Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation, systemic therapy with high-dose methotrexate or cytarabine, or with intrathecal chemotherapy. Children with brain tumors or acute lymphoblastic leukemia are most likely to be affected. Risk factors for the development of neurocognitive side effects are female gender, young age at the time of treatment, higher radiation dose, and treatment with both cranial radiation and chemotherapy (systemic or intrathecal).[1,2,3,4]
Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects due to their illness and associated treatments are emerging. In childhood and adolescent brain tumor survivors, tumor site, treatment of hydrocephalus with a shunt, paralysis, auditory difficulties, or history of a stroke have emerged as risk factors for adverse neurocognitive effects.[5,6,7]
Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity particularly in younger children. There is an established dose-response relationship with those getting higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures. The negative impact of radiation treatment has been characterized by changes in intelligence quotient (IQ) scores, which have been noted to drop about 2 to 5 years after diagnosis and an attenuation of the decline 5 to 10 years afterward, followed by stabilization of the IQ scores 20 to 40 years after diagnosis.[9,10,11] The decline over time is typically reflective of the child's failure to acquire new abilities or information at a rate similar to peers, rather than a progressive loss of skills and knowledge. Affected children may experience information-processing deficits resulting in academic difficulties, and are prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills.[10,12,13] These changes in intellectual functioning may be partially explained by radiation-induced or chemotherapy-induced reduction of normal white matter volume as evaluated through magnetic resonance imaging (MRI). Using lower doses of radiation and more targeted volumes have demonstrated improved results in neurocognitive effects of therapy.[7,15] In this regard, a report from St. Jude Children's Research Hospital showed cognitive decline after conformal radiation therapy in 78 children younger than 20 years (mean, 9.7 years) with low-grade glioma treated with 54 Gy (see Figure 3). In fact, age at time of irradiation was more important than radiation dose in predicting cognitive decline. Children younger than 5 years showed the most cognitive decline.
Figure 3. Modeled intelligence quotient (IQ) scores after conformal radiation therapy (CRT) by age for pediatric low-grade glioma. Age is measured in years, and time is measured in months after the start of CRT. Thomas E. Merchant, Heather M. Conklin, Shengjie Wu, Robert H. Lustig, and Xiaoping Xiong, Late Effects of Conformal Radiation Therapy for Pediatric Patients With Low-Grade Glioma: Prospective Evaluation of Cognitive, Endocrine, and Hearing Deficits, Journal of Clinical Oncology, volume 27, issue 22, pages 3691-3697. Reprinted with permission. © (2009) American Society of Clinical Oncology. All rights reserved.