Cannula placement for effective convection-enhanced delivery in the nonhuman primate thalamus and brainstem: implications for clinical delivery of therapeutics

Laboratory investigation

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Object

The purpose of this study was to optimize stereotactic coordinates for delivery of therapeutic agents into the thalamus and brainstem, using convection-enhanced delivery (CED) to avoid leakage into surrounding anatomical structures while maximizing CED of therapeutics within the target volume.

Methods

The authors recently published targeting data for the nonhuman primate putamen in which they defined infusion parameters, referred to as “red,” “blue,” and “green” zones, that describe cannula placements resulting in poor, suboptimal, and optimal volumes of distribution, respectively. In the present study, the authors retrospectively analyzed 22 MR images with gadoteridol as a contrast reagent, which were obtained during CED infusions into the thalamus (14 cases) and brainstem (8 cases) of nonhuman primates.

Results

Excellent distribution of gadoteridol within the thalamus was obtained in 8 cases and these were used to define an optimal target locus (or green zone). Good distribution in the thalamus, with variable leakage into adjacent anatomical structures, was noted in 6 cases, defining a blue zone. Quantitative containment (99.7 ± 0.2%) of gadoteridol within the thalamus was obtained when the cannula was placed in the green zone, and less containment (85.4 ± 3.8%) was achieved with cannula placement in the blue zone. Similarly, a green zone was also defined in the brainstem, and quantitative containment of infused gadoteridol within the brainstem was 99.4 ± 0.6% when the cannula was placed in the green zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for infusions intended to cover the thalamus and brainstem of nonhuman primates.

Conclusions

The present study provides quantitative analysis of cannula placement and infusate distribution using real-time MR imaging and defines an optimal zone for infusion in the nonhuman primate thalamus and brainstem. Cannula placement recommendations developed from such translational nonhuman primate studies have significant implications for the design of anticipated clinical trials featuring CED therapy into the thalamus and brainstem for CNS diseases.

Abbreviations used in this paper: AC = anterior commissure; CED = convection-enhanced delivery; MCP = mid-commissural point; PACS = picture archiving and communication system; PC = posterior commissure; RGB = red, green, blue; ROI = region of interest; Vd = volume of distribution; Vi = volume of infusion.

Article Information

Address correspondence to: Krystof S. Bankiewicz, M.D., Ph.D., Department of Neurosurgery, University of California, San Francisco, 1855 Folsom Street, MCB 226, San Francisco, California 94103. email: krystof.bankiewicz@ucsf.edu.

Please include this information when citing this paper: published online April 2, 2010; DOI: 10.3171/2010.2.JNS091744.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Graphs showing the correlations between spatial coordinates and distribution of MR imaging tracer in the thalamus (Th). The MR images were used to measure the distance from the cannula step to the midline (step-midline), to cannula entry point (step-entry) in the target region (thalamus or brainstem), and to the lateral borders (step-lateral) of the target regions. The green points represent data points in the green zone, and the blue points represent data points in the blue zone.

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    Graphs showing correlations between spatial coordinates and distribution of MR imaging tracer in the brainstem (BS).

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    Images representing step cannula placement procedure and results in the thalamus. A: Schematic of the step cannula placement in the thalamus. Both the step and tip portion of the cannula placement in the green and blue zones for each case are shown. CC = corpus callosum; CR = corona radiata; Lenf = lenticular fasciculus; Put = putamen; 3rd V = third ventricle. B: Graph showing success of tracer distribution, defined as Vd in thalamus versus total Vd for each zone. **p < 0.01. C–J: Representative MR images showing distribution of gadoteridol in the thalamus for the green (D–F) and blue (H–J) zones. Cannula placement and initial infusion are shown in panels C and G for each zone. Note slight leakage into white matter tracts in panels H–J (blue zone). Infusion into the green zone (D–F) resulted in tracer distribution in the thalamus only.

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    Three-dimensional image reconstruction of Vd in the thalamus (green) and brainstem (red).

  • View in gallery

    Images representing step cannula placement procedure and results in the brainstem (BS). A: Schematic of the step cannula placement in the brainstem. Both the step and tip portion of the cannula placement in the green zone for each case are shown. Cis = cistern; SM&H = stria medullaris and habenula. B: Graph showing success of tracer distribution, defined as Vd in brainstem versus total Vd, for each zone. C–F: Representative MR images showing distribution of gadoteridol in the brainstem for the green zone. Cannula placement and initial infusion are shown in panel C for the green zone, whereas D–F show distribution of gadoteridol in the brainstem coronal, axial, and sagittal planes, respectively. Infusion into the green zone (D–F) resulted in tracer distribution within the brainstem only.

  • View in gallery

    Three-dimensional reconstruction of the green zone, and representative volumes of the green zone, in the nonhuman primate (upper) and human (lower) thalamus, respectively. The area of the green zone was defined from MR images as a volume at least 2.8 mm ventral to the entry point, at least 5.8 mm away from the lower border (2.8 mm from cannula tip to lower border plus 3 mm of tip length) vertically, greater than 2.2 mm from the lateral border laterally, and more than 5 mm from the midline medially.

  • View in gallery

    Three-dimensional reconstruction of the green zone, and representative volumes of the green zone, in the nonhuman primate (upper) and human (lower) brainstem, respectively. The area of the green zone was defined from MR images as a volume at least 3.6 mm ventral to the entry point, at least 6.6 mm away from the lower border (3.6 mm from cannula tip to lower border plus 3 mm of tip length) vertically, greater than 2.9 mm from the lateral border laterally, and more than 1.6 mm from the midline medially.

  • View in gallery

    Blue and green zones for cannula step placement outlined in the thalamus of nonhuman primate (NHP, A) and human thalamus (B) based on the RGB parameters obtained in the nonhuman primate and compared on the same scale.

  • View in gallery

    Blue and green zones for cannula step placement outlined in the brainstem of nonhuman primate (A) and human brainstem (B) based on the RGB parameters obtained in the nonhuman primates and compared on the same scale.

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