CME Late cognitive and radiographic

changes related to radiotherapy

Initial prospective findings
C.L. Armstrong, PhD; J.V. Hunter, MD; G.E. Ledakis, PhD; B. Cohen, PhD; E.M. Tallent, BA;
B.H. Goldstein, PhD; Z. Tochner, MD; R. Lustig, MD; K.D. Judy, MD; A. Pruitt, MD; J.E. Mollman, MD;
E.M. Stanczak, PhD; M.Y. Jo, PsyD; T.L. Than, BS; and P. Phillips, MD

Abstract—Background: Assumptions about the damaging effects of radiotherapy (XRT) are based on studies in which
total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic
comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose
and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension)
were excluded. Methods: The effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade,
supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6
years were examined. Radiographic findings were examined regionally. Results: Selective cognitive declines (in visual
memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperinten-
sities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total
hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures,
and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-
related hyperintensities. Conclusions: There was no evidence of a general cognitive decline or progression of white matter
changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence
of other clinical risk factors.
NEUROLOGY 2002;59:40 –48

Radiotherapeutic damage is characterized by multi- ranged from little cognitive deterioration in adults at
ple phases including the acute, subacute, and late 4 years after treatment2 to mental retardation as
delayed.1-3 Late-delayed changes have been reported early as 2 years in children (although some surviving
as early as 1 year and as late as 20 years after untreated children also met criteria for mental retar-
treatment. Current techniques have decreased the dation).20 Many studies, though limited by their ret-
toxic burden to normal tissue,3 and radiation necro- rospective designs, report 20% to 80% of patients
sis has become rare. However, there is abundant with some degree of cognitive impairment on formal
evidence that cognitive deterioration occurs in testing from 2 to 20 years later.20-22
adults4-6 and children7,8 who receive restricted fields We measured the course of cognitive decline and
or whole brain irradiation (XRT), despite little or no radiographic change over 6 years of the late-delayed
neurologic impairment. There is little agreement on phase of XRT effects. Patient selection was consid-
the time course of the late-delayed changes. ered critical to understanding XRT effects; patients
Previous studies suggest that no significant dete- were recruited whose cognitive functioning was not
rioration on either neuroimaging or neuropsycholog- confounded by malignancy or concomitant neurologic
ical testing occurs before 18 months after XRT.6,7,9-16 complication, and who would receive 100% of dose to
Malignancy is a confounding factor due to paraneo- the cortex.
plastic phenomena. Retrospective studies show that
XRT-related dementia is characterized as progres- Methods. Patient selection and characteristics. We
sive subcortical dementia,17,18 and occurred in 2% of studied patients with primary, low-grade supratentorial
adult patients with cured metastatic brain tumors brain tumors (gliomas [WHO grades I and II], pituitary
treated with whole brain XRT.19 Findings have and pineal tumors, and noninvasive meningiomas), treated

See also pages 8, 48, and 121

From the Departments of Neurology (Drs. Armstrong, Pruitt, Mollman, and Phillips), Radiology (Dr. Hunter), Radiation Oncology (Drs. Tochner and Lustig),
and Neurosurgery (Dr. Judy), University of Pennsylvania Medical School; and Divisions of Neurology (Drs. Armstrong, Ledakis, Tallent, Goldstein, Stanczak,
Jo, and Than), Radiology (Dr. Hunter), and Biostatistics (Dr. Cohen), Children’s Hospital of Philadelphia, PA.
Supported by grant RO1 #CA65438 from the National Cancer Institute, and by grant #IRG-135N from the American Cancer Society.
Received August 31, 2001. Accepted in final form March 23, 2002.
Address correspondence and reprint requests to Dr. Carol L. Armstrong, Children’s Hospital of Philadelphia, Division of Neurology, Main A232, 34th and
Civic Center Boulevard, Philadelphia, PA 19104; e-mail: armstrongc@email.chop.edu

