Cerebrospinal Fluid Circulation Research Articles

The relationship between compensatory hyperplasia of the myodural bridge complex and reduced compliance of the various structures within the cranio-cervical junction.

The myodural bridge complex (MDBC) is described as a functional anatomic structure that involves the dense connective tissue fibers, muscles, and ligaments in the suboccipital region. It has recently been proposed that the MDBC can influence cerebrospinal fluid (CSF) circulation. In the present study, bleomycin (BLM), a type of antibiotic that is poisonous to cells, was injected into the posterior atlanto-occipital interspace (PAOiS) of rats to induce fibrous hyperplasia of structures in PAOiS. Sagittal sections of tissues obtained from the posterior-occipital region of the rats were stained utilizing the Masson Trichrome staining method. Semiquantitative analysis evidenced that the collagen volume fraction of collagen fibers of the MDBC, as well as the sum of the area of the spinal dura mater and the posterior atlanto-occipital membrane in the BLM group were significantly increased (p < .05) compared to that of the other groups. This finding illustrates that the MDBC fibers as well as other tissues in the PAOiS of rats in the BLM group developed fibrotic changes which reduced compliance of the spinal dura mater. Indeed, the sectional area of the rectus capitis dorsal minor muscle in the BLM group was measured to be increased. These changes may further restrict CSF flow. The present research provides support for the recent hypothesis proposed by Labuda et al. concerning the pathophysiology observed in symptomatic adult Chiari malformation Type I patients, that there exists a relationship between the altered compliance of the anatomic structures within the craniocervical region and the resultant compensatory hyperplasia of the MDBC.

Ependymal Cilia: Physiology and Role in Hydrocephalus.

Cerebrospinal fluid (CSF), a colorless liquid that generally circulates from the lateral ventricles to the third and fourth ventricles, provides essential nutrients for brain homeostasis and growth factors during development. As evidenced by an increasing corpus of research, CSF serves a range of important functions. While it is considered that decreased CSF flow is associated to the development of hydrocephalus, it has recently been postulated that motile cilia, which line the apical surfaces of ependymal cells (ECs), play a role in stimulating CSF circulation by cilia beating. Ependymal cilia protrude from ECs, and their synchronous pulsing transports CSF from the lateral ventricle to the third and fourth ventricles, and then to the subarachnoid cavity for absorption. As a result, we postulated that malfunctioning ependymal cilia could disrupt normal CSF flow, raising the risk of hydrocephalus. This review aims to demonstrate the physiological functions of ependymal cilia, as well as how cilia immobility or disorientation causes problems. We also conclude conceivable ways of treatment of hydrocephalus currently for clinical application and provide theoretical support for regimen improvements by investigating the relationship between ependymal cilia and hydrocephalus development.

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery.

Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.

Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain.

Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer's biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment. This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening. The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection. Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation.

Abstract LB201: Optimizing adeno-associated viral vector-mediated delivery of trastuzumab to the central nervous system for the treatment of Her2 positive brain metastasis

Abstract Breast cancer is the most common cause of brain metastases in women, affecting 15-30% of all patients. Despite the success of systemic Her2-targeted therapies, up to half of patients with Her2+ primary breast cancer develop breast cancer brain metastases (BCBM). Subtype switching from Her2- primary breast tumors account for an additional 15% of Her2+ BCBM, bringing total Her2 positivity in the BCBM setting to nearly 65% of cases. Even though direct delivery of Her2-targeted therapies to the central nervous system (CNS) has shown promising clinical results, long-term feasibility is limited, at least in part, by the need for repeated dosing to overcome the shorter drug half-life in the cerebrospinal fluid vs. systemic circulation (e.g., ~1 vs. 5 days, respectively). To achieve sustained CNS expression of trastuzumab without frequent dosing, we developed a gene therapy approach to treat BCBM comprising a single local administration of AAV vector encoding trastuzumab. Previous work from our group has shown that intracerebroventricular (ICV) injection of trastuzumab-expressing AAV doubled the life expectancy of Rag1 knockout (KO) mice bearing BT-474 breast cancer brain tumors. Rag1 KO mice who received AAV-trastuzumab prior to implantation of BT-474 tumor cells into the brain showed a dose-dependent delay in tumorigenesis. Following these proof-of-concept studies, we performed extensive gene therapy vector optimization and in vivo evaluation. The concentration of trastuzumab achieved in the brain parenchyma after a single ICV administration of the optimized vectors into Rag1 KO mice ranged from 10-165 ng/mg of brain protein by day 28. Previous studies utilizing CNS delivery of gene therapy vectors have shown vector leakage into the systemic circulation, which results in detectable transgene expression in the blood following peripheral transduction. To mitigate the potential risk of trastuzumab-induced cardiotoxicity, we investigated using intravenously administered, plasma-derived, pooled human immunoglobulin (IVIG) as a source of anti-AAV neutralizing antibodies to reduce peripheral transduction. Compared to controls that received naïve mouse serum, Rag1 KO mice receiving IVIG two hours prior to ICV administration of AAV-trastuzumab exhibited similar levels of trastuzumab within the brain while displaying a 10-fold reduction in serum trastuzumab concentrations. Vector biodistribution analysis suggested that reduced serum trastuzumab levels resulted from effective blockade of liver transduction following IVIG pre-treatment. These data suggest that AAV vector administration to the CNS to achieve sustained expression of trastuzumab may effectively treat Her2+ BCBM. Additionally, patients with pre-existing neutralizing antibodies to the AAV vector capsid need not be excluded from future clinical trials. Citation Format: Marcela Salazar Werner, Shweta Aras, Ashleigh Morgan, Nesteene J. Param, Jenny Greig, James M. Wilson. Optimizing adeno-associated viral vector-mediated delivery of trastuzumab to the central nervous system for the treatment of Her2 positive brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB201.

