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.

  • Review Article
  • Published:

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

Abstract

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, et al. One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2:e91–100.

    Article  PubMed  Google Scholar 

  2. Carreras J. A total of 1 million stem cell transplants have been performed worldwide. 2017; http://www.fcarreras.org/en/a-total-of-1-million-stem-cell-transplants-have-been-performed-worldwide_147898. Accessed 2 Mar 2017.

  3. World Health Organization. Transplantation. n.d.; http://www.who.int/transplantation/hsctx/en/. Accessed 2 Mar 2017.

  4. 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: J Am Soc Blood Marrow Transplant. 2013;19:1498–501.

    Article  Google Scholar 

  5. Bhatia S, Robison LL, Francisco L, Carter A, Liu Y, Grant M, et al. Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood. 2005;105:4215–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Askins MA, Moore BD 3rd. Preventing neurocognitive late effects in childhood cancer survivors. J Child Neurol. 2008;23: 1160–71.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Meyers CA. Neurocognitive dysfunction in cancer patients. Oncol (Williston Park, NY). 2000;14:75–9. discussion 79,81–72, 85

    CAS  Google Scholar 

  9. Rizzo JD, Wingard JR, Tichelli A, Lee SJ, van Lint MT, Burns LJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2006;12:138–51.

    Article  Google Scholar 

  10. Harder H, Cornelissen JJ, Van Gool AR, Duivenvoorden HJ, Eijkenboom WM, van den Bent MJ. Cognitive functioning and quality of life in long-term adult survivors of bone marrow transplantation. Cancer. 2002;95:183–92.

    Article  PubMed  Google Scholar 

  11. Harder H, Duivenvoorden HJ, van Gool AR, Cornelissen JJ, van den Bent MJ. Neurocognitive functions and quality of life in haematological patients receiving haematopoietic stem cell grafts: a one-year follow-up pilot study. J Clin Exp Neuropsychol. 2006;28:283–93.

    Article  PubMed  Google Scholar 

  12. Sostak P, Padovan CS, Yousry TA, Ledderose G, Kolb HJ, Straube A. Prospective evaluation of neurological complications after allogeneic bone marrow transplantation. Neurology. 2003;60:842–8.

    Article  CAS  PubMed  Google Scholar 

  13. Scherwath A, Schirmer L, Kruse M, Ernst G, Eder M, Dinkel A, et al. Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology. 2013;22:1509–16.

    Article  PubMed  Google Scholar 

  14. Jim HS, Small B, Hartman S, Franzen J, Millary S, Phillips K, et al. Clinical predictors of cognitive function in adults treated with hematopoietic cell transplantation. Cancer. 2012;118: 3407–16.

    Article  PubMed  Google Scholar 

  15. Smedler AC, Winiarski J. Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning. Bone Marrow Transplant. 2008;42:515–22.

    Article  PubMed  Google Scholar 

  16. Syrjala KL, Dikmen S, Langer SL, Roth-Roemer S, Abrams JR. Neuropsychologic changes from before transplantation to 1 year in patients receiving myeloablative allogeneic hematopoietic cell transplant. Blood. 2004;104:3386–92.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. Scott JG, Ostermeyer B, Shah AA. Neuropsychological assessment in neurocognitive disorders. Psychiatr Ann. 2016;46:118–26.

    Article  Google Scholar 

  19. Jones D, Vichaya EG, Wang XS, Sailors MH, Cleeland CS, Wefel JS. Acute cognitive impairment in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplant. Cancer. 2013;119:4188–95.

    Article  PubMed  Google Scholar 

  20. van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst. 1998;90:210–8.

    Article  PubMed  Google Scholar 

  21. Booth-Jones M, Jacobsen PB, Ransom S, Soety E. Characteristics and correlates of cognitive functioning following bone marrow transplantation. Bone Marrow Transplant. 2005;36:695–702.

