There is a growing consensus that blood in the cerebrospinal fluid (CSF) is deleterious to outcomes in patients with aneurysmal subarachnoid hemorrhage. The extracorporeal filtration of subarachnoid hemorrhage via spinal catheter extension study evaluated the safety, tolerability, and filtration curve of blood and its lysis products from hemorrhagic CSF using the Neurapheresis CSF Management System. After aneurysm repair, a dual-lumen intrathecal catheter was inserted into the study participant’s spinal canal. CSF was extracorporeally filtered for up to 72 h, removing blood products from the lumbar cistern, and reintroducing filtered CSF to the thoracic subarachnoid space. Neurological examinations were performed every 2 h, computed tomography scans were captured five times, and CSF samples were evaluated for cell counts every 8 h. Clinical follow-up evaluations were conducted 2 and 30 days after treatment. Twenty-seven of 29 study participants (93

Modification of cerebrospinal fluid (CSF) transport dynamics is an expanding method for treating central nervous system injury and diseases. One application of this route is to modify the distribution of solutes in the CSF; however, few tools currently exist for this purpose. The present study describes the use of a subject-specific in vitro CSF phantom to perform a parametric evaluation of the Neurapheresis™ CSF Management System (NP) for both CSF filtration and intrathecal drug circulation. An in vitro CSF phantom was constructed which included realistic anatomy for the complete subarachnoid space (SAS). This platform was configured to test multiple parametric modifications of a dual-lumen catheter and filtration system. Calibrated mapping of tracer distribution and area under the curve (AUC) measurements were used to compare filtration and intrathecal-circulation schemes using the NP device versus the clinical standards of care. The NP device showed potential advantages over lumbar drain (LD) for clearance of simulated subarachnoid hemorrhage (SAH), especially in the spinal canal. Use of the NP device in combination with simulated intracerebroventricular (ICV) drug infusion resulted in an increased extent and uniformity of tracer spread compared to ICV alone. NP improved clearance of simulated subarachnoid hemorrhage compared to LD and increased uniformity of tracer concentration via simulated ICV, providing support for NP use in these scenarios. The in vitro CSF phantom system presented here quantitatively described the effects of parametric boundary modification on solute distribution in the intrathecal space.

OBJECTIVENontraumatic, primary intracerebral hemorrhage (ICH) accounts for 2 million strokes worldwide annually and has a 1-year survival rate of 50%. Recent studies examining functional outcomes from ICH evacuation have been performed, but limited work has been done quantifying the incidence of subsequent complications and their healthcare economic impact. The purpose of this study was to quantify the incidence and healthcare resource utilization (HCRU) for major complications that can arise from ICH.METHODSThe IBM MarketScan Research databases were used to retrospectively identify patients with ICH from 2010 to 2015. Complications examined included cerebral edema, hydrocephalus, venous thromboembolic events (VTEs), pneumonia, urinary tract infections (UTIs), and seizures. For each complication, inpatient mortality and HCRU were assessed.RESULTSOf 25,322 adult patients included, 10,619 (42%) developed complications during the initial admission of ICH: 22% had cerebral edema, 11% hydrocephalus, 10% pneumonia, 6% UTIs, 5% seizures, and 5% VTEs. The inpatient mortality rates at 7 and 30 days for each complication of ICH ranked from highest to lowest were hydrocephalus (24% and 32%), cerebral edema (15% and 20%), pneumonia (8% and 18%), seizure (7% and 13%), VTE (4% and 11%), and UTI (4% and 8%). Hydrocephalus had the highest total cost (median $92,776, IQR $39,308-$180,716) at 7 days post-ICH diagnosis and the highest cumulative total cost (median $170,839, IQR $91,462-$330,673) at 1 year post-ICH diagnosis.CONCLUSIONSThis study characterizes one of the largest cohorts of patients with nontraumatic ICH in the US. More than 42% of the patients with ICH developed complications during initial admission, which resulted in high inpatient mortality and considerable HCRU.