40 Copyright © 2002 by AAN Enterprises, Inc.

with standard XRT after surgical biopsy, resection, or no
surgical intervention. Patients were recruited for inclusion
in a longitudinal study by neuro-oncology physician refer-
ral or the brain tumor conferences of the Hospital of the
University of Pennsylvania and Thomas Jefferson Univer-
sity Hospital in Philadelphia. Informed consent was ob-
tained through discussion regarding the nature of the
procedures and study.
Tumor grading was based on pathologic or neuroradio-
logic findings in the absence of surgery. Additional inclu-
sionary criteria were life expectancy of at least 3 years and
age between 18 and 69 years. Exclusionary criteria in-
cluded extensive neuropsychological impairment, amnesia
(i.e., inability to learn new material), aphasia (i.e., inabil-
ity to understand task instructions or express thoughts
fluently), neurologic comorbidity (e.g., meningitis), or his-
tory of coronary artery disease, hypertension, diabetes, Figure 1. Average MRI ratings for global measures over 6
pulmonary disease, kidney disease, other cancer, and im- years (excluding reoccurrence and hypertensive data
munosuppressive disease. points). Black squares represent average white matter at-
Of the 55 patients who had been in the longitudinal rophy rating; white circles represent average hyperinten-
study for at least 1 year, 33 patients were irradiated. sity rating; black triangles represent average gray matter
Three patients were excluded after the initial neuropsy- atrophy rating. Higher scores represent a greater number
chological evaluation. One patient was excluded who had a of abnormalities visible on MRI.
large meningioma, severe memory encoding and retrieval
deficits, and impairment in three cognitive domains. One
patient was excluded after developing bacterial meningitis scans was added for which there was no corresponding
from an infected shunt. A third patient had a 1-cm menin- cognitive test points, and this larger set of scans was ana-
gioma arising from the anteroinferior portion of the falx, lyzed separately. The number of scans over time included
and severe and widespread cognitive deficits that were in this analysis is also shown in figure 1.
thought to represent an etiology unrelated to her tumor. A total of 26 patients were included in the comparisons
Three more patients excluded themselves after the initial over time of the cognitive changes, but a total of 22 pa-
neuropsychological evaluation for personal reasons. One tients were included in the analyses of the radiographic
patient had tumor regrowth 1.5 years after baseline, so the changes due to the unavailability of some scans such as
data of this patient were also excluded from any analysis. baseline scans. The patient groups were composed of glio-
The remaining 26 patients included 13 patients who had mas (65%), neuroendocrine tumors (15%), meningiomas
received neuropsychological evaluation 6 years after treat- (12%), and other (8%). The group was composed of 13 left
ment. Some patients were tested up to 10 years after treat- hemisphere and 7 right hemisphere lesioned patients, as
ment, but there were an insufficient number of cases to well as 6 patients whose tumors were not lateralized. The
group them by later time points. One patient was diag- median age was 42.5 years, and the mean age was 41.12
nosed with diabetes and hypertension about 5 years after (SD ⫽ 11.83). The mean education was 15.31 years (SD ⫽
entry into the study and the results from that point on 2.56); 23% did not continue their education beyond high
were excluded from analyses, although we continued to school, 42% had some college or were college graduates,
follow this patient. This patient demonstrated rapid and and 35% had some postgraduate education. Patients were
major atrophy, white matter hyperintensities, and eventu- primarily dextral (81%), with 15% sinistral, and 1 patient
ally thalamic and pontine infarcts beginning 1 year after with mixed dominance. Men comprised 58% of the group.
diagnosis of uncontrolled diabetes and hypertension. Cog- The data of the 22 nonirradiated patients, whose re-
nitive scores for this patient also demonstrated rapid and cruitment began later, were not sufficiently longitudinal to
major declines. Three other patients had tumor reoccur- provide a control group at this time.
rence, and their data were included in the analyses until Radiotherapy. XRT was administered similarly at
the date of the radiographic diagnosis of recurrence, al- both institutions by the use of megavoltage machines, with
though we continued to follow them. The number of cogni- the selection of optimal photon energy based on dose distri-
tive data points and radiographic scans used in the final bution within the clinical target volumes and maximal
analyses are displayed in table 1. An additional set of MRI sparing of normal brain parenchyma. The criterion for in-
cluding a tumor type was that the total XRT dose would be
significant to the cortex and subcortical areas that are
Table 1 Number of patients included in each year of study critical for cognition. Pineal and pituitary tumors met this
excluding time points after recurrence and development or criterion. As an example, dose reconstruction for one study
comorbidity patient with a pineal tumor showed that the parietal lobe
received the lowest dose (21% to 52% of total dose of 5580
Outcome Year Year Year Year Year Year
Gy), the occipital lobe received 57% to 63%, the temporal
measure Baseline 1 2 3 4 5 6
lobe received 73% to 99%, the frontal lobe received 73% to
Neurocognitive 26 26 14 11 8 8 9 79%, the corpus callosum received 97% to 102%, the cere-
bellum received 83% to 86%, the basal ganglia received
MRI scan 22 22 10 10 6 7 4
97% to 106%, the thalamus received 99% to 101%, and the
July (1 of 2) 2002 NEUROLOGY 59 41
anterior cingulate received 98% of the total dose. A mean neuropsychological test indices, a single measure of cogni-
