Abstract
Abnormalities on CT or MRI and neuropsychological performance in patients with low-grade glioma, with (n = 23) or without (n = 16) prior cerebral radiotherapy, were evaluated. Cerebral atrophy was observed in 14 of 23 patients (61%) treated with prior radiotherapy, and in 1 of 16 patients (6%) without prior radiotherapy. White matter abnormalities were observed in six patients, all of whom were treated with prior radiotherapy. These radiologic cerebral abnormalities correlated with cognitive performance.
The timing of radiotherapy in the treatment of patients with low-grade glioma (LGG) is controversial. Some advocate early radiotherapy (RT), whereas others defer RT because the survival benefit of early RT is questionable in this patient population.1
An important argument for delaying cerebral RT is the CNS toxicity this treatment may cause. Radiation-induced white matter changes and cerebral atrophy are well known entities, related to radiation dose, volume, and patient age.2,3⇓ In long-term survivors with high-grade glioma or brain metastases, radiation-induced cognitive deficits have been described.4,5⇓ In our former study of patients with LGG, no differences in cognitive, affective, or psychological status were observed between patients who had been treated with focal RT and those who had not.6 More recently, however, leukoencephalopathy, related to poor memory performance as a long-term side effect, was observed in patients with LGG treated with whole-brain or focal irradiation.7
The exact relationship between radiation-induced cerebral changes and cognitive functioning is not clear.2 The aim of the current study was to test the hypothesis that radiotherapy-induced radiologic cerebral changes, such as atrophy and white matter abnormalities, and cognitive performance are correlated.
Methods.
Recently, a nationwide study was performed in the Netherlands among 195 patients with LGG. In this study, a comprehensive set of neuropsychological and quality of life measurements was incorporated to determine the impact of glioma and its treatment on cognition and quality of life.8 The study was cross-sectional in design, and included patients with LGG without evidence of tumor recurrence for at least 1 year after initial treatment. The current report focuses on all patients with a supratentorial LGG recruited in the study from two of the participating centers (Vrije Universiteit Medical Center, Amsterdam; and University Medical Center, Utrecht) for whom radiologic assessments (CT, MRI, or both) within 6 months of neuropsychological evaluation were available. Data on age, sex, histology, location of tumor, concomitant diseases, previous history, concomitant use of antiepileptic drugs, extent of resection, and RT were collected. CT and MRI scans were evaluated (by T.P., C.V., J.B., M.S.) with emphasis on cerebral atrophy and white matter abnormalities. White matter changes were scored as 0, 1, or 2, depending on the amount, confluence, and spread of these changes in both the anterior or posterior white matter, leading to a score ranging from 0 to 4.9 Scoring was as follows: MRI grade 0: no lesion or only a single one; MRI grade 1: multiple focal lesions; MRI grade 2: multiple confluent lesions scattered throughout the white matter; CT grade 0: no lesions; CT grade 1: white matter lesions restricted to the region adjoining the ventricles; CT grade 2: hypodensities involving the entire region from lateral ventricle to the cortex. The scoring system for cerebral atrophy consisted of a systematic evaluation of 13 different regions to determine sulcal dilatation (frontal, parieto-occipital, and temporal, on both sides) and dilatation of the ventricles (frontal horn, occipital and temporal horns on both sides, third ventricle).10 In these 13 regions, atrophy is qualified as 0 (absent), 1 (mild), 2 (moderate), and 3 (severe), leading to a composite score ranging from 0 to 39. The raters were blinded to the neuropsychological status of the patients and whether patients had received RT. In case of discordance between observers, a single score was obtained after discussion. Abnormalities in the region of the tumor (e.g., postoperative changes) were not taken into account in this analysis.
