Neurological complications of pediatric cancer

  • Caren Armstrong
  • Lisa R. SunEmail author


Both the onset of various malignancies as well as the treatment of cancer can lead to neurologic symptoms which can be difficult to diagnose. In this review, we highlight the varied ways in which neurologic sequelae of cancer and its treatment manifest in children. Initial neurologic presentation may be secondary to mass effect or to immune-mediated paraneoplastic syndromes. Treatment effects on the nervous system may arise from surgery, chemotherapy, radiation, or bone marrow transplantation. In addition, the rapidly expanding field of immunotherapies for cancer has generated numerous new approaches to eradicating cancer including monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor T cells (CAR-T cells), which have neurologic side effects mediated by immune responses that are also being recognized. Here we review common consult questions to the neurologist and our general approach to these scenarios including altered mental status, headaches, seizures, and sensorimotor complaints, considering the multifactorial nature of each.


Childhood cancer Neurology Chemotherapy Immunotherapy 



We thank Stacy Cooper for her assistance with the chemotherapy section of this manuscript.

Author contributions

C.A. and L.S. wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Dobrovoljac, M., Hengartner, H., Boltshauser, E., & Grotzer, M. (2002). Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr, 161(12), 663–667. Scholar
  2. 2.
    Reulecke, B. C., Erker, C. G., Fiedler, B. J., Niederstadt, T.-U., & Kurlemann, G. (2008). Brain tumors in children: Initial symptoms and their influence on the time span between symptom onset and diagnosis. J Child Neurol, 23(2), 178–183. Scholar
  3. 3.
    Ullrich, N. J. (2009). Neurologic sequelae of brain tumors in children. J Child Neurol, 24(11), 1446–1454. Scholar
  4. 4.
    Wells, E. M., & Packer, R. J. (2015). Pediatric brain tumors. CONTINUUM: Lifelong Learning in Neurology, 21(2), 373–396. Scholar
  5. 5.
    Malbari, F., Gershon, T. R., Garvin, J. H., Allen, J. C., Khakoo, Y., Levy, A. S., & Dunkel, I. J. (2016). Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series. Childs Nerv Syst, 32(8), 1359–1362. Scholar
  6. 6.
    Taylor M, Couto-Silva, A-C, Adan L, Trivin C, Sainte-Rose C, Zerah M, … Brauner R (2012). Hypothalamic-pituitary lesions in pediatric patients: endocrine symptoms often precede neuro-ophthalmic presenting symptoms. J Pediatr, 161(5), 855–63. doi: Scholar
  7. 7.
    Pretell-Mazzini, J., Chikwava, K. R., & Dormans, J. P. (2012). Low back pain in a child associated with acute onset cauda equina syndrome: a rare presentation of an aggressive vertebral hemangioma: a case report. J Pediatr Orthop, 32(3), 271–276. Scholar
  8. 8.
    Mora, J., & Wollner, N. (1999). Primary epidural non-Hodgkin lymphoma: spinal cord compression syndrome as the initial form of presentation in childhood non-Hodgkin lymphoma. Med Pediatr Oncol, 32(2), 102–105.<102::AID-MPO6>3.0.CO;2-Y.CrossRefPubMedGoogle Scholar
  9. 9.
    Da Silva, A. N., Lopes, M. B., & Schiff, D. (2006). Rare pathological variants and presentations of primary central nervous system lymphomas. Neurosurg Focus, 21(5), E1–E7. Scholar
  10. 10.
    Wilson, R. E., Oleszek, J. L., & Clayton, G. H. (2007). Pediatric spinal cord tumors and masses. J Spinal Cord Med, 30(sup1), S15–S20. Scholar
  11. 11.
    Ma, G. M., Chow, J. S., & Taylor, G. A. (2019). Review of paraneoplastic syndromes in children. Pediatr Radiol, 49(4), 534–550. Scholar
  12. 12.
    Nikolic, D. M., Nikolic, A. V., Lavrnic, D. V., Medjo, B. P., & Ivanovski, P. I. (2012). Childhood-onset myasthenia gravis with thymoma. Pediatr Neurol, 46(5), 329–331. Scholar
  13. 13.
    Wells, E. M., & Dalmau, J. (2011). Paraneoplastic neurologic disorders in children. Curr Neurol Neuroscie Rep, 11(2), 187–194. Scholar
  14. 14.
    Dalmau, J., & Rosenfeld, M. R. (2008). Paraneoplastic syndromes of the CNS. Lancet Neurol, 7(4), 327–340. Scholar
  15. 15.
    Graus, F., Delattre, J. Y., Antoine, J. C., Dalmau, J., Giometto, B., Grisold, W., Honnorat, J., Smitt, P. S., Vedeler Ch, Verschuuren, J. J., Vincent, A., & Voltz, R. (2004). Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 75(8), 1135–1140. Scholar
