Cerebrospinal Fluid Flow Research Articles

Reduced coupling between global signal and cerebrospinal fluid inflow in patients with depressive disorder: A resting state functional MRI study

BackgroundDepressed patients often suffer from sleep disturbance, which has been recognized to be responsible for glymphatic dysfunction. The purpose of this study was to investigate the coupling strength of global blood‑oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) inflow dynamics, which is a biomarker for glymphatic function, in depressed patients and to explore its potential relationship with sleep disturbance by using resting-state functional MRI. MethodsA total of 138 depressed patients (112 females, age: 34.70 ± 13.11 years) and 84 healthy controls (29 females, age: 36.6 ± 11.75 years) participated in this study. The gBOLD-CSF coupling strength was calculated to evaluate glymphatic function. Sleep disturbance was evaluated using the insomnia items (item 4 for insomnia-early, item 5 for insomnia-middle, and item 6 for insomnia-late) of The 17-item Hamilton Depression Rating Scale for depressed patients, which was correlated with the gBOLD-CSF coupling strength. ResultsThe depressed patients exhibited weaker gBOLD-CSF coupling relative to healthy controls (p = 0.022), possibly due to impairment of the glymphatic system. Moreover, the gBOLD-CSF coupling strength correlated with insomnia-middle (r = 0.097, p = 0.008) in depressed patients.LimitationsThis study is a cross-sectional study. ConclusionOur findings shed light on the pathophysiology of depression, indicating that cerebral waste clearance system deficits are correlated with poor sleep quality in depressed patients.

Cerebellar Tonsillar Herniation an Incidental Finding in Asymptomatic Patient

Cerebellar tonsillar herniation, often associated with Chiari malformation, involves the downward displacement of the cerebellar tonsils below the foramen magnum. This condition can lead to significant complications due to the limited intracranial space within the rigid skull. Timely diagnosis is crucial given its potentially fatal nature, with brain structural displacement evident on imaging studies. We present a case of a 27-year-old female with continuous headaches and dizziness, diagnosed with tonsillar herniation through MRI revealing 16 mm of tonsillar descent without associated hydrocephalus or syrinx. Tonsillar herniation, characterized by inferior descent of the cerebellar tonsils, may be congenital or acquired, with measurements typically referenced from the McRae line to the displaced tonsil tip. Complications include brainstem compression, obstruction of cerebrospinal fluid flow, syringomyelia, impaired blood flow, and various neurological and psychological symptoms. Management options vary based on symptom severity and may involve observation, medication, or surgical intervention to alleviate compression and improve cerebrospinal fluid flow. Consultation with a neurologist or neurosurgeon is essential for comprehensive evaluation and tailored management plans aiming to relieve pressure on the brainstem and spinal cord in tonsillar herniation cases.

Validating the accuracy of real-time phase-contrast MRI and quantifying the effects of free breathing on cerebrospinal fluid dynamics

BackgroundUnderstanding of the cerebrospinal fluid (CSF) circulation is essential for physiological studies and clinical diagnosis. Real-time phase contrast sequences (RT-PC) can quantify beat-to-beat CSF flow signals. However, the detailed effects of free-breathing on CSF parameters are not fully understood. This study aims to validate RT-PC’s accuracy by comparing it with the conventional phase-contrast sequence (CINE-PC) and quantify the effect of free-breathing on CSF parameters at the intracranial and extracranial levels using a time-domain multiparametric analysis method.MethodsThirty-six healthy participants underwent MRI in a 3T scanner for CSF oscillations quantification at the cervical spine (C2-C3) and Sylvian aqueduct, using CINE-PC and RT-PC. CINE-PC uses 32 velocity maps to represent dynamic CSF flow over an average cardiac cycle, while RT-PC continuously quantifies CSF flow over 45-seconds. Free-breathing signals were recorded from 25 participants. RT-PC signal was segmented into independent cardiac cycle flow curves (Qt) and reconstructed into an averaged Qt. To assess RT-PC’s accuracy, parameters such as segmented area, flow amplitude, and stroke volume (SV) of the reconstructed Qt from RT-PC were compared with those derived from the averaged Qt generated by CINE-PC. The breathing signal was used to categorize the Qt into expiratory or inspiratory phases, enabling the reconstruction of two Qt for inspiration and expiration. The breathing effects on various CSF parameters can be quantified by comparing these two reconstructed Qt.ResultsRT-PC overestimated CSF area (82.7% at aqueduct, 11.5% at C2-C3) compared to CINE-PC. Stroke volumes for CINE-PC were 615 mm³ (aqueduct) and 43 mm³ (spinal), and 581 mm³ (aqueduct) and 46 mm³ (spinal) for RT-PC. During thoracic pressure increase, spinal CSF net flow, flow amplitude, SV, and cardiac period increased by 6.3%, 6.8%, 14%, and 6%, respectively. Breathing effects on net flow showed a significant phase difference compared to the other parameters. Aqueduct-CSF flows were more affected by breathing than spinal-CSF.ConclusionsRT-PC accurately quantifies CSF oscillations in real-time and eliminates the need for cardiac synchronization, enabling the quantification of the cardiac and breathing components of CSF flow. This study quantifies the impact of free-breathing on CSF parameters, offering valuable physiological references for understanding the effects of breathing on CSF dynamics.

