Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy

Smilnak, Gordon; Charalambous, Lefko T; Cutshaw, Drew; Premji, Alykhan; Giamberardino, Charles; Ballard, Christi; Bartuska, Andrew; Ejikeme, Tiffany; Sheng, Huaxin; Verbick, Laura Zitella; Hedstrom, Blake; Pagadala, Promila; McCabe, Aaron; Perfect, John R.; Lad, Shivanand P.

doi:10.1093/infdis/jiy286

Cited by 31 publications

(24 citation statements)

References 34 publications

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“…A research group in the USA have recently published a proof of concept using an animal model wherein they filtered cryptococcus out of the CSF of rabbits using a process called neurapheresis (40). This approach is in its infancy but warrants further exploration.…”

Section: Neurapheresismentioning

confidence: 99%

Emerging concepts in HIV-associated cryptococcal meningitis

Lawrence

Boyer-Chammard

Jarvis

2019

Current Opinion in Infectious Diseases

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Purpose of review: HIV-associated cryptococcal meningitis (CM) remains a significant contributor to AIDS-related mortality despite widened access to antiretroviral therapy. Even in clinical trial settings 10-week mortality is roughly 40%. A number of important clinical trials have either recently concluded or are actively recruiting. Recent findings: Global burden of disease etimates suggest CM causes 181,100 deaths annualy. Screening blood for cryptococcal antigen (CrAg) in HIV-infected individuals with CD4 cell counts <100 cells/µL and pre-emptive antifungal treatment for those with detectable CrAg reduces the incidence of CM and is likely to reduce mortality. CM treatment with conventional 14-day courses of amphotericin are associated with high toxicity and mortality and can be reduced to seven days if given alongside flucytosine. Flucytosine is a significantly superior adjunct to amphotericin treatment compared to fluconazole. In settings without amphotericin B dual oral antifungal combinations of flucytosine and fluconazole offer an effective alternative treatment. A single, high-dose of liposomal amphotericin is effective at reducing fungal burden and is being tested in a phase III trial. Summary: Recently completed and ongoing clinical trials are increasing our understanding of how to optimise induction therapy for CM. Advocacy efforts are needed to broaden access to amphotericin formulations and flucytosine.

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Section: Neurapheresismentioning

confidence: 99%

Emerging concepts in HIV-associated cryptococcal meningitis

Lawrence

Boyer-Chammard

Jarvis

2019

Current Opinion in Infectious Diseases

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“…A rabbit model was used to investigate Neurapheresis therapy in the context of cryptococcal meningitis. This study showed a 5-log reduction in yeast concentration and 1-log reduction in its polysaccharide antigen over 24-h. A drawback of the study was that the rabbit model has an extremely small SAS, thus it is unclear how rabbit CSF dynamics compare to humans [27]. A study by Tangen et al [28] presented a computational and in vitro model of SAH clearance from CSF.…”

Section: Introductionmentioning

confidence: 99%

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

Khani

Sass

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'

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“…Researchers have investigated safety, tolerability, and pharmacodynamics of IT injection for a range of ALS therapeutics [6]. Additionally, filtration of cerebrospinal fluid (CSF) is actively being developed as a treatment for cryptococcal meningitis [8], subarachnoid hemorrhage [9] and has been used experimentally in ALS [10,11].…”

mentioning

confidence: 99%

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

Sass

Khani

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.

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Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy

Cited by 31 publications

References 34 publications

Emerging concepts in HIV-associated cryptococcal meningitis

Emerging concepts in HIV-associated cryptococcal meningitis

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

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

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