    Article  CAS  PubMed  Google Scholar 

  22. Meyers CA, Weitzner M, Byrne K, Valentine A, Champlin RE, Przepiorka D. Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation. J Clin Oncol: Off J Am Soc Clin Oncol. 1994;12:820–6.

    Article  CAS  Google Scholar 

  23. Byrd D, Arentoft A, Scheiner D, Westerveld M, Baron IS. State of multicultural neuropsychological assessment in children: current research issues. Neuropsychol Rev. 2008;18:214–22.

    Article  PubMed  Google Scholar 

  24. Bevans MF, Mitchell SA, Barrett JA, Bishop MR, Childs R, Fowler D, et al. Symptom distress predicts long-term health and well-being in allogeneic stem cell transplantation survivors. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2014;20:387–95.

    Article  Google Scholar 

  25. Hoogland AI, Nelson AM, Small BJ, Hyland KA, Gonzalez BD, Booth-Jones M, et al. The role of age in neurocognitive functioning among adult allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2017; 23: 1974–1979.

  26. Syrjala KL, Artherholt SB, Kurland BF, Langer SL, Roth-Roemer S, Elrod JB, et al. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29: 2397–404.

    Article  Google Scholar 

  27. Phillips KM, McGinty HL, Cessna J, Asvat Y, Gonzalez B, Cases MG, et al. A systematic review and meta-analysis of changes in cognitive functioning in adults undergoing hematopoietic cell transplantation. Bone Marrow Transplant. 2013;48:1350–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ahles TA, Saykin A. Cognitive effects of standard-dose chemotherapy in patients with cancer. Cancer Invest. 2001;19:812–20.

    Article  CAS  PubMed  Google Scholar 

  29. Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C. Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev. 2012;38:926–34.

    Article  PubMed  Google Scholar 

  30. Mayo S, Messner HA, Rourke SB, Howell D, Victor JC, Kuruvilla J, et al. Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:841–7.

    Article  CAS  PubMed  Google Scholar 

  31. Cool VA. Long-term neuropsychological risks in pediatric bone marrow transplant: What do we know? Bone Marrow Transplant. 1996;18:S45–9.

    PubMed  Google Scholar 

  32. 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.

    Article  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Phipps S, Dunavant M, Srivastava DK, Bowman L, Mulhern RK. Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol: Off J Am Soc Clin Oncol. 2000;18:1004–11.

    Article  CAS  Google Scholar 

  36. 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 

  37. Phipps S, Rai SN, Leung WH, Lensing S, Dunavant M. Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26: 2027–33.

    Article  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Barrera M, Atenafu E, Andrews GS, Saunders F. Factors related to changes in cognitive, educational and visual motor integration in children who undergo hematopoietic stem cell transplant. J Pediatr Psychol. 2008;33:536–46.

    Article  PubMed  Google Scholar 

  40. 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.

    Article  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

  42. Phipps S, Brenner M, Heslop H, Krance R, Jayawardene D, Mulhern R. Psychological effects of bone marrow transplantation on children and adolescents: preliminary report of a longitudinal study. Bone Marrow Transplant. 1995;15:829–35.

    CAS  PubMed  Google Scholar 

  43. Smedler AC, Bolme P. Neuropsychological deficits in very young bone marrow transplant recipients. Acta Paediatr (Oslo, Nor: 1992). 1995;84:429–33.

    Article  CAS  Google Scholar 

  44. Notteghem P, Soler C, Dellatolas G, Kieffer-Renaux V, Valteau-Couanet D, Raimondo G, et al. Neuropsychological outcome in long-term survivors of a childhood extracranial solid tumor who have undergone autologous bone marrow transplantation. Bone Marrow Transplant. 2003;31:599–606.

    Article  CAS  PubMed  Google Scholar 

  45. Armstrong FD. Acute and long-term neurodevelopmental outcomes in children following bone marrow transplantation. Front Biosci. 2001;6:G6–12.

    Article  CAS  PubMed  Google Scholar 

  46. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76: 1867–71.

