Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neurocognitive functioning in long-term survivors of pediatric hematopoietic cell transplantation

Bone Marrow Transplantation volume 56, pages 873–882 (2021)Cite this article

Subjects

Abstract

Survivors of pediatric hematopoietic cell transplantation (HCT) are at risk for impairment in cognitive and academic function. Most research to date has focused on the first years following transplant, and less is known about the long-term effects. We examined global and specific neurocognitive functioning in long-term (>5 years post HCT) survivors in comparison to both normative data and a sample of demographically similar healthy peers. A comprehensive battery of neurocognitive measures was obtained from 83 long-term survivors and 50 healthy comparisons. Analyses were conducted to assess for differences in neurocognitive functions between survivors, normative means, and healthy comparisons, and to examine the impact of medical and demographic variables on neurocognitive performance. Survivors’ performance was within the Average range across most measures, although significantly lower than both test norms and healthy comparisons on several measures. Despite generally intact neurocognitive functioning in the survivor group as a whole, survivors who experienced graft-vs.-host disease demonstrated slower processing speed and weaker verbal learning. Use of total body irradiation was not associated with any performance-based measure of neurocognitive functioning. Although subgroups of patients may be at relatively higher risk of neurocognitive impairment, the long-term neurocognitive impact for most survivors is relatively small.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IQ scores and academic function.
Fig. 2: Executive function.
Fig. 3: Memory and fine motor skills.

Similar content being viewed by others

References

  1. Bhatia S, Francisco L, Carter A, Sun CL, Baker KS, Gurney JG, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110:3784–92. https://doi.org/10.1182/blood-2007-03-082933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Majhail NS, Tao L, Bredeson C, Davies S, Dehn J, Gajewski JL, et al. Prevalence of hematopoietic cell transplant survivors in the United States. Biol Blood Marrow Transplant. 2013;19:1498–501. https://doi.org/10.1016/j.bbmt.2013.07.020.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mulcahy Levy JM, Tello T, Giller R, Wilkening G, Quinones R, Keating AK, et al. Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age. Pediatr Blood Cancer. 2013;60:700–4. https://doi.org/10.1002/pbc.24252.

    Article  PubMed  Google Scholar 

  4. Smedler AC, Winiarski J. Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning. Bone Marrow Transplant. 2008;42:515–22. https://doi.org/10.1038/bmt.2008.217.

    Article  PubMed  Google Scholar 

  5. Buchbinder D, Kelly DL, Duarte RF, Auletta JJ, Bhatt N, Byrne M, et al. Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT. Bone Marrow Transplant. 2018;53:535–55. https://doi.org/10.1038/s41409-017-0055-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Coley SC, Porter DA, Calamante F, Chong WK, Connelly A. Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. AJNR Am J Neuroradiol. 1999;20:1507–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Phipps S, Rai SN, Leung WH, Lensing S, Dunavant M. Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol. 2008;26:2027–33. https://doi.org/10.1200/jco.2007.13.6135.

    Article  PubMed  Google Scholar 

  8. Aiello AE, Haan M, Blythe L, Moore K, Gonzalez JM, Jagust W. The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc. 2006;54:1046–54. https://doi.org/10.1111/j.1532-5415.2006.00796.x.

    Article  PubMed  Google Scholar 

  9. Sittinger H, Muller M, Schweizer I, Merkelbach S. Mild cognitive impairment after viral meningitis in adults. J Neurol. 2002;249:554–60. https://doi.org/10.1007/s004150200064.

    Article  Google Scholar 

  10. Wang W, Enos L, Gallagher D, Thompson R, Guarini L, Vichinsky E, et al. Neuropsychologic performance in school-aged children with sickle cell disease: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr. 2001;139:391–7. https://doi.org/10.1067/mpd.2001.116935.

    Article  CAS  PubMed  Google Scholar 

  11. Jacola LM, Krull KR, Pui CH, Pei D, Cheng C, Reddick WE, et al. Longitudinal assessment of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy protocol. J Clin Oncol. 2016;34:1239–47. https://doi.org/10.1200/jco.2015.64.3205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jim HS, Small B, Hartman S, Franzen J, Millay S, Phillips K, et al. Clinical predictors of cognitive function in adults treated with hematopoietic cell transplantation. Cancer. 2012;118:3407–16. https://doi.org/10.1002/cncr.26645.

