Infuse-as-you-go convective delivery to enhance coverage of elongated brain targets: technical note

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OBJECTIVE

To develop and assess a convective delivery technique that enhances the effectiveness of drug delivery to nonspherical brain nuclei, the authors developed an occipital “infuse-as-you-go” approach to the putamen and compared it to the currently used transfrontal approach.

METHODS

Eleven nonhuman primates received a bilateral putamen injection of adeno-associated virus with 2 mM gadolinium-DTPA by real-time MR-guided convective perfusion via either a transfrontal (n = 5) or occipital infuse-as-you-go (n = 6) approach.

RESULTS

MRI provided contemporaneous assessment and monitoring of putaminal infusions for transfrontal (2 to 3 infusion deposits) and occipital infuse-as-you-go (stepwise infusions) putaminal approaches. The infuse-as-you-go technique was more efficient than the transfrontal approach (mean 35 ± 1.1 vs 88 ± 8.3 minutes [SEM; p < 0.001]). More effective perfusion of the postcommissural and total putamen was achieved with the infuse-as-you-go versus transfronatal approaches (100-µl infusion volumes; mean posterior commissural coverage 76.2% ± 5.0% vs 32.8% ± 2.9% [p < 0.001]; and mean total coverage 53.5% ± 3.0% vs 38.9% ± 2.3% [p < 0.01]).

CONCLUSIONS

The infuse-as-you-go approach, paralleling the longitudinal axis of the target structure, provides a more effective and efficient method for convective infusate coverage of elongated, irregularly shaped subcortical brain nuclei.

ABBREVIATIONS AC-PC = anterior commissure–posterior commissure; CED = convection-enhanced delivery; MCP = midcommissural point; NHP = nonhuman primate; PD = Parkinson’s disease.

Article Information

Correspondence Krystof Bankiewicz: University of California, San Francisco, CA. krystof.bankiewicz@ucsf.edu.

INCLUDE WHEN CITING Published online July 12, 2019; DOI: 10.3171/2019.4.JNS19826.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Comparison of representative transfrontal infusions with the novel occipital infuse-as-you-go approach for CED to the NHP putamen. A: Axial MR images showing the whole putamen (green) and postcommissural putamen (pink) following two deposits of infusate. The first infusion deposit was 65 μl and the second deposit was 35 μl (upper to lower; deposits in teal). Axial view and 3D reconstruction showing total putaminal coverage of 35% and coverage of the postcommissural putamen (PC) of 38%. B: MR images showing the single occipital trajectory to the putamen, utilizing the infuse-as-you-go method of infusion (left to right) in axial MR views (upper: whole putamen [green] and postcommissural putamen [pink]) and putaminal 3D reconstruction views (lower). The cannula ceramic (black) signal void can be seen at the posterior edge of the putamen at baseline extending toward the putamen. Following delivery of 15 μl, gadolinium solution was readily visualized (infusion time 5 minutes). The cannula was then advanced in a stepwise manner after 27 μl and again after 51 μl of infusate were delivered. The cannula can be seen advancing within the tail of the putamen. A total of 100 μl was delivered over 32 minutes. Three-dimensional reconstructions of the putamen and delivered volumes via infusion cannula, showing increasing infusate volume of distribution within the target putamen using the infuse-as-you-go method. The depicted stepped-cannula design consists of 3 regions: the ceramic body (white), a 5-mm intermediate sized step (red), and a 3-mm infusion tip (black). Estimates of tip location on MR images are made by measuring 8 mm beyond the ceramic trajectory. The cannula tip location is indicated by the colored arrowheads. C: The final postcommissural putamen coverage was 68%, and the total putamen coverage was 61%. The final cannula advancement was 8 mm from baseline. Colored arrowheads represent tip locations following an advancement.

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    Putaminal coverage analysis with transfrontal compared with the infuse-as-you-go approach. Two deposits in the transfrontal approach resulted in a mean total putaminal coverage of 38.9% ± 2.3% compared with 53.3% ± 3.0% with the occipital infuse-as-you-go approach (**p < 0.01). The occipital infuse-as-you-go approach resulted in a significantly greater coverage of the postcommissural putamen 76.2% ± 5.0% compared with 32.8% ± 2.9% with the transfrontal approach (***p < 0.001). There was no significant difference in precommissural putamen coverage with the transfrontal approach compared with the occipital infuse-as-you-go approach (42.9% ± 5.3% vs 36.8% ± 5.0%; p > 0.05). Error bars represent SEM.

  • View in gallery

    Putaminal coverage analysis following 150-μl infusions. One NHP underwent bilateral infusions with 150 μl to assess the performance of high-volume infusions. The putamen is shown in green, with the initial 100-μl volume outlined in blue and the additional 50-μl volume outlined in yellow. The mean precommissural putamen coverage was 62%, and the mean postcommissural coverage was 87%. Mean total putaminal coverage was 75%, consistent with an association between increased infusion volume and putaminal coverage.

  • View in gallery

    Red, blue, and green zones for the occipital infuse-as-you-go approach. A: Mean postcommissural putamen coverage for the red zone was 39.9%; the blue zone, 71.3%, and the green zone, 87.3%. There was a statistically significant difference between the coverage of green zone insertions and blue zone insertions (p < 0.01). No statistical comparisons were made with the red zone, as n = 1. B: Distances from the mid–AC-PC point were plotted. Zones were stratified based on the postcommissural putamen coverage. Green zone insertions were at least 14.5 mm lateral from and at least 0.4 mm above the mid–AC-PC point. C: Representative red, blue, and green trajectories demonstrate that the more lateral trajectories cover more of the postcommissural putamen, leading to a higher coverage with the occipital infuse-as-you-go approach. D: A multivariable regression generated a predictive equation of Y = 25.88 × (MLdistance) + 4.80 × (SIdistance) + 15.41. Statistical analysis demonstrated that both the medial-to-lateral and the superior-to-inferior coefficient significantly impact postcommissural putamen coverage.

  • View in gallery

    Representative infuse-as-you-go trajectories in the human brain. Two representative infuse-as-you-go trajectories (red) targeting the putamen (green) are shown. The AC-PC line is shown as a dotted line in the axial and sagittal views, and the MCP is represented as an orange dot.

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