Evaluation of Neurapheresis Therapy In Vitro: A Novel Approach for the Treatment of Leptomeningeal Metastases

April 18, 2020

Neuro-Oncology Advances

Tiffany Ejikeme, George C. de Castro, Katelyn Ripple, Yutong Chen, Charles Giamberardino, Andrew Bartuska, Gordon Smilnak, Choiselle Marius, Jane-Valeriane Boua, Pakawat Chongsathidkiet, Sarah Hodges, Promila Pagadala, Laura Zitella Verbick, Aaron R. McCabe, and Shivanand P. Lad

Leptomeningeal metastases (LM), late-stage cancer when malignant cells migrate to the subarachnoid space (SAS), have an extremely poor prognosis. Current treatment regimens fall short in effectively reducing SAS tumor burden. Neurapheresis therapy is a novel approach employing filtration and enhanced circulation of the cerebrospinal fluid (CSF). Here, we examine the in vitro use of neurapheresis therapy as a novel, adjunctive treatment option for LM by filtering cells and augmenting the distribution of drugs that may have the potential to enhance the current clinical approach.

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

March 16, 2020

Fluid and Barriers of the CNS

Mohammadreza Khani, Lucas R. Sass, M. Keith Sharp, Aaron R. McCabe, Laura M. Zitella Verbick, Shivanand P. Lad, Bryn A. Martin

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.

Impact of Neurapheresis System on Intrathecal Cerebrospinal Fluid Dynamics: A Computational Fluid Dynamics Study

February 1, 2020

Journal of Biomechanical Engineering

Mohammadreza Khani, Lucas R. Sass, Aaron R. McCabe, Laura M. Zitella Verbick, Shivanand P. Lad, M. Keith Sharp, Bryn A. Martin

It has been hypothesized that early and rapid filtration of blood from cerebrospinal fluid (CSF) in postsubarachnoid hemorrhage patients may reduce hospital stay and related adverse events. In this study, we formulated a subject-specific computational fluid dynamics (CFD) model to parametrically investigate the impact of a novel dual-lumen catheter-based CSF filtration system, the Neurapheresis™ system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics.

Prospective Trial of Cerebrospinal Fluid Filtration After Aneurysmal Subarachnoid Hemorrhage via Lumbar Catheter (PILLAR)

July 26, 2019

Stroke

Spiros L. Blackburn, MD; Andrew W. Grande, MD; Christa B. Swisher, MD; Erik F. Hauck, MD; Bharathi Jagadeesan, MD; J. Javier Provencio, MD

The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm.

Prospective Trial of Cerebrospinal Fluid Filtration After Aneurysmal Subarachnoid Hemorrhage via Lumbar Catheter (PILLAR)

July 26, 2019

Stroke

Spiros L. Blackburnm Andrew W. Grande, Christa B. Swisher, Erik F. Hauck, Bharathi Jagadeesan, J. Javier Provencio

The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm.

In Vitro Anthropomorphic Model of the Cerebrospinal Fluid System: Application to Subarachnoid Hemorrhage Filtration

June 25 – 28, 2019

Summer Biomechanics, Bioengineering, and Biotransport Conference – Seven Springs, Pennsylvania

Lucas R. Sass , Mohammadreza Khani , Gabryel Conley Natividad , Elliott Marsden , Shavaine Byass , Omolola Bangudu, Aaron R. McCabe, Laura M. Zitella Verbick, Shivanand P. Lad , Bryn A. Martin

Complications following subarachnoid hemorrhage (SAH) such as delayed cerebral ischemia, vasospasm and hydrocephalus account for the poor prognosis and death of many patients[1]. SAH releases blood into the cerebrospinal fluid (CSF) exposing the surrounding tissue to inflammatory clotting byproducts[2]. Removal of blood via lumbar drain has been shown to positively impact clinical outcomes and the rapid removal of blood from the CSF is the target of a new device aimed at improving patient outcomes. The presented work outlines the assembly and testing of an in vitro platform (Figure 3) modeling active clearance of SAH using a dual lumen catheter-based CSF filtration device[3][4] (NeurapheresisTM System; Minnetronix Neuro, St. Paul, MN). This device introduces a flow loop aimed at improving particle clearance from the CSF.