    Article  PubMed  Google Scholar 

  13. Arvidson J, Kihlgren M, Hall C, Lonnerholm G. Neuropsychological functioning after treatment for hematological malignancies in childhood, including autologous bone marrow transplantation. Pediatr Hematol Oncol. 1999;16:9–21.

    Article  CAS  Google Scholar 

  14. Barrera M, Atenafu E. Cognitive, educational, psychosocial adjustment and quality of life of children who survive hematopoietic SCT and their siblings. Bone Marrow Transplant. 2008;42:15–21. https://doi.org/10.1038/bmt.2008.84.

    Article  CAS  PubMed  Google Scholar 

  15. Hiniker SM, Agarwal R, Modlin LA, Gray CC, Harris JP, Million L, et al. Survival and neurocognitive outcomes after cranial or craniospinal irradiation plus total-body irradiation before stem cell transplantation in pediatric leukemia patients with central nervous system involvement. Int J Radiat Oncol Biol Phys. 2014;89:67–74. https://doi.org/10.1016/j.ijrobp.2014.01.056.

    Article  PubMed  Google Scholar 

  16. Kupst MJ, Penati B, Debban B, Camitta B, Pietryga D, Margolis D, et al. Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study. Bone Marrow Transplant. 2002;30:609–17. https://doi.org/10.1038/sj.bmt.1703683.

    Article  CAS  PubMed  Google Scholar 

  17. Simms S, Kazak AE, Golomb V, Goldwein J, Bunin N. Cognitive, behavioral, and social outcome in survivors of childhood stem cell transplantation. J Pediatr Hematol Oncol. 2002;24:115–9.

    Article  Google Scholar 

  18. Kramer JH, Crittenden MR, DeSantes K, Cowan MJ. Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation. Bone Marrow Transplant. 1997;19:607–13. https://doi.org/10.1038/sj.bmt.1700699.

    Article  CAS  PubMed  Google Scholar 

  19. Shah AJ, Epport K, Azen C, Killen R, Wilson K, De Clerck D, et al. Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J Pediatr Hematol Oncol. 2008;30:411–8. https://doi.org/10.1097/MPH.0b013e318168e750.

    Article  PubMed  Google Scholar 

  20. Willard VW, Leung W, Huang Q, Zhang H, Phipps S. Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation. J Clin Oncol. 2014;32:3982–8. https://doi.org/10.1200/jco.2014.56.2223.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lajiness-O’Neill R, Hoodin F, Kentor R, Heinrich K, Colbert A, Connelly JA. Alterations in Memory and Impact on Academic Outcomes in Children following Allogeneic Hematopoietic Cell Transplantation. Arch Clin Neuropsychol. 2015;30:657–69. https://doi.org/10.1093/arclin/acv053.

    Article  PubMed  Google Scholar 

  22. Perkins JL, Kunin-Batson AS, Youngren NM, Ness KK, Ulrich KJ, Hansen MJ, et al. Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer. 2007;49:958–63. https://doi.org/10.1002/pbc.21207.

    Article  PubMed  Google Scholar 

  23. Gragert MN, Ris MD. Neuropsychological late effects and rehabilitation following pediatric brain tumor. J Pediatr Rehabil Med. 2011;4:47–58. https://doi.org/10.3233/prm-2011-0153.

    Article  PubMed  Google Scholar 

  24. Reddick WE, Conklin HM. Impact of acute lymphoblastic leukemia therapy on attention and working memory in children. Expert Rev Hematol. 2010;3:655–9. https://doi.org/10.1586/ehm.10.65.

    Article  PubMed  Google Scholar 

  25. Biederman J, Monuteaux MC, Doyle AE, Seidman LJ, Wilens TE, Ferrero F, et al. Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. J Consult Clin Psychol. 2004;72:757–66. https://doi.org/10.1037/0022-006x.72.5.757.

    Article  PubMed  Google Scholar 

  26. Ness KK, Gurney JG, Zeltzer LK, Leisenring W, Mulrooney DA, Nathan PC, et al. The impact of limitations in physical, executive, and emotional function on health-related quality of life among adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Arch Phys Med Rehabil. 2008;89:128–36. https://doi.org/10.1016/j.apmr.2007.08.123.

