Intrathecal Therapeutics: Device Design, Access Methods, and Complication Mitigation

Nagel, Sean J.; Reddy, Chandan G.; Frizon, Leonardo A.; Holland, Marshall T.; Machado, André G.; Gillies, G. T.; Howard, Matthew A.

doi:10.1111/ner.12693

Cited by 25 publications

(15 citation statements)

References 134 publications

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“…The proximity of CSF with the CNS tissue makes it a potential route for ALS treatment using intrathecal drug delivery. While IT drug delivery is a growing field, due to a gap in foundational knowledge and higher associated risks, IT devices and therapeutics are not common clinically [46]. Intrathecal delivery baclofen is among the only IT therapy regularly prescribed for ALS where systemic side-effects are dose limiting and pain due to severe spasticity cannot be effectively managed by other means [47][48][49].…”

Section: Potential Implications For Intrathecal Als Therapeuticsmentioning

confidence: 99%

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Sass

Khani

Romm

et al. 2020

Fluids Barriers CNS

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Background: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. Methods: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. Results: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. Conclusion: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.

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Section: Potential Implications For Intrathecal Als Therapeuticsmentioning

confidence: 99%

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Sass

Khani

Romm

et al. 2020

Fluids Barriers CNS

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“…The average catheter diameter of 1.5 mm used in this study for cynomolgus monkeys is within the range of catheter diameters used in humans, ranging from 1.2 to 1.65 mm in outer diameter (31). Given the relatively smaller catheter diameter applied in adult humans, the potential impact of catheter implantation on CSF flow dynamics in adult humans may be relatively small.…”

Section: Potential Relevance Of Results With Respect To Intrathecal Dmentioning

confidence: 85%

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys

Martin

Khani

Pluid

et al. 2020

Preprint

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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

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“…The needle dimensions in IDDS depend on the catheter size; the IDDS catheter system is usually packaged with a 15 or 16‐gauge Tuohy needle. The catheter itself has an outer diameter of 1.2–1.4 mm .…”

Section: Discussionmentioning

confidence: 99%

Removal of Intrathecal Catheters Used in Drug Delivery Systems

Frizon

Sabharwal

Maiti

et al. 2018

Neuromodulation: Technology at the Neural Interface

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Intrathecal Therapeutics: Device Design, Access Methods, and Complication Mitigation

Cited by 25 publications

References 134 publications

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys

Removal of Intrathecal Catheters Used in Drug Delivery Systems

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