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Review Articles

Measurement of neurodevelopmental changes in children treated with radiation for brain tumors: what is a true ‘baseline?’

, , , &
Pages 307-328 | Received 13 Apr 2016, Accepted 18 Jul 2016, Published online: 05 Oct 2016

References

  • Annett, R. D., Patel, S. K., & Phipps, S. (2015). Monitoring and assessment of neuropsychological outcomes as a standard of care in pediatric oncology. Pediatric Blood & Cancer, 62, S460–S513.
  • Aukema, E. J., Caan, M. W. A., Oudhuis, N., Majoie, C. B. L. M., Vos, F. M., Reneman, L., … Schouten-van Meeteren, A. Y. (2009). White matter fractional anisotropy correlates with speed of processing and motor speed in young childhood cancer survivors. International Journal of Radiation Oncology, Biology, Physics, 74, 837–843.10.1016/j.ijrobp.2008.08.060
  • Baade, L. E., Heinrichs, R. J., Coady, E. L., & Stropes, J. (2011). Assessment of premorbid functioning in pediatric populations. In A. S. Davis (Ed.), The Handbook of Pediatric Neuropsychology (pp. 191–200). New York: Springer.
  • Barona, A., Reynolds, C. R., & Chastain, R. (1984). A demographically based index of premorbid intelligence for the WAIS-R. Journal of Consulting and Clinical Psychology, 52, 885–887.10.1037/0022-006X.52.5.885
  • Briere, M. E., Scott, J. G., McNall-Knapp, R. Y., & Adams, R. L. (2008). Cognitive outcome in pediatric brain tumor survivors: Delayed attention deficit at long-term follow-up. Pediatric Blood & Cancer, 50, 337–340.
  • Callu, D., Viguier, D., Laroussinie, F., Puget, S., Boddaert, N., Kieffer, V., … Dellatolal, G. (2009). Cognitive and academic outcome after benign or malignant cerebellar tumor in children. Cognitive & Behavioral Neurology, 22, 270–278.
  • Campbell, D. P., & Fiske, D. W. (1959). Convergent and discriminant validation by the multitrait-multimethod matrix. Psychological Bulletin, 56, 81–105.10.1037/h0046016
  • CBTRUS. (2011). CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2004-2007. Source: Central Brain Tumor Registry of the United States, Hinsdale, IL. www.cbtrus.org
  • Conklin, H. M., Ashford, J. M., Di Pinto, M., Vaughan, C. G., Gioia, G. A., Merchant, T. E., … Wu, S. (2013). Computerized assessment of cognitive late effects among adolescent brain tumor survivors. Journal of Neuro-oncology, 113, 333–340.10.1007/s11060-013-1123-5
  • Conklin, H. M., Li, C., Xiong, X., Ogg, R. J., & Merchant, T. E. (2008). Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. Journal of Clinical Oncology, 26, 3965–3970.10.1200/JCO.2007.15.9970
  • Copeland, D. R., deMoor, C., Moore, B. D., III, & Ater, J. L. (1999). Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study. Journal of Clinical Oncology, 17, 3476–3486.
  • Dennis, M. (1989). Language and the young damaged brain. In T. Boll & B. K. Bryant (Eds.), Clinical neuropsychology and brain function: Research, measurement, and practice (pp. 89–123). Washington, DC: American Psychological Association.
  • Dennis, M., Spiegler, B. J., & Hetherington, R. (2000). New survivors for the new millennium: Cognitive risk and reserve in adults with childhood brain insults. Brain and Cognition, 42, 102–105.10.1006/brcg.1999.1174
  • Dennis, M., Spiegler, B. J., Hetherington, C. R., & Greenberg, M. L. (1996). Neuropsychological sequelae of the treatment of children with medulloblastoma. Journal of Neuro-oncology, 29, 91–101.10.1007/BF00165522
  • Dennis, M., Spiegler, B. J., Simic, N., Sinopoli, K. J., Wilkinson, A., Yeates, K. O., … Fletcher, J. M. (2014). Functional plasticity in childhood brain disorders: When, what, how, and whom to assess. Neuropsychology Review, 24, 389–408.10.1007/s11065-014-9261-x
  • Di Pinto, M., Conklin, H. M., Li, C., & Merchant, T. E. (2012). Learning and memory following conformal radiation therapy for pediatric craniopharyngioma and low-grade glioma. International Journal of Radiation Oncology, Biology, Physics, 84, e363–e369.10.1016/j.ijrobp.2012.03.066
  • Elliot, C. D. (2007). Differential abilities scales (2nd ed.). Minneapolis, MN: Pearson.
