Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys

A detailed understanding of the CSF dynamics is essential for testing and evaluation of intrathecal drug delivery. Preclinical work using large-animal models (e.g., monkeys, dogs and sheep) has great utility for defining spinal drug distribution/pharmacokinetics and provide an important tool for defining safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there is a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with the cervical implantation. CSF flow rate decreased up to 54.7% when the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation

Each NHP was scanned with an identical MRI protocol (see MRI methods) across all study 115 time points (Fig 1). MRI PRE-1 and MRI PRE-2 were spaced 14 days apart prior to catheter 116 placement. MRI PRE-1 and MRI PRE-2 were used in our previous publication (19) to quantify 117 reliability of CSF flow parameters. At day 17, the NHP's were randomly assigned to have  )). An intrathecal catheter was implanted 133 within the cervical SAS (C5, n=4) and lumbar SAS (L1, n=4 144 During each scan, heart rate and respiration were monitored continuously with ~ 1 liter/minute of 145 oxygen and 1-3% isoflurane anesthetic administered via an endotracheal tube for sedation.

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A stack of high-resolution axial T2-weighted MR images of the complete spinal SAS 147 geometry was acquired for each NHP. The anatomical region scanned was ~30 cm in length, which 148 included the intrathecal SAS below the lower brain stem extending caudally to the filum terminale.

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Thru-plane (head-foot, z-direction) CSF flow was measured by phase-contrast MRI (PC-MRI) 150 images collected at six axial locations along the spine for each NHP. Axial locations were marked 151 at the foramen magnum (FM), C2-C3, C5-C6, T4-T5, T10-T11, and L3-L4. The slice location for 152 each scan was oriented approximately perpendicular to the CSF flow direction with slice planes 153 intersecting vertebral discs (Fig 2). 167 (20), which provided semi-automatic segmentation using active contour methods, as well as 168 manual delineation and image navigation (Fig 2A). The manual segmentation tool was used most 169 frequently with the view of the three orthogonal planes. The catheter was considered to be an 170 empty region within the spinal SAS, because it was not possible to consistently identify within the 171 MR images due to its small lumen diameter. Once the segmentation was complete, the 3D model 172 (Fig 2B) was exported in a .STL (Stereo Lithography) format for subsequent analysis as outlined 173 below. Detailed information on the segmentation procedure is provided by Khani et al. (18).

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CSF flow was quantified at six axial locations along the spine (Fig 2C)

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Results indicated that cervical catheter insertion altered spinal SAS geometry to a greater 280 degree than lumbar catheter insertion (Fig 3). Overall, 33 out of 42 geometric parameters did not 281 change statistically across MRI measurement time points or depending on catheter location 282 ( Table 3).

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Axial distribution of geometric parameters showed relatively small changes across the 284 lumbar and cervical implantation groups for A d , A c , A sas , P d , and P c at all time points (Fig 3A   285 through E). However, P sas (Fig 3F) for the MRI POST-1C and MRI POST-2C groups increased 286 significantly below the catheter tip after insertion (

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Catheter implantation was found to decrease CSF flow pulsations along the entire spine and 303 this impact was greater for cervical catheter implantation compared to lumbar implantation (Fig   304 4). For example, MRI POST-1C flow rate was lower than MRI PRE-2C for all axial locations. Catheter 305 implantation was found to decrease CSF flow pulsations even 31 days after catheter insertion 306 (MRI POST-2C and MRI POST-2L ). These findings were supported by statistical analysis that showed 307 changes in hydrodynamic parameters with cervical and lumbar catheter implantation to be highly 308 significant for 40 out of 49 hydrodynamic parameters with p values < 0.05/91 (Table 3).

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CSF flow rate of each NHP group quantified along the spine had a similar waveform shape, 310 and axial distribution (Fig 4). CSF flow waveform showed a systolic peak at 100 to 150 ms in 311 the cervical spine ranging from 0.2 -0.6 (ml/s) for all NHPs. CSF flow rate at the C5-C6 for 312 MRI POST-1C and MRI POST-2C was markedly smaller than both MRI PRE-2C and 2L , and MRI POST-1L 313 and MRI POST-2L due to catheter placement within cervical SAS in those cases.

