Relationship Between Radiation Dose and Microbleed Formation in Patients With Malignant Glioma

Abstract

Background: Cranial irradiation is associated with long-term cognitive changes. Cerebral microbleeds (CMBs) have been identified on susceptibility-weighted MRI (SWI) in patients who have received prior cranial radiation, and serve as radiographic markers for microvascular injury thought to contribute to late cognitive decline. The relationship between CMB formation and radiation dose has not previously been quantified. Methods: SWI was performed on 13 patients with stable WHO grade III-IV gliomas between 2 and 4 years after chemoradiotherapy to 60 Gy. The median age at the time of treatment was 41 years (range 25 -74 years). CMBs were identified as discrete foci of susceptibility on SWI that did not correspond to vessels. CMB density for low (<30 Gy), median (30-45 Gy), and high (>45 Gy) dose regions was computed. Results: Twelve of 13 patients exhibited CMBs. The number of CMBs was significantly higher for late (>3 years from treatment) compared to early (<3 years) timepoints (early median 6 CMBs; late median 27 CMBs; p = 0.001), and there were proportionally more CMBs at lower doses for late scans (p = 0.006). 88% of all CMBs were observed in regions receiving at least 30 Gy, but the CMB density within medium and high dose regions was not significantly different (p = 0.33 and p = 0.9, respectively, for early and late time points). Conclusions: CMBs predominantly form in regions receiving at least 30 Gy, but form in lower dose regions with longer follow-up. We do not observe a clear dose-response relationship at doses above 30 Gy. These findings provide important information to assess the risk of late microvascular sequelae from cranial irradiation.

Non-Human Primates Receiving High-Dose Total-Body Irradiation are at Risk of Developing Cerebrovascular Injury Years Postirradiation

“…Thus these sequences can be used to identify hemorrhage and necrosis with mineralization in affected subjects. The SWI sequence is routinely used in clinical practice to identify blood products and small-volume microhemorrhages in human patients, and SWI hypointensities have been reported in cancer patients receiving brain radiotherapy (73,74,77,78,(84)(85)(86)(87)(88). Use of these non-invasive, in vivo imaging protocols allows for monitoring of the progression of brain pathology longitudinally, often years prior to death, and offers the potential to map MRI abnormalities to neurologic deficits.…”

“…Although the long-term consequences of single-highdose TBI on the adult brain are unclear, fWBI for the treatment of brain cancer may result in neuroinflammation, white matter necrosis, vascular injury and cognitive impairment (69)(70)(71)(72). In affected patients, scattered foci of hemorrhage and necrosis consistent with small blood vessel injury are detectable on susceptibility-weighted (SWI) magnetic resonance images (MRI) (73)(74)(75)(76)(77)(78). In the current study, we hypothesized that non-human primate long-term survivors of high-dose TBI would develop lesions on imaging that were similar to those observed after fWBI, although less severe and with a longer latency period.…”

Risk factors of radiotherapy‐induced cerebral microbleeds and serial analysis of their size compared with white matter changes: A 7T MRI study in 113 adult patients with brain tumors

“…These negative findings likely reflect the unsuitability of this measure for patients treated with focal RT since the dose is distributed nonuniformly and the spatial extent varies with tumor volume. The volume of the higher dose region should be a more appropriate metric for evaluation, as Wahl et al in 2017 found significantly more CMBs in this region in the first 3 years following RT. Unfortunately, radiation dosimetry maps were not available for enough patients included in our analysis to appropriately assess associations between CMB development and dosimetry volumes and/or the extent of treatment.…”

“…These can be detected with susceptibility‐weighted imaging (SWI) as early as 8 months following treatment, although in most adult patients the onset of vascular injury is usually observed 2 years post‐RT . Prior smaller studies have shown increases in the formation of CMBs over time in patients treated with RT for malignant gliomas that were spatially dependent on the RT dose, and an absence of CMBs in patients treated with chemotherapy alone . One of the largest and most comprehensive studies to date in adult survivors of childhood brain tumors reported increases in total CMB burden with accumulated time since RT and with greater spatial extent of treatment .…”

Cerebral hemodynamic and metabolic dysregulation in the postradiation brain

“…Intracerebral microbleeds generally occur several years postradiation, with a cumulative incidence ranging from 40% to 90% by 5-10 years after radiation, with the detection range dependent on the sensitivity of the imaging technique; for example, susceptibility-weighted imaging is superior to T2*-weighted gradient echo. [63][64][65]…”