  • Embry, L., Annett, R. D., Kunin-Batson, A., Patel, S. K., Sands, S., Reaman, G., & Noll, R. B. (2012). Implementation of multi-site neurocognitive assessments within a pediatric cooperative group: Can it be done? Pediatric Blood and Cancer, 59, 536–539.10.1002/pbc.v59.3
  • Feigle, H. (1956). Some major issues and developments in the philosophy of science of logical empiricism. In H. Feigle & M. Scriven (Eds.), Minnesota studies in the philosophy of science (Vol. 1, pp. 3–37), Minnesota: University of Minnesota Press.
  • Flynn, J. R. (1999). Searching for justice: The discovery of IQ gains over time. American Psychologist, 54, 5–20.10.1037/0003-066X.54.1.5
  • Fouladi, M., Chintagumpala, M., Laningham, F. H., Ashley, D., Kellie, S. J., Langston, J. W., … Gahar, A. (2004). White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. Journal of Clinical Oncology, 22, 4551–4560.10.1200/JCO.2004.03.058
  • Fouladi, M., Gilger, E., Kocak, M., Wallace, D., Buchanan, G., Reeves, C., … Mulhern, R. (2005). Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies. Journal of Clinical Oncology, 23, 7152–7160.10.1200/JCO.2005.01.214
  • Fouladi, M., Wallace, D., Langston, J. W., Mulhern, R., Rose, S. R., Gajjar, A., … Heideman, R. L. (2003). Survival and functional outcome of children with hypothalamic/chiasmatic tumors. Cancer, 97, 1084–1092.10.1002/(ISSN)1097-0142
  • Francis, D. J., Fletcher, J. M., Stuebing, K. K., Davidson, K. C., & Thompson, N. M. (1991). Analysis of change: Modeling individual growth. Journal of Consulting and Clinical Psychology., 59, 27–37.10.1037/0022-006X.59.1.27
  • George, A. P., Kuehn, S. M., Vassilyadi, M., Richards, P. M., Parlow, S. E., Keene, D. L., … Ventureyra, E. C. (2003). Cognitive sequelae in children with posterior fossa tumors. Pediatric Neurology, 28, 42–47.10.1016/S0887-8994(02)00471-X
  • Goldwein, J. W., Radcliffe, J., Johnson, J., Moshang, T., Packer, R. J., Sutton, L. N., … D’Ango, G. J. (1996). Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). International Journal of Radiation Oncology, Biology, Physics, 34, 899–904.10.1016/0360-3016(95)02080-2
  • Goldwein, J. W., Radcliffe, J., Packer, R. J., Sutton, L. N., Lange, B., Rorke, L. B., … D’Angelo, G. J. (1993). Results of a pilot study of low-dose craniospinal radiation therapy plus chemotherapy for children younger than 5 years with primitive neuroectodermal tumors. Cancer, 71, 2647–2652.10.1002/(ISSN)1097-0142
  • Gupta, T., Jalali, R., Goswami, S., Nair, V., Moiyadi, A., Epari, S., & Sarin, R. (2012). Early clinical outcomes demonstrate preserved cognitive functioning in children with average-risk medulloblastoma when treated with hyperfractionated radiation therapy. International Journal of Radiation Oncology, Biology Physics, 83, 1534–1540.
  • Hardy, K. K., Willard, V. W., Allen, T. M., & Bonner, M. J. (2013). Working memory training in survivors of pediatric cancer: A randomized pilot study. Psycho-Oncology, 22, 1856–1865.10.1002/pon.3222
  • Huse, J. T., & Holland, E. C. (2010). Targeting brain cancer: Advances in the molecular pathology of malignant glioma and medulloblastoma. Nature Reviews Cancer, 10, 319–331.10.1038/nrc2818
  • Kahalley, L. S., Winter, A., Stancel, H. H., Ris, M. D., & Gragert, M. (in press). Utility of the General Ability Index (GAI) with survivors of pediatric brain tumors: Comparison to full scale IQ and premorbid estimates. Journal of Clinical and Experimental Neuropsychology. doi:10.1080/13803395.2016.1189883
  • Kao, G. D., Goldwein, J. W., Schultz, D. J., Radcliffe, J., Sutton, L., & Lange, B. (1994). The impact of perioperative factors on subsequent intelligence quotient deficits in children treated for medulloblastoma/posterior fossa primitive neuroectodermal tumors. Cancer, 74, 965–971.10.1002/(ISSN)1097-0142
  • Kazak, A., Alderfer, M., Streisand, R., Simms, S., Rourke, M., Barakat, L. P., … Cnaan, A. (2004). Treatment of posttraumatic stress symptoms in adolescent survivors of childhood cancer and their families: A randomized clinical trial. Journal of Family Psychology, 18, 493–504.10.1037/0893-3200.18.3.493
  • Kieffer-Renaur, V., Viguier, D., Raquin, M., Laurent-Vannier, A., Habrand, J., Dellatolas, G., … Grill, J. (2005). Therapeutic schedules influence the pattern of intellectual decline after irradiation of posterior fossa tumors. Pediatric Blood & Cancer, 45, 814–819.