Impact of Cerebrospinal Fluid Filtration on Subarachnoid Hemorrhage Clearance: A Computational Fluid Dynamics Study

June 25 – 28, 2019

Summer Biomechanics, Bioengineering, and Biotransport Conference – Seven Springs, Pennsylvania

Spiros L. Blackburn, MD; Andrew W. Grande, MD; Christa B. Swisher, MD; Erik F. Hauck, MD; Bharathi Jagadeesan, MD; J. Javier Provencio, MD

The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm.

Healthcare Economics of Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage in the United States

April 13, 2019

American Association of Neurological Surgeons – San Diego, CA

Syed M. Adil, Beiyu Liu, Lefko T. Charalambous, Musa Kiyani, Robert Gramer, Christa B. Swisher, Laura Zitella Verbick, Aaron McCabe, Beth A. Parente, Promila Pagadala, Shivanand P. Lad

Aneurysmal subarachnoid hemorrhage (aSAH) is a common but devastating condition, with fatality rates of 8-61% in the 1-month after diagnosis.¹

Hydrocephalus is one of the most common sequelae after aSAH, with its incidence ranging from 15-58.4% in the acute stage (48-72 hours after SAH) to 4.3-37% in the chronic stage (>14 days after SAH).²

Management of hydrocephalus involves longer lengths of stay³ and requires placing extraventricular drains, sometimes followed by conversion to ventriculoperitoneal (VP) shunts or endoscopic third ventriculostomy (ETV).

Though post-aSAH hydrocephalus is recognized as a common and significant concern, there is scarce literature determining its actual monetary or resource cost.

Healthcare Economics of Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage in the United States

March 13, 2019

Translational Stroke Research

Syed M. Adil, Beiyu Liu, Lefko T. Charalambous, Musa Kiyani, Robert Gramer, Christa B. Swisher, Laura Zitella Verbick, Aaron McCabe, Beth A. Parente, Promila Pagadala, Shivanand P. Lad

Abstract – Hydrocephalus is one of the most common sequelae after aneurysmal subarachnoid hemorrhage (aSAH), and it is a large contributor to the condition’s high rates of readmission and mortality. Our objective was to quantify the healthcare resource utilization (HCRU) and health economic burden incurred by the US health system due to post-aSAH hydrocephalus. The Truven Health MarketScan® Research database was used to retrospectively quantify the prevalence and HCRU associated with hydrocephalus in aSAH patients undergoing surgical clipping or endovascular coiling from 2008 to 2015. Multivariable longitudinal analysis was conducted to model the relationship between annual cost and hydrocephalus status. In total, 2374 patients were included; hydrocephalus was diagnosed in 959 (40.4%). Those with hydrocephalus had significantly longer initial lengths of stay (median 19.0 days vs. 12.0 days, p < .001) and higher 30-day readmission rates (20.5% vs. 10.4%, p < .001). With other covariates held fixed, in the first 90 days after aSAH diagnosis, the average cost multiplier relative to annual baseline for hydrocephalus patients was 24.60 (95% CI, 20.13 to 30.06; p < .001) whereas for non-hydrocephalus patients, it was 11.52 (95% CI, 9.89 to 13.41; p < .001). The 5-year cumulative median total cost for the hydrocephalus group was $230,282.38 (IQR, 166,023.65 to 318,962.35) versus $174,897.72 (IQR, 110,474.24 to 271,404.80) for those without hydrocephalus. We characterize one of the largest cohorts of post-aSAH hydrocephalus patients in the USA. Importantly, the substantial health economic impact and long-term morbidity and costs from this condition are quantified and reviewed.

Novel Dual Lumen Catheter and Filtration Device for Removal of Subarachnoid Hemorrhage: First Case Report

June 5, 2018

Operative Neurosurgery

Spiros L. Blackburn, MD, Christa B. Swisher, MD, Andrew W. Grande, MD, Alba Rubi, BS, Laura Zitella Verbick, PhD, Aaron McCabe, PhD, Shivanand P. Lad, MD, PhD

The amount of subarachnoid blood and the presence of toxic blood breakdown products in the cerebrospinal fluid (CSF) have long been associated with poor outcomes in aneurysmal subarachnoid hemorrhage. The Neurapheresis™ system (Minnetronix Inc, St. Paul, Minnesota) has been developed to filter CSF and remove blood products, and is being investigated for safety and feasibility in the Extracorporeal FIltration of subarachnoid hemorrhage via SpinaL Catheter (PILLAR) study. We report the first case using this novel device.