    Article  CAS  PubMed  Google Scholar 

  47. Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman SI, Petersen FB, et al. Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood. 1991;77:1660–5.

    Article  CAS  PubMed  Google Scholar 

  48. Schulz-Kindermann F, Mehnert A, Scherwath A, Schirmer B, Schleimer B, Zander AR, et al. Cognitive function in the acute course of allogeneic hematopoietic stem cell transplantation for hematological malignancies. Bone Marrow Transplant. 2007;39: 789–99.

    Article  CAS  PubMed  Google Scholar 

  49. Smedler AC, Nilsson C, Bolme P. Total body irradiation: a neuropsychological risk factor in pediatric bone marrow transplant recipients. Acta Paediatr. 1995;84:325–30.

    Article  CAS  PubMed  Google Scholar 

  50. Itzhaki RF, Wozniak MA. Viral infection and cognitive decline. J Am Geriatr Soc. 2007;55:131.

    Article  PubMed  Google Scholar 

  51. Bollard CM, Heslop HE. T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood. 2016;127: 3331–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sittinger H, Muller M, Schweizer I, Merkelbach S. Mild cognitive impairment after viral meningitis in adults. J Neurol. 2002;249:554–60.

    Article  PubMed  Google Scholar 

  53. delaTorre JC, Mallory M, Brot M, Gold L, Koob G, Oldstone MB, et al. Viral persistence in neurons alters synaptic plasticity and cognitive functions without destruction of brain cells. Virology. 1996;220:508–15.

    Article  CAS  Google Scholar 

  54. Titman P, Pink E, Skucek E, O’Hanlon K, Cole TJ, Gaspar J, et al. Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies. Blood. 2008;112:3907–13.

    Article  CAS  PubMed  Google Scholar 

  55. Lin M, Epport K, Azen C, Parkman R, Kohn DB, Shah AJ. Long-term neurocognitive function of pediatric patients with severe combined immune deficiency (SCID): pre- and post-hematopoietic stem cell transplant (HSCT). J Clin Immunol. 2009;29:231–7.

    Article  PubMed  CAS  Google Scholar 

  56. Allewelt H, El-Khorazaty J, Mendizabal A, Taskindoust M, Martin PL, Prasad V, et al. Late effects after umbilical cord blood transplantation in very young children after busulfan-based, myeloablative conditioning. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2016;22:1627–35.

    Article  Google Scholar 

  57. Smith A. Viral infections, immune responses and cognitive performance. Int J Neurosci. 1990;51:355–6.

    Article  CAS  PubMed  Google Scholar 

  58. Braamse AMJ, Yi JC, Visser OJ, Heymans MW, van Meijel B, Dekker J, et al. Developing a Risk Prediction Model for Long-Term Physical and Psychological Functioning after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016;22:549–56.

    Article  PubMed  Google Scholar 

  59. Menefee LA, Frank ED, Crerand C, Jalali S, Park J, Sarschagrin K, et al. The effects of transdermal fentanyl on driving, cognitive performance, and balance in patients with chronic nonmalignant pain conditions. Pain Med (Malden, Mass). 2004;5:42–9.

    Article  Google Scholar 

  60. Lim J, Dinges DF. A meta-analysis of the impact of short-term sleep deprivation on cognitive variables. Psychol Bull. 2010;136:375–89.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gruber SA, Silveri MM, Yurgelun-Todd DA. Neuropsychological consequences of opiate use. Neuropsychol Rev. 2007;17: 299–315.

    Article  PubMed  Google Scholar 

  62. Albers CA, Grieve AJ, Test Review, Bayley N. . Bayley Scales of Infant and Toddler Development–Third Edition. San Antonio, TX: Harcourt Assessment. J Psychoeduc Assess. 2007;25:180–90.

    Article  Google Scholar 

  63. Cohen MJ. Children’s Memory Scale. In: Kreutzer JS, DeLuca J, Caplan B, editors. Encyclopedia of clinical neuropsychology. New York, NY: Springer New York; 2011. p. 556–9.