BACKGROUND: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. METHODS:Clinically relevant concentrations of VX2 carcinoma cells were suspended in artificial CSF. The neurapheresis system's ability to clear VX2 carcinoma cells was tested with and without the chemotherapeutic presence (methotrexate [MTX]). The VX2 cell concentration following each filtration cycle and the number of cycles required to reach the limit of detection were calculated. The ability of neurapheresis therapy to circulate, distribute, and maintain therapeutic levels of MTX was assessed using a cranial-spinal model of the SAS. The distribution of a 6 mg dose was monitored for 48 h. An MTX-specific ELISA measured drug concentration at ventricular, cervical, and lumbar sites in the model over time. RESULTS:In vitro filtration of VX2 cancer cells with neurapheresis therapy alone resulted in a 2.3-log reduction in cancer cell concentration in 7.5 h and a 2.4-log reduction in live-cancer cell concentration in 7.5 h when used with MTX. Cranial-spinal model experiments demonstrated the ability of neurapheresis therapy to enhance the circulation of MTX in CSF along the neuraxis. CONCLUSION:Neurapheresis has the potential to act as an adjunct therapy for LM patients and significantly improve the standard of care.

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.

Abstract Leptomeningeal Metastases, a severe late stage form of cancer progression in which malignant cells metastasize to the subarachnoid space (SAS) and leptomeninges, has a mean survival rate of 3–6 months with treatment. Standard of care intrathecal chemotherapy, delivered via an Ommaya reservoir, is limited by poor diffusion within the SAS and acute drug-related neurotoxicity. Neurapheresis™ therapy (NA) is a novel therapy that uses a dual lumen intrathecal catheter and extracorporeal filtration system to filter cerebrospinal fluid (CSF) in a closed-loop. We have previously demonstrated the ability of NA to decrease cancer cell burden in artificial CSF in vitro. Here, NA is shown to enhance chemotherapeutic drug circulation, delivered intraventricularly, throughout the SAS in vitro. NA was tested with a cranial-spinal model of the SAS that included ventricular, cervical and lumbar sampling sites. Drug distribution was tested by comparing the circulation of a 6mg, 3mL ventricular bolus injection of Methotrexate (MTX) in PBS over 48 hours with and without NA (2.0 mL/min flow rate). Ventricular, cervical, and lumbar samples were collected at t=0.5, 4, 8, 12, 24, and 48 hours following drug administration and analyzed by a MTX-specific enzyme-linked immunosorbent assay (ELISA). Compared to controls, NA demonstrated increased, faster distribution of MTX throughout the neuraxis, with an average increase in MTX concentration of 63.7% and 171.5% in the cervical and lumbar sites, respectively, across time points from 4 to 24 hours. The NA system also rapidly decreased the high, potentially neurotoxic concentration of MTX in the ventricles immediately following drug administration and out to 12 hours post-injection. Future in vivo and in vitro testing focuses on pharmacokinetics (PK) in both animals and an advanced 3D-printed human cranial-spinal model to further evaluate the ability of the NA system to enhance MTX distribution throughout the SAS, while simultaneously removing circulating tumor cells.

BACKGROUND AND IMPORTANCE 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. CLINICAL PRESENTATION A 65-yr-old female presented with a ruptured left posterior communicating artery aneurysm. Following placement of a ventriculostomy and coil embolization of her aneurysm, the patient underwent placement of a lumbar dual lumen catheter for CSF filtration as part of the PILLAR study. In this case, a total of 9 h of filtration during 31 h of catheter indwelling resulted in 309.47 mL of processed CSF without complication. Computed tomography images demonstrated an interval reduction of subarachnoid hemorrhage immediately after filtration. The patient was discharged home on postbleed day 11 and at 30 d showed good recovery. CONCLUSION Safety of the Neurapheresis procedure was confirmed in this first case, and we will continue to evaluate safety of the Neurapheresis system through the PILLAR trial.

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.

