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Krystof S. Bankiewicz, Tomasz Pasterski, Daniel Kreatsoulas, Jakub Onikijuk, Krzysztof Mozgiel, Vikas Munjal, J. Bradley Elder, Russell R. Lonser, and Mirosław Zabek

OBJECTIVE

The objective of this study was to assess the feasibility, accuracy, effectiveness, and safety of an MRI-compatible frameless stereotactic ball-joint guide array (BJGA) as a platform for cannula placement and convection-enhanced delivery (CED).

METHODS

The authors analyzed the clinical and imaging data from consecutive patients with aromatic l-amino acid decarboxylase (AADC) deficiency who underwent infusion of adeno-associated virus (AAV) containing the AADC gene (AAV2-AADC).

RESULTS

Eleven patients (7 females, 4 males) underwent bilateral MRI-guided BJGA cannula placement and CED of AAV2-AADC (22 brainstem infusions). The mean age at infusion was 10.5 ± 5.2 years (range 4–19 years). MRI allowed for accurate real-time planning, confirmed precise cannula placement after single-pass placement, and permitted on-the-fly adjustment. Overall, the mean bilateral depth to the target was 137.0 ± 5.2 mm (range 124.0–145.5 mm). The mean bilateral depth error was 0.9 ± 0.7 mm (range 0–2.2 mm), and the bilateral radial error was 0.9 ± 0.6 mm (range 0.1–2.3 mm). The bilateral absolute tip error was 1.4 ± 0.8 mm (range 0.4–3.0 mm). Target depth and absolute tip error were not correlated (Pearson product-moment correlation coefficient, r = 0.01).

CONCLUSIONS

Use of the BJGA is feasible, accurate, effective, and safe for cannula placement, infusion MRI monitoring, and cannula adjustment during CED. The low-profile universal applicability of the BJGA streamlines and facilitates MRI-guided CED.

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Krystof S. Bankiewicz, Tomasz Pasterski, Daniel Kreatsoulas, Jakub Onikijuk, Krzysztof Mozgiel, Vikas Munjal, J. Bradley Elder, Russell R. Lonser, and Mirosław Zabek

OBJECTIVE

The objective of this study was to assess the feasibility, accuracy, effectiveness, and safety of an MRI-compatible frameless stereotactic ball-joint guide array (BJGA) as a platform for cannula placement and convection-enhanced delivery (CED).

METHODS

The authors analyzed the clinical and imaging data from consecutive patients with aromatic l-amino acid decarboxylase (AADC) deficiency who underwent infusion of adeno-associated virus (AAV) containing the AADC gene (AAV2-AADC).

RESULTS

Eleven patients (7 females, 4 males) underwent bilateral MRI-guided BJGA cannula placement and CED of AAV2-AADC (22 brainstem infusions). The mean age at infusion was 10.5 ± 5.2 years (range 4–19 years). MRI allowed for accurate real-time planning, confirmed precise cannula placement after single-pass placement, and permitted on-the-fly adjustment. Overall, the mean bilateral depth to the target was 137.0 ± 5.2 mm (range 124.0–145.5 mm). The mean bilateral depth error was 0.9 ± 0.7 mm (range 0–2.2 mm), and the bilateral radial error was 0.9 ± 0.6 mm (range 0.1–2.3 mm). The bilateral absolute tip error was 1.4 ± 0.8 mm (range 0.4–3.0 mm). Target depth and absolute tip error were not correlated (Pearson product-moment correlation coefficient, r = 0.01).

CONCLUSIONS

Use of the BJGA is feasible, accurate, effective, and safe for cannula placement, infusion MRI monitoring, and cannula adjustment during CED. The low-profile universal applicability of the BJGA streamlines and facilitates MRI-guided CED.

Free access

Russell R. Lonser, Asad S. Akhter, Mirosław Zabek, J. Bradley Elder, and Krystof S. Bankiewicz

Molecular biological insights have led to a fundamental understanding of the underlying genomic mechanisms of nervous system disease. These findings have resulted in the identification of therapeutic genes that can be packaged in viral capsids for the treatment of a variety of neurological conditions, including neurodegenerative, metabolic, and enzyme deficiency disorders. Recent data have demonstrated that gene-carrying viral vectors (most often adeno-associated viruses) can be effectively distributed by convection-enhanced delivery (CED) in a safe, reliable, targeted, and homogeneous manner across the blood-brain barrier. Critically, these vectors can be monitored using real-time MRI of a co-infused surrogate tracer to accurately predict vector distribution and transgene expression at the perfused site. The unique properties of CED of adeno-associated virus vectors allow for cell-specific transgene manipulation of the infused anatomical site and/or widespread interconnected sites via antero- and/or retrograde transport. The authors review the convective properties of viral vectors, associated technology, and clinical applications.

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Vivek Sudhakar, Jerusha Naidoo, Lluis Samaranch, John R. Bringas, Russell R. Lonser, Massimo S. Fiandaca, and Krystof S. Bankiewicz

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.