CRN is a complication caused by RT used for treating high-grade intracranial neoplasms (4–16). The actual incidence of CRN is uncertain but ranges from 2.5–24% (4, 5). It typically occurs two years after radiation (5). In most patients, it tends to regress once diagnosed radiographically with a probability of regression 40% at six months to 76% at 18 months (6), though it can progress as in our case. Although CRN influenced by various risk factors such as total radiation dose, dose per fraction, treatment duration, irradiated volume, and concurrent use of chemotherapy, the rapidly progressive course of CRN raises the susceptibility of underlying genetic mechanisms (4–7). A prospective cohort study by Wang TM et al. in 2019, implicated a radiation injury susceptibility gene (Cep128) as an underlying mechanism of radiation-induced brain injury, as it tightly interacts with multiple radiation-resistant genes (7).
The pathophysiology of CRN is not well understood. However, two main hypotheses suggested. The first hypothesis postulates that radiation causes damage to endothelial cells by upregulating ceramide, resulting in vascular insufficiency and infarction, followed by brain necrosis (4, 6, 8, 9). Hypoxia caused by endothelial cell damage leads to the liberation of hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) (4, 6, 8, 9).VEGF induce new vessel formation, but these tend to be leaky capillaries, resulting in perilesional edema (6, 8, 9). The second hypothesis postulates that radiation damages the glial cells, especially oligodendrocytes, aggravating capillary permeability defects and causing demyelination of the white matter (4, 6).
The clinical features of CRN vary depending upon the location and size, including features of increased intracranial pressure. The characteristic findings are seizures, hemiparesis, headache, vomiting, poor concentration, and altered level of consciousness (4–6, 10). The literature also reported Neurocognitive impairment (hippocampus), especially in children, which includes poor academic performance, distorted self-image, and psychological distress (6, 11).
MRI of the brain will demonstrate some degree of contrast enhancement surrounded by edema (4–6, 9, 10). Although, the patterns of enhancement described in the literature as swiss cheese, cut green-paper or soup bubble, are believed to favor CRN, these patterns posse a 88% negative predictive value (12). MRS is used to assess the metabolite composition of the lesion (13, 14). On MRS, the peak of Cho and the depression of NAA and Cr correlated with recurrent neoplasm than CRN (13). Anbarloui et al. demonstrated that Cho/NAA > 1.8 or Cho/lipid ratio > 1 had increased odds of being pure neoplastic lesions rather than pure necrosis, with sensitivity and specificity of 73% and 75%, respectively, for Cho/NAA ratio, and 87% for Cho/lipid ratio (13).
However, a recent study by Hellstrom J et al. detected false-positive MRS findings in 51/208 cases, altering the clinical management (14). We also reported similar findings, in which the histopathology did not support the MRS diagnosis. It may reflect the difficulty of MRS in differentiating radiation-induced cytolytic changes from reactive gliosis from a recurrent tumor (14). Positron emission tomography (PET) scan uses 18F-fluorodeoxyglucose (FDG) to assess the tissue activity (4, 6, 10). Necrotic tissue will demonstrate low FDG uptake (4, 6, 10). However, a PET scan can provide false-positive findings when epileptic activity coexist (hypermetabolism) (10). As the viable tumor has an intact vasculature, perfusion MRI can be used to distinguish CRN from recurrent tumor (4, 6, 12, 14). Sugahara et al. suggested a relative cerebral blood volume (rCBV) >2.1 favor tumor recurrence, while an rCBV value < 0.6 favor radiation necrosis (15). However, as the clinic of our patient had a progressive deterioration, we could not be able to spare time for this advanced imaging method. We applied emergency surgical intervention to relieve the mass effects.
CRN treatment aims to minimize further loss of neurological functions, preventing progression and, if possible, reversing the pathological process (4, 6, 9, 12). A corticosteroid as the first measure is frequently administered (6, 9, 12). Other supportive treatments include antiplatelet, anticoagulant, and a high dose of vitamins (6, 9). HBOT believed to improve tissue oxygenation and neovascularization (4, 6). However, the efficacy of HBOT is difficult to assess in patients already treated with steroids (4). Only a few studies have discussed the role of HBOT, with no randomized clinical trials (RCTs) published (4, 6). The efficacy of Bevacizumab proven as an anti-vascular endothelial growth factor monoclonal antibody in treating radiation-induced brain edema (4, 6, 8, 9). However, the safety of Bevacizumab warrants further validation as the only RCT published by Zhuang H et al. in 2011 involved a limited number of 14 patients (9). Debulking surgery is the least favorable option and mainly preserved to relieve the mass effect (4, 6, 9, 12). Recently, laser interstitial thermal therapy (LITT) has become a treatment option for lesions that are difficult to access or for patients who are not candidates for surgery (16). A review study by Katherine G et al. documented a favorable clinical response after LITT for CRN (16). Unfortunately, none of the mentioned treatment approaches utilized halted the progression of CRN in this patient.