Characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging

Romm

et al. 2020

Fluids Barriers CNS

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Background: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. Methods: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. Results: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. Conclusion: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.

Section: Potential Implications For Intrathecal Als Therapeuticsmentioning

confidence: 89%

Section: Reliability Of Mri Based Measurements Of Csf Hydrodynamicsmentioning

confidence: 94%

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Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Romm

et al. 2020

Fluids Barriers CNS

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“…Results from this real-time visualization could be used to estimate and compare the efficiency of the Neurapheresis therapy to traditional lumbar drain at each time point. Also, in principle, a nonhuman primate experimental model of SAH could be developed, but such studies are expensive, are only available at limited research centers, and do not provide similar CSF dynamics to humans [25,26].…”

Section: Introductionmentioning

confidence: 99%

In vitro and numerical simulation of blood removal from cerebrospinal fluid: comparison of lumbar drain to Neurapheresis therapy

Sharp

et al. 2020

Fluids Barriers CNS

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Background: Blood removal from cerebrospinal fluid (CSF) in post-subarachnoid hemorrhage patients may reduce the risk of related secondary brain injury. We formulated a computational fluid dynamics (CFD) model to investigate the impact of a dual-lumen catheter-based CSF filtration system, called Neurapheresis ™ therapy, on blood removal from CSF compared to lumbar drain. Methods:A subject-specific multiphase CFD model of CSF system-wide solute transport was constructed based on MRI measurements. The Neurapheresis catheter geometry was added to the model within the spinal subarachnoid space (SAS). Neurapheresis flow aspiration and return rate was 2.0 and 1.8 mL/min, versus 0.2 mL/min drainage for lumbar drain. Blood was modeled as a bulk fluid phase within CSF with a 10% initial tracer concentration and identical viscosity and density as CSF. Subject-specific oscillatory CSF flow was applied at the model inlet. The dura and spinal cord geometry were considered to be stationary. Spatial-temporal tracer concentration was quantified based on time-average steady-streaming velocities throughout the domain under Neurapheresis therapy and lumbar drain. To help verify CFD results, an optically clear in vitro CSF model was constructed with fluorescein used as a blood surrogate. Quantitative comparison of numerical and in vitro results was performed by linear regression of spatial-temporal tracer concentration over 24-h. Results:After 24-h, tracer concentration was reduced to 4.9% under Neurapheresis therapy compared to 6.5% under lumbar drain. Tracer clearance was most rapid between the catheter aspiration and return ports. Neurapheresis therapy was found to have a greater impact on steady-streaming compared to lumbar drain. Steady-streaming in the cranial SAS was ~ 50× smaller than in the spinal SAS for both cases. CFD results were strongly correlated with the in vitro spatial-temporal tracer concentration under Neurapheresis therapy (R 2 = 0.89 with + 2.13% and − 1.93% tracer concentration confidence interval). Conclusion:A subject-specific CFD model of CSF system-wide solute transport was used to investigate the impact of Neurapheresis therapy on tracer removal from CSF compared to lumbar drain over a 24-h period. Neurapheresis therapy was found to substantially increase tracer clearance compared to lumbar drain. The multiphase CFD results were verified by in vitro fluorescein tracer experiments. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

“…Human clinical trials of Neurapheresis therapy in SAH patients are being conducted (PILLAR trial (21)(22)(23)), but these studies lack real-time visualization of blood distribution and are only able to sample CSF from select locations. Also, in principle, a nonhuman primate experimental model of SAH could be developed, but such studies are expensive, are only available at limited research centers, and do not provide similitude of CSF dynamics to humans (24,25).…”

Section: Introductionmentioning

confidence: 99%

In vitro and Numerical Simulation of Blood Removal from Cerebrospinal Fluid: Comparison of Lumbar Drain to Neurapheresis Therapy

Sharp

et al. 2020

Preprint

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Background: Blood removal from cerebrospinal fluid (CSF) in post-subarachnoid hemorrhage patients may reduce the risk of related secondary brain injury. We formulated a computational fluid dynamics (CFD) model to investigate the impact of a dual-lumen catheter-based CSF filtration system, called Neurapheresis TM therapy, on blood removal from CSF compared to lumbar drain. Methods: A subject-specific multiphase CFD model of CSF system-wide solute transport was constructed based on MRI measurements. The Neurapheresis catheter geometry was added to the model within the spinal subarachnoid space. Neurapheresis flow aspiration and return rate was 2.0 and 1.8 (mL/min), versus 0.2 (mL/min) drainage for lumbar drain. Blood was modeled as a bulk fluid phase within CSF with a 10% initial tracer concentration and identical viscosity and density as CSF. Subject-specific oscillatory CSF flow was applied at the model inlet. The dura and spinal cord geometry were considered to be stationary. Spatial-temporal tracer concentration was quantified based on time-average steady-streaming velocities throughout the domain under Neurapheresis therapy and lumbar drain. To help verify CFD results, an optically clear in vitro CSF model was constructed with fluorescein used as a blood surrogate. Quantitative comparison of numerical and in vitro results was performed by linear regression of spatial-temporal tracer concentration over 24-hours. Results: After 24-hours, tracer concentration was reduced to 4.9% under Neurapheresis therapy compared to 6.5% under lumbar drain. Tracer clearance was most rapid between the catheter aspiration and return ports. Neurapheresis therapy was found to have a greater impact on steady-streaming compared to lumbar drain. Steady-streaming in the cranial SAS was ~50X smaller than in the spinal subarachnoid space for both cases. CFD results were strongly correlated with the in vitro spatial-temporal tracer concentration under Neurapheresis therapy (R 2 =0.89 with +2.13% and -1.93% tracer concentration confidence interval). Conclusion: A subject-specific CFD model of CSF system-wide solute transport was used to investigate the impact of Neurapheresis therapy on tracer removal from CSF compared to lumbar drain over a 24-hour period. Neurapheresis therapy was found to substantially increase tracer clearance compared to lumbar drain. The multiphase CFD results were verified by in vitro fluorescein tracer experiments.