Global and Focal Effects of Radiation Therapy on the Cerebral Vasculature in Pediatric Brain Tumor Survivors using simultaneous MRA-SWI at 7T
Sivakami Avadiappan1, Melanie A Morrison1, Angela Jakary1, Erin Felton2, Schuyler Stoller2, Christopher P Hess1,2, Sabine Mueller2,3, and Janine M Lupo1

1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2Department of Neurology, University of California, San Francisco, San Francisco, CA, United States, 3Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States


With the improved survival of children with brain tumors, understanding the late effects of the treatment has become critical. This study explores the effects of RT on vascular structure using a combined MRA-SWI sequence at 7T and a new method for arterial segmentation and quantification. Normalized arterial volume was significantly reduced with increasing RT treatment volume, number of CMBs, and at follow-up. CMBs were located closer to veins than arteries and were larger when further away. Our findings demonstrate the feasibility of our approach for quantifying subtle vascular changes in arterial structure and CMB properties due to RT.


Although radiation therapy (RT) is a common treatment for pediatric brain tumors, it can have detrimental long-term effects such as impaired cognition and heightened risk for ischemic stroke1,2. RT-induced endothelial damage preceding these events causes vascular injury, one manifestation of which is cerebral microbleeds (CMBs). Previous studies using SWI in adult patients with gliomas demonstrated that CMBs appeared in irradiated patients 1-2 years after treatment onset, with an increasing number of lesions over time that spatially varied based on dose received3,4. In children, significant risk factors for development of CMBs include younger age at time of RT, higher maximum radiation therapy dose, and higher percentage and volume of brain exposed to ≥30Gy5,6. As survival improves in these children, understanding the evolution of CMBs and their association with surrounding vascular integrity could serve as a risk factor for evaluating the severity of radiation related injury whose cognitive impairment persists into adulthood. The goal of this study was to explore the effects of uniform whole brain RT on arterial structure 1) globally throughout the brain, 2) surrounding CMBs, and 3) as a function of CMB volume.


Patients and Data Acquisition: 15 patients (ages 10-24) treated with whole-brain (WB) or whole-ventricular (WV) RT for a pediatric brain tumor 2 months to 16 years prior to imaging were scanned on a 7-Tesla MRI scanner using a novel simultaneous MRA-SWI acquisition7 that enables concurrent visualization of arteries, veins, and CMBs on a single image (Figure 1). Five patients had repeat scans ~1 year after their baseline scan. Two patients with juvenile pilocytic astrocytomas (ages 14 and 16) who did not receive RT as part of their treatment were included as controls.

Calculation of Vascular Metrics: The arteries from the MRA volume were automatically segmented using a novel pipeline8 that employed an adaptive Frangi filter to retain the thickness of the radii in the original image. A Euclidean Distance Transform was then applied to the segmented arteries in order to calculate a map vessel radii map as shown in Figure 2C for a 2D Maximum Intensity Projection. The same pipeline was used to segment arteries and obtain a distribution of vessel radii from non-overlapping 8mm projections through the entire brain. Total vessel volume and the proportion of small vessels normalized by brain volume were compared with time since RT and number of CMBs for each gender and type of RT. Serial changes were evaluated in the 5 patients with repeat scans.

Relationship Between Vascular Metrics and CMB Evolution: Veins from SWI images were segmented similarly as arteries on the MRA images. A semi-automated algorithm that included a user-guided GUI to removed CMB mimics was used for identifying, counting, and segmenting CMBs9,10 from SWI. From the skeleton of the segmented arteries and veins the nearest end points of artery and vein with respect to each CMB were automatically determined to calculate respective distance measures that were plotted as a function of CMB volume.

Results & Discussion

Global normalized arterial volume was significantly reduced with increasing RT treatment volume (p<0.02 Kruskal Wallis test; Figure 3A). Whole brain arterial volume also decreased with increasing number of CMBs (Figure 3B) and at follow-up scan compared to baseline for 4/5 patients imaged serially (Figure 3C).

Figure 4 shows the vessel distribution normalized by the total vessel volume plotted separately for males and females since vessel radii depend on gender11. The proportion of small arteries (0.23-0.46 mm) increased with respect to time since RT for both males and females, suggesting gradual luminal narrowing for years following RT. No trends were observed in arteries with larger radii. This is consistent with reports in animal models that smaller arterioles are more susceptible to RT-induced injury.

Although initially, larger CMBs were farther from the nearest vein, over time, CMBs far from surrounding vasculature tended to decrease in size (Figure 5A). These results suggest that after a CMB forms, the surrounding vasculature narrows and eventually recedes. Although CMB distance from nearest vein vs nearest artery was highly correlated within each patient (Figure 5B), overall, CMBs were located closer to veins than arteries (Figure 5B,C).


Our findings demonstrate the feasibility of our approach for quantifying subtle vascular changes in arterial structure and CMB properties due to RT. We anticipate that the methods developed here will enable future analyses that assess radiation-induced vascular injury in larger cohorts. Current work is investigating the spatial distribution of these findings throughout the brain and how they relate to measured cognitive deficits in these children.


The authors would like to acknowledge the support received from grant R01HD079568


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Figure 1. Patient Demographics. The type of brain tumors are Anaplastic Ganglioma(AG), Pleomorphic Xanthoastrocytoma(PXA), Germinoma(GE), Medulloblastoma(MB), Juvenile Pilocytic Astrocytoma(JPA); WV= whole ventricular RT; WB = whole brain RT.

Figure 2. (A) Original TOF MRA Maximum Intensity Projection. (B) Vessel segmentation using our adaptive Frangi method. (C) Color coded vessel thickness map. Thickness values are given in terms of number of pixels. 1 pixel = 0.23 mm

Figure 3. (A) Normalized arterial volume for different treatment groups: no RT, whole ventricular RT (WV) and whole brain RT (WB). (B) Vessel volume as a function CMB count plotted on a logarithmic scale. (C) Serial changes decreases in vessel volume at ~1 year follow-up compared to baseline for 4/5 patients imaged serially.

Figure 4. Normalized fraction of small arteries for females(A) and males(B) plotted separately as a function of time since RT.

Figure 5. Relationship to CMBs. A)Mean distance from nearest artery plotted as a function of individual CMB volume for CMBs having volumes of less than 15 voxels (3.75mm3). Only volumes up to 15 voxels are shown due to lack of sufficient data to bin for CMBs larger than this size. B)Correlation between the distance of a CMB from nearest artery and distance from nearest vein for one patient (r =0.84). C)Correlation between the distance of a CMB from nearest artery and distance from nearest vein for all patients(r =0.64), demonstrating how nearly all CMBs are closer to veins than arteries.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)