  • Kiehna, E. N., Mulhern, R. K., Li, C., Xiong, X., & Merchant, T. E. (2006). Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy. Journal of Clinical Oncology, 24, 5283–5290.10.1200/JCO.2005.03.8547
  • Krull, K. R., Scott, J. G., & Sherer, M. (1995). Estimation of premorbid intelligence from combined performance and demographic variables. The Clinical Neuropsychologist, 9, 83–88.10.1080/13854049508402063
  • Mabbott, D. J., Monsalves, E., Spiegler. B. J., Bartels: U., Janzen, L., Guger, S., … Bouffet, E. (2011). Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer, 117, 5402–5411.10.1002/cncr.v117.23
  • Mabbott, D. J., Penkman, L., Witol, A., Strother, D., Bouffet E. (2008). Core neurocognitive functions in children treated for posterior fossa tumors. Neuropsychology, 22, 159–168.10.1037/0894-4105.22.2.159
  • Mabbott, D. J., Spiegler, B. J., Greenberg, M. L., Rutka, J. T., Hyder, D. J., & Bouffet, E. (2005). Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. Journal of Clinical Oncology, 23, 2256–2263.10.1200/JCO.2005.01.158
  • Maddrey, A. M., Bergeron, J. A., Lombardo, E. R., McDonald, N. K., Mulne, A. F., Barenberg, P. D., … Bowers, D. C. (2005). Neuropsychological performance and quality of life of 10 year survivors of childhood medulloblastoma. Journal of Neuro-oncology, 72, 245–253.10.1007/s11060-004-3009-z
  • McGrew, K. S., LaForte, E. M., & Schrank, F. A. (2014). Woodcock Johnson IV Technical Manual. Riverside: Riverside Publishing Company.
  • McSweeny, A. J., Naugle, R. I., Chelune, G. J., & Lüders, H. (1993). T scores for change: An illustration of a regression approach to depicting change in clinical neuropsychology. Clinical Neuropsychologist, 7, 300–312.10.1080/13854049308401901
  • Merchant, T. E., Conklin, H. M., Wu, S., Lustig, R. H., & Xiong, X. (2009). 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, 27, 3691–3697.10.1200/JCO.2008.21.2738
  • Merchant, T. E., Kiehna, E. N., Li, C., Shukla, H., Sengupta, S., Xiong, X., … Mulhern, R. K. (2006). Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma. International Journal of Radiation Oncology, Biology, Physics, 65, 210–221.10.1016/j.ijrobp.2005.10.038
  • Merchant, T. E., Kiehna, E. N., Li, C., Xiong, X., & Mulhern, R. K. (2005). Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma. International Journal of Radiation Oncology, Biology, Physics, 63, 1546–1554.10.1016/j.ijrobp.2005.05.028
  • Merchant, T.E., Kiehna, E. N., Sanford, R. A., Mulhern, R. K., Thompson, S. J., Wilson, M.W., … Kun, L. E. (2002). Craniopharyngioma: the St. Jude Children’s Research Hospital experience 1984–2001. International Journal of Radiation Oncology, Biology, Physics, 53, 533–542.10.1016/S0360-3016(02)02799-2
  • Merchant, T. E., Lee, H., Zhu, J., Xiong, X., Wheeler, G., Phipps, S., … Saufaro, R. A. (2004). The effects of hydrocephalus on intelligence quotient in children with localized infratentorial ependymoma before and after focal radiation therapy. Journal of Neurosurgery, 101, 159–168.
  • Moher, D., Tetzlaff, J., Tricco, A. C., Sampson, M., & Altman, D. G. (2007). Epidemiology and reporting characteristics of systematic reviews. PloS Medicine, 4, 0447–0455.
