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.


OBJECTIVE
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.
Therataxis LLC, Baltimore, MD 21218, USA. mbrady@therataxis.com
Martin L
ML
Brady
Raghu
R
Raghavan
Andrew
A
Alexander
Ken
K
Kubota
Karl
K
Sillay
Marina E
ME
Emborg
D000818:Animals; D001978:Bromphenol Blue / Q000008:administration & dosage*; D002404:Catheterization / Q000295:instrumentation / Q000379:methods; D018481:Convection; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005260:Female; D005682:Gadolinium / Q000008:administration & dosage; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D007260:Infusion Pumps; D057967:Infusions, Intraventricular; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009942:Organometallic Compounds / Q000008:administration & dosage*; D011699:Putamen / Q000502:physiology*
D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C062402:gadoteridol; D001978:Bromphenol Blue; D005682:Gadolinium