Prevalence, Healthcare Resource Utilization and Overall Burden of Fungal Meningitis in the United States

February 1, 2018

Journal of Medical Microbiology

Lefko T. Charalambous, Alykhan Premji, Caroline Tybout, Anastasia Hunt, Drew Cutshaw, Aladine A. Elsamadicy, Siyun Yang, Jichun Xie, Charles Giamberardino, Promila Pagadala, John R. Perfect and Shivanand P. Lad

Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States.

A Novel Therapeutic Approach for Leptomeningeal Metastases

December 14-16, 2017

Mayo Clinic Neuroscience and Oncology Innovation Summit 2017 – Orlando, FL

Tiffany Ejikeme, Pakawat Chongsathidkiet, Christi Ballard, Charles Giamberardino, Promila Pagadala, Laura Zitella Verbick, Blake Hedstrom, Aaron McCabe, Peter E. Fecci, Shivanand Lad

Leptomeningeal Metastases (LM) occurs when primary tumor cells metastasize, invade the subarachnoid space, and spread throughout the cerebrospinal fluid (CSF). As novel cancer therapies extend survival, LM has become increasingly prevalent, with approximately 110,000 diagnoses per year in the U.S.1 Despite advances in targeted radiation and chemotherapy, survival averages 3-6 months after LM diagnosis.2,3 Reducing tumor burden is the primary goal to extend survival and quality of life. We propose an intrathecal catheter-based extracorporeal filtration system (NeurapheresisTM therapy) as an alternative mechanical intervention for the filtration of tumor cells and distribution of chemotherapeutics in the CSF. Here, we demonstrate the ability of our system to reduce VX2 carcinoma cells in vitro.

In Vitro Characterization of the Neurapheresis™ System for the Treatment of Cryptococcal Meningitis

October 4-8, 2017

Duke University Medical Center/Minnetronix Neuro ID Week 2017 – San Diego, CA

Lefko Charalambous, Christi Ballard, Tiffany Ejikeme, Bilal Ashraf, Promila Pagadala, Charles Giamberardino, Blake Hedstrom, Laura Zitella Verbick, Aaron McCabe, Shivanand P. Lad, John R Perfect

Cryptococcal Meningitis is caused by Cryptococcus neoformans and is the most common cause of fungal meningitis in adults. Treatment for Cryptococcal Meningitis is based on an induction, consolidation, and maintenance approach with antifungals, but is associated with continued high morbidity and mortality. A catheter-based extracorporeal filtration system (Neurapheresis™ Therapy) for the filtration of infected CSF is a potential alternate or adjunctive intervention. This poster, produced with Duke University describes the in vitro characterization of Neurapheresis™ Therapy as an alternative mechanical intervention for filtration of C. neoformans cells, polysaccharide antigen, and inflammatory mediators from infected CSF.

Feasibility of Neurapheresis™ Therapy for Multidrug Resistant Gram-negative Bacterial Meningitis

October 4-8, 2017

Duke University Medical Center/Minnetronix Neuro ID Week 2017 – San Diego, CA

Christi G. Ballard, Bilal Ashraf, Tiffany Ejikeme, Brenda Hansen, Lefko Charalambous, Promila Pagadala, Batu K. Sharma-Kuinkel, Charles Giamberardino, Blake Hedstrom, Laura Zitella Verbick, Aaron McCabe, Shivanand Lad, Vance G. Fowler, John R. PerfectA

Pseudomonas, Acinetobacter and Klebsiella are three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. Patients in hospitals or nursing homes, and with devices such as intravenous catheters or ventilators are at increased risk of Gram-negative bacterial meningitis (GBM) from these bacteria. GBM manifests when these bacteria invade the central nervous system. Increasingly antibiotic resistant bacteria strains cause high mortality associated with MDR GBM. This poster demonstrates the feasibility of Neurapheresis™ Therapy for MDR GBM, and characterizes system parameters for bacterial, endotoxin, and cytokine clearance.