  • Moxon-Emre, I., Bouffet, E., Taylor, M. D., Laperriere, N., Scantlebury, N., Law, N., … Mabbott, D. (2014). Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients With medulloblastoma. Journal of Clinical Oncology, 32, 1760–1768.10.1200/JCO.2013.52.3290
  • Mulhern, R. K., Palmer, S. L., Merchant, T. E., Wallace, D., Kocak, M., Brouwers, P., … Gajjar, A. (2005). Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. Journal of Clinical Oncology, 23, 5511–5519.10.1200/JCO.2005.00.703
  • Mulhern, R. K., Palmer, S. L., Reddick, W. E., Glass, J. O., Kun, L. E., Taylor, J., … Gajjar, A. (2001). Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. Journal of Clinical Oncology, 19, 472–479.
  • Mulhern, R. K., Reddick, W. E., Palmer, S. L., Glass, J. O., Elkin, T. D., Kun, L. E., … Gajjar, A. (1999). Neurocognitive deficits in medulloblastoma survivors and white matter loss. Annals of Neurology, 46, 834–841.10.1002/(ISSN)1531-8249
  • Nagel, B. J., Delis, D. C., Palmer, S. L., Reeves, C., Gajjar, A., & Mulhern, R. K. (2006). Early patterns of verbal memory impairment in children treated for medulloblastoma. Neuropsychology, 20, 105–112.10.1037/0894-4105.20.1.105
  • Neglia, J. P., Robison, L. L., Stovall, M., Liu, Y., Packer, R. J., Hammond, S., et al. (2006). New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood cancer survivor study. JNCI Journal of the National Cancer Institute, 98, 1528–1537.10.1093/jnci/djj411
  • Netson, K. L., Conklin, H. M., Wu, S., Xiong, X., & Merchant, T. E. (2012). A 5-year investigation of children’s adaptive functioning following conformal radiation therapy for localized ependymoma. International Journal of Radiation Oncolology, Biology, Physics, 84, 217–223.10.1016/j.ijrobp.2011.10.043
  • Nicholson, S. H., Fennell, L., & Butler, R. W. (2008). Childhood brain tumors. In C. Meyers & J. Perry (Eds.), Cognition and Cancer (pp. 198–210). Cambridge: Cambridge University Press.10.1017/CBO9780511545900
  • Noll, R. B., Patel, S. K., Embry, L., Hardy, K. K., Pelletier, W., Annett, R. D., … Barakat, L. P. (2013). Children’s oncology group’s 2013 blueprint for research: Behavioral science. Pediatric Blood & Cancer, 60, 1048–1054.
  • O'Neil, S., Ji, L., Buranahirun, C., Azoff, J., Dhall, G., Khatua, S., Patel, S., … Finlay, J. (2011). Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatric Blood & Cancer, 57, 669–673.
  • Packer, R. J., Sposto, R., Atkins, T. E., Sutton, L. N., Bruce, D. A., Seigle, K.R., … Schut, L. (1987). Quality of life in children with primitive neuroectodermal tumors (medulloblastoma) of posterior fossa. Pediatric Neuroscience, 13, 169–175.
  • Palmer, S. L., Gajjar, A., Reddick, W. E., Glass, J. O., Kun, L.E., Wu, S., … Mulhern, R. K. (2003). Predicting intellectual outcome among children treated with 35–40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology, 17, 548–555.10.1037/0894-4105.17.4.548
  • Palmer, S. L., Goloubeva, O., Reddick, W. E., Glass, J. O., Gajjar, A., Kun, L., … Mulhern, R. K. (2001). Patterns of intellectual development among survivors of pediatric medulloblastoma: A longitudinal analysis. Journal of Clinical Oncology, 19, 2302–2308.
  • Porter, K. R., McCarthy, B. J., Freels, S., Kim, Y., & Davis, F. G. (2010). Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro-Oncology, 12, 520–527.10.1093/neuonc/nop066
  • Radcliffe, J., Bunin, G. R., Sutton, L. N., Goldwein, J. W., & Phillips, P. C. (1994). Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: Age-dependent effects of whole brain radiation. International Journal of Developmental Neuroscience, 12, 327–334.10.1016/0736-5748(94)90081-7
  • Reddick, W. E., Glass, J. O., Palmer, S. L., Wu, S., Gajjar, A., Langston, J. W., … Mulhern, R. K. (2005). Atypical white matter volume development in children following craniospinal irradiation. Neuro-Oncology, 7, 12–19.10.1215/S1152851704000079
  • St. James-Roberts, I. (1979). Neurological plasticity, recovery from brain insult, and child development. In H. W. Reese & L. P. Lipsitt (Eds.), Advances in child development and behavior (pp. 3–61). New York, NY: Academic Press.