Study of the possibilities of non-invasive assessment of increased intracranial pressure according to MRI data on the example of patients with secondary intracranial hypertension

Modern methods of neuroimaging make it possible to develop approaches for assessing intracranial pressure as a replacement for the “gold standard” of invasive monitoring. Aim of the study was to investigate the possibility of using magnetic resonance (MR) characteristics to assess the increase in intracranial pressure in patients with secondary intracranial hypertension. Material and methods. Group 1 – 40 patients with brain tumors, group 2 – 15 patients with communicating hydrocephalus, control group – 36 individuals. The patients underwent MRI with measurement and evaluation of the optic nerve sheath diameter (ONSD), the optochiasmal cistern and the pituitary gland vertical sizes, and tortuosity of the ON. Patients of the 2nd group underwent a phase-contrast MRI with an assessment of the velocity and volumetric characteristics of blood and cerebrospinal fluid flows with the calculation of the intracranial compliance index (ICC). Using the FreeSurfer program, the brain volumes were estimated. Results and discussion. A statistically significant increase in ONSD was found in the groups of patients compared with the control group (by 24 %, p < 0.05), decrease in the vertical size of the pituitary gland and an increase in the vertical size of the optochiasmal cistern (p < 0.05), as well as ICC lowering in group 2 (by 1.7 times, p < 0.05). Tortuosity of ON in group 1 was observed more often than in other groups. A statistically significant positive correlation between ONSD and brain volumes in group 1 (r = 0.55, p < 0.05) and a negative correlation between brain volumes and ICC in group 2 (r = –0.86, p < 0.05) has been found. Conclusions. Based on the presented results, we believe that the combined use of qualitative and quantitative MRI criteria can expand the diagnostic capabilities of non-invasive assessment of increased intracranial pressure.

Effect of nitric oxide modulators on cerebrospinal fluid outflow through the cribriform plate of C57Bl/6 mice

Introduction. Beside the excretion of metabolic wastes, the lymphatic system in CNS play a crucial role in the regulation of intracranial pressure that is vital for the organism. One of the possible pathways of cerebrospinal fluid (CSF) drainage is its flow through the foramen of the cribriform plate (CP) into the nasal cavity. Despite the significant contribution of the nasal tract to the overall dynamics of the liquor, not much is known about the mechanisms of this process and how it is regulated. Due to its influence on the tone of blood vessels and peristalsis of lymphatic vessels, nitric oxide (NO) is a powerful modulator of liquor outflow, but its effects on nasal CSF outflow have not been studied yet. Aim and Methods. Using diffusion-weighted magnetic resonance imaging (DW MRI), we characterized the changes in CSF outflow through the CP of C57Bl/6 mice influenced by intranasal application of NO synthesis modulators. Results. In our study, using DW MRI and computer tomography (CT) mapping of the CP, we detected significant CSF outflow through its large dorsal and ventral foramen located along the nasal septum. At the same time, the CSF flow rate through the dorsal orifices of the CP was the highest. In addition, we showed that intranasal introduction of NO donor after 30 min leads to a significant decrease of water diffusion through the CP whereas application of a nonspecific NO synthase inhibitor into the nasal cavity enhances nasal outflow. The effects of the NO modulators did not have any significant spatial patterns; CSF outflow was significantly altered across all CP orifices regardless of their size or localization. Conclusion. The obtained results demonstrate the potential possibility of noninvasive local regulation of liquor dynamics, which may be used in the development of new approaches to the therapy of intracranial hypertension of various etiologies and methods of CNS detoxification.