    Chapter  Google Scholar 

  64. Conners CK, Epstein JN, Angold A, Klaric J. Continuous performance test performance in a normative epidemiological sample. J Abnorm Child Psychol. 2003;31:555–62.

    Article  PubMed  Google Scholar 

  65. Wechsler D. WISC-III: Wechsler intelligence scale for children: Manual. Psychological Corporation; San Antonio, TX, 1991.

  66. Gioia GA, Isquith PK, Guy SC, Kenworthy L, Baron IS. Test review: Behavior rating inventory of executive function. Child Neuropsychol. 2000;6:235–8.

    Article  Google Scholar 

  67. Delis DC, Freeland J, Kramer JH, Kaplan E. Integrating clinical assessment with cognitive neuroscience: construct validation of the California Verbal Learning Test. J Consult Clin Psychol. 1988;56:123–30.

    Article  CAS  PubMed  Google Scholar 

  68. Cullen B, O’Neill B, Evans JJ, Coen RF, Lawlor BA. A review of screening tests for cognitive impairment. J Neurol, Neurosurg & Psychiatry. 2007;78:790–9.

    Article  Google Scholar 

  69. Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry. 1987;48:314–8.

    CAS  PubMed  Google Scholar 

  70. Teng EL, Hasegawa K, Homma A, Imai Y, Larson E, Graves A, et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr. 1994;6:45–58.

    Article  CAS  PubMed  Google Scholar 

  71. Robbins TW, James M, Owen A, Shakian BJ, McInnes L, Rabbit PMv. Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dement Geriatr Cogn Disord. 1994;5:266–81.

  72. Randolph C, Tierney MC, Mohr E, Chase TN. The repeatable battery for the assessment of neuropsychological status (RBANS): Preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9.

    Article  CAS  PubMed  Google Scholar 

  73. Golden CJ, Freshwater SM. Stroop color and word test; Stoelting Co., Chicago, IL, USA, 1978.

  74. Heaton RK. Wisconsin card sorting test: computer version 2. Odessa: Psychological Assessment Resources; 1993.

    Google Scholar 

  75. Tombaugh TN. Trail Making Test A and B: Normative data stratified by age and education. Arch Clin Neuropsychol. 2004;19:203–14.

    Article  PubMed  Google Scholar 

  76. Benedict RHB, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test Revised: Normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol. 1998;12:43–55.

    Article  Google Scholar 

  77. Fastenau PS, Denburg NL, Hufford BJ. Adult norms for the Rey-Osterrieth complex figure test and for supplemental recognition and matching trials from the extended complex figure test. Clin Neuropsychol. 1999;13:30–47.

    Article  CAS  PubMed  Google Scholar 

  78. Ruff RM, Parker SB. Gender-and age-specific changes in motor speed and eye-hand coordination in adults: normative values for the Finger Tapping and Grooved Pegboard Tests. Percept Mot Skills. 1993;76:1219–30.

    Article  CAS  PubMed  Google Scholar 

  79. Drachman DA, Swearer JM, Kane K, Osgood D, Otoole C, Moonis M. The Cognitive Assessment Screening Test (CAST) for dementia. J Geriatr Psychiatry Neurol. 1996;9:200–8.

    Article  CAS  PubMed  Google Scholar 

  80. Denlinger CS, Ligibel JA, Are M, Baker KS, Denmark-Wahnefried W, Friedman DL, et al. Survivorship: cognitive function, version 1.2014. J Natl Compr Cancer Netw: Jnccn. 2014;12:976–86.

    Article  Google Scholar 

  81. Jacobs SR, Small BJ, Booth-Jones M, Jacobsen PB, Fields KK. Changes in cognitive functioning in the year after hematopoietic stem cell transplantation. Cancer. 2007;110:1560–7.

