Historically, the association between LE and neurocognitive deficits has been a matter of controversy. Measurements of LE usually consisted of detection and sometimes subjective grading of the extent. The developing brain may be more susceptible to damage because newly synthesized myelin has higher metabolic activity and lower stability, which makes it more vulnerable to the toxic effects of therapy [23
]. The location, extent, and intensity of LE may have a direct impact on the maturation of WM in specific regions. Disruption of the normal maturation of WM by even transient LE may result in lower volumes of WM with decreased integrity of the myelin compared to age-matched healthy peers. Cognitive deficits may be related to the total volume of WM, and region-specific thresholds may need to be surpassed before deficits become evident [82
Both IV-MTX and IT-MTX are associated with demyelination, loss of oligodendroglia, and atrophy of the deep cerebral WM. Rollins et al. [76
] reported that acute neurotoxicity was closely associated with IT-MTX treatment in five subjects. However, Kishi et al. [83
] failed to show an association between IV-MTX and acute neurologic toxicity. Both of these findings are consistent with our own experience in which acute neurologic toxicity is most often associated with IT-MTX, and chronic neurotoxicity such as decreased cognitive functioning is more likely associated with IV-MTX and LE. Montour-Proulx et al. [84
] found that children treated with chemotherapy alone on the POG9605 protocol experienced substantial adverse effects on intelligence and memory functioning: 78% of 23 subjects showed LE on at least one MR image.
Subtle cognitive deficits have been observed in as many as 60% of patients with ALL and are one of the most serious long-term adverse effects associated with MTX therapy [13
]. Children treated for ALL with moderate-dose IV- or IT-MTX have shown declines in IQ scores comparable to those seen in children treated with low-dose cranial irradiation [17
]. Brown et al. [85
] found specific attention and learning problems in children with ALL treated with chemotherapy alone. This result is consistent with the findings of Copeland et al. [86
] who later showed that patients with ALL who received higher cumulative doses of IV-MTX (17 g vs. 3 g) scored significantly lower on memory-domain tests. In a study of 25 patients, Wilson et al. [25
] found that 60% of the children showed neuropsychologic deficits.
The emerging consensus is that the substantial decline in IQ and academic achievement observed in childhood cancer survivors is the result of one or more cognitive-processing deficits involving attention, short-term memory, speed of processing, visuomotor coordination, or sequencing abilities [16
]. Some of the most convincing evidence for these specific deficits has come from the work of Brouwers et al. [16
], who conducted two studies using both neuropsychologic testing and CT or MR neuroimaging to evaluate long-term survivors of childhood ALL treated with chemotherapy and cranial irradiation. When combined, the data from these studies demonstrated three primary results: first, problems with reaction time, shifting of attention, and sustained attention are common among childhood ALL survivors; second, children with more severe CNS lesions (i.e. intracerebral calcifications) have the greatest deficits on these tasks; and third, problems with attention are significantly correlated with problems in higher-order cognitive processes such as memory and learning tasks. These results suggest that attention problems provide the underlying basis for difficulties with more complex cognitive tasks and academic achievement.
Hertzberg et al. [22
] from the German Late Effects Group reported similar findings from a much larger sample of ALL survivors. They showed that children surviving ALL achieved low scores on the Freedom from Distractibility Factor on the Wechsler Scales and demonstrated low abilities in arithmetic computation and mental concentration. All of these deficits were correlated with imaging abnormalities. Other studies of ALL survivors have found specific deficits in measures of reaction time, processing speed, attention, concentration, and memory that cannot be explained solely on the basis of generally lowered intellectual ability [88
]. The attention ability most affected in survivors of ALL appears to be sustained attention, which is defined as the ability to maintain a consistent state of behavioral vigilance and persistence for an extended period.
Nathan et al. [94
] studied neurocognitive function in ALL survivors who were not treated with cranial irradiation and demonstrated that very high-dose MTX does not have the same long-term affect on intelligence that is often associated with cranial irradiation. These findings were verified in a recent longitudinal, prospective, sibling-controled study by Jansen et al. [95
] which found no significant decline in intelligence during therapy but did observe a small relative decline in performance IQ in young children. While elimination of cranial irradiation has led to a reduction in neuropsychologic sequelae, age- and sex-related differences still exist as demonstrated by von der Weid et al. [96
]. One of the most extensive studies of long-term neurocognitive outcomes in children whose treatment for ALL did not include cranial irradiation was recently conducted by Spiegler et al. [97
]. They reported that survivors scored near the population mean on 17 of 18 measures of intelligence, academic achievement, attention, and memory. No differences were detected on any neurocognitive measure between patients treated on different doses of MTX. This study was discussed in the context of the reports by Buizer et al. [98
] who identified subtle deficits in attention and visuomotor control in ALL survivors who received higher doses of IV-MTX. ALL survivors also have more behavioral and educational problems [100
]. One possible explanation for a lack of difference in neurocognitive function between patients treated with different doses of MTX is differences in the dosages of leucovorin rescue, i.e. patients who received higher IV-MTX also received higher initial leucovorin doses. However, other results have suggested that high doses of leucovorin increase the risk of relapse [101
The association between MR-diagnosed LE and cognitive deficits is not well established. Wilson et al. [25
] subjectively graded MR images and detected transient WM abnormalities in 16 of 25 (65%) patients during consolidation therapy. These researchers defined psychological deficits as “any score more than one standard deviation below the population mean”. This type of cross-sectional analysis ignores the patients’ neurocognitive performance before therapy. However, although LE and neuropsychological deficits were more prevalent in patients younger than 5 years, no correlation was detected between the imaging findings and the neuropsychological findings. Additional small studies by Bakke et al. [26
] and Kingma et al. [24
] were also unable to detect a correlation between MR abnormalities and neuropsychological deficits. Both of these studies used subjective scoring of the MR examinations and cross-sectional analysis of the patients with respect to the normal population regardless of initial performance before therapy. The inability of these studies to detect a significant correlation may be due to small patient samples, the variance in subjective grading of the MR studies, cross-sectional analysis of neuropsychological deficits, or all three factors. Nevertheless, these results prompted a letter by Bleyer [102
], in which he cautioned researchers not to overestimate the clinical significance of MR findings of LE until a relationship between the MR abnormalities and neuropsychological deficits could be determined. This relationship is still under investigation with more objective quantitative measures of LE and more targeted neurocognitive testing to more sensitively assess the impact of treatment for childhood leukemia on measures of attention, working memory, and executive functioning.