EPIBRAINRAD : Study of Neurological Complication After Radiotherapy for Glioblastoma High Grade

Context The survival time and the number of long time survivors after radiotherapy in brain cancer patients have increased for the last decades. Therefore the topic of late-delayed neurotoxic effects of this therapy gains more and more importance. Among these side effects, the main and most frequent one is the leukoencephalopathy, a diffused and progressive damage of the white matter characterized by myelin loss, loss of axons and vascular lesions. The incidence rate assessment, as well as the occurrence time, is based on retrospective studies with low numbers of patients, but seems to reach 30 to 50 % of the patients according to the follow-up. The risk seems to be increased during the first two years after the radiotherapy, but persists for decades.

No complete characterization of this cognitive impairment has been done yet due to crucial discrepancies in the neuropsychological assessments that were used (namely missing of pre-treatment assessment), in the follow-up of patients and in the applied treatment. However, based on previous studies, it can be said that the short term memory and the frontal functions are mainly affected and the quality of life is exceedingly impaired. Irradiation schemes, in particular high doses and large irradiated volume, have been identified as risk factors of leukoencephalopathy. However, in spite of modified protocols that tended to limit the risk, the remaining occurrence of the disease suggests a high dependency on individual risk factors, that are still poorly known and make the individual sensitivity to develop these secondary effects unpredictable. Other factors such as cardio-vascular factors, smoking, old age and combined radio-chemotherapy are linked to leukoencephalopathy as well, although only few of these associations were proved in large studies. Moreover, some specific bio-markers could complete clinical examinations to predict risk of cognitive impairment in these patients. Several biomarkers could be of interest:

The protein S-100B is a protein synthesized mainly by glial cells and cells of Schwann. It is an intracellular protein regulating the cytosolic availability of calcium. Its concentration is 30-100 times brought up in the cerebral tissue that in the other tissues. Its plasmatic half-life is a 1 hour, its elimination is renal. So, the protein S-100B is a marker of traumatic brain injury, certain neurodegenerative disorders and malignant gliomas. The dosage maybe so realized in serum and urines.

• Growing evidence implicates oxidative/nitrative damage in the pathogenesis of neurodegenerative disorders. Subsequent studies were undertaken showing that specific isoprostanes (iPs) levels are elevated in urine and blood of Alzheimer Disease patients and that these values correlate with memory impairments. This suggests that iPs are useful biomarkers in neurological diseases. Their levels could be measured in urine and plasma of patients.
• Homocysteine is a sulfur-containing amino acid, derived from the metabolism of methionine. Higher levels of homocysteine were associated with worse memory performance in a large group of older subjects. While homocysteine is not a diagnostic test, it may represent a modifiable risk factor for dementia.

Highlighting neuropsychological disorders including at an early stage requires a reliable and reproducible assessment of the patient's cognitive state. However, a comprehensive neuropsychological assessment takes several hours and a qualified staff, making it difficult to implement in the conventional patient monitoring. The use of a simple and fast tool to detect cognitive impairment would help to develop a systematic approach for screening these disorders. A detection computerized neuropsychological standardized test (Computerized Cognitive Speed Test - CSCT) assessing processing speed of information, attention and working memory has been validated in multiple sclerosis patients compared to healthy volunteers. CSCT quickly detects patients with cognitive impairment, who could be then tested with more complete tests. It can be conducted by people with no neuropsychology training and the testing time is less than 2 minutes.