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

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.

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

“…Furthermore, in the present cohort of 94 individuals, average time from lumbar injection of tracer until first appearance in cranio-cervical junction was 17.2 ± 16.1 min. The underlying mechanisms need to be clarified, but this short spinal transit time may be attributed to a potent dispersion effect within the spinal canal [ 40 ].…”

Dispersion in porous media in oscillatory flow between flat plates: applications to intrathecal, periarterial and paraarterial solute transport in the central nervous system

“…While again not quantifying effective diffusivity, they noted transport speed for an injection into the lumbar spine in in vitro and computer models in the range of 0.013 mm/s. Pizzichelli et al [65] and Haga et al [66] investigated the effect of catheter position and orientation on intrathecal isobaric drug dispersion within the cervical spine with anatomically realistic nerve roots. In both of these studies they found local solute dispersion to be sensitive to catheter position, orientation and anatomy (nerve roots).…”

Anthropomorphic Model of Intrathecal Cerebrospinal Fluid Dynamics Within the Spinal Subarachnoid Space: Spinal Cord Nerve Roots Increase Steady-Streaming

“…Increased CSF pulse frequency and magnitude increase drug spread Cheng et al [28] Finite volume x x x x FSI between CSF and SC Caused up to 2 mm of SC displacement Tangen et al [29] Finite volume x x x x Infusion settings, drug chemistry and anatomy Drug dispersion is impacted by infusion, chemistry and anatomy Tangen et al [23] Finite volume x x x x Lumbar CSF drainage after subarachnoid hemorrhage Body position and CSF drainage rate impact blood removal from CSF Kuttler et al [30] Finite volume x x x Impact of slow or fast bolus dose Pulsation and breathing dominated longterm bolus spread (not bolus speed) Pizzichelli et al [31] Finite element x x x Catheter position and angle and tissue permeability Injection perpendicular to cord increased penetration to the cord tissue Haga et al [32] Finite element x x x Catheter position, angle, and injection flow rates Catheter position, angle and injection flow rates impact solute distribution Heidari Pahlavian et al [33,34] Finite volume x x x Comparison of in vivo and in vitro MRI with CFD results in vitro MRI compared well with CFD results, in vivo compared poorly with CFD Heidari Pahlavian et al [35] Finite volume x x x Presence of NR and DL Increased peak CSF velocities, mixing and bi-directional flow Stockman [20] Lattice Boltzmann x x x NR, DL, and AT Increased nonstreamwise components of CSF velocity Pahlavian et al [9] Finite volume x x x Pulsatile motion of cerebellar tonsils Increased peak CSF velocities, mixing, and bidirectional flow Bertram et al [36] Finite element x x SC and dura compliance Pressure wave propagation impacted by the elastic properties of tissue Bertram et al [37] Finite element x x SC tethering due to arachnoiditis Increased tensile radial stress and decreased pressure in the SC material Elliott et al [38] Finite difference x x Posttraumatic syringomyelia Stress induced by syrinx fluid sloshing diminishes as syrinx expands Elliott [39] Analytic x x Syrinx filling due to CSF wave mechanics Syrinx filling impacted by CSF flow obstruction and tissue properties Jain et al [40] Lattice Boltzmann x x Highly resolved direct numerical simulation Onset of transitional CSF flow in Chiari patients Cheng et al [41] Finite volume x x Arachnoiditis permeability Increased bidirectional flow, peak CSF pressure timing shifted Rutkowska et al [42] Finite volume x x Presence of tonsillar herniation Increased peak CSF velocities, gradient, and bidirectional flow Yiallourou et al [43] Finite volume x x Presence of tonsillar herniation Increased peak systolic CSF velocities, flow jets near foramen magnum Clarke et al [44] Finite volume x...…”

“…(c) Microstructure and tissue motion: spinal cord NR and/or arachnoid trabeculae (AT), prescribed boundary motion, and fluid-structure interaction. (d) Focus of the investigations: impact of NR and AT on CSF mixing [35], fluid structure interaction of dynamically deforming spinal cord tissue [41], intrathecal drug solute [31][32] and blood [29] transport, and anatomic alterations within disease states such as Chiari malformation and syringomyelia [46]. Several studies have included anatomically idealized NR.…”