A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space.

Per Thomas Haga,Mikael Mortensen,Kent-Andre Mardal,Bryn A Martin,Soroush Heidari Pahlavian,Miroslav Kuchta,Giulia Pizzichelli,Edoardo Sinibaldi

doi:10.1371/journal.pone.0173680

Abstract

Intrathecal drug and gene vector delivery is a procedure to release a solute within the cerebrospinal fluid. This procedure is currently used in clinical practice and shows promise for treatment of several central nervous system pathologies. However, intrathecal delivery protocols and systems are not yet optimized. The aim of this study was to investigate the effects of injection parameters on solute distribution within the cervical subarachnoid space using a numerical platform. We developed a numerical model based on a patient-specific three dimensional geometry of the cervical subarachnoid space with idealized dorsal and ventral nerve roots and denticulate ligament anatomy. We considered the drug as massless particles within the flow field and with similar properties as the CSF, and we analyzed the effects of anatomy, catheter position, angle and injection flow rate on solute distribution within the cerebrospinal fluid by performing a series of numerical simulations. Results were compared quantitatively in terms of drug peak concentration, spread, accumulation rate and appearance instant over 15 seconds following the injection. Results indicated that solute distribution within the cervical spine was altered by all parameters investigated within the time range analyzed following the injection. The presence of spinal cord nerve roots and denticulate ligaments increased drug spread by 60% compared to simulations without these anatomical features. Catheter position and angle were both found to alter spread rate up to 86%, and catheter flow rate altered drug peak concentration up to 78%. The presented numerical platform fills a first gap towards the realization of a tool to parametrically assess and optimize intrathecal drug and gene vector delivery protocols and systems. Further investigation is needed to analyze drug spread over a longer clinically relevant time frame.

Highlights

Intrathecal drug and gene vector delivery (IT) to the central nervous system (CNS) is a procedure involving the release of therapeutic agents into the cerebrospinal fluid (CSF) via an inserted catheter [1]
We present a numerical model of catheter drug injection based on a patient-specific 3D geometry of the cervical subarachnoid space (SAS) with idealized anatomical structures, namely dorsal and ventral spinal cord nerve rootlets and denticulate ligaments (NRDL)
The effects of NRDL on the CSF fluid flow are shown in Figs 2–4 and Table 2

Summary

Introduction

Intrathecal drug and gene vector delivery (IT) to the central nervous system (CNS) is a procedure involving the release of therapeutic agents into the cerebrospinal fluid (CSF) via an inserted catheter [1]. The CSF is a water-like fluid that resides in the subarachnoid space (SAS) surrounding the brain and spinal cord and is contained within four fluid filled reservoirs within the brain called ventricles. CSF in the SAS is bounded on the outside by the arachnoid membrane and dura and on the inside, covering the CNS tissue surface, by the delicate pia mater. Thanks to the proximity of the CSF to the brain and spinal cord parenchyma, IT allows many drugs to directly penetrate into the CNS tissue by the leptomeningeal spaces [4,5,6,7] thereby requiring a lower drug dosage and resulting in less potential toxic effects [8, 9]

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