Leptomeningeal Disease: Current Diagnostic and Therapeutic Strategies

August 16, 2017

Gautam Nayar, Tiffany Ejikeme, et al Oncotarget

Gautam Nayar, Tiffany Ejikeme, Pakawat Chongsathidkiet, Aladine A. Elsamadicy, Kimberly L. Blackwell, Jeffrey M. Clarke, Shivanand P. Lad, Peter E. Fecci

Abstract: Leptomeningeal disease has become increasingly prevalent as novel therapeutic interventions extend the survival of cancer patients. Although a majority of leptomeningeal spread occurs secondary to breast cancer, lung cancer, and melanoma, a wide variety of malignancies have been reported as primary sources. Symptoms on presentation are equally diverse, often involving a combination of neurological deficits with the possibility of obstructive hydrocephalus. Diagnosis is definitively made via cerebrospinal fluid cytology for malignant cells, but neuro-imaging with high quality T1-weighted magnetic resonance imaging can aid diagnosis and localization. While leptomeningeal disease is still a terminal, late-stage complication, a variety of treatment modalities, such as intrathecal chemotherapeutics and radiation therapy, have improved median survival from 4–6 weeks to 3–6 months. Positive prognosticative factors for survival include younger age, high performance scores, and controlled systemic disease. In looking to the future, diagnostics that improve early detection and chemotherapeutics tailored to the primary malignancy will likely be the most significant advances in improving survival.

Novel Dual Lumen Catheter and Filtration Device for Removal of Subarachnoid Hemorrhage: First Case Report

June 5, 2017

Journal of Operative Neurosurgery

Spiros Blackburn, Christa B Swisher, Andrew W Grande, Alba Rubi, Laura Zitella Verbick, Aaron McCabe, Shivanand P Lad

The amount of subarachnoid blood and the presence of toxic blood breakdown products in the cerebrospinal fluid (CSF) have long been associated with poor outcomes in aneurysmal subarachnoid hemorrhage. The Neurapheresis™ system (Minnetronix Inc, St. Paul, Minnesota) has been developed to filter CSF and remove blood products, and is being investigated for safety and feasibility in the ExtracorPoreal FILtration of subarachnoid hemorrhage via SpinaL CAtheteR (PILLAR) study. We report the first case using this novel device.

Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy

June 5, 2017

The Journal of Infectious Diseases, Volume 218, Issue 7, 24 August 2018, Pages 1147–1154, June 5 2017

Gordon J Smilnak, Lefko T Charalambous, Drew Cutshaw, Alykhan M Premji, Charles D Giamberardino, Christi G Ballard, Andrew P Bartuska, Tiffany U Ejikeme, Huaxin Sheng, Laura Zitella Verbick, Blake A Hedstrom, Promila C Pagadala, Aaron R McCabe, John R Perfect, Shivanand P Lad

Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours…

A Novel Therapeutic Approach for Cryptococcal Meningitis

October 26-30, 2016

Duke University School of Medicine/Minnetronix Neuro ID Week 2016 – New Orleans, LA

Alykhan Premji , Drew Cutshaw , Blake Hedstrom, Charles Giamberardino , Promila Pagadala, Aaron McCabe, Shivanand Lad, John Perfect

Cryptococcal meningitis (CM) is a devastating opportunistic infection that primarily presents in immunocompromised patients. CM is caused when Cryptococcus neoformans, a basidiomycete fungal pathogen, invades the central nervous system (CNS) and circulates within cerebospinal fluid (CSF) around the brain and spinal cord in the subarachnoid space. Current treatment guidelines include two weeks of continuous intravenous administration of amphotericin B and flucytosine, and maintaining a fungicidal regimen for six months. The single most important factor impacting survival has been shown to be rapid reduction of C. neoformans organisms in CSF during the first two weeks of infection. This poster describes an experimental filtration system, demonstrating a 1-2 log reduction in CSF organism burden using an infected rabbit model of CM.