Atypical white matter volume development in children following craniospinal irradiation

Brain tumors constitute approximately 20% of pediatric malignancies. Because of the inherent risk of these tumors, patients receive aggressive CNS therapy that often comprises maximal surgical resection, local and craniospinal irradiation (CSI), and adjuvant chemotherapy. Consequently, long-term survivors are at risk of cognitive delays or deficits that impair their academic performance, employment opportunities, and quality of life (Dennis et al., 1996; Mulhern et al., 1998; Ris et al., 2001). In survivors of childhood medulloblastoma (MB), deficits in IQ and academic achievement appear to reflect a diminished ability to acquire new information (Palmer et al., 2001). One or more cognitive processing mechanisms, including attention, short-term memory, speed of processing, visual-motor coordination, and sequencing ability, may be impaired (Schatz et al., 2000). These processes depend on the integrity of widely distributed neural networks supported by interhemispheric and intrahemispheric white matter tracts. Recent findings have shown that in pediatric patients treated for brain tumors, a reduced volume of normal-appearing white matter (NAWM)3 is associated with reduced attentional ability and a decline in IQ and academic achievement (Reddick et al., 2003). The proportion of intracranial volume that is NAWM is normally expected to increase into early adulthood. This increase is usually modeled as a quadratic function in which growth is most rapid in the first five years, continues to rise at a moderate rate over the next 10 years, and then slows to asymptotically approach the adult volume (Giedd et al., 1999; Sowell et al., 2002). Previous studies of the association between NAWM and cognitive function have yielded mixed results (Andreasen et al., 1993; Reiss et al., 1996). NAWM volume is not strongly related to IQ in healthy children but is significantly associated in other populations with pathological conditions such as attention deficit-hyperactivity disorder (Castellanos et al., 2002). At least one author has suggested a threshold effect in which cognitive impairment becomes apparent only below a certain volume of NAWM (Inzitari, 2000). Studies that have quantified toxic effects on white matter and investigated the association between neurotoxicity and cognitive deficits in children have focused primarily on survivors of MB of the posterior fossa (approximately 20% of pediatric brain tumors). One such study compared patients treated for MB with age-similar controls who had received surgery alone for low-grade tumors of the posterior fossa; the survivors of MB had a significantly smaller volume of NAWM, a substantially greater volume of cerebrospinal fluid (CSF), and an equal volume of gray matter (Reddick et al., 1998). This study also demonstrated that chemotherapy did not have a significant detectable impact on tissue volumes. The MB patients also had significantly lower IQs (Mulhern et al., 1999). However, because of their cross-sectional design, these studies could not discern whether the smaller NAWM volume reflected loss of tissue, decreased myelination, or both. A subsequent longitudinal study revealed a significant loss of NAWM volume in patients undergoing treatment for MB; this loss was more rapid among patients who received a CSI dose of 36 Gy versus CSI of 23.4 Gy (Reddick et al., 2000). However, this study was limited by a relatively short median follow-up period of one year. NAWM volume can explain approximately 70% of the association between IQ impairment and age at the time of irradiation (Mulhern et al., 2001). In a recent cross-sectional study, patients treated for MB showed significantly impaired performance on all neurocognitive measures of intellect, attention, memory, and academic achievement (Reddick et al., 2003). The study produced a developmental model in which academic achievement was predicted by NAWM volume, attentional ability, and IQ; these factors explained approximately 60% of the variance observed in reading and spelling and almost 80% of the variance observed in mathematics. The primary consequence of reduced NAWM volume was decreased attentional ability, which reduced patients’ IQ and academic achievement (Reddick et al., 2003). We designed a retrospective longitudinal study to compare brain volume development of patients treated for MB with that of healthy, age-similar peers. To control for the effect of irradiation dose, we included only patients who received a CSI dose of 35 to 40 Gy (once used to treat all cases of MB and now used for patients at high risk). This retrospective design has three limitations that could conceivably cause results to differ from more comprehensive prospective trials: (1) Imaging was limited to a single representative section, (2) diffusion tensor imaging was not acquired as a routine part of clinical imaging during this period, and (3) extent and incidence of regions of T2 hyperintensity in other locations could not be assessed by the single index section. However, this retrospective study was designed to comprise as homogeneous a group of subjects as possible: Patients received similar doses of CSI to treat the same type of tumor, which arose in the same location. This study builds on previous work by including serial magnetic resonance (MR) studies to determine the effect of age at irradiation, time since irradiation, gender, use of chemotherapy, and use of ventricular shunt on the development of brain parenchyma (Reddick et al., 1998).