Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function.

Advances in the treatment of childhood cancers have greatly improved survivorship. Success has not come without cost, however, as survivors are at risk for late effects of treatment, including neurocognitive late effects (e.g., difficulties with thinking and reasoning). In the advent of chemotherapy-only protocols, researchers are examining neurocognitive sequelae of these agents to understand the specific role of chemotherapy in neurocognitive changes and the mechanism through which these occur. In this review, we examine the state of the literature on neurocognitive late effects after chemotherapy and their proposed neural mechanisms.

White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood.

Current theory suggests that neurocognitive late effects of treatments for childhood cancer such as difficulties with attention, processing speed and visual-motor ability are the result of white matter damage. Neuroimaging studies have produced a variety of white matter findings. However, although white matter is thought to be differentially affected, previous studies have not demonstrated a discrepancy between white and gray matter function. The present study included 36 children treated for childhood leukemia with hematopoietic stem cell transplant (HCT). Their performance on neurocognitive measures traditionally thought to measure white matter was compared to performance on measures thought to measure gray matter function. Composite white and gray matter standard scores were created based on neuropsychological measures that individuals with known white or gray matter damage perform poorly. As predicted, composite white matter scores (mean = 98.1) were significantly lower (t = 2.26, p = 0.03) than composite gray matter scores (mean = 102.5). Additionally, as gray matter performance increased, the difference between gray and white matter scores increased (R = 0.353, p = 0.035). Overall, the results of this study support the current theory that white matter damage is responsible for the more subtle neurocognitive late effects resulting from treatment for childhood leukemia.

Diffusion tensor imaging identifies deficits in white matter microstructure in subjects with type 1 diabetes that correlate with reduced neurocognitive function.

OBJECTIVE: Long-standing type 1 diabetes is associated with deficits on neurocognitive testing that suggest central white matter dysfunction. This study investigated whether diffusion tensor imaging (DTI), a type of magnetic resonance imaging that measures white matter integrity quantitatively, could identify white matter microstructural deficits in patients with long-standing type 1 diabetes and whether these differences would be associated with deficits found by neurocognitive tests. RESEARCH DESIGN AND METHODS: Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects completed DTI on a 3.0 Tesla scanner and a battery of neurocognitive tests. Fractional anisotropy was calculated for the major white matter tracts of the brain. RESULTS: Diabetic subjects had significantly lower mean fractional anisotropy than control subjects in the posterior corona radiata and the optic radiation (P < 0.002). In type 1 diabetic subjects, reduced fractional anisotropy correlated with poorer performance on the copy portion of the Rey-Osterreith Complex Figure Drawing Test and the Grooved Peg Board Test, both of which are believed to assess white matter function. Reduced fractional anisotropy also correlated with duration of diabetes and increased A1C. A history of severe hypoglycemia did not correlate with fractional anisotropy. CONCLUSIONS: DTI can detect white matter microstructural deficits in subjects with long-standing type 1 diabetes. These deficits correlate with poorer performance on selected neurocognitive tests of white matter function.

Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.

BACKGROUND: Hematopoeitic cell transplantation (HCT) in childhood has been associated with late complications including endocrine, neurocognitive, and cardiopulmonary abnormalities. Little is known about the complications of transplantation in infants. PROCEDURE: Eligible subjects underwent HCT for acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) at less than 3 years of age. Seventeen out of 33 eligible patients were evaluated, transplanted between 1981-2000. Eleven patients had AML, 11 were female. Preparative regimen included total body irradiation (TBI) for eleven. Age at HCT ranged from 0.58 to 2.97 years, and survival 3.25 to 22.33 years. Patients underwent physical and laboratory evaluation, dual-energy X-ray absorptiometry (DXA) scan, bone age X-ray, neuropsychological, and quality of life (QOL) evaluation. RESULTS: Identified abnormalities included: growth hormone deficiency (59%), hypothyroidism (35%), osteochondromas (24%), decreased bone mineral density (24%), and dyslipidemias (59%). Two patients developed a second malignancy. Neuropsychological testing revealed average intelligence quotient (IQ) with attention deficits and other weaknesses for most patients. There were no overall differences between QOL in these children when compared to population norms. CONCLUSIONS: Of the survivors evaluated, typical late effects seen after radiation exposure are common, yet most subjects were doing well without major ongoing medical issues. Dyslipidemias affect more than half of patients and may be associated with metabolic syndrome, placing patients at increased risk for early cardiovascular disease. Even in this group of patients where the majority was exposed to TBI at a very young age, most are functioning at an average or above-average level.