INTRODUCTION: Intracerebral hemorrhage (ICH) is a major cause of morbidity and mortality worldwide, with a 1-mo mortality rate between 30% and 50%. Our goal was to quantify additional healthcare resource utilization (HCRU) incurred by the US health system due to complications sustained during initial ICH hospital admissions, including a cost comparison of complications treated invasively vs noninvasively. METHODS: The IBM MarketScan databases were used to retrospectively identify ICH patients and quantify the prevalence and HCRU of associated complications. HCRU variables included total service costs and length of hospital stay (LOS). Complications studied included cerebral edema, hydrocephalus, delayed ischemic stroke, venous thromboembolic events (VTE), infections (urinary tract infection (UTI) and pneumonia), and seizures. Invasive interventions included craniotomies/craniectomies and CSF diversion. Costs were assessed at 7, 30, 60, and 365 d post-ICH diagnosis for complications. RESULTS: A total of 29 989 adult patients were included. Of those, 18 387 (61%) developed at least 1 complication during their initial ICH admission: 35% delayed ischemic stroke, 23% cerebral edema, 15% infections, 11% hydrocephalus, 5% seizures, and 5% VTE. Overall median LOS for all ICH was 5 d (IQR 2-10 d). Patients developing VTE had the longest median LOS at 17 d (IQR 8-27 d) and highest 7-d inpatient cost (median $67,222; IQR $24,384-157,919). Hydrocephalus had similar median LOS (15 d; IQR 6-23 d) and second highest median 7-d inpatient cost (median $59,553; IQR $22,129-143,835). Patients suffering cerebral edema, hydrocephalus, or delayed ischemic stroke requiring invasive treatments had higher costs at all times, especially during the first 7 d, with differences ranging from $61,852 for hydrocephalus to $84,699 for delayed ischemic stroke. CONCLUSION: Delayed ischemic stroke and cerebral edema were the most common complications during initial ICH admission. VTE and hydrocephalus had the longest LOS and highest service costs at all times after diagnosis.

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 catheterbased CSF filtration system, the NeurapheresisTM system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics. The operating principle of this system is to remove CSF from one location along the spine (aspiration port), externally filter the CSF routing the retentate to a waste bag, and return permeate (uncontaminated CSF) to another location along the spine (return port). The CFD model allowed parametric simulation of how the Neurapheresis system impacts intrathecal CSF velocities and steady-steady streaming under various Neurapheresis flow settings ranging from 0.5 to 2.0 ml/min and with a constant retentate removal rate of 0.2 ml/min simulation of the Neurapheresis system were compared to a lumbar drain simulation with a typical CSF removal rate setting of 0.2 ml/min. Results showed that the Neurapheresis system at a maximum flow of 2.0 ml/min increased average steady streaming CSF velocity 2x in comparison to lumbar drain (0.190 +/- 0.133 versus 0.093 +/- 0.107 mm/s, respectively). This affect was localized to the region within the Neurapheresis flow loop. The mean velocities introduced by the flow loop were relatively small in comparison to normal cardiac-induced CSF velocities.