Investigation of Antibody Pharmacokinetics in the Brain Following Intra-CNS Administration and Development of PBPK Model to Characterize the Data.

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders.

Abstract B026: Rotational magnetic drug targeting for leptomeningeal metastases

Abstract Background: Magnetic nanoparticles (MNPs) have potential for enhancing the delivery of therapeutic molecules to cancer cells and micronodules, including non-obstructing metastases within cerebrospinal fluid (CSF) pathways. Rotational magnetic drug targeting (rMDT) takes advantage of the surface-walking capability of clusters of MNPs, which can be activated remotely. Here, we present data related to 1) the creation, characterization, and in vitro testing of a variety of MNPs utilized with bound or unbound chemotherapeutic agents, and 2) the design and construction of four different magnetomotive systems used to propel MNPs at clinically-relevant distances. The goal was to create an in vitro model mimicking conditions found in patients with leptomeningeal metastases. Methods: Gold-iron alloy nanoparticles were combined with biotinylated etoposide via the streptavidin-biotin interaction. Unbound MNPs were tested with etoposide and doxorubicin. MNPs were characterized by techniques including electron microscopy, Zeta potential analysis, and dynamic light scattering. 3D-printed and acrylic trays were used as conduits for measuring translational motion over distances up to 30 cm through saline, culture media, and artifical CSF. MNP velocities were determined by videography. For propelling the MNPs, one electromagnetic system used a Helmholtz pair of coils on each side of an underlying perpendicular coil. The second electromagnetic system utilized 2 angled coils. Two rotating permanent magnet systems used neodymium-boron-iron magnets of different sizes and rotational speeds. Cultured cells included fibroblasts, lung cancer, glioblastoma, and medulloblastoma cell lines. Light microscopy and cytotoxicty assays (by MTT and trypan blue exclusion) were used to assess preservation of tumoricidal activity. Results: In unbound MNP studies, both etoposide and doxorubin could be dispersed over physiologic distances through saline and artificial CSF at velocities exceeding 1 cm/sec - much faster than by diffusion alone. Drugs conveyed in this manner could be transported at 37°C across cell surfaces and retain tumoricidal effect on cultured cells. With rotating magnets, MNPs could be moved against a saline flow rate of 1 cm/sec. In bound MNP studies, true rMDT was possible - all four magnetomotive systems could be shut off, depositing the MNP-drug conjugate at the desired location. Rotating permanent magnets were found to be advantageous for unilateral device design; electromagnetic devices, however, are more likely to be compatible with concurrent magnetic particle imaging (currently under development). Conclusions: These in vitro findings indicate that rMDT within CSF pathways is feasible and should advance to animal studies. Bound MNPs may prove to be more useful for intrathecal use (administered via lumbar puncture or Ommaya reservoir), considering dilutional effects and CSF flow. An improved ability to direct therapeutic agents within CSF would represent a major step forward in the treatment of patients with leptomeningeal metastases. Citation Format: Herbert Engelhard, Alexander Willis, Tolou Shokuhfar, Lamar Mair. Rotational magnetic drug targeting for leptomeningeal metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B026.

Anatomical surgical approach to lateral vetricle masses and histopathological findings of the brain.