Role of Diffusion Tensor Imaging in Diagnosis and Estimation of Shunt Effect for Hydrocephalus in Stroke Patients: A Narrative Review

Hydrocephalus is a dilatation of the brain ventricular system by the accumulation of cerebrospinal fluid within the ventricle caused by impaired cerebrospinal fluid circulation or clearance. A diagnosis of hydrocephalus at the chronic stage of stroke has been mainly made by clinical features and radiologic findings on brain computed tomography and magnetic resonance imaging. On the other hand, it could not determine the effect of hydrocephalus or shunt effect on the periventricular neural structures. By contrast, these effects on the periventricular neural structures can be estimated using diffusion tensor imaging (DTI). This article reviewed 10 DTI-based studies related to the diagnosis and estimation of the shunt effect for hydrocephalus in stroke patients. These studies suggest that DTI could be a useful diagnostic and estimation tool of the shunt effect for hydrocephalus in stroke patients. In particular, some studies suggested that fractional anisotropy value in the periventricular white matter could be a diagnostic biomarker for hydrocephalus. As a result, the role of DTI in diagnosing and estimating the shunt effect for hydrocephalus in stroke patients appears to be promising. However, the number of studies and patients of all reviewed studies were limited (10 studies including a total of 58 stroke patients with heterogenous brain pathologies).

Review of Cerebrospinal Fluid Physiology and Dynamics: A Call for Medical Education Reform

The flow of cerebrospinal fluid (CSF) has been described as a unidirectional system with the choroid plexus serving as the primary secretor of CSF and the arachnoid granulations as primary reabsorption site. This theory of neurosurgical forefathers has been universally adopted and taught as dogma. Many neuroscientists have found difficulty reconciling this theory with common pathologies, and recent studies have found that this "classic" hypothesis may not represent the full picture. To review modern CSF dynamic theories and to call for medical education reform. We reviewed the literature from January 1990 to December 2020. We searched the PubMed database using key terms "cerebrospinal fluid circulation," "cerebrospinal fluid dynamics," "cerebrospinal fluid physiology," "glymphatic system," and "glymphatic pathway." We selected articles with a primary aim to discuss either CSF dynamics and/or the glymphatic system. The Bulat-Klarica-Orešković hypothesis purports that CSF is secreted and reabsorbed throughout the craniospinal axis. CSF demonstrates similar physiology to that of water elsewhere in the body. CSF "circulates" throughout the subarachnoid space in a pulsatile to-and-fro fashion. Osmolarity plays a critical role in CSF dynamics. Aquaporin-4 and the glymphatic system contribute to CSF volume and flow by establishing osmolarity gradients and facilitating CSF movement. Multiple studies demonstrate that the choroid plexus does not play any significant role in CSF circulation. We have highlighted major studies to illustrate modern principles of CSF dynamics. Despite these, the medical education system has been slow to reform curricula and update learning resources.

Postural control in Chiari I malformation: protocol for a paediatric prospective, observational cohort – potential role of posturography for surgical indication

IntroductionChiari I malformation (CM1) is an anatomical abnormality characterised by the cerebellar tonsils descending at least 5 mm below the foramen magnum. CM1 causes obstruction of cerebrospinal fluid (CSF) circulation...

Shunt Over-drainage, Slit Ventricle Syndrome, Programmable Valves and Anti-Siphon Devices. A Narrative Review of a Multifactorial and Intractable Problem.