Background and Importance: The amount of subarachnoid blood and the presence of toxic blood breakdown products in the cerebrospinal fluid (CSF) has long been associated with poor outcomes in aneurysmal subarachnoid hemorrhage (aSAH). The NeurapheresisTM system 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. Clinical Presentation: A 65-year-old female presented with a ruptured left posterior communicating artery aneurysm. Following placement of a ventriculostomy and coil embolization of her aneurysm, the patient underwent placement of a lumbar dual lumen catheter for CSF filtration as part of the PILLAR study. In this case, a total of 9 hours of filtration during 31 hours of catheter indwelling resulted in 309.47 mL of processed CSF without complication. CT images demonstrated an interval reduction of SAH immediately after filtration. The patient was discharged home on post-bleed day 11 and at 30 days showed good recovery. Conclusion: Safety of the Neurapheresis procedure was confirmed in this first case, and we will continue to evaluate safety of the Neurapheresis system through the PILLAR trial. BACKGROUND AND IMPORTANCE Aneurysmal subarachnoid hemorrhage (aSAH) is a catastrophic result of a ruptured aneurysm. There are roughly 30,000 cases/year in the US, with worldwide incidence between 4.2-22.7 people per 100,0001. Blood and blood breakdown products (BBP) in the subarachnoid space (SAS) have long been associated with complications leading to poor outcomes after aSAH, including vasospasm, microthrombosis, and delayed cerebral ischemia (DCI)2–4. Hemolysis of red blood cells (RBCs) in the cerebrospinal fluid (CSF) results in release of hemoglobin which triggers oxidative reactions, neuroinflammation, depletion of nitric oxide, and disruption of the blood brain barrier5–8. There have been a number of studies on removal of blood and BBPs via lumbar drain (LD) 9–12. However, LDs are not broadly used in this patient population. A system that removes blood and BBPs from the CSF more quickly and efficiently may reduce delayed complications following aSAH. We introduce the NeurapheresisTM therapy system (Minnetronix, Inc., St. Paul, MN), an investigational lumbar dual lumen catheter and filtration system designed to rapidly remove blood from CSF. CSF is simultaneously removed via proximal fenestrations (lumbar cistern) and returned post-filtration into the patient through distal fenestrations (mid-thoracic). This case report represents the first in the ExtracorPoreal FILtration of Subarachnoid Hemorrhage via SpinaL CAtheteR (PILLAR) safety study. CLINICAL PRESENTATION A 65-year-old female and presented to an outside hospital after a thunderclap headache. An external ventricular drain (EVD) was placed and the patient was transferred. On admission, Glasgow Coma Scale was 14, World Federation of Neurosurgical Societies (WFNS) 2, Hunt-Hess (HH) 3. She had neither family history of aSAH or cerebral aneurysm. A brain CT showed diffuse aSAH (modified Fisher Grade 3); CTA demonstrated a left posterior communicating artery aneurysm confirmed by angiography (7.3 x 4.6 x 2.9 mm) as a wide neck aneurysm. Informed consent for PILLAR was obtained from a legally authorized representative. The aneurysm was secured via coil embolization (Raymond Class 2). Neurapheresis catheter placement began at 18 hours postbleed immediately following coiling. Entry was at L3/L4, and fluoroscopy provided visual confirmation of CSF access and spinal level. The guidewire and catheter were placed without complication, and final placement was verified on fluoroscopy with the proximal radiopaque marker bands at L2/L3 and distal marker bands at T1 (Figure 1). A successful filtration flow test

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. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.

Cryptococcal Meningitis (CM) is the most common cause of fungal meningitis in adults. Treatment for CM is an induction, consolidation, and maintenance approach with antifungal agents. but is associated with continued high morbidity and mortality. Here we describe the in vitro characterization of a catheter-based extracorporeal filtration system (Neurapheresis™) as an alternative mechanical intervention for the filtration of C. neoformans cells, polysaccharide antigen, and inflammatory mediators from infected cerebrospinal fluid (CSF). H99, a clinical strain of C. neoformans, was grown overnight in YPD before being transferred to diluted Saboraud/MOPS media for 24 hours to induce cell proliferation and capsule growth, respectively. Cells were diluted to clinically relevant concentrations (1 × 107 and 1 × 105 cells/mL) in 150 mL of Saboraud/MOPS and passed through the closed-loop system with either 100 or 5 kDa tangential flow filters. Samples were taken every full CSF volume filtration cycle (150 mL) for quantification of yeast load, antigen, and cytokines. Infected human CSF was used to obtain cytokine data. Both tangential flow filter sizes thoroughly cleared yeasts. Over 24 cycles, we consistently observed a 5-log drop (≥99%) in colony forming units (CFUs), which resulted in complete elimination at a starting concentration of 1 × 105 cells/mL. Both 100 and 5kDa achieved a substantial antigen reduction (using CrAg LFA [initial titer]-[final titer]; [1:105]–[1:104] and [1:105]–[1:102], respectively). A similar reduction in cytokine levels (IL-1ra, IL-6, TNF, CRP, and CXCL10) in infected human CSF was also achieved (100 kDa reduced all cytokines except IL-1ra by >95% baseline, and 5kDa removed >95% of all quantified cytokines). Continuous filtration via Neurapheresis is capable of eliminating CSF CFU burden in an in vitro CM model. Future iterations may include adjunctive infusions with drug therapies to further accelerate eradication of yeasts. Significant reduction of cryptococcal antigen and inflammatory cytokines also has potential for controlling the neuro-inflammatory storm that accompanies CM. B. Hedstrom, Minnetronix, Inc.: Employee, Salary; L. Zitella Verbick, Minnetronix, Inc.: Employee, Salary; A. Mccabe, Minnetronix, Inc.: Employee, Salary; S. P. Lad, Minnetronix, Inc.: Collaborator and Scientific Advisor, Licensing agreement or royalty, Research grant and Research support