    Article  PubMed  Google Scholar 

  82. Atherton PJ, Sloan JA. Rising importance of patient-reported outcomes. Lancet Oncol. 2006;7:883–4.

    Article  PubMed  Google Scholar 

  83. Kenzik KM, Huang IC, Brinkman TM, Baughman B, Ness KK, Shenkman EA, et al. The Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) revised: item response analysis and concurrent validity. Neuropsychology. 2015;29:31–44.

    Article  PubMed  Google Scholar 

  84. Dyson GJ, Thompson K, Palmer S, Thomas DM, Schofield P. The relationship between unmet needs and distress amongst young people with cancer. Support Care Cancer. 2012;20:75–85.

    Article  PubMed  Google Scholar 

  85. Gordijn MS, van Litsenburg RR, Gemke RJ, Huisman J, Bierings MB, Hoogerbrugge PM, et al. Sleep, fatigue, depression, and quality of life in survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:479–85.

    Article  PubMed  Google Scholar 

  86. Grulke N, Albani C, Bailer H. Quality of life in patients before and after haematopoietic stem cell transplantation measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire QLQ-C30. Bone Marrow Transplant. 2012;47:473–82.

    Article  CAS  PubMed  Google Scholar 

  87. Kanellopoulos A, Hamre HM, Dahl AA, Fossa SD, Ruud E. Factors associated with poor quality of life in survivors of childhood acute lymphoblastic leukemia and lymphoma. Pediatr Blood Cancer. 2013;60:849–55.

    Article  PubMed  Google Scholar 

  88. Khan AG, Irfan M, Shamsi TS, Hussain M. Psychiatric disorders in bone marrow transplant patients. J Coll Physicians Surg--Pak: Jcpsp. 2007;17:98–100.

    PubMed  Google Scholar 

  89. Langeveld NE, Stam H, Grootenhuis MA, Last BF. Quality of life in young adult survivors of childhood cancer. Support Care Cancer. 2002;10:579–600.

    Article  CAS  PubMed  Google Scholar 

  90. Masule MS, Arbabi M, Ghaeli P, Hadjibabaie M, Torkamandi H. Assessing cognition, depression and anxiety in hospitalized patients during pre and post-Bone Marrow Transplantation. Iran J Psychiatry. 2014;9:64.

    Google Scholar 

  91. Artherholt SB, Hong F, Berry DL, Fann JR. Risk factors for depression in patients undergoing hematopoietic cell transplantation. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2014;20:946–50.

    Article  Google Scholar 

  92. Cohen MZ, Rozmus CL, Mendoza TR, Padhye NS, Neumann J, Gning I, et al. Symptoms and quality of life in diverse patients undergoing hematopoietic stem cell transplantation. J Pain Symptom Manag. 2012;44:168–80.

    Article  Google Scholar 

  93. van de Pol M, Twijnstra A, ten Velde GPM, Menheere PPCA. Neuron-specific enolase as a marker of brain metastasis in patients with small-cell lung carcinoma. J Neurooncol. 1994;19: 149–54.

    Article  PubMed  Google Scholar 

  94. Jacot W, Quantin X, Boher JM, Andre F, Moreau L, Gainet M, et al. Brain metastases at the time of presentation of non-small cell lung cancer: a multi-centric AERIO analysis of prognostic factors. Br J Cancer. 2001;84:903–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Foerch C, du Mesnil de Rochemont R, Singer O, Neumann-Haefelin T, Buchkremer M, Zanella FE, et al. S100B as a surrogate marker for successful clot lysis in hyperacute middle cerebral artery occlusion. J Neurol Neurosurg Psychiatry. 2003;74:322–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vogelbaum MA, Masaryk T, Mazzone P, Mekhail T, Fazio V, McCartney S, et al. S100beta as a predictor of brain metastases: brain versus cerebrovascular damage. Cancer. 2005;104:817–24.

    Article  CAS  PubMed  Google Scholar 

  97. Kaskel P, Berking C, Sander S, Volkenandt M, Peter RU, Krahn G. S-100 protein in peripheral blood: a marker for melanoma metastases: a prospective 2-center study of 570 patients with melanoma. J Am Acad Dermatol. 1999;41:962–9.

