Supplementary Material for: Pathways of Infusate Loss during Convection-Enhanced Delivery into the Putamen Nucleus

Background: New strategies aiming to treat Parkinson’s disease, such as delivery of trophic factors via protein infusion or gene transfer, depend upon localized intracerebral infusion, mainly into the putamen nucleus. Convection-enhanced delivery (CED) has been proposed as a method to improve intracerebral distribution of therapies. Yet analysis of controversial results during the clinical translation of these strategies suggests that intracerebral misdistribution of infusate may have affected the outcomes by limiting the amount of treatment into the target region. Objectives: This study aimed to identify possible pathways of infusate loss and their relative impact in the success of targeted CED into the postcommissural ventral putamen nucleus. Methods: Thirteen adult macaque monkeys received intraputaminal CED infusions of 100 µl of 2.0 mM gadoteridol and bromophenol blue (0.16 mg/ml) solution at a rate of 1.0 µl/min under intraoperative magnetic resonance imaging (MRI) guidance. Quantitative maps of infusate concentration were computed at 10-min intervals throughout the procedure in a 3-Tesla MRI scanner. The fraction of tracer lost from the putamen as well as the path of loss were evaluated and quantified for each infusion. Results: All injections (total 22) were successfully placed in the ventral postcommissural putamen nucleus. Four major paths of infusate loss from the putamen were observed: overflow across putamen boundaries, perivascular flow along large blood vessels, backflow along the inserted catheter and catheter tract leakage into the vacated catheter tract upon catheter removal. Overflow loss was observed within the first 30 µl of infusion in all cases. Measurable tracer loss following the path of an artery out of the putamen was observed in 15 cases, and in 8 of these cases, the loss was greater than 10% of infusate. Backflow that exited the putamen was observed in 4 cases and led to large loss of infusate (80% in 1 case) into the corona radiata. Loss into the vacated catheter tract amounted only to a few microliters. Conclusions: Our analysis demonstrates that after controlling for targeting, catheter type, infusion rate and infusate, the main issues during surgical planning are the identification of appropriate infusate volume that matches the target area, as well as mapping the regional vasculature as it may become a pathway for infusate loss. Most importantly, these results underscore the significance of presurgical planning for catheter placement and infusion, and the value of imaging guidance to ensure targeting accuracy.研究背景：旨在治疗帕金森病的新型策略，例如通过蛋白输注或基因转移递送神经营养因子，主要依赖于脑内局部输注，尤其是向壳核（putamen nucleus）。对流增强输注（Convection-enhanced delivery, CED）已被提出作为改善治疗药物脑内分布的有效手段。然而，对这类策略临床转化过程中存在争议的研究结果进行分析后发现，输注液在脑内的分布不当可能因限制了靶区域内的治疗给药剂量，从而对治疗结局产生负面影响。 研究目的：本研究旨在明确输注液流失的可能途径及其对连合后腹侧壳核（postcommissural ventral putamen nucleus）靶向CED成功实施的相对影响。 研究方法：13只成年猕猴在术中磁共振成像（intraoperative magnetic resonance imaging, MRI）引导下，以1.0 µl/min的速率向壳核内输注100 µl浓度为2.0 mM的钆特醇（gadoteridol）与溴酚蓝（bromophenol blue，0.16 mg/ml）混合溶液。在3特斯拉磁共振成像扫描仪中，于整个输注过程中每10分钟生成一次输注液浓度的定量分布图像。针对每一次输注，均评估并量化了从壳核流失的示踪剂占比及其流失路径。 研究结果：全部22次注射均成功定位至连合后腹侧壳核。共观察到4种主要的输注液从壳核流失的路径：越过壳核边界的溢出、沿大血管的血管周流动、沿插入导管的反流，以及导管拔除后向原导管通路空腔的渗漏。所有病例在输注初始的30 µl内均出现了溢出流失。15例中观察到沿动脉通路从壳核流失的可检测示踪剂，其中8例的流失量超过输注液总量的10%。4例出现了流出壳核的反流，导致大量输注液流失（其中1例流失量达80%）至放射冠（corona radiata）。向原导管通路空腔的流失量仅为数微升。 研究结论：本研究分析表明，在控制靶向定位、导管类型、输注速率及输注液参数的前提下，外科手术规划中的核心问题在于确定与靶区域匹配的适宜输注液体积，同时需对局部血管系统进行成像定位，因为血管可能成为输注液流失的通路。尤为关键的是，本研究结果凸显了术前规划导管置入与输注流程的重要性，以及成像引导对确保靶向定位准确性的价值。