low-grade glioma dose of 55.6 Gy (range ⫽ 54 to 63 Gy), a tive performance at each contact point was computed. This
mean pituitary dose of 46 Gy, and mean meningioma measure was defined as the intrasubject variation in cog-
dose of 54.6 Gy (range ⫽ 54 to 55.8 Gy) were delivered nitive performance among all tests, calculated in three
in fractions of 1.8 to 2.0 Gy per treatment day over 4.5 to ways. The three measures of cognitive variation were de-
7.0 weeks. Two patients received bischloronitrosourea rived by applying normative values to a patient’s test
(BCNU) concurrently with XRT, and one completed BCNU score, converting it to a standard z-score, and then calcu-
before XRT. lating: 1) the maximum variation—the total range of
Neuropsychological assessment. An extensive test bat- z-scores by subtracting the minimum z-score from the
tery was administered in a single 4-hour session that in- maximum z-score; 2) the 90% range—the z-score range
cluded a neurodiagnostic interview by a neuropsychologist from the 5th percentile to the 95th percentile; and 3) the
or by doctoral psychology students and postdoctoral fellows 80% range—the z-score range from the 10th percentile to
under the supervision of a neuropsychologist (C.L.A.). the 90th percentile. We hypothesized that if late-delayed
Rests were provided as needed. radiation damage was not based on the vulnerability of
The battery included standardized neuropsychological certain brain regions, or if the effects of XRT were not
indices from the domains of motor function (Praxis, Finger anatomically systematic because of differing tumor loca-
Tapping Test23 [Right and Left]), attention (selective visual tions and dose distributions, or if other patient character-
attention [Bells Test24], Auditory Selective Attention Test,25 istics contributed to variability in susceptibility to XRT
sustained visual attention [Continuous Performance Test26]), damage, then specific tests might not be sufficiently sensi-
language (Sentence Repetition Test,27 Controlled Oral Word tive. Our rationale for using a measure of variability was
Association Test,27 Animal Naming Test27 [category fluency]), that it would encompass all the instability within a pa-
cognitive processing speed (Paced Auditory Serial Addition tient’s performance. The percentile distributions were used
Test28 [PASAT], Symbol Digit Modalities Test23 [oral ver- to eliminate biasing of the results due to scores that were
sion]), verbal memory (Digit Span Test23 [Forward], Word at the extremes of the patients’ data distribution, or to the
Span Test,29 Rey Auditory Verbal Learning Test30 [Learning non-normal distributions of some test scores. The total
(total for Trials 1 to 5), Post-Interference Retrieval (T6), Re- z-score range was included to maximize the potential sen-
tention (T6/T5), Delayed Recall (T7), Retention after Delay sitivity of the variability measurement.
(T7/T6), Total Recognition Hits, Total Recognition False Neuropsychological measures that were hypothesized a
Alarm Responses]), visuospatial perception (Road Map priori to be sensitive to late-delayed XRT damage were
Test,31 Visual Pursuits Test23 [number of items completed, limited to the measures that demonstrated a treatment
percent accurate responses], Rey Osterrieth Complex Fig- effect in our studies of the early-delayed radiation ef-
ure Test23 [copy of figure]), visual memory (Visual Memory fect.34,35 These were the postencoding retrieval measures
Span Test23 [Forward], Revised Benton Visual Retention from the Rey Auditory Verbal Learning Test, indices that
Test32 [total correct], Rey Osterrieth Complex Figure Test23 had demonstrated a selective decline at the early-delayed
[immediate recall, delayed recall], Biber Figure Learning radiotherapy phase. The remaining neuropsychological
Test33 [Learning (total for Trials 1 to 5), Post-Interference measures were also analyzed.
Retrieval (T6), Retention (T6/T5), Delayed Recall (T7), Re- Neuroimaging. All available clinical MRI scans were
tention after Delay (T7/T6), Total Recognition Hits, Total gathered for each patient, requiring the amassing of scans
Recognition False Alarm Responses]), and conceptual set from several hospitals and imaging centers. Although this
shifting (Wisconsin Card Sorting Test [number of catego- resulted in varying TR/TE lengths and sequences, it also
ries achieved, perseverative errors]). resulted in a more complete set of data for patients who
The data points for this study were: baseline (4 to 6 often received surgery, radiation treatments, and follow-up
weeks after surgery and just prior to beginning XRT), 1 examinations with different doctors and centers. In all
year after baseline, and yearly for 6 years after treatment. cases, multiple slice, contiguous spin-echo images were
All patients were tested at baseline and at subsequent test performed on a 1.5 T superconducting magnet.
points on the identical set of tests. However, to partially MRI images were rated by a single neuroradiologist
control for practice effects, multiple forms34 were used ran- (J.V.H) who was informed of the patient’s age but was
domly across contact points for the Auditory Selective At- blinded to treatment status (XRT vs no irradiation) and
tention Test (2 forms), Rey Auditory Verbal Learning Test time after treatment. All MR scans were judged by in-
(4 forms), Complex Figure Test (2 forms), Revised Benton creased signal intensity on T2-weighted axial images. Hy-
Visual Retention Test (3 forms), and Biber Figure Learn- perintensities were rated for severity using a 7-point scale
ing Test (4 forms). Over the course of the study, some reflecting the magnitude of the white matter disease: (0)
changes in the test battery were made to answer evolving no focal hyperintensities, (1) 1 to 3 small scattered foci, (2)
study hypotheses about the effects of XRT.2 Some tests 1 to 3 large focal hyperintensities, (3) confluent hyperin-
that were insensitive or psychometrically poor were elimi- tensities, (4) periventricular cloaking defined as a hyperin-