The current management strategy of hydrocephalus mainly involves the insertion of a ventriculoperitoneal shunt and is inherently related with a complication widely known as shunt over-drainage. Albeit this is a well-recognized complication, the true incidence and severity of this phenomenon remains undefined and most probably underdiagnosed, necessitating a more comprehensive pathophysiologic and therapeutic consideration. The slit ventricle syndrome is intimately related with the entity of shunt over-drainage, although who's the definition of the former is implicated by a lack of universally accepted inclusion criteria. Another point of controversy is related with the absence of widely accepted criteria that would be able to discriminate the existing differentiations between these two entities. This is reflected in the fact that there are many proposed, relevant, treatment protocols. The background for all this data is based on the uncertainty and ambiguity regarding the pathophysiological mechanisms that are implicated. Current efforts are centered on the implementation of precautionary measures, as well as on treatment of both of these entities. Currently, there are enough evidence that support the concept that prevention of siphoning via the use of gravitational valves or antisiphon devices is the most efficacious means contained in our current therapeutic armamentarium. We attempt to present an overview of this complex entity, emphasizing on the hydrodynamics of the cerebrospinal fluid circulation in conditions harboring a ventriculoperitoneal shunt, the effect of the siphoning effect and the role of programmable valves and anti-siphon devices in our effort to eliminate this phenomenon. Based on an extensive literature review and on expert opinion, we concluded that the insertion of an anti-siphon device (gravitational shunt valves) could reliably address the issue of over-drainage, when a patient assumes a vertical position. Besides that, there are ongoing prospective studies centered on the safety and efficacy of adjustable gravitational valves, whose results are of ultimate importance. It is of paramount importance to be recognized that, due to the complexity of the pathophysiology of shunted hydrocephalus, lifelong follow-up of patients with ventriculoperitoneal shunts is necessary.

Study of the effectiveness of ventriculosubarachnoid drainage in neonatal hydrocephalus according to the data of the Republic of Crimea for the period 2000–2018

Despite the achieved success in the treatment of neonatal hydrocephalus, the task of restoring circulation, outflow, and absorption of cerebrospinal fluid (CSF) remains urgent.The aim of the study was to investigate the effectiveness of ventriculosubarachnoid drainage in compensating hydrocephalus without shunt implantation.Materials and methods. We collected and studied clinical material for the period from 2000 to 2018 according to the data of the Republic of Crimea. We identified groups of premature (n = 184) and full-term (n = 107) infants who underwent standard treatment with lumbar puncture, subgaleal drainage, and ventriculoperitoneal shunting (VPS). In case of ventricular occlusion in 143 premature and 46 full-term infants, at the initial stage of treatment, the option of coronary – lambdoid subarachnoid ventriculostomy (RF Patent No. 2715535) in combination with lumbar punctures was included. With progression of hydrocephalus, ventriculosubarachnoid stenting (RF Patent No. 2721455) with subgaleal drainage was considered as an option.Results. The inclusion of the proposed options made it possible to increase the rate of hydrocephalus compensation without VPS to 75.5% in premature infants and to 80.4% in full-term infants versus 28.3% and 20.6%, respectively, according to the standard protocol (p &lt; 0.001). In other cases, the imbalance between CSF production and absorption persisted, which required integration of a stent with a peritoneal part of the shunt, without replacing the system.Conclusion. The obtained result allows to consider the inclusion of the proposed options in the modern treatment algorithm for neonatal hydrocephalus.

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Headache and neuroimaging findings in conditions of cerebrospinal fluid (CSF) circulation disorders: in hydrocephalus, pseudotumor cerebri, and CSF hypotension syndrome

The authors wish in this narrative minireview show and comment on some neuroimaging findings encountered in patients with conditions of cerebrospinal fluid circulation disorders, such as in the hydrocephalus, pseudotumor cerebri, and CSF hypotension syndrome. The MRI of a young woman with a clinical diagnosis of post-dural puncture headache, performed on the fourth postpartum day after cesarean delivery, evolving with headache and diplopia, is shown. Non-contrast-enhanced sagittal T1 magnetic resonance imaging shows that the cerebellar tonsils are at the level of the foramen magnum, therefore still within normal limits, but, despite that, the opening of the cerebral aqueduct in the third ventricle is below the imaginary line connecting the anterior clinoid to the vein of Galen, therefore considered abnormally lower than the expected anatomical position. The axial T1-weighted images with post-contrast fat suppression also show impregnation and thickening of the dura mater. There is also mild engorgement of the cerebral venous sinuses, best demonstrated on T1 with post-contrast fat suppression, which is also identified on post-contrast magnetic resonance angiography, with no signs of venous thrombosis. We conclude that the diagnosis of a patient with intracranial hypotension syndrome can be suspected or confirmed with typical neuroimaging findings.