    Article  CAS  PubMed  Google Scholar 

  98. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.

    Article  CAS  PubMed  Google Scholar 

  99. Kaiser E, Kuzmits R, Pregant P, Burghuber O, Worofka W. Clinical biochemistry of neuron specific enolase. Clin Chim Acta. 1989;183:13–31.

    Article  CAS  PubMed  Google Scholar 

  100. Kanner AA, Marchi N, Fazio V, Mayberg MR, Koltz MT, Siomin V, et al. Serum s100 beta - A noninvasive marker of blood-brain barrier function and brain lesions. Cancer. 2003;97:2806–13.

    Article  CAS  PubMed  Google Scholar 

  101. Castillo J, Davalos A, Noya M. Progression of ischaemic stroke and excitotoxic aminoacids. Lancet (Lond, Engl). 1997;349: 79–83.

    Article  CAS  Google Scholar 

  102. Serena J, Leira R, Castillo J, Pumar JM, Castellanos M, Davalos A. Neurological deterioration in acute lacunar infarctions: the role of excitatory and inhibitory neurotransmitters. Stroke. 2001;32:1154–61.

    Article  CAS  PubMed  Google Scholar 

  103. Hong JH, Chiang CS, Campbell IL, Sun JR, Withers HR, McBride WH. Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys. 1995;33:619–26.

    Article  CAS  PubMed  Google Scholar 

  104. Wickremesekera JK, Chen W, Cannan RJ, Stubbs RS. Serum proinflammatory cytokine response in patients with advanced liver tumors following selective internal radiation therapy (SIRT) with (90)Yttrium microspheres. Int J Radiat Oncol Biol Phys. 2001;49:1015–21.

    Article  CAS  PubMed  Google Scholar 

  105. Castellanos M, Castillo J, Garcia MM, Leira R, Serena J, Chamorro A, et al. Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke. 2002;33:982–7.

    Article  PubMed  Google Scholar 

  106. Vila N, Castillo J, Davalos A, Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31:2325–9.

    Article  CAS  PubMed  Google Scholar 

  107. Patel SK, Wong AL, Wong FL, Breen EC, Hurria A, Smith M, et al. Inflammatory biomarkers, comorbidity, and neurocognition in women with newly diagnosed breast cancer. J Natl Cancer Inst. 2015;107:djv131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Caron JE, Krull KR, Hockenberry M, Jain N, Kaemingk K, Moore IM. Oxidative stress and executive function in children receiving chemotherapy for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009;53:551–6.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Sharafeldin N, Bosworth A, Chen Y, Patel SK, Singh P, Wang X, et al. Single nucleotide polymorphisms (SNPs) associated with cognitive impairment in patients treated with hematopoietic cell transplantation (HCT): A Longitudinal Study. Am Soc Hematology. 2016;128:824.

  110. Cao Y, Tsien CI, Sundgren PC, Nagesh V, Normille D, Buchtel H, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for prediction of radiation-induced neurocognitive dysfunction. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15:1747–54.

    Article  CAS  Google Scholar 

  111. Zeller B, Tamnes CK, Kanellopoulos A, Amlien IK, Andersson S, Due-Tonnessen P, et al. Reduced neuroanatomic volumes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31:2078–85.

    Article  Google Scholar 

  112. Correa DD, Root JC, Baser R, Moore D, Peck KK, Lis E, et al. A prospective evaluation of changes in brain structure and cognitive functions in adult stem cell transplant recipients. Brain Imaging Behav. 2013;7:478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lyon DE, Cohen R, Chen H, Kelly DL, Starkweather A, Ahn HC, et al. The relationship of cognitive performance to concurrent symptoms, cancer- and cancer-treatment-related variables in women with early-stage breast cancer: a 2-year longitudinal study. J Cancer Res Clin Oncol. 2016;142:1461–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chou RH, Wong GB, Kramer JH, Wara WM, Cowan MJ. Toxicities of total-body irradiation for pediatric bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1996;34:843–51.