    Article  PubMed  Google Scholar 

  27. Rackley S, Pao M, Seratti GF, Giri N, Rasimas JJ, Alter BP, et al. Neuropsychiatric conditions among patients with dyskeratosis congenita: a link with telomere biology? Psychosomatics. 2012;53:230–5. https://doi.org/10.1016/j.psym.2011.09.003.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sun A. Lysosomal storage disease overview. Ann Transl Med. 2018;6:476. https://doi.org/10.21037/atm.2018.11.39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu CC, Econs MJ, DiMeglio LA, Insogna KL, Levine MA, Orchard PJ, et al. Diagnosis and management of osteopetrosis: consensus guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102:3111–23. https://doi.org/10.1210/jc.2017-01127.

    Article  PubMed  Google Scholar 

  30. Marr C, Seasman A, Bishop N. Managing the patient with osteogenesis imperfecta: a multidisciplinary approach. J Multidiscip Healthc. 2017;10:145–55. https://doi.org/10.2147/JMDH.S113483.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wechsler D. Wechsler intelligence scale for children, fourth edition (WISC-IV). San Antionio, TX: The Psychological Corporation; 2003.

  32. Wechsler D. Wechsler adult intelligence scale, fourth edition (WAIS-IV). San Antonio, TX: The Psychological Corporation; 2008.

  33. Wilkinson GS, Robertson GJ. WIde range achievement test—fourth edition (WRAT-4). Lutz, FL: Psychological Assessment Resources, Inc.; 2006.

  34. Delis DC, Kaplan E, Kramer JH. Delis-Kaplan executive function system (D-KEFS). San Antonio, TX: The Psychological Corporation; 2001.

    Google Scholar 

  35. Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior rating inventory of executive function (BRIEF). Lutx, FL: Psychological Assessment Resources, Inc.; 2000.

    Google Scholar 

  36. Delis DC, Kramer JH, Kaplan E, Ober BA. California verbal learning test—children’s version (CVLT-C). San Antonio, TX: The Psychological Corporation; 1994.

    Google Scholar 

  37. Delis DC, Kramer JH, Kaplan E, Ober BA. California verbal learning test—second edition (CVLT-II). San Antonio, TX: The Psychological Corporation; 2000.

  38. Lafayette Instrument Company. The Grooved Pegboard test. Lafayette, IN: Lafayette Instrument; 2002.

  39. Walsh KS, Noll RB, Annett RD, Patel SK, Patenaude AF, Embry L, et al. Standard of care for neuropsychological monitoring in pediatric neuro-oncology: Lessons from the Children’s Oncology Group (COG). Pediatr Blood Cancer. 2016;63:191–5. https://doi.org/10.1002/pbc25759.

    Article  PubMed  Google Scholar 

  40. Annett RD, Patel SK, Phipps S. Monitoring and assessment of neuropsychological outcomes as a standard of care in pediatric oncology. Pediatr Blood Cancer. 2015;62:S460–513. https://doi.org/10.1002/pbc25749.

    Article  PubMed  Google Scholar 

  41. Belanoff JK, Gross K, Yager A, Schatzberg AF. Corticosteroids and cognition. J Psychiatr Res. 2001;35:127–45. https://doi.org/10.1016/s0022-3956(01)00018-8.

    Article  CAS  PubMed  Google Scholar 

  42. Brown ES, Woolston D, Frol A, Bobadilla L, Khan DA, Hanczyc M, et al. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55:538–45. https://doi.org/10.1016/j.biopsych.2003.09.010.

    Article  CAS  PubMed  Google Scholar 

  43. Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress ME, Yaldoo DT. The effect on memory of chronic prednisone treatment in patients with systemic disease. Neurology. 1996;47:1396–402. https://doi.org/10.1212/wnl.47.6.1396.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge and thank the following individuals for their assistance with this study: Karen Martin-Elbahesh, Alanna Long, Hui Zhang, Christine Hartford, and Wing Leung. The study is supported in part by a grant from the St. Baldrick’s Foundation (ID 246618), and by the American Lebanese-Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

  1. Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Kendra R. Parris, Kathryn M. Russell & Sean Phipps

  2. Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Brandon M. Triplett

Authors
  1. Kendra R. Parris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathryn M. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brandon M. Triplett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sean Phipps
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kendra R. Parris.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parris, K.R., Russell, K.M., Triplett, B.M. et al. Neurocognitive functioning in long-term survivors of pediatric hematopoietic cell transplantation. Bone Marrow Transplant 56, 873–882 (2021). https://doi.org/10.1038/s41409-020-01125-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-020-01125-5

This article is cited by

Search

Advanced search

Quick links