Nicholas A. Butowski, John R. Bringas, Krystof S. Bankiewicz and Manish K. Aghi
Vivek Sudhakar, Jerusha Naidoo, Lluis Samaranch, John R. Bringas, Russell R. Lonser, Massimo S. Fiandaca and Krystof S. Bankiewicz
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.
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.
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]).
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.
Vivek Sudhakar, Amin Mahmoodi, John R. Bringas, Jerusha Naidoo, Adrian Kells, Lluis Samaranch, Massimo S. Fiandaca and Krystof S. Bankiewicz
Successful convection-enhanced delivery of therapeutic agents to subcortical brain structures requires accurate cannula placement. Stereotactic guiding devices have been developed to accurately target brain nuclei. However, technologies remain limited by a lack of MRI compatibility, or by devices’ size, making them suboptimal for direct gene delivery to brain parenchyma. The goal of this study was to validate the accuracy of a novel frameless skull-mounted ball-joint guide array (BJGA) in targeting the nonhuman primate (NHP) brain.
Fifteen MRI-guided cannula insertions were performed on 9 NHPs, each targeting the putamen. Optimal trajectories were planned on a standard MRI console using 3D multiplanar baseline images. After cannula insertion, the intended trajectory was compared to the final trajectory to assess deviation (euclidean error) of the cannula tip.
The average cannula tip deviation was 1.18 ± 0.60 mm (mean ± SD) as measured by 2 independent reviewers. Topological analysis showed a superior, posterior, and rightward directional bias, and the intra- and interclass correlation coefficients were > 0.85, indicating valid and reliable intra- and interobserver evaluation.
The data demonstrate that the BJGA can be used to reliably target subcortical brain structures by using MRI guidance, with accuracy comparable to current frameless stereotactic systems. The size and versatility of the BJGA, combined with a streamlined workflow, allows for its potential applicability to a variety of intracranial neurosurgical procedures, and for greater flexibility in executing MRI-guided experiments within the NHP brain.
Dali Yin, R. Mark Richardson, Massimo S. Fiandaca, John Bringas, John Forsayeth, Mitchel S. Berger and Krystof S. Bankiewicz
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.
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.
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.
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.
Peter J. Dickinson, Richard A. Lecouteur, Robert J. Higgins, John R. Bringas, Byron Roberts, Richard F. Larson, Yoji Yamashita, Michal Krauze, Charles O. Noble, Daryl Drummond, Dmitri B. Kirpotin, John W. Park, Mitchel S. Berger and Krystof S. Bankiewicz
Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging–compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery.
Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution.
Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog.
Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.
John H. Sampson, Gamal Akabani, Allan H. Friedman, Darell Bigner, Sandeep Kunwar, Mitchel S. Berger and Krystof S. Bankiewicz
Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection.
Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human–murine chimeric mAb Ch81C6, which had been labeled with the 123I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a 131I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography.
Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.