    Article  CAS  PubMed  Google Scholar 

  115. Kramer JH, Crittenden MR, Halberg FE, Wara WM, Cowan MJ. A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation. Pediatrics. 1992;90:447–50.

    Article  CAS  PubMed  Google Scholar 

  116. Siegal D, Keller A, Xu W, Bhuta S, Kim DH, Kuruvilla J, et al. Central nervous system complications after allogeneic hematopoietic stem cell transplantation: incidence, manifestations, and clinical significance. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2007;13:1369–79.

    Article  Google Scholar 

  117. Schmidt V, Prell T, Treschl A, Klink A, Hochhaus A, Sayer HG. Clinical management of posterior reversible encephalopathy syndrome after allogeneic hematopoietic stem cell transplantation: A case series and review of the literature. Acta Haematol. 2016;135:1–10.

    Article  CAS  PubMed  Google Scholar 

  118. Moskowitz A, Nolan C, Lis E, Castro-Malaspina H, Perales MA. Posterior reversible encephalopathy syndrome due to sirolimus. Bone Marrow Transplant. 2007;39:653–4.

    Article  CAS  PubMed  Google Scholar 

  119. Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016;127:989–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. de Fontbrune FS, Galambrun C, Sirvent A, Huynh A, Faguer S, Nguyen S, et al. Use of Eculizumab in Patients With Allogeneic Stem Cell Transplant-Associated Thrombotic Microangiopathy: A Study From the SFGM-TC. Transplantation. 2015;99:1953–9.

    Article  PubMed  CAS  Google Scholar 

  121. Butler RW, Fairclough DL, Mulhern RK, Katz ER, Kazak AE, Noll RB, et al. A multicenter, randomized clinical trial of a Cognitive Remediation Program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. 2008;76:367–78.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Castellino SM, Ullrich NJ, Whelen MJ, Lange BJ. Developing interventions for cancer-related cognitive dysfunction in childhood cancer survivors. J Natl Cancer Inst. 2014;106:dju186.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Patel SK, Katz ER, Richardson R, Rimmer M, Kilian S. Cognitive and problem solving training in children with cancer: a pilot project. J Pediatr Hematol/Oncol. 2009;31:670–7.

    Article  Google Scholar 

  124. Conklin HM, Ogg RJ, Ashford JM, Scoggins MA, Zou P, Clark KN, et al. Computerized Cognitive Training for Amelioration of Cognitive Late Effects Among Childhood Cancer Survivors: A Randomized Controlled Trial. J Clin Oncol. 2015;33:3894.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Hardy KK, Willard VW, Bonner MJ. Computerized cognitive training in survivors of childhood cancer: A pilot study. J Pediatr Oncol Nurs. 2011;28:27–33.

    Article  PubMed  Google Scholar 

  126. Campbell KL, Kam JW, Neil-Sztramko SE, Liu Ambrose T, Handy TC, Lim HJ, et al. Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT. Psycho-oncology. 2017.

  127. Thompson SJ, Leigh L, Christensen R, Xiong X, Kun LE, Heideman RL, et al. Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer. J Clin Oncol. 2001;19:1802–8.

    Article  CAS  PubMed  Google Scholar 

  128. Netson KL, Conklin HM, Ashford JM, Kahalley LS, Wu S, Xiong X. Parent and teacher ratings of attention during a year-long methylphenidate trial in children treated for cancer. J Pediatr Psychol. 2011;36:438–50.

    Article  PubMed  Google Scholar 

  129. Shaw EG, Rosdhal R, D’Agostino RB, Lovato J, Naughton MJ, Robbins ME, et al. Phase II study of donepezil in irradiated brain tumor patients: Effect on cognitive function, mood, and quality of life. J Clin Oncol. 2006;24:1415–20.