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults

BackgroundRecent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport.MethodsWe re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20–83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05).ResultsA significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman’s-rho = 0.6), CSF volume (p < 0.001, Spearman’s-rho = 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow.ConclusionsFindings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

Clinical and evolutionary aspects of classification and treatment for pediatric hydrocephalic syndrome: a bibliographic review

Introduction: The term hydrocephalus comes from the Greek and means “water in the head”. It is characterized by an increase in the amount and pressure of cerebrospinal fluid or cerebrospinal fluid, leading to dilatation of the ventricles and compression of nervous tissue. Hydrocephalus is not a specific disease. Rather, it represents a diverse group of disorders, which result from impaired circulation and absorption of cerebrospinal fluid (CSF) or, in rare circumstances, increased production by a choroid plexus papilloma. Objective: to review clinical and evolutionary aspects of the classification and treatment for pediatric hydrocephalus syndrome, its clinical presentations and procedures that provide a better resolution of this neurosurgical emergency. Method: a computerized bibliographic search was carried out, using the keywords (Endoscopic third ventriculostomy (ETV); ventriculoperitoneal shunt for hydrocephalus (VP ​​shunt); Treatment and Diagnosis.), in the following databases (SciELO, Google Scholar, Brazilian Journal of Neurosurgery, Arquivos Ciência Saúde, American Journal of Neurosurgery and Publab). Conclusion: there are few references in the Brazilian literature that address the topic on clinical and evolutionary aspects of classification and treatment for pediatric hydrocephalus syndrome. Thus, it is important to encourage research on the subject, enabling the strengthening and expansion of their professional practice in this area, as critical training and the development of skills to assist children with neurological disorders are fundamental.

A deformation model of pulsating brain tissue for neurosurgery simulation

Background and objectives: For neurological simulation, an accurate deformation model of brain tissue is of key importance for faithful visual feedback. Existing models, however, do not take into account intracranial pulsation, which degrades significantly the realism of visual feedback.Methods: In this paper, a finite element model incorporating intracranial pressure is proposed for simulating brain tissue deformation with pulsation. An implicit Euler method is developed to calculate the deformation of brain tissue. A circuit model of intracranial pressure dynamics is established based on cerebral blood and cerebrospinal fluid circulations. The intracranial pulsation of pressure is introduced into the deformation model, so that the simulated brain tissues pulsate with a rhythm in accord with the changes of intracranial pressure, which resembles real-life neurosurgery.Results and Conclusions: The experimental implementation of the proposed deformation model and the calculation method shows that it provides realistic simulation of brain tissue pulsation and real-time performance is achieved on an ordinary computer for certain procedures of neurosurgery.

Normal pressure hydrocephalus due to an iatrogenic giant lumbar pseudomeningocele after posterior lumbar interbody fusion: illustrative case.

BACKGROUNDIatrogenic pseudomeningocele incidence after lumbar surgery is 0.068%–2%, and most lumbar pseudomeningoceles are smaller than 5 cm; however, in rare cases, “giant” pseudomeningoceles greater than 8 cm in size may develop. Normal pressure hydrocephalus (NPH) is another rare condition in which the ventricles expand despite the presence of normal intracranial pressure. To date, pseudomeningocele associated with NPH has not been reported.OBSERVATIONSAn 80-year-old woman underwent L3–5 laminectomy and posterior lumbar interbody fusion, and her symptoms improved after surgery. However, dementia appeared 1 month after surgery. Repeated brain computed tomography showed ventricular enlargement, and lumbar magnetic resonance imaging showed a long pseudomeningocele in the subcutaneous tissues at the L4 level. Here, the authors report a rare case of an iatrogenic giant pseudomeningocele accompanied by NPH after lumbar surgery. The symptoms of NPH in the present case occurred after spinal surgery and recovered after dural repair surgery, indicating that the changes in cerebrospinal fluid circulation and/or pressure due to pseudomeningoceles may cause NPH.LESSONSThe prevention of dural tears through precise surgical technique and primary repair of dural tears are the best approaches to prevent pseudomeningocele incidence and subsequent events.