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Average spatial-temporal distribution of the CSF flow along the spine showed a 315 relatively smooth decrease in amplitude with a caudally directed CSF pulse wave velocity (Fig   316 5). Pulse wave velocity magnitude was similar across the groups and ranged from 1.09 -1.24 317 m/s. Maximum CSF flow rate occurred for the MRI PRE-2 measurement within the cervical spine. Maximum number for MRI PRE-2C was 80 at C3-C4 level (Fig 6A). MRI POST-2C had the 332 lowest value of 28 due to the cervical catheter implantation. Catheter implantation also 333 decreased CSF flow rate amplitude (Fig 6B) and stroke volume (Fig 6C) (Fig 6D) and α (Fig 6E) decreased a great degree with cervical catheter implantation and 338 to a lesser degree with lumbar implantation. Maximum D h and α was 4 and 8 located near the 339 FM. The peak value of the mean velocity ranged from +1.8 to -2.9 cm/s in MRI PRE-2 and 340 occurred at the C3-C4 level (Fig 6F). Based on Hagen-Poiseuille equation, CSF flow reduction 341 was predicted to be 48% after cervical implantation and 6% after lumbar implantation. These 342 predictions were comparable to the MRI-measured Q peak-sys reduction of 55% after cervical 343 implantation and 21% after lumbar implantation (  (Fig 4 and 5). Additionally, nearly 364 all measures of CSF dynamics were altered to a greater degree for cervical implantation 365 compared to lumbar implantation ( Table 2). These results were further supported by estimation 366 of CSF flow reduction, based on the Hagen-Poiseuille equation, indicating that the CSF flow 367 reduction was likely due to increased hydraulic resistance stemming from the catheter's 368 reduction in subarachnoid space hydraulic diameter (Fig 3 and Table 2).

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The reduction in CSF flow could also potentially be attributed to inflammatory and/or 370 infection post-catheter insertion, as documented in previous research (24). However, given that 371 a) the reduction in CSF flow remained weeks following catheter insertion, b) the magnitude of 372 flow reduction agreed with the estimated reduction based on fluid physics, and c) CSF flow 373 reduction was greater for cervical catheter insertion, we believe the most probable source of CSF 374 flow reduction to be increased hydraulic resistance directly due to the catheter.

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Average PWV was found to be 1.15 m/s across all NHPs and was not impacted by catheter 385 implantation (Fig 5). This is a potential indicator that spinal compliance, and likely intracranial 386 pressure, was not affected due to catheter implantation. CSF PWV was previously measured by  (Fig 6). was 395 computed to represent the ratio of steady inertial forces to viscous forces and help indicate Re Re 396 whether laminar flow (<2300) was present at each phase-contrast slice location (Fig 2). A 397 laminar CSF flow indicates that the flow is smooth with relatively little lateral mixing. This is 398 different from a turbulent flow, where chaotic changes in pressure and velocity occur and can 399 lead to a large increase in lateral mixing. Chaotic CSF velocity or pressure fluctuations are not 400 expected to occur before or after catheter placement. However, it is possible that disease states 401 that result in strongly elevated CSF flow velocities (jets) could result in turbulence (26).

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Inertial effects are expected to dominate the SAS CSF flow field for normal physiological 403 flow rates, frequencies and CSF fluid properties. varied along the spine in a similar fashion as 404 with a minimum and maximum value of 3.8 and 8.1 (Fig 6). was computed to quantify 405 the ratio of unsteady inertial forces to viscous forces that impact the CSF velocity profile shape 406 (27). For <2 , the CSF velocity profiles will be parabolic in shape and considered quasi-static.
407 For 2< <10 velocity profiles will be M-shaped and, for >10, velocity profiles will be 408 relatively flat (plug shaped) (28). The maximum value of α in the thoracic region decreased to ~4 409 after cervical catheter insertion. This means that the CSF velocity profiles will have a M-shape