    Article  CAS  PubMed  Google Scholar 

  130. Kohli S, Fisher SG, Tra Y, Adams MJ, Mapstone ME, Wesnes KA, et al. The effect of modafinil on cognitive function in breast cancer survivors. Cancer . 2009;115:2605–16.

    Article  CAS  PubMed  Google Scholar 

  131. Huisman J, Aukema EJ, Deijen JB, van Coeverden SC, Kaspers GJ, van der pal HJ, et al. The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study. BMC Pediatr. 2008;8:8.

    Article  Google Scholar 

  132. Vakil E. Neuropsychological assessment: Principles, rationale, and challenges. J Clin Exp Neuropsychol. 2012;34:135–50.

    Article  PubMed  Google Scholar 

  133. Manly T, Fish J, Mattingley JB. Adult neuropsychology: visuo-spatial and attentional disorders. Wiley, Chichester, UK; 2012.

  134. Evans JJ. Disorders of memory. Wiley-Blackwell, Chichester, UK; 2012.

  135. Burgess PW, Alderman N. Executive dysfunction. Wiley-Blackwell, Chichester, UK; 2012.

  136. Johnson DW, Cagnoni PJ, Schossau TM, Stemmer SM, Grayeb DE, Baron AE, et al. Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support. Bone Marrow Transplant. 1999;24:785–92.

    Article  CAS  PubMed  Google Scholar 

  137. Burger PC, Kamenar E, Schold SC, Fay JW, Phillips GL, Herzig GP. Encephalomyelopathy following high dose BCNU therapy. Cancer. 1981;48:1318–27.

    Article  Google Scholar 

  138. Baker WJ, Royer GL, Weiss RB. Cytarabine and neurologic toxicit. J Clin Oncol. 1991;9:679–93.

    Article  CAS  PubMed  Google Scholar 

  139. Leff RS, Thompson JM, Daly MB, Johnson DB, Harden EA, Mercier RJ, et al. Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Cancer. 1988;62:32–35.

    Article  CAS  PubMed  Google Scholar 

  140. Pratt CB, Goren MP, Meyer WH, Singh B, Dodge RK. Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors. J Clin Oncol: Off J Am Soc Clin Oncol. 1990;8:1399–401.

    Article  CAS  Google Scholar 

  141. DiMaggio JR, Brown R, Baile WF, Schapira D. Hallucinations and ifosfamide-induced neurotoxicity. Cancer. 1994;73: 1509–14.

    Article  CAS  PubMed  Google Scholar 

  142. McKinney AM, Short J, Truwit CL, McKinney CJ, Kozak OS, SantaCruz KS, et al. Posterior reversible encephalopathy syndrome: Incidence of atypical regions of involvement and imaging findings. Am J Roentgenol. 2007;189:904–12.

    Article  Google Scholar 

  143. Schwartz RB, Bravo SM, Klufas RA, Hsu L, Barnes PD, Robson CD, et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol. 1995;165:627–31.

    Article  CAS  PubMed  Google Scholar 

  144. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500.

    Article  CAS  PubMed  Google Scholar 

  145. Yoshikawa T. Human herpesvirus-6 and-7 infections in transplantation. Pediatr Transplant. 2003;7:11–17.

    Article  CAS  PubMed  Google Scholar 

  146. Gorniak RJT, Young GS, Wiese DE, Marty FM, Schwartz RB. MR imaging of human herpesvirus-6-associated encephalitis in 4 patients with anterograde amnesia after allogeneic hematopoietic stem-cell transplantation. Am J Neuroradiol. 2006;27:887–91.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

CIBMTR Support List

The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia and Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck and Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd.—Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.

*Corporate Members

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Buchbinder.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

David Buchbinder and Debra Lynch Kelly contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buchbinder, D., Kelly, D.L., Duarte, R.F. 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 53, 535–555 (2018). https://doi.org/10.1038/s41409-017-0055-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-017-0055-7

This article is cited by

Search

Quick links