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation for BNCT in a Rat Melanoma Model

Simple SummaryThe blood–brain barrier (BBB) is formed by the brain capillary endothelium and prevents almost all therapeutic agents from reaching the brain. The importance of the BBB in brain tumor treatments has not been recognized until recently, including in the case of boron neutron capture therapy (BNCT), although it affects therapeutic efficacy when treating brain tumors. Recently, some drug delivery systems to bypass the BBB have been developed for brain tumor therapy, and our laboratory has been developing a system for boron delivery to brain cells using cerebrospinal fluid (CSF) circulation, which we call the “boron CSF administration method”. In this study, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. As a result, we found that boron injected using the CSF administration method accumulates to high levels in tumor cells, with a high T/N ratio. In addition, the dose required for the boron drug was much lower than that used in the intravenous (IV) administration method for equivalent effects. This approach makes it possible for clinicians to inject a lower drug dose into patient, thus reducing the potential side effects of excessive amounts of the drug and decreasing its cost. We hope our findings will inspire additional studies on boron delivery to brain tumors for BNCT.Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the “boron CSF administration method”. In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method.

197 Gold Nanoparticle Enhanced X-ray Nanotomography Reveals Region-Specific CSF Pathways Through the Brain and Spinal Cord that are Altered in Post-hemorrhagic Hydrocephalus

INTRODUCTION: Cerebrospinal fluid (CSF) is essential for the healthy development and function of the brain, but understanding the mechanisms of its distribution in and around the central nervous system (CNS) remains a major challenge. To address this need, we developed a new technique, gold nanoparticle-enhanced x-ray nanotomography (AuNp-XRM), to achieve micrometer-scale resolution visualization of CSF pathways across the entire brain and spinal cord of rodents with further applications to a model of interventricular hemorrhage/post-hemorrhagic hydrocephalus (IVH/PHH). METHODS: P4 rodents were injected with aCSF or hemoglobin to create the control and IVH conditions. 72 hours later, animals underwent MRIs to determine onset of PHH. Animals were then injected with 1.9 nm and 15 nm gold nanoparticles and imaged using XRM. Following XRM, the brains, spines and meninges were harvested for histology. RESULTS: Using AuNp-XRM, we demonstrate visualization of previously characterized glymphatic, cranial nerve, and choroid plexus-mediated CSF circulation patterns, and present evidence to further identify CSF interactions with the leptomeninges, choroid plexus, and parenchyma of the brain and spinal cord. We also identified an intraparenchymal CSF circulation that targets stem-cell rich and cholinergic neuronal populations. CSF distribution to these areas was mediated by flow of CSF through the paravascular spaces of perforators originating from the large blood vessels of the basal cisterns and was significantly decreased in an animal model of PHH. CONCLUSION: Our findings using AuNp-XRM show that cholinergic cell populations in the brain and spinal cord differentially handle CSF, and that PHH alters CSF distribution to these areas of the brain. These region-specific patterns of CSF distribution may have critical relevance to normal brain development, brain development following PHH, and other neuropathological conditions.

Diagnosis and Therapy for Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension is a pathological state of increased intracranial pressure without intracranial mass lesion, vascular lesion, or hydrocephalus. For the diagnosis of this pathology, various secondary and primary headaches, such as migraine and medication overuse headaches should be excluded. Radiological imaging, including diffusion tensor imaging may show secondary findings of intracranial hypertension. These imaging techniques may be useful to diagnose intracranial hypertension, because at present there is no reliable non-invasive method to measure intracranial pressure. The pathophysiology of idiopathic intracranial hypertension has not been revealed; however there are some theories include, the disorder of cerebrospinal fluid circulation, disturbance of intracranial venous circulation, and metabolic disorders. Headache, nausea, and optic disc edema are frequently observed. The disease is frequently seen in obese females of childbearing age. Several therapies, including weight reduction, medication, and surgery have been studied; however the level of evidence for these therapies remains low.

Treatment for Hydrocephalus Caused by Intraventricular Tumors

Intraventricular tumors often cause hydrocephalus because their location in the ventricles affect cerebrospinal fluid circulation. Even small tumors can lead to acute hydrocephalus when they block the cerebrospinal fluid flow. They may also be found as large tumors occurring in large spaces, such as in lateral ventricles. Since various histological tumors occur in ventricles, it is important to consider the treatment strategy according to the expected histological type before treating hydrocephalus in the early stage. In addition, it is beneficial to predict and evaluate the site and size of the tumor, the cause of hydrocephalus, and the effect of postoperative chemotherapy and radiation therapy. Some tumors are sensitive to chemotherapy and radiation therapy, so there is an advantage in performing a biopsy at the same time as hydrocephalus treatment. Ventricular drainage and ventricular peritoneal shunts for patients with high intracranial pressure are at risk of developing ascending hernias, so we should be careful with the procedure.