nated to “make room” for new tests. However, the within- tense band of variable thickness with smooth lateral
subject design determined that the battery taken by an margins surrounding the ventricles, (5) periventricular
individual remained unchanged from baseline. cloaking plus widespread white matter disease, (6) homo-
All missing data were due to the above research design geneously, diffusely abnormal white matter defined as hy-
issue and technical failure. Those principal measures with perintensity extending from the ventricular lining to the
the largest number of missing values were eliminated from cortico-medullary junction involving most of the white
further analysis. A total of 37 different neuropsychological matter. In addition, a 4-point rating scale was used to rate
measures remained for analysis. In addition to individual the atrophy of the white and the gray matter separately:
42 NEUROLOGY 59 July (1 of 2) 2002
(0) Normal, (1) Minimal (slightly prominent extra-axial
CSF spaces, normal ventricles), (2) Moderate (prominent
extra-axial CSF spaces, slightly enlarged ventricles), (3)
Severe (marked prominence of extra-axial CSF spaces,
marked increase in size of ventricles). Thirty-nine stan-
dardized regions of interest (ROI) were defined before
grading of the scans. To test the intrareader reliability of
these ratings, the neuroradiologist performed blind double
ratings at a later time point (at least 2 weeks after the
initial rating) on 1,958 ROI from 51 scans. The rate of
agreement was 0.91, which was considered an acceptable
level of reliability. Inconsistencies between the double rat-
ings were resolved using FLAIR images.
The Hyperintensity variable was composed of the mean
score for all brain regions combined. Mean White Matter
Atrophy and mean Gray Matter Atrophy (frontotemporal,
occipital-parietal, and cerebellum) measures were also
computed for each scan. Regional subgroup scores were
additionally computed by grouping the ROI into subgroups
that were selected based on published reports of their sen-
sitivity to XRT damage. The seven regional subgroups
were defined as follows: 1) Frontal White Matter, Occipital
White Matter, Centrum Seminovale, Periventricular
White Matter, Internal Capsules; 2) Genu, Body of Corpus
Callosum, Splenium; 3) Basal Ganglia, Thalamus; 4) Cere-
bellar Peduncle, Cerebellum, Vermis; 5) Frontal Gray Mat-
ter, Temporal Gray Matter, Parietal Gray Matter,
Occipital Gray Matter; 6) Pons; 7) Cerebral Peduncle. The
regional subgroup scores were the average of the scores for
the ROI that comprised that regional subgroup. Differen-
tial abnormalities in the left vs right hemisphere were
computed by subtracting the MRI rating for the right side
from that for the left side for the 15 ROI that had lateral-
ized ratings. Figure 2. Significant cognitive improvements over 6 years
The patients’ clinical MRI were matched to the neuro- (excluding reoccurrence and hypertensive data points). (A)
psychological data points; the mean time between MRI and Paced Auditory Serial Addition Test (PASAT) scores (low-
neuropsychological data point was 2.18 months (SD ⫽ er scores indicate faster processing). (B) Symbol Digit Mo-
2.19). dalities Test correct scores.
Analyses. A mixed model repeated analysis of variance
using the Statistical Analysis System (SAS) was used to ana-
lyze the data, with the advantage that the model adjusts Controlled Oral Word Association Test (F(1,72) ⫽ 4.08, p ⬍
estimates for missing observations. The linear and quadratic 0.05), Sentence Repetition (F(1,61) ⫽ 13.58, p ⬍ 0.0005),
trends in neuropsychological test indices, cognitive variation Symbol Digit Modalities (F(1,74) ⫽ 8.27, p ⬍ 0.005), and
score, and MRI ratings over 6 years after treatment were Auditory Selective Attention Test (F(1,74) ⫽ 3.82, p ⬍
analyzed. To look for consistent trends over time, the linear 0.05). If we use a liberal correction factor to control for
slopes over time for each subject on each cognitive measure, multiple comparisons, accepting an alpha of 0.005, then
the variation scores, and each anatomic variable were ob- three measures remain significant. Two examples of the
tained from the mixed model program and used in a correla- characteristic slopes of improvement are shown in figure 2.
tion matrix for the purpose of identifying correlated slopes of A second pattern was found that suggested improve-
change over time. Demographic variables of age, education, ment until a decline at 5 years after XRT, and this pattern
and sex, as well as fatigue and depression, were entered as a was thought to reflect the late-delayed damaging effects of
first step in a secondary mixed model program, and the lin- treatment (see table 2). Three measures from the Biber
ear and curvilinear trends on the cognitive measures were Figure Learning Test demonstrated improvement and
entered as a second step to see if cognitive effects existed then decline on curvilinear analyses: Learning—total for
beyond the demographic variables. Trials 1 to 5 (F(1,44) ⫽ 16.17, p ⬍ 0.0002; Post Interfer-
ence Retrieval-T6 (F(1,44) ⫽ 27.54, p ⬍ 0.0001); and De-
Results. Neurocognitive findings. Seven of the 37 neu- layed Recall-T7 (F(1,44) ⫽ 8.78, p ⬍ 0.005). Notably, only
ropsychological indices showed significant slopes of im- measures of learning and absolute recall reached signifi-
provement over 6 years, 6 of which showed a significant cance, and not the relative measures of retention. Figure 3
linear pattern. The measures of improvement (table 2) depicts the XRT-related cognitive declines. Individual
were found in the PASAT (F(1,73) ⫽ 16.72, p ⬍ 0.0001), analyses demonstrated the selective nature of the cogni-
Immediate Recall (F(1,71) ⫽ 6.30, p ⬍ 0.01) and Delayed tive impairments. We examined the percentage of patients
Recall (F(1,70) ⫽ 4.80, p ⬍ 0.03) of the Complex Figure, who were clinically impaired, using one z-score less than
July (1 of 2) 2002 NEUROLOGY 59 43
Table 2 Significant trends in cognition over 6 years after
treatment with XRT