The selection of surgical approach to the lateral ventricular masses includes difficulties due to their deep localizations, close proximity to the vascular and the eloquent brain structures. The most appropriate approach that should be chosen in surgical treatment of lateral ventricular masses is still controversial. In this study, the factors in the choice of surgical approach to the lateral ventricle masses and the results of them were investigated. In this study, 80 patients who underwent surgery in our clinic due to the lateral ventricular masses were retrospectively analyzed between the years 2002-2013. All of the cases were evaluated in terms of clinical and neuroradiological results pre and postoperatively. In 24 cases the anterior interhemispheric transcallosal, in 4 cases the posterior interhemispheric transcallosal, in 30 cases the posterior interhemispheric precuneal, in 14 cases the transcortical and in 8 cases the combined surgical approaches were performed. Gender distribution of the cases were 45 male/35 female and the mean age of them was 31.7 years (7 month - 73 years). In 64 patients the gross total resection was performed, whereas in 16 patients subtotal resection was performed due to the infiltration of eloquent brain areas. In the histopathological examination; 52 neuroepithelial, 8 mixed neuroglial, 3 meningeal, 2 lympho-hematopoietic system, 1 pine blastoma, 1 germ cell, 5 metastatic and 8 other benign masses were observed. After surgery, additional neurological deficits developed in 9 patients. The mortality was observed in 6 patients postoperatively. The average follow-up time was 13 (1-83) months. The essential factors which affect the results of surgical treatment of lateral ventricular masses are; the size of the mass, histopathology, location, extension, and the relationship to the neurovascular structures. The goal of surgery is to provide the histopathological diagnosis, gross total resection, if it is possible, and to normalize the flow of cerebrospinal fluid by eliminating the mass effect of pressure.

Subdural hygromas After Decompressive Craniotomies

Subdural hygromas occur after various brain interventions, are often asymptomatic but sometimes may require surgical treatment. They can develop in the immediate postoperative period, but they are more common a few weeks or even months after surgery. Subdural hygromas are particularly common after decompressive craniotomy in patients with traumatic brain injury or massive stroke. The pathogenesis is explained by the fact that a large bone defect causes a pressure difference in the skull, and a concomitant displacement of the ventricular system disrupts the normal cerebrospinal fluid circulation, contributing to the redistribution of cerebrospinal fluid flow into the subdural space.We review data from contemporary studies on subdural hygromas after decompressive craniotomy, their risk factors, and management strategies. We also present our case of recurrent subdural hygroma in a patient operated on for a ruptured aneurysm of the middle cerebral artery.

Ventriculoperitoneal shunt entry points in patients undergoing shunt placement: A single-center study

BackgroundThe ventriculoperitoneal (VP) shunt redirects cerebrospinal fluid flow, with the selection of entry points crucial for optimal outcomes. Anatomical landmarks and specific entry points, such as Kocher's, Frazier's, Keen's, and Dandy's points, have been utilized for shunt catheter placement. This study investigates the impact of various entry points on outcomes, particularly the necessity for revision procedures, in patients undergoing VP shunt placement. MethodsIn this retrospective cohort study, we analyzed data from patients in our center's database, collected from October 2017 to October 2022. Participants were classified based on ventriculoperitoneal shunt entry points. The study followed STROBE guidelines. Continuous variables were presented as means with standard deviations (SD) and categorical variables as frequencies and percentages. Linear Model ANOVA and Pearson's Chi-squared tests were used for comparisons. Data analysis was conducted using Jamovi software. ResultsOur study included 94 patients who underwent shunt procedures. The patients were categorized into four treatment groups: Dandy point (10), Frazier point (21), Keen point (43), and Kocher point (20). ConclusionOur study found no significant differences in age, FOHR, and indication for shunt placement among catheter entry point subgroups. However, gender distribution, catheter length, and catheter tip location significantly varied. The proportion of patients requiring revision surgery varied among the groups, with the highest rate in the Dandy point group and the lowest in the Keen group; however, the difference among the entry groups was insignificant.

