM as well as for gray matter and cerebrospinal fluid compartments in all voxels, using MRtrix3Tissue. A study‐specific unbiased FOD template was generated and used for FBA processing. Whole‐brain FBA maps, including fibre density (FD), fibre cross‐section (FC), and combination of fibre density and cross‐section (FDC), were generated. Statistical analyses were performed using connectivity based fixel enhancement at each fixel using general linear model (Raffelt et al., 2015)(Figure1).ResultThe whole‐brain FBA showed significant reduction in FD in individuals with AD compared to MCI, in regions including splenium of corpus callosum, fornix, and the left uncinate fasciculus (Figure2). Furthermore, AD individuals showed significant reduction in FD in the left uncinate fasciculus compared to controls. We observed subtle reduction in FD and FDC metrics (although not statistically significant after FWE corrections) in regions including corpus callosum, forceps majors, and uncinate fasciculus in AD(Figure3). We did not observe significant difference in FC between groups.ConclusionFBA‐derived measures demonstrated sensitivity in detecting microstructural white matter alterations in AD. These findings highlight the utility of FBA as a promising tool for providing valuable insights into pathophysiologic changes in AD.

Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1-anchored membrane domains.

B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific recombinant monoclonal IgG1 Abs (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68+ phagocyte infiltration. Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment. Abs against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients, but not in inflammatory and noninflammatory neurologic controls. CSF PLP1 complex Abs provide a pathogenic autoantibody biomarker specific for MS.

Distinct Pattern of Membrane Formation With Spinal Cerebrospinal Fluid Leaks in Spontaneous Intracranial Hypotension.

To systematically describe pertinent, intraoperative anatomic findings encountered when approaching spinal cerebrospinal fluid (CSF) leaks and CSF-venous fistulas in spontaneous intracranial hypotension (SIH). In a retrospective study, we included surgically treated patients suffering from SIH at our institution from April 2018 to March 2022. Anatomic, intraoperative data were extracted from operative notes and supplemented with data from surgical videos and images. Prominent anatomic features were compared among different types of CSF leaks. The study cohort consists of 120 patients with a mean age of 45.2 years. We found four distinct patterns of spinal membranes specifically associated with different types of CSF leaks: (i) thick, dorsal membranes, which were hypervascular and may mimic the dura (pseudodura); (ii) thin, lateral membranes encapsulating a ventral epidural CSF compartment (confining the spinal longitudinal extradural CSF collection); (iii) ventral membranes constituting a transdural funnel-like CSF channel; and (iv) lateral membranes forming spinal cysts/meningeal diverticulae associated with lateral CSF leaks. The latter three types resemble a layer of arachnoid herniated through the dural defect. We describe four distinct spinal (neo-)membranes in association with spinal CSF leaks. Formation of these membranes, or emergence by herniation of arachnoid through a dural defect, constitutes a specific pathoanatomic feature of patients with SIH and CSF leaks. Recognition of these membranes is of paramount importance for diagnosis and treatment of patients with spinal CSF leaks.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.