  • Reeves, C. B., Palmer, S. L., Reddick, W. E., Merchant, T. E., Buchanan, G. M., Gajjar, A., … Mulhern, R. K. (2006). Attention and memory functioning among pediatric patients with medulloblastoma. Journal of Pediatric Psychology, 31, 272–280.
  • Ries, L. A. G., Harkins, D., Krapcho, M., Mariotto, A., Miller, B. A., Feuer, E. J., … Eowardg, B. K. (Eds.), (2006). SEER cancer statistics review, 1975-2003. Retrieved from seer.cancer.gov/csr/1975_2003/
  • Ris, M. D. (2007). Lessons in pediatric neuropsycho-oncology: What we have learned since Johnny Gunther. Journal of Pediatric Psychology, 32, 1029–1037.10.1093/jpepsy/jsm018
  • Ris, M. D., & Hiscock, M. (2013). Modeling cognitive aging following CNS injury: Reserve and the Flynn effect. In I. S. Baron & C. Rey-Casserly (Eds.), Pediatric Neuropsychology: Medical Advances and Lifespan Outcomes (pp. 395–421). Oxford: Oxford University Press.
  • Ris, M. D., & Noll, R. B. (1994). Long-term neurobehavioral outcome in pediatric brain tumor patients: Review and methodological critique. Journal of Clinical and Experimental Neuropsychology, 16, 21–42.10.1080/01688639408402615
  • Ris, M. D., Packer, R., Goldwein, J., Jones-Wallace, D., & Boyett, J. M. (2001). Neurocognitive outcome following reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: A Children’s Cancer Group Study. Journal of Clinical Oncology, 19, 3470–3476.
  • Ris, M. D., Walsh, K., Wallace, D., Armstrong, F. D., Holmes, E., Gajjar, A., … Packer, R. J. (2013). Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. Pediatric Blood & Cancer, 60, 1350–1357.
  • Riva, D., Giorgi, C., Nichelli, F., Bulgheroni, S., Massimino, M., Cefalo, G., … Pantaleoni, C. (2002). Intrathecal methotrexate affects higher functions in children with medulloblastoma. Neurology, 59, 1561–1563.
  • Robertson, P. L., Murasko, K. M., Holmes, E. J., Sposto, R., Packer, R. J., Gajjar, A., … Allen, J. C. (2006). Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: A prospective study by the Children’s Oncology Group. Journal of Neurosurgery, 105, 444–451.
  • Sands, S. A., Kellie, S. J., Davidow, A. L., Diez, B., Villablanca, J., Weiner, H. L., … Finlay, J. L. (2001). Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: From the First International CNS Germ-Cell Tumor Study. Neuro-Oncology, 3, 174–183.
  • Sattler, J. M. (2008). Assessment of Children: Cognitive Foundations (5th ed.). San Diego, CA: Jerome Sattler.
  • Saury, J. M., & Emanuelson, I. (2011). Cognitive consequences of the treatment of medulloblastoma among children. Pediatric Neurology, 44, 21–30.10.1016/j.pediatrneurol.2010.07.004
  • Sparrow, S. S., Cicchetti, D. V., & Balla, D. A. (2005). Vineland Adaptive Behavior Scales (2nd ed.). Circle Pines, MN: AGS Publishing.
  • Spiegler, B. J., Bouffet, E., Greenberg, M. L., Rutka, J. T., & Mabbott, D. J. (2004). Change in neurocognitive functioning after treatment with cranial radiation in childhood. Journal of Clinical Oncology, 22, 706–713.10.1200/JCO.2004.05.186
  • Stargatt, R., Rosenfeld, J. V., Anderson, V., Hassall, T., Maixner, W., & Ashley, D. (2006). Intelligence and adaptive function in children diagnosed with brain tumour during infancy. Journal of Neuro-oncology, 80, 295–303.10.1007/s11060-006-9187-0
  • Stargatt, R., Rosenfeld, J. V., Maixner, W., & Ashley, D. (2007). Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Developmental Neuropsychology, 32, 729–748.10.1080/87565640701376151
  • Stuss, D. T., & Alexander, M. P. (2000). Executive functions and the frontal lobes: A conceptual view. Psychological Research, 63, 289–298.10.1007/s004269900007
  • Trahan, L. H., Stuebing, K. K., Fletcher, J. M., & Hiscock, M. (2014). The Flynn effect: A meta-analysis. Psychological Bulletin, 140, 1332–1360.10.1037/a0037173
  • Wong, C. S., & Van der Kogel, A. J. (2004). Mechanisms of radiation injury to the central nervous system: Implications for neuroprotection. Molecular Interventions, 4, 273–284.10.1124/mi.4.5.7

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