Assessment of the Diagnostic Utility of Cerebrospinal Fluid Flow Cytometry Immunophenotyping and Cytology in Acute Leukemias at a Public Chilean Hospital

We analyzed three hundred and eight CSF samples belonging to 175 patients, 57% male, with a median age of 46 years (1-70 years) were analyzed. Diagnoses were acute B lymphoblastic leukemia (B-ALL, 84%), acute T lymphoblastic leukemia (T-ALL 5%), acute myeloblastic leukemia (AML, 11%). The immunophenotype was performed with an 8-color panel adapted to the diagnosis. The proportion of non-assessable CSF samples in LA was higher for CC (46%) than FCM (4%) (p<0.05). Overall, infiltration was found in 78/308 samples by FCM (25.3%) and in 8/77 by CC (10.4%) (p<0.0001). Seventy of 259 samples were positive in B-ALL (27%) and 6/34 in AML (17%). There were no CC+ cases in AML or T-ALL. The samples that were FCM+/CC+ had more significant infiltration (59.5%) than CMF+/CC-ones (30%) (p<0.0001). CMF detects more than twice as many CSF blast-positive cases in LA as CC and is, therefore, suitable for routine use along with CC.

IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve

BackgroundThe spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure.MethodsA chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION’s CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain.ResultsCCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION’s CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION’s CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION.ConclusionIL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.Graphical abstract

Large-scale in-silico analysis of CSF dynamics within the subarachnoid space of the optic nerve

BackgroundImpaired cerebrospinal fluid (CSF) dynamics is involved in the pathophysiology of neurodegenerative diseases of the central nervous system and the optic nerve (ON), including Alzheimer’s and Parkinson’s disease, as well as frontotemporal dementia. The smallness and intricate architecture of the optic nerve subarachnoid space (ONSAS) hamper accurate measurements of CSF dynamics in this space, and effects of geometrical changes due to pathophysiological processes remain unclear. The aim of this study is to investigate CSF dynamics and its response to structural alterations of the ONSAS, from first principles, with supercomputers.MethodsLarge-scale in-silico investigations were performed by means of computational fluid dynamics (CFD) analysis. High-order direct numerical simulations (DNS) have been carried out on ONSAS geometry at a resolution of 1.625 μm/pixel. Morphological changes on the ONSAS microstructure have been examined in relation to CSF pressure gradient (CSFPG) and wall strain rate, a quantitative proxy for mass transfer of solutes.ResultsA physiological flow speed of 0.5 mm/s is achieved by imposing a hydrostatic pressure gradient of 0.37–0.67 Pa/mm across the ONSAS structure. At constant volumetric rate, the relationship between pressure gradient and CSF-accessible volume is well captured by an exponential curve. The ONSAS microstructure exhibits superior mass transfer compared to other geometrical shapes considered. An ONSAS featuring no microstructure displays a threefold smaller surface area, and a 17-fold decrease in mass transfer rate. Moreover, ONSAS trabeculae seem key players in mass transfer.ConclusionsThe present analysis suggests that a pressure drop of 0.1–0.2 mmHg over 4 cm is sufficient to steadily drive CSF through the entire subarachnoid space. Despite low hydraulic resistance, great heterogeneity in flow speeds puts certain areas of the ONSAS at risk of stagnation. Alterations of the ONSAS architecture aimed at mimicking pathological conditions highlight direct relationships between CSF volume and drainage capability. Compared to the morphological manipulations considered herein, the original ONSAS architecture seems optimized towards providing maximum mass transfer across a wide range of pressure gradients and volumetric rates, with emphasis on trabecular structures. This might shed light on pathophysiological processes leading to damage associated with insufficient CSF flow in patients with optic nerve compartment syndrome.

CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2-induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

Assessment of Reversibility of Transverse Venous Sinus Stenosis in Patients With Papilledema.

