Child's Nervous System

, Volume 33, Issue 6, pp 965–972 | Cite as

A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors

  • Arif Rashid
  • Ashwin N. Ram
  • Wendy R. Kates
  • Kristin J. Redmond
  • Moody Wharam
  • E. Mark Mahone
  • Alena Horska
  • Stephanie Terezakis
Original Paper



Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT.


Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start.


The mean age at CRT was 9.41 (range 1.2–15.7) years. The median prescription dose was 54 (range 18–59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits—most notably in motor dexterity and visual working memory (both p < 0.0001).


These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.


CNS tumors Radiation therapy Neurocognitive side effects Neurotoxicity of therapy Volumetric MRI 


Compliance with ethical standards

This prospective study was approved by the Institutional Review Board. Written informed consent was obtained from participating families before enrollment.

Conflict of interest

None to declare.


  1. 1.
    Chintagumpala M, Gajjar A (2015) Brain tumors. Pediatr Clin N Am 62:167–178. doi: 10.1016/j.pcl.2014.09.011 CrossRefGoogle Scholar
  2. 2.
    Packer RJ, Meadows AT, Rorke LB, Goldwein JL, D’Angio G (1987) Long-term sequelae of cancer treatment on the central nervous system in childhood. Med Pediatr Oncol 15:241–253CrossRefPubMedGoogle Scholar
  3. 3.
    Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE (2004) Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 5:399–408. doi: 10.1016/S1470-2045(04)01507-4 CrossRefPubMedGoogle Scholar
  4. 4.
    Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P et al (2005) Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 23:5511–5519. doi: 10.1200/JCO.2005.00.703 CrossRefPubMedGoogle Scholar
  5. 5.
    Reddick WE, Glass JO, Palmer SL, Wu S, Gajjar A, Langston JW et al (2005) Atypical white matter volume development in children following craniospinal irradiation. Neuro-Oncology 7:12–19. doi: 10.1215/S1152851704000079 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Reddick WE, White HA, Glass JO, Wheeler GC, Thompson SJ, Gajjar A et al (2003) Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors. Cancer 97:2512–2519. doi: 10.1002/cncr.11355 CrossRefPubMedGoogle Scholar
  7. 7.
    Palmer SL, Reddick WE, Glass JO, Gajjar A, Goloubeva O, Mulhern RK (2002) Decline in corpus callosum volume among pediatric patients with medulloblastoma: longitudinal MR imaging study. Am J Neuroradiol 23:1088–1094PubMedGoogle Scholar
  8. 8.
    Giedd JN, Blumenthal J, Jeffries NO, Rajapakse JC, Vaituzis AC, Liu H, et al. Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study. Prog Neuro-Psychopharmacology Biol Psychiatry 1999;23:571–588. doi: 10.1016/S0278-5846(99)00017-2.
  9. 9.
    Reich W, Welner Z, Herjanic B (1997) The diagnostic interview for children and adolescents-IV. North Tonawanda, NY, Multi-Health SystemsGoogle Scholar
  10. 10.
    Tiffin J (1968) Purdue pegboard: examiner manual. Chicago, IL, Science Research AssociatesGoogle Scholar
  11. 11.
    Beery K, Beery N (2004) Developmental test of visual perception, 5th edn. Pearson, Inc., Minneapolis, MNGoogle Scholar
  12. 12.
    Thorndike R, Hagen EP, Sattler J (1986) Technical manual for the Stanford Binet, 4th edn. Riverside Publishing, Chicago, ILGoogle Scholar
  13. 13.
    Woodcock RW, McGrew KS, Mather N. Woodcock-Johnson-III, tests of cognitive abilities. 3rd ed. Itasca, IL: Riverside Publishing; 2001; 2001.Google Scholar
  14. 14.
    Reddick WE, Russell JM, Glass JO, Xiong X, Mulhern RK, Langston JW et al (2000) Subtle white matter volume differences in children treated for medulloblastoma with conventional or reduced dose craniospinal irradiation. Magn Reson Imaging 18:787–793. doi: 10.1016/S0730-725X(00)00182-X CrossRefPubMedGoogle Scholar
  15. 15.
    Paus T, Collins DL, Evans AC, Leonard G, Pike B, Zijdenbos A (2001) Maturation of white matter in the human brain: a review of magnetic resonance studies. Brain Res Bull 54:255–266. doi: 10.1016/S0361-9230(00)00434-2 CrossRefPubMedGoogle Scholar
  16. 16.
    Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR (2003) Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 63:4021–4027PubMedGoogle Scholar
  17. 17.
    Madsen TM, Kristjansen PEG, Bolwig TG, Wörtwein G (2003) Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119:635–642. doi: 10.1016/S0306-4522(03)00199-4 CrossRefPubMedGoogle Scholar
  18. 18.
    Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962. doi: 10.1038/nm749 CrossRefPubMedGoogle Scholar
  19. 19.
    Rola R, Raber J, Rizk A, Otsuka S, Vandenberg SR, Morhardt DR et al (2004) Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188:316–330. doi: 10.1016/j.expneurol.2004.05.005 CrossRefPubMedGoogle Scholar
  20. 20.
    de Lacoste MC, Kirkpatrick JB, Ross ED (1985) Topography of the human corpus callosum. J Neuropathol Exp Neurol 44:578–591CrossRefPubMedGoogle Scholar
  21. 21.
    Eliassen JC, Baynes K, Gazzaniga MS (2000) Anterior and posterior callosal contributions to simultaneous bimanual movements of the hands and fingers. Brain 123(Pt 12):2501–2511. doi: 10.1093/brain/123.12.2501 CrossRefPubMedGoogle Scholar
  22. 22.
    Mulhern RK, Kepner JL, Thomas PR, Armstrong FD, Friedman HS, Kun LE (1998) Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a pediatric oncology group study. J Clin Oncol 16:1723–1728CrossRefPubMedGoogle Scholar
  23. 23.
    Overall JE, Doyle SR (1994) Implications of chance baseline differences in repeated measurement designs. J Biopharm Stat 4:199–216. doi: 10.1080/10543409408835083 CrossRefPubMedGoogle Scholar
  24. 24.
    Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a children’s cancer group study. J Clin Oncol 19:3470–3476CrossRefPubMedGoogle Scholar
  25. 25.
    Armstrong GT, Jain N, Liu W, Merchant TE, Stovall M, Srivastava DK et al (2010) Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro-Oncology 12:1173–1186CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Radiation Oncology and Molecular Radiation SciencesThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.Russell H. Morgan Department of Radiology and Radiological ScienceBaltimoreUSA
  3. 3.Department of NeuropsychologyKennedy Krieger InstituteBaltimoreUSA
  4. 4.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of Psychiatry and Behavioral SciencesState University of New York at Upstate Medical UniversitySyracuseUSA

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