p Value

Test Index Linear Curvilinear

Improvements
Auditory Selective Attention Test 0.82 0.05
Paced Auditory Serial Addition Test 0.009 0.0001
(PASAT)
Controlled Oral Word Association 0.003 0.05
Test
Sentence Repetition Test 0.0005 0.22
Symbol Digit Modalities Test—oral 0.005 0.91
version
Rey Osterrieth Complex Figure Test
Immediate Recall 0.003 0.01
Delayed Recall 0.001 0.03
Declines
Biber Figure Learning
Total for Trials 1 to 5 0.37 0.0002
Post Interference Retrieval (T6) 0.40 0.0001
Delayed Recall (T7) 0.41 0.005
Retention after Delay (T7/T6) 0.70 0.008
Continuous Performance 0.18 0.04

the mean as the criterion for impairment. Results indicate

that the rate of clinical impairment in the group dimin-
ished after high levels at baseline (25% to 44%), with the
lowest level of impairment reached at year 4 (0%); this
result parallels the analysis of variance results. By year 5 Figure 3. Significant cognitive declines over 6 years (ex-
(20% to 40%) and year 6 (20% to 67%) impairment levels cluding reoccurrence and hypertensive data points). (A)
increased again. The mean decline in each cognitive score Biber Learning (total for Trials 1 to 5) total score. (B)
was less than 1 SD at years 5 and 6. Biber Post Interference Retrieval (T6) and Biber Delayed
Measures of fatigue and depression were examined for Recall (T7) scores. Black squares represent Biber T6
significant effects over time. Neither the Fatigue Severity scores; white circles represent Biber T7 score.
Scale (linear p ⬍ 0.27, curvilinear p ⬍ 0.75), Beck Depres-
sion Inventory (linear p ⬍ 0.88, curvilinear p ⬍ 0.13), nor
MMPI-2 Depression Scale (linear p ⬍ 0.93, curvilinear p ⬍ MRI ratings. The changes over time in the mean white
0.69) showed change. Age, gender, and fatigue when covar- matter atrophy, mean hyperintensity, and mean gray mat-
ied with the significant cognitive variables, also did not ter scores are shown in figure 1. For the same set of pa-
account for a significant amount of the variance over time. tients for whom the cognitive data were available at the
Although education did account for some of the variance in same time points, the White Matter Atrophy (F(1,53) ⫽
the changes in the three Biber variables, the cognitive 5.62, p ⬍ 0.02) and the Hyperintensities (F(1,53) ⫽ 5.97,
changes over time remained (Biber Learning—total for p ⬍ 0.02) ratings demonstrated curvilinear effects over
Trials 1 to 5 (F(1,30) ⫽ 7.10, p ⬍ 0.05); Biber Post Interfer- time. The mean Gray Matter Atrophy rating showed no
ence Retrieval-T6 (F(1,30) ⫽ 13.18, p ⬍ 0.001); Biber De- change over time (p ⬍ 0.24). These analyses were followed
layed Recall-T7 (F(1,30) ⫽ 4.56, p ⬍ 0.05)). Patients with by analyses of our seven regional subgroups. Both linear
extra-axial tumors (pituitary adenomas: n ⫽ 2 at year 4, 1 and curvilinear changes in regional subgroup 1 were found
at year 5, and 3 at year 6) had mean scores that were (linear F(1,55) ⫽ 8.49, p ⬍ 0.005) and curvilinear F(1,55) ⫽
similar to or better than the mean for the group. 7.16, p ⬍ 0.01). Regional subgroup 1 was composed of the
The cognitive variation measure yielded no effect of bihemispheric subcortical white matter including the cen-
irradiation over the 6 years after treatment. The 3 mea- trum semiovale, periventricular areas, and internal cap-
sures of cognitive variation demonstrated trends (z sules. This regional subgroup appeared to account for the
range F(1,74) ⫽ 6.43, p ⬍ 0.01; 90% range F(1,74) ⫽ changes over time in the Hyperintensities variable. Within
4.65, p ⬍ 0.03; 80% range F(1,74) ⫽ 3.79, p ⬍ 0.06) that this subgroup, the left frontal white matter (curvilinear
showed that each of the cognitive variation mean scores F(1,55) ⫽ 9.31, p ⬍ 0.004), left centrum semiovale (linear
were greatest at baseline and generally declined over the F(1,55) ⫽ 8.57), p ⬍ 0.005), and left periventricular
next few years, with no clear increase at 6 years (figure 4). white matter ratings (linear F(1,55) ⫽ 9.71, p ⬍ 0.003; curvi-
44 NEUROLOGY 59 July (1 of 2) 2002
 ment, with the exception of an unsustained additional
peak at about 5 years after treatment (linear F(1,141) ⫽
38.80, p ⬍ 0.0001). White matter hyperintensities also
showed a peak at 30 to 35 months, which was the stron-
gest effect (linear F(1,141) ⫽ 27.61, p ⬍ 0.0001). Hyperin-
tensities were predominantly in the immediate region of
the tumor locus, with rare exceptions. Regional subgroup 1
again showed the largest effect (F(1,141) ⫽ 33.97, p ⬍
0.0001), accounted for by both left and right frontal white
matter, left and right centrum semiovale, and left and
right periventricular areas. Regional subgroup 2 comprised
three parts of the corpus callosum (F(1,141) ⫽ 8.23, p ⬍
0.005), regional subgroup 4 comprised cerebellar struc-
tures (F(1,141) ⫽ 4.31, p ⬍ 0.04), and regional subgroup 6
comprised the pons (F(1,141) ⫽ 5.84, p ⬍ 0.02); all showed
some contribution to the variance in white matter hyperin-
tensities over time. In all analyses, data were removed at
the time when recurrence was radiographically identified,
Figure 4. Variation of standardized cognitive scores at and for the patient with secondary effects from hyperten-
yearly contact points (excluding reoccurrence and hyper- sion and diabetes.
tensive data points). Squares indicate the min/max range; Individual analyses showed that 54% of the 26 patients
triangles represent the 90th percentile range; diamonds demonstrated some progression in the rated score of white
represent the 80th percentile range. Higher scores indicate matter hyperintensities over time, although the progres-
greater within-subject variability. sion was often not continuous. Individual progression was
identified if a score increased in relation to the pre-XRT
linear F(1,55) ⫽ 7.78, p ⬍ 0.007) increased over time (see baseline that was not related to recurrence or growth of
figure 5). the tumor, defined as a temporal and spatial proximity to
A second set of analyses was done with all the clinical the time of growth and tumor location. Two of the three
MRI collected on the same set of patients. This analysis patients who received BCNU developed XRT-related white
examined the radiographic changes independent of cogni- matter abnormalities that emerged before 1 year, and in
tive data points. For this analysis there were 171 MRI both cases, the BCNU overlapped with XRT and continued
scans that had been rated using our rating systems, vs a after. A third patient, who also received BCNU but com-
total of 81 that corresponded with the cognitive data pleted treatment before starting radiotherapy, did not
points. Again, the mean white matter atrophy and white show evidence of white matter abnormalities.
matter hyperintensities showed linear and curvilinear in- Of the remaining 12 (46%) patients who demonstrated
creases (see figure 5). White matter atrophy appeared to white matter hyperintensities that were associated with
peak about 2 1/2 to 3 years (30 to 35 months) after treat- XRT excluding BCNU, 5 (42%) showed some increase in
scores in the white matter whose onset preceded 1 year
after XRT (between 5.1 to 10.7 months after initiation of
XRT). White matter abnormalities increased or had onset
between 1 and 2 years in 4 of 12 (33%) patients who
showed XRT-related changes, and at approximately 36
months in 3 of 12 (25%) patients. No progression occurred
after 3 years after treatment during the course of time
included in this report.
Correlation of MRI and cognitive findings. The slopes
of late treatment-related cognitive decline did not correlate
significantly with the slopes of increasing radiographic hy-
perintensities. This was primarily because the increase in
hyperintensities increased until a peak around 30 to 36
months after treatment, but cognitive function was im-
proving at this same time. No further increase in hyperin-
tensities was found when the selective cognitive measures
showed significant declines at 4 years (see figures 1 and 3).