Bilateral transverse venous sinus stenosis (TVSS) or stenosis of a dominant venous sinus has been found to be very sensitive radiological findings in patients with intracranial hypertension (IH), yet there is still an ongoing debate whether they constitute reversible or permanent phenomena. Thus, the purpose of this study was to investigate the reversibility of TVSS in patients with IH, including conservatively treated patients with signs of IH as defined by the presence of papilledema. This was a retrospective chart review of all patients diagnosed with IH between 2016 and 2022, assessed from 2 tertiary university-affiliated neuro-ophthalmology practices. Inclusion criteria were the presence of papilledema, as quantified by optical coherence tomography, and bilateral TVSS, which is considered typical of IH on neuroimaging. During follow-up, included patients must have had confirmation of papilledema resolution as well as subsequent neuroimaging after conservative treatment or cerebrospinal fluid flow diversion. Patients with dural sinus vein thrombosis or intrinsic stenosis from sinus trabeculations or significant arachnoid granulations were excluded from the study. Either CT venography or MRI/MR venography was reviewed by a fellowship-trained neuroradiologist, and the degree of stenosis was scored through the combined conduit score (CCS), as described by Farb et al. The primary outcome was to assess TVSS changes after resolution or improvement of papilledema. From 435 patients, we identified a subset of 10 who satisfied all inclusion criteria. Our cohort comprised entirely women with a median age of 29.5 years and a median BMI of 32.5 kg/m2. Treatment consisted of acetazolamide in 7 patients, of which 1 had additional topiramate and 2 underwent cerebrospinal fluid flow diversion. Furthermore, 6 patients demonstrated significant weight loss during follow-up. For the primary outcome, 5 of 10 patients exhibited no appreciable TVSS change, and 5 patients demonstrated significant improvement in TVSS, of which 4 received conservative treatment only. Papilledema resolution or improvement was statistically significantly associated with increasing average CCS, TVSS diameter, and grade. We were able to demonstrate that TVSS can be both irreversible and reversible in patients with resolved papilledema. The finding of TVSS reversibility from conservative treatment alone is novel and has important implications to optimize patient care. Future studies should work to identify factors associated with irreversible TVSS for subsequent targeted intervention and prevention.

Direction-selective Resistance to Cerebrospinal Fluid Flow as the Cause of Syringomyelia.

The pathophysiology of syringomyelia remains poorly understood. Two prevailing challenges stand out: the need for a comprehensive understanding of its diverse types and the yet-to-be-explained mechanism of cerebrospinal fluid (CSF) retention in the syrinx despite its higher pressure than that in the adjacent subarachnoid space. Expanding on our previous proposal that direction-selective resistance to subarachnoid CSF flow drives syringomyelia genesis, this study uses a computer model to explore this mechanism further. We developed a computer simulation model to study spinal CSF dynamics, employing a lumped parameter approach with multiple compartments. This model replicated the to-and-fro movement of CSF in the spinal subarachnoid space and within an intraspinal channel. Subsequently, a direction-selective resistance-opposing only the caudal subarachnoid CSF flow-was introduced at a specific location within the subarachnoid space. Following the introduction of the direction-selective resistance, a consistent pressure increase was observed in the intraspinal channel downstream of the resistance. Importantly, this increase in pressure accumulated with every cycle of to-and-fro CSF flow. The accumulation results from the pressure drop across the resistance, and its effect on the spinal cord matrix creates a pumping action in the intraspinal channel. Our findings elucidate the mechanisms underlying our hypothesis that a direction-selective resistance to subarachnoid CSF flow causes syringomyelia. This comprehensively explains the various types of syringomyelia and resolves the puzzle of CSF retention in the syrinx despite a pressure gradient.

Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury: a randomized controlled study.

JOURNAL/nrgr/04.03/01300535-202412000-00032/figure1/v/2024-04-08T165401Z/r/image-tiff For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Blood pressure lowering enhances cerebrospinal fluid efflux to the systemic circulation primarily via the lymphatic vasculature