A battery of standard tests was used to assess cognitive performance. Because of the heterogeneity of both origin and severity of cognitive disturbances in patients with glioma,4,6⇓ the cognitive test battery assessed a wide range of functions, including information processing capacity (Letter-Digit Substitution Test), memory performance (Visual Verbal Learning Test), attention (Stroop Color-Word Test), and graphomotor speed (Concept Shifting Test). The total time required to complete the battery of tests was approximately 60 minutes.
Mann–Whitney U tests for independent samples were used to determine differences between the groups of patients with LGG with (RT+) and without (RT−) RT. To explore the association between cognitive performance and the extent of cerebral atrophy or white matter abnormalities, Spearman’s rho tests were carried out.
Results.
Twenty-three of 39 patients included had received RT. In most of these patients (n = 19), the target volume of RT encompassed the primary tumor site with a 1 to 2 cm margin; in the other four patients, whole brain radiotherapy (WBRT) with a boost to the tumor site was given.
Patient characteristics such as sex, median age at the time of neuropsychological testing, median interval between neuropsychological testing and prior RT (5 years) or initial diagnosis in case no RT had been applied (4 years), level of education, dexterity, history of epilepsy, use of antiepileptic drugs, prior surgery, histology, and localization of the tumor were equally distributed without significant differences between the groups (table 1). None of the patients had a history of hypertension, diabetes mellitus, or recent use of dexamethasone.
Low grade glioma patient characteristics
CT was available for 11 patients (10 RT+). MRI was available for 28 patients (13 RT+). Cerebral atrophy was observed in 15 patients (38%). Fourteen of those 15 patients (93%) had been treated with RT (11 patients with focal RT, 3 with WBRT + boost). Atrophy was usually mild to moderate (score range 1 to 17, median 4). Sulcal dilatation occurred in four patients, ventricular enlargement in seven patients, and both sulcal and ventricular enlargement in four patients. These abnormalities were not restricted to the side of the tumor. Ventricular enlargement was pronounced (score 12) in 3 of 4 patients treated with WBRT + boost, and in 2 of 19 patients treated with focal RT.
White matter changes were observed in 6 patients (15%), with scores ranging from 1 to 4 (median 2). All six patients had been treated with RT (three patients with WBRT + boost, three with focal RT). Four of those six patients also had cerebral atrophy.
In table 2, correlations are shown between radiologic abnormalities and cognitive performance. The presence and extent of cerebral atrophy correlated significantly with graphomotor speed, information processing capacity, and memory performance. The existence of white matter abnormalities correlated significantly with attention, information processing capacity, and memory performance. When we excluded the four patients with WBRT, cerebral atrophy correlated with memory performance (p < 0.01), whereas white matter abnormalities correlated with attention (p = 0.04), and with information processing capacity (p = 0.05).
Correlations between radiologic abnormalities and cognitive performance
Discussion.
In this study, cerebral atrophy was observed in 14 of 23 patients (61%) treated with prior RT, and in 1 of 16 patients (6%) without prior RT. In patients treated with WBRT + boost, pronounced ventricular enlargement occurred more frequently. The observed radiologic changes due to cerebral RT are in line with the literature.2,3⇓ The relatively low frequency of white matter abnormalities in our cohort may be due to the high proportion of CT in irradiated patients.
Furthermore, modest significant associations were found between the extent of radiologic cerebral abnormalities and cognitive performance. Apparently, not only white matter abnormalities7 but also cerebral atrophy relate to some extent with cognitive performance.
The current study has its limitations. The number of patients in this study was relatively small, which precluded an analysis of the correlation between neuropsychological data and exact tumor location (e.g., frontal vs parietal location), or extent of residual tumor. Furthermore, the large nationwide study will ultimately yield data on the effects of the brain tumor itself and its treatment on cognitive performance.8
Based on our findings, it may be tentatively concluded that long-term cognitive performance and radiation-induced radiologic cerebral abnormalities are correlated in patients with LGG.
Footnotes
See also pages 8, 40, and 48
- Received August 7, 2001.
- Accepted in final form February 16, 2002.
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