Figure 5. Average MRI ratings for seven regional sub-

groups of the brain over 6 years (excluding reoccurrence Discussion. A late-delayed effect of XRT damage
and hypertensive data points). Black squares represent was demonstrated by declines in selective cognitive
regional subgroup 1; black triangles represent regional functions that began 5 years after XRT. The selectiv-
subgroup 2; black dashes represent regional subgroup 3; ity of the cognitive decline is initial evidence that
white circles represent regional subgroup 4; white squares widespread cognitive impairment or dementia does
represent regional subgroup 5; white triangles represent not occur precipitously after XRT in adult low-grade
regional subgroup 6; black circles represent regional sub- brain tumor patients without risk factors for vascu-
group 7. lar damage. The chronic clinical period, 1 to 5 years
July (1 of 2) 2002 NEUROLOGY 59 45
after treatment, is thought to be based on deteriora- characterize the late clinical period, and ischemic
tion of vascular structure and secondary parenchy- injury in the subcortical and deep white matter is
mal degeneration that can result in loss of resistance the most abundant evidence of late XRT damage.6
to various types of stress.36 We found elevated fa- The potential biologic basis for the sensitivity of vi-
tigue but no other indicators of predictable cognitive sual memory to XRT is the sensitivity of the CA1
decline during this period. There was relatively little neurons of the hippocampus to ischemia,44-46 and the
cognitive decline during the late clinical period (⬎5 CA3 region to repeated stresses of various kinds.47
years after treatment36) in our patients who were There is also converging evidence for the expected
screened for vascular risk factors before enrollment rate of white matter abnormalities seen on MRI. A
in the study. In contrast, the patient with uncon- minimal degree of leukoencephalopathy was found
trolled diabetes and hypertension with onset 5 years around the tumor sites, primarily in the subcortical
after treatment demonstrated precipitous cognitive and deep white matter, with smaller changes in the
and radiographic changes. Another prospective study corpus callosum, cerebellar structures, and the pons.
of late-delayed cognitive change in adults with low- Although 54% of our series of patients showed mini-
grade and anaplastic brain tumors found no evidence mal white matter hyperintensities (WMH), a larger
of predictable decline in cognition 4 years after treat- study of mixed tumor grades reported 46% with
ment.2 In this study, two patients improved signifi- WMH after 1 year after treatment.16 We did not find
cantly, one remained stable, and one, who had the hyperintensities to progress beyond 3 years after
resection of a right temporal anaplastic oligodendro- treatment, which has also been reported in other
glioma, XRT, and IV nitrosoureas, showed mild leu- studies.11,16 One exception is a report of progressive
koencephalopathy in the radiated field and onset of cerebral atrophy in 61% of small-cell lung cancer
global cognition deterioration 6 months after begin- patients up to 8 years after treatment.48 However,
ning XRT. Thus, prospective studies agree that par- small-cell lung cancer patients are known to have
tial field radiotherapy alone with current treatment high rates of cognitive impairment before treatment
methods (approximately 55 Gy in fractions of 1.8 Gy because of paraneoplastic effects, brain metastases
over 6 weeks) does not, without other risk for mor- in some cases, higher fractions of XRT (2 to 3 Gy),
bidity, carry a burden of cognitive decline in adults and concurrent chemotherapy.
for at least 4 years after treatment. WMH preceded the onset of cognitive decline; the
The cognitive measures of late vulnerability to accrual of mild WMH reached a peak 2 to 3 years
XRT were not those that marked the early-delayed after XRT while cognitive functions were still im-
effects of XRT,1,37 suggesting differential pathophysi- proving. This is predicted by the threshold effect: a
ologic mechanisms for these two phases. The early- critical burden of white matter abnormalities must
delayed effect appears mediated by temporary accumulate before adverse cognitive effects become
demyelination.38 The pathologic mechanism for the evident.49 Lack of correlation between cognitive mea-
late-delayed effect may be caused by damage to cere- sures and normal appearing white matter volume in
bral blood vessels based on the radiosensitivity of children with cerebellar tumors and craniospinal
endothelium,3 as well as empirical and case reports XRT has also been reported.50
of vascular vulnerability to XRT.39-41 A selective de- Adult age and depression were not associated with
cline in visual memory, in contrast to the unim- cognitive decline in our study, but other factors that
paired or improved measures of verbal memory, can present high risk in interaction with XRT in-
attention, language, complex processing speed, mo- clude chemotherapy immediately before, during, or
tor function, visuospatial perception, and problem after XRT, malignancy, risk for vascular injury (e.g.,
solving, could be associated with this mechanism. hypertension, diabetes, hypercholesterolemia), and
The visual memory tests (Biber) used in this study very young age. The addition of other risk factors
required the learning and retrieval of novel though may prognosticate a separate group of patients who
regular shapes and more “shallow” processing of the are likely to develop both radiographic and cognitive
structural features of the simple designs, whereas decline within 5 years of treatment. This determina-
the verbal memory tests contain word stimuli of high tion will require direct comparison of groups of pa-
frequency and familiarity that are “deeply” pro- tients with and without risk factors.
cessed. Current memory theory proposes that novel Another constraint of our study was the small
stimuli, such as those in the Biber, require the number of patient visits available after the first 2
hippocampus-based configural memory system, years after XRT. The decrease in sample size is par-
whereas semantically driven data are processed by tially attributable to loss of contact with patients
the neocortical associative semantic memory net- when they moved (10.2%), refusal to continue in the
works.42,43 The continuing slope of improvement in study when they returned to work (9.1%), and death
the Biber for 4 years followed by a decline at year 5 (7.8%). Another limitation is the lack of a low-grade
suggests that the configural memory system, with its tumor control group. Some of these limitations can
theorized basis in the hippocampal memory system, be addressed as we continue to accrue and follow
is sensitive to late-delayed physiologic effects. Slow patients over a 10- to 20-year period. However, these
progression of residual radiation damage and forma- results indicate that we cannot extrapolate the de-
tion of dense fibrous tissue caused by hypoperfusion3 gree of cognitive and radiographic damage from
46 NEUROLOGY 59 July (1 of 2) 2002
whole brain XRT or from higher doses to that caused 19. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced de-
mentia in patients cured of brain metastases. Neurology 1989;
by restricted field XRT given to patients with low- 39:789 –796.
grade brain tumors. The reduction of noise through 20. North CA, North RB, Epstein JA, Piantadosi S, Wharam MD.
the patient selection methods and the emphasis on Low-grade cerebral astrocytomas: survival and quality of life
prospective studies has permitted us to describe the after radiation therapy. Cancer 1990;66:6 –14.
21. Meyers CA, Geara F, Wong PF, Morrison WH. Neurocognitive
XRT-related changes from moderate dose, restricted effects of therapeutic irradiation for base of skull tumors. Int
field treatment, that are not due to malignancy, che- J Radiat Oncol Biol Phys 2000;46:51–55.
motherapy, or other clinical factors that also cause 22. Sichez N, Chatellier G, Poisson M, Delattre JY. Supratento-
vascular brain damage or radiographic changes. rial gliomas: neuropsychological study of long-term survivors.
Rev Neurol (Paris) 1996;152:261–266.
23. Lezak M. Neuropsychological assessment, 3rd ed. New York:
Oxford University Press, 1995.
References 24. Vanier M, Gauthier L, Lambert J, et al. Evaluation of left
1. Armstrong C, Ruffer J, Corn B, DeVries K, Mollman J. Bipha- visuospatial neglect: norms and discrimination power of two
sic patterns of memory deficits following moderate-dose tests. Neuropsychology 1990;4:87–96.
partial-brain irradiation: neuropsychologic outcome and pro- 25. Armstrong C. Selective versus sustained attention: a continu-
posed mechanisms. J Clin Onc 1995;13:2263–2271. ous performance test revisited. Clin Neuropsychol 1997;11:
2. Vigliani MC, Sichez N, Poisson M, Delattre JY. A prospective 18 –33.
study of cognitive functions following conventional radiother- 26. Loong J. The continuous performance test. San Luis Obispo,
apy for supratentorial gliomas in young adults: 4-year results. CA: Wang Neuropsychological Laboratory, 1991.
Int J Radiat Oncol Biol Phys 1996;35:527–533. 27. Spreen O, Strauss E. A compendium of neuropsychological
3. Mettler FA, Upton AC. Medical effects of ionizing radiation, tests. New York: Oxford University Press, 1991.
2nd ed. Philadelphia: WB Saunders, 1995. 28. Gronwall D. Paced auditory serial-addition task: a measures
4. Surma-aho O, Niemela M, Vilkki J, et al. Adverse long-term of recovery from concussion. Percept Mot Skills 1977;44:367–
effects of brain radiotherapy in adult low-grade glioma pa- 373.
tients. Neurology 2001;56:1285–1290. 29. Grossman M, Armstrong C, Onishi K, et al. Patterns of cogni-
5. Hua MS, Chen ST, Tang LM, Leung WM. Neuropsychological tive impairment in relapsing-remitting and chronic progres-
function in patients with nasopharyngeal carcinoma after ra- sive multiple sclerosis. Neuropsychiat Neuropsychol Behav
diotherapy. J Clin Exp Neuropsychol 1998;20:684 – 693. Neurol 1994;7:194 –210.
6. Johnson BE, Patronas N, Hayes W, et al. Neurologic, computed 30. Armstrong C, Onishi K, Robinson K, et al. Serial position and
cranial tomographic, and magnetic resonance imaging abnormal- temporal cue effects in multiple sclerosis: two subtypes of
ities in patients with small cell lung cancer: further follow-up of defective memory mechanisms. Neuropsychologia 1996;34:
6- to 13-year survivors. J Clin Oncol 1990;8:48–56. 853– 86.
7. Chadderton RD, West CGH, Schulz S, Quirke DC, Gattaman- 31. Money J, Alexander D, Walker HT Jr. A standardized Road
eni R, Taylor R. Radiotherapy in the treatment of low-grade Map Test of direction sense. Baltimore: Johns Hopkins Press,
astrocytomas: II. The physical and cognitive sequelae. Childs 1965.
Nerv Syst 1995;11:443– 448. 32. Benton A. Revised visual retention test: clinical and experi-
8. Butler RW, Hill JM, Steinherz PG, Meyers PA, Finlay JL. mental application, 4th ed. San Antonio, TX: The Psychologi-
Neuropsychologic effects of cranial irradiation, intrathecal cal Corporation, 1974.
methotrexate, and systemic methotrexate in childhood cancer. 33. Drachman D, Glosser G, Fleming P, Longenecker G. Memory
J Clin Onc 1994;12:2621–2629. decline in the aged: treatment with lecithin and physostig-
9. Archibald YM, Lunn D, Ruttan LA, et al. Cognitive function- mine. Neurology 1982;32:944 –950.
ing in long-term survivors of high-grade glioma. J Neurosurg 34. Armstrong C, Mollman J, Corn B, Alavi J, Grossman M. The
1994;80:247–253. effects of radiation therapy on adult brain functioning: evi-
10. Komaki R, Meyers CA, Shin DM, et al. Evaluation of cognitive dence for a rebound phenomenon in a phase I trial. Neurology
function in patients with limited small cell lung cancer prior 1993;43:1961–1965.
to and shortly following prophylactic cranial irradiation. Int J 35. Armstrong CL, Stern CH, Corn B. Memory performance used
Radiat Oncol Biol Phys 1995;33:179 –182. to detect radiation effects on cognitive functioning. Appl Neu-
11. Corn BW, Yousem DM, Scott CB, et al. White matter changes ropsychol 2001;8:129 –139.
are correlated significantly with radiation dose. Cancer 1994; 36. Rubin P, Casarett GW. Clinical radiation pathology. Philadel-
74:2828 –2835. phia: WB Saunders, 1968.
12. Lee YY, Nauert C, Glass P. Treatment-related white matter 37. Armstrong CL, Corn BW, Ruffer JE, Pruitt AA, Mollman JE,
changes in cancer patients. Cancer 1986;57:1473–1482. Phillips PC. Radiotherapeutic effects on brain function: double
13. Taphoorn MJB, Schiphorst AK, Snoek FJ, et al. Cognitive dissociation of memory systems. Neuropsychiat Neuropsychol
functions and quality of life in patients with low-grade glio- Behav Neurol 2000;13:101–111.
mas: the impact of radiotherapy. Ann Neurol 1994;36:48 –54. 38. Dunbar SF, Loeffler JS. Stereotactic radiation therapy. In:
14. Laukkanen E, Klonoff H, Allan B, Graeb D, Murray N. The Mauch PM, Leoffler JS, ed. Radiation oncology: technology
role of prophylactic brain irradiation in limited stage small and biology. Philadelphia: WB Saunders, 1994:237–251.
cell lung cancer: clinical, neuropsychologic, and CT sequelae. J 39. Murros KE, Toole JF. The effect of radiation on carotid arter-
Radiat Oncol Biol Phys 1988;14:1109 –1117. ies: a review article. Arch Neurol 1989;46:449 – 455.
15. Ahles TA, Silberfarb PM, Herndon J, et al. Psychological and 40. Groothuis DR, Michael MA. Focal cerebral vasculitis associ-
neuropsychologic functioning of patients with limited small- ated with circulating immune complexes and brain irradia-
cell lung cancer treated with chemotherapy and radiation tion. Ann Neurol 1986;19:590 –592.
therapy with or without warfarin: a study by the Cancer and 41. Omura M, Aida N, Sekido K, Kakehi M, Matsubara S. Large
Leukemia Group C. J Clin Oncol 1998;16:1954 –1960. intracranial vessel occlusive vasculopathy after radiation
16. Curran WJ, Hecht-Leavitt C, Schut L, Zimmerman RA, Nel- therapy in children: Clinical features and usefulness of mag-
son DF. Magnetic resonance imaging of cranial radiation le- netic resonance imaging. Int J Radiat Oncol Biol Phys 1997;
sions. Int J Radiat Oncol Biol Phys 1987;13:1093–1098. 38:241–249.
17. Vigliani MC, Duyckaerts C, Hauw JJ, Poisson M, Magdelenat 42. McClelland JL, McNaughton BL, O’Reilly RC. Why there are
H, Delattre JY. Dementia following treatment of brain tumors complementary learning systems in the hippocampus and
with radiotherapy administered alone or in combination with neocortex: insights from the successes and failures of connec-
nitrosourea-based chemotherapy: a clinical and pathological tionist models of learning and memory. Psychol Rev 1995;3:
study. J Neuro-Oncol 1999;41:137–149. 419 – 457.
18. Grossman H, Caine ED, Ketonen L. Progressive irradiation 43. Sutherland RJ, Rudy JW. Configural association theory: the
dementia and psychosis. Neuropsychiatry Neuropsychol Be- role of the hippocampal formation in learning, memory, and
hav Neurol 1994;7:125–129. amnesia. Psychobiology 1989;17:129 –144.
July (1 of 2) 2002 NEUROLOGY 59 47
44. Nogami M, Takatsu A, Endo N, Ishiyama I. An immunohisto- 48. Johnson BE, Becker B, Goff WB, et al. Neurologic, neuropsy-
chemical study on cathepsin D in human hippocampus. Histo- chologic, and computed cranial tomography scan abnormali-
chemical J 2000;32:505–508. ties in 2- to 10-year survivors of small-cell lung cancer. J Clin
45. Kirino T. Delayed neuronal death. Neuropathology 2000; Oncol 1985;3:1659 –1667.
20(suppl):S95-S97. 49. Boone KB, Miller BL, Lesser IM, et al. Neuropsychological
46. Kawahara H, Takeda Y, Tanaka A, et al. Does diffusion- correlates of white-matter lesions in healthy elderly subjects:
weighted magnetic resonance imaging enable detection of a threshold effect. Arch Neurol 1992;49:549 –554.
early ischemic change following transient cerebral ischemia? 50. Mulhern RK, Palmer SL, Reddick WE, et al. Risks of young
J Neurol Sci 2000;181:73– 81. age for selected neurocognitive deficits in medulloblastoma
47. McEwen BS. Effects of adverse experiences for brain structure are associated with white matter loss. J Clin Oncol 2001;19:
and function. Biol Psychiatry 2000;48:721–731. 472– 479.

CME Intrathecal methotrexate affects

cognitive function in children
with medulloblastoma
D. Riva, MD; C. Giorgi, MD; F. Nichelli, DN; S. Bulgheroni, DN; M. Massimino, MD; G. Cefalo, MD;
L. Gandola, MD; M. Giannotta, MD; I. Bagnasco, MD; V. Saletti, MD; and C. Pantaleoni, MD

Abstract—Background: Cognitive impairment occurs after malignant brain tumor treatment in children, following brain
radiotherapy and systemic and intrathecal chemotherapy. Objectives: 1) To compare two groups of children who under-
went surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function,
attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy–
chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX⫹). 2) To relate these measures
to MRI findings (leukomalacia). Results: The two groups performed worse than their control subjects in all tests. The
MTX⫹ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group
older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed
significantly worse than controls only in some neuropsychological measures; there were no differences between older
patients and control subjects. Only in the MTX⫹ group was there a direct correlation between extent of leukomalacia and
performance in some tests. Conclusions: The administration of intrathecal methotrexate to children with medulloblastoma
worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the
treatment of medulloblastoma and other malignancies should be reassessed.
NEUROLOGY 2002;59:48 –53

Medulloblastoma, the most common malignant CNS therefore, to accurately assess the cognitive sequelae
tumor in childhood, mainly occurs in the posterior of brain tumor treatment to guide the development
fossa, where 50% of all childhood brain tumors de- of risk-adapted therapies. This is particularly germane
velop. Children with medulloblastoma and other ma- in children with medulloblastoma for whom current
lignant brain tumors are at risk for late CNS research aims to replace radiotherapy with chemother-
sequelae from external radiotherapy1-3 and systemic apy or at least reduce the overall radiation dose. We
and intrathecal chemotherapy.4-7 The resulting cog- report neuropsychological assessment in two groups
nitive impairment is often disabling and persists of children with cerebellar medulloblastoma. Both
throughout life. This impairment manifests as de- received the same combined radiotherapy– chemo-
cline in IQ, poor scholastic achievement, and a series therapy after surgery, but differed in that one only
of neuropsychologic deficits that are often aggra- group received intrathecal methotrexate. We (1) as-
vated by endocrinologic damage. It is important, sessed differences between the groups in terms of

See also pages 8, 40, and 121

From the Developmental Neurology Unit (Drs. Riva, Giannotta, Bagnasco, Saletti, and Pantaleoni, and F. Nichelli, and S. Bulgheroni) and Functional and
Stereotactic Neurosurgery Unit (Dr. Giorgi), Istituto Nazionale Neurologico C. Besta; and Oncologic Pediatric Unit (Drs. Massimino and Cefalo) and
Radiotherapy Unit (Dr. Gandola), Istituto Nazionale per la Cura dei Tumori, Milano, Italy.
Received August 23, 2001. Accepted in final form March 28, 2002.
Address correspondence and reprint requests to Dr. Daria Riva, Divisione di Neurologia dello Sviluppo, Istituto Nazionale Neurologico, Via Celoria, 11, 20133
Milano, Italy; e-mail: driva@istituto-besta.it

48 Copyright © 2002 by AAN Enterprises, Inc.