BackgroundInside the incompressible cranium, the volume of cerebrospinal fluid is directly linked to blood volume: a change in either will induce a compensatory change in the other. Vasodilatory lowering of blood pressure has been shown to result in an increase of intracranial pressure, which, in normal circumstances should return to equilibrium by increased fluid efflux. In this study, we investigated the effect of blood pressure lowering on fluorescent cerebrospinal fluid tracer absorption into the systemic blood circulation.MethodsBlood pressure lowering was performed by an i.v. administration of nitric oxide donor (sodium nitroprusside, 5 µg kg−1 min−1) or the Ca2+-channel blocker (nicardipine hydrochloride, 0.5 µg kg−1 min−1) for 10, and 15 to 40 min, respectively. The effect of blood pressure lowering on cerebrospinal fluid clearance was investigated by measuring the efflux of fluorescent tracers (40 kDa FITC-dextran, 45 kDa Texas Red-conjugated ovalbumin) into blood and deep cervical lymph nodes. The effect of nicardipine on cerebral hemodynamics was investigated by near-infrared spectroscopy. The distribution of cerebrospinal fluid tracers (40 kDa horse radish peroxidase,160 kDa nanogold-conjugated IgG) in exit pathways was also analyzed at an ultrastructural level using electron microscopy.ResultsNicardipine and sodium nitroprusside reduced blood pressure by 32.0 ± 19.6% and 24.0 ± 13.3%, while temporarily elevating intracranial pressure by 14.0 ± 7.0% and 18.2 ± 15.0%, respectively. Blood pressure lowering significantly increased tracer accumulation into dorsal dura, deep cervical lymph nodes and systemic circulation, but reduced perivascular inflow along penetrating arteries in the brain. The enhanced tracer efflux by blood pressure lowering into the systemic circulation was markedly reduced (− 66.7%) by ligation of lymphatic vessels draining into deep cervical lymph nodes.ConclusionsThis is the first study showing that cerebrospinal fluid clearance can be improved with acute hypotensive treatment and that the effect of the treatment is reduced by ligation of a lymphatic drainage pathway. Enhanced cerebrospinal fluid clearance by blood pressure lowering may have therapeutic potential in diseases with dysregulated cerebrospinal fluid flow.

The Anatomy and Physiology of the Glymphatic System and Its Role in Craniectomies and Syndrome of the Trephined

Background: The glymphatic system, a relatively recently discovered system for transport of cerebrospinal fluid (CSF) and waste products in the central nervous system, has been implicated in several neurologic disorders. Altered CSF dynamics are seen after decompressive craniectomy, suggesting this procedure may impact glymphatic function. We aimed to systematically review the current literature to understand the effect of the glymphatic system on patients with decompressive craniectomies and Syndrome of the Trephined (SoT). Methods: PubMed and Embase were searched for preclinical and clinical studies investigating the glymphatic system and craniectomy, cranioplasty, or SoT in years 2012 to 2023. Results: Sixty-three studies were identified for review. Intracranial oscillations, cerebral perfusion, and arterial pulsations have been identified as major drivers of glymphatic influx. Each of these processes are diminished following craniectomy, suggesting craniectomy may impair glymphatic function. Reductions in brain pulsatility and alterations in glymphatic drainage after craniectomy were accompanied by impaired functional outcomes, as seen in SoT. Radiologically, CSF flow alterations are seen after craniectomies, which improve with cranioplasty. Conclusions: Glymphatic system dysfunction after craniectomy and in SoT may be a potential therapeutic target for patients with iatrogenically altered cranial vault anatomy.

Higher intracranial arterial pulsatility is associated with presumed imaging markers of the glymphatic system: An explorative study

BackgroundArterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation of glymphatic clearance. However, whether intracranial arterial pulsatility is associated with glymphatic markers in humans has not yet been studied. MethodsSeventy-three community participants were enrolled in the study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify the hemodynamic parameters including flow pulsatility index (PIflow) and area pulsatility index (PIarea) from 13 major intracerebral arterial segments. Three presumed neuroimaging markers of the glymphatic system were measured: including dilation of perivascular space (PVS), diffusivity along the perivascular space (ALPS), and volume fraction of free water (FW) in white matter. We explored the relationships between PIarea, PIflow, and the presumed glymphatic markers, controlling for related covariates. ResultsPIflow in the internal carotid artery (ICA) C2 segment (OR, 1.05; 95 % CI, 1.01–1.10, per 0.01 increase in PI) and C4 segment (OR, 1.05; 95 % CI, 1.01–1.09) was positively associated with the dilation of basal ganglia PVS, and PIflow in the ICA C4 segment (OR, 1.06, 95 % CI, 1.02–1.10) was correlated with the dilation of PVS in the white matter. ALPS was associated with PIflow in the basilar artery (β, -0.273, p, 0.046) and PIarea in the ICA C2 (β, -0.239, p, 0.041) and C7 segments (β, -0.238, p, 0.037). Conclusions: Intracranial arterial pulsatility was associated with presumed neuroimaging markers of the glymphatic system, but the results were not consistent across different markers. Further studies are warranted to confirm these findings.