Aims: To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED.Methods: 13 children diagnosed with DIPG received between 3.8 and 5.7 ml of infusate, through two pairs of catheters to encompass tumor volume on day 1 of cycle one of treatment. Volumetric T2-weighted (T2W) and diffusion-weighted MRI imaging (DWI) were performed before and after day 1 of CED. Apparent diffusion coefficient (ADC) maps were calculated. The tumor volume pre and post CED was automatically segmented on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were aligned and subtracted to visualize the infusate distribution.Results: There was a significant increase (p < 0.001) in mean ADC and T2W signal intensity (SI) ratio and a significant (p < 0.001) increase in mean tumor volume defined by ADC and T2W SI post infusion (mean ADC volume pre: 19.8 ml, post: 24.4 ml; mean T2W volume pre: 19.4 ml, post: 23.4 ml). A significant correlation (p < 0.001) between infusate volume and difference in ADC/T2W SI defined tumor volume was observed (ADC, r = 0.76; T2W, r = 0.70). Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion demonstrated a volume of high signal intensity, presumed infusate distribution.Conclusions: ADC and T2W MRI are proposed as a combined parameter method for evaluation of CED infusate distribution in brainstem tumors in future clinical trials.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

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.

New techniques of intraoperative magnetic resonance imaging (MRI)-guided stereotaxy enable minimally invasive approaches to intracranial pathology. Laser interstitial thermal therapy (LITT), convection-enhanced drug delivery, and stereotactic biopsy can be performed with a real-time confirmation of location and the ability to adjust for intracranial shift during the procedure. However, these procedures are constrained by patient positioning and the need for trajectories that avoid collision between stereotactic elements and the small MRI bore. To our knowledge, this is the first report to outline the technical details of safe intraoperative MRI (iMRI)-guided stereotaxy, performed with prone positioning. To present technical pearls to guide the safe conduction of iMRI-guided stereotaxy and LITT while in the prone position. The details of the positioning and trajectories for a series of patients who underwent Clearpoint® (MRI Interventions Inc) frameless real-time MRI-guided stereotaxis using a posterior approach were reviewed. In this series, 5 patients underwent selective amygdalohippocampectomy, and 2 underwent tumor biopsy/ablation while in the prone position without any complications. Prone iMRI procedures can be performed safely even in a 60-cm MRI bore.

Diffuse midline gliomas harboring the H3 K27M mutation—including the previously named diffuse intrinsic pontine glioma (DIPG)—are lethal high-grade pediatric brain tumors that are inoperable and without cure. Despite numerous clinical trials, the prognosis remains poor, with a median survival of ~1 year from diagnosis. Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation.