Atypical white matter volume development in children following craniospinal irradiation

Abstract

Most children with medulloblastoma (MB), the second most common pediatric brain tumor, have a 70% probability of survival. However, survivors who receive aggressive therapy are at significant risk of cognitive deficits that have been associated with lower volumes of normal-appearing white matter (NAWM). We hypothesized that cranial irradiation inhibited normal brain volume development in these survivors. We retrospectively analyzed 324 MRI studies of 52 patients with histologically proven MB treated with surgery and 35 to 40 Gy craniospinal irradiation, with or without chemotherapy. The volume of NAWM and that of cerebrospinal fluid were quantified from a single index section and compared with those of healthy, age-similar control subjects. A quadratic random coefficient model was used to identify trends in brain volume with increasing age. Patients treated for MB at younger ages demonstrated substantially less development of NAWM volume than did their healthy peers. Younger age at the time of irradiation and the need for a ventricular shunt were significantly associated with reduced NAWM volume. NAWM and craniospinal fluid volume differences between patients who had shunts and those without resolved over a period of four to five years. NAWM volume is known to be associated with neurocognitive test performance, which shows deficiencies after cranial irradiation early in life. Therefore, volumetric monitoring of brain development can be used to guide the care of survivors, assess the toxicity of previous and current clinical trials, and aid in the design of therapies that minimize toxicity.

Fig. 1

Number of MR examinations performed at each time interval postirradiation.

Fig. 2

Examples of types of MR images acquired. From left to right: T1-weighted, T2-weighted, and proton density images at the level of the index section. Far right: the resulting segmented map used to quantify the volume of normal-appearing white matter (green) and CSF (blue).

Fig. 3

Estimated volume of normal-appearing white matter and CSF projected by the study data over a five-year period after treatment of medulloblastoma at the age of 6 years (A) or 12 years (B). Patients did (solid lines) or did not (dashed lines) have ventricular shunts. Values represent absolute volume calculated for the index section. The curves were generated by using the quadratic random coefficient model.

Fig. 4

Change in the volume of normal-appearing white matter (NAWM) projected by the model in healthy control subjects (HC) and patients treated for medulloblastoma (MB) without ventricular shunts starting at the age of 6 years (A) or 12 years (B). A solid line at zero change is shown for reference. Absolute volume is standardized to the intercept at ages 6 and 12 to facilitate comparison. The curves were generated by using quadratic regression models.

Fig. 5

Volume of normal-appearing white matter (NAWM) observed in healthy control subjects (solid circles) and NAWM volume at the most recent examination observed in patients treated for medulloblastoma (empty circles) without ventricular shunts plotted against age of the subject at the time of examination.