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A retrospective analysis of the clinical presentations and neuroimaging characteristics of 33 patients with a primary central nervous system lymphoma (PCNL) who received cranial radiotherapy was performed to assess incidence of and risk factors for radiation-induced encephalopathy. CT and MRI scans were revised by a neurologist and a radiologist in conference. White matter abnormalities before and after radiotherapy on the last scan before recurrence were quantified according to a semi-quantitative scale. All available medical records were retrieved and reviewed with respect to demographic and tumor-related variables, treatment modalities, disease-free and overall survival and clinical symptoms and signs of encephalopathy. CT and MRI scans showed severe white matter lesions in 75% of 20 patients and in 86% of patients aged more than 60 years. Forty percent of patients presented with new clinical signs of cognitive impairment a median of 14.5 months after initial diagnosis (8.5 months after radiotherapy). The risk of white matter lesions appeared greater in patients aged >60 (RR 1.2, 95% CI = 0.8-2.0), in patients with prior white matter lesions (RR 1.3, 95% CI = 0.8-2.1) and in patients with multifocal cerebral lymphoma (RR 1.5, 95% CI = 1.0-2.1). In conclusion, the risk of white matter lesions and clinical symptoms and signs of encephalopathy is high in patients treated by radiotherapy for PCNL. The risk appears to be greatest in older patients, patients with multifocal tumor and in those with prior white matter lesions on CT or MRI.