The World Health Organization has identified Pseudomonas, Acinetobacter and Klebsiella (PAK) as three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. The greatest threat lies in hospitals, nursing homes, and patients with devices such as intravenous catheters and ventilators. Gram-negative bacterial meningitis (GBM) manifests when these bacteria invade the central nervous system. Due to the threat of increasing antibiotic resistance and the high mortality associated with MDR GBM, we have tested a closed-loop, extracorporeal cerebrospinal fluid (CSF) filtration system (NeurapheresisTM) for its applicability in this context. Here we demonstrate feasibility of Neurapheresis for MDR GBM and characterize system parameters for bacterial clearance. PAK cultures were grown and diluted to 1 × 107 cells/mL in artificial CSF or Luria-Miller broth. Both single pass and closed loop filtration were performed with various tangential flow filtration (TFF) and dead-end filter paradigms. Samples were taken either immediately post-filter or after every full CSF volume cycle (150 mL) during a long-term closed loop experiment. Bacterial load, endotoxin and cytokines were quantified. In single pass tests, 5kDa and 100kDa TFF filters and 0.2µm and 0.45µm dead-end filters excluded all PAK organisms completely. The 100kDa and 5kDa TFF filters significantly reduced endotoxin concentration by >95% and >99% of baseline, respectively. The 5 kDa TFF filters produced a 2-log (>99%) reduction in cytokines (IL-1ra, IL-6, TNF, CRP, and CXCL10). In closed-loop experiments, both TFF filters demonstrated a 1–2 Log CFU (90–99%) reduction of all PAK organisms over 4 filtration cycles. Neurapheresis shows potential to be an efficient multi-modal tool for controlling and treating MDR GBM in this in vitro model. Extending closed loop filtration over time demonstrates capability for rapid sterilization of the CSF. Future iterations may include adjunctive intrathecal drug delivery to further accelerate elimination of bacteria. Reduction of both endotoxin and cytokines by Neurapheresis may have significant implications for controlling the damaging neuro-inflammatory response during MDR GBM. B. Hedstrom, Minnetronix, Inc.: Employee, Salary; L. Zitella Verbick, Minnetronix, Inc.: Employee, Salary; A. Mccabe, Minnetronix, Inc.: Employee, Salary; S. P. Lad, Minnetronix, Inc.: Collaborator and Scientific Advisor, Licensing agreement or royalty, Research grant and Research support; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Grant recipient; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: Royalties, Royalties

CM is caused when Cryptococcus neoformans, a basidiomycete fungal pathogen, invades the central nervous system (CNS) and circulates around the brain and spinal cord in the subarachnoid space (SAS). C. neoformans is a budding yeast that has a diameter ranging in size between 5-10 um, with an extracellular polysaccharide capsule that can reach a diameter upwards of 50-60um total. Cryptococcal cells can mechanically occlude arachnoid villi by shedding their polysaccharide antigen glucuronoxylomannan (GXM), commonly known as Cryptococcal antigen (CrAg). Since the production rate of CSF is independent of intracranial pressure (ICP), this interruption in CSF flow puts infected patients at serious risk of developing elevated ICP and hydrocephalus.