  16. 16.
    Pranzatelli, M. R., Tate, E. D., Swan, J. A., Travelstead, A. L., Colliver, J. A., Verhulst, S. J., Crosley, C. J., Graf, W. D., Joseph, S. A., Kelfer, H. M., & Raju, G. P. (2010). B cell depletion therapy for new-onset opsoclonus-myoclonus. Mov Disord, 25(2), 238–242. Scholar
  17. 17.
    Shams’ili, S., de Beukelaar, J., Gratama, J. W., Hooijkaas, H., van den Bent, M., van’t Veer, M., & Sillevis Smitt, P. (2006). An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol, 253(1), 16–20. Scholar
  18. 18.
    Honnorat, J., Didelot, A., Karantoni, E., Ville, D., Ducray, F., Lambert, L., Deiva, K., Garcia, M., Pichit, P., Cavillon, G., Rogemond, V., DeLattre, J., & Tardieu, M. (2013). Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. Neurology, 80(24), 2226–2232. Scholar
  19. 19.
    Florance-Ryan, N., & Dalmau, J. (2010). Update on anti-N-methyl-D-aspartate receptor encephalitis in children and adolescents. Curr Opin Pediatr, 22(6), 739–744. Scholar
  20. 20.
    Lebas, A., Husson, B., Didelot, A., Honnorat, J., & Tardieu, M. (2010). Expanding spectrum of encephalitis with NMDA receptor antibodies in young children. J Child Neurol, 25(6), 742–745. Scholar
  21. 21.
    Haberlandt, E., Bast, T., Ebner, A., Holthausen, H., Kluger, G., Kravljanac, R., Kröll-Seger, J., Kurlemann, G., Makowski, C., Rostasy, K., Tuschen-Hofstätter, E., Weber, G., Vincent, A., & Bien, C. G. (2011). Limbic encephalitis in children and adolescents. Arch Dis Child, 96(2), 186–191. Scholar
  22. 22.
    Nosadini M, Toldo I, Tascini B, Bien CG, Parmeggiani L, De Gaspari P, … Sartori S (2019). LGI1 and CASPR2 autoimmunity in children: systematic literature review and report of a young girl with Morvan syndrome. J Neuroimmunol, 335, 577008. doi: Scholar
  23. 23.
    Nikolaus, M., Jackowski-Dohrmann, S., Prüss, H., Schuelke, M., & Knierim, E. (2018). Morvan syndrome associated with CASPR2 and LGI1 antibodies in a child. Neurology, 90(4), 183–185. Scholar
  24. 24.
    Allen, N. M., McKeon, A., O’Rourke, D. J., O’Meara, A., & King, M. D. (2012). Excessive blinking and ataxia in a child with occult neuroblastoma and voltage-gated potassium channel antibodies. Pediatrics, 129(5), e1348–e1352. Scholar
  25. 25.
    Rosenfeld, M. R. (2018). Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia. Up To Date, 12, 1–12.Google Scholar
  26. 26.
    Sharp, L., & Vernino, S. (2012). Paraneoplastic neuromuscular disorders. Muscle Nerve, 46(6), 839–840. Scholar
  27. 27.
    Amini, A., Lang, B., Heaney, D., & Irani, S. R. (2016). Multiple sequential antibody-associated syndromes with a recurrent mutated neuroblastoma. Neurology, 87(6), 634–636. Scholar
  28. 28.
    Younes-Mhenni S, Janier MF, Cinotti L, Antoine JC, Tronc F, Cottin V, … Honnorat J (2004). FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain, 127(10), 2331–2338. doi: Scholar
  29. 29.
    Linke, R., Schroeder, M., Helmberger, T., & Voltz, R. (2004). Antibody-positive paraneoplastic neurologic syndromes: Value of CT and PET for tumor diagnosis. Neurology, 63(2), 282–286. Scholar
  30. 30.
    Blaes, F., Pike, M. G., & Lang, B. (2008). Autoantibodies in childhood opsoclonus-myoclonus syndrome. J Neuroimmunol, 201, 221–226. Scholar
  31. 31.
    van Vuurden, D. G., Plötz, F. B., de Jong, M., Bokenkamp, A., & van Wijk, J. A. E. (2005). Therapeutic total plasma exchange in a child with neuroblastoma-related anti-Hu syndrome. Pediatr Nephrol, 20(11), 1655–1656. Scholar
  32. 32.
    Sillevis Smitt, P., Grefkens, J., De Leeuw, B., Van Den Bent, M., Van Putten, W., Hooijkaas, H., & Vecht, C. (2002). Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol, 249(6), 745–753. Scholar
  33. 33.
    Chong, C., Soon, D. T. L., & Yeo, L. L. L. (2019). Opsoclonus - myoclonus syndrome. J Clin Neurosci, 61, 254–255. Scholar
  34. 34.
    Tate, E. D., Allison, T. J., Pranzatelli, M. R., & Verhulst, S. J. (2005). Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs, 22(1), 8–19. Scholar
  35. 35.
    Morales La Madrid, A., Rubin, C. M., Kohrman, M., Pytel, P., & Cohn, S. L. (2012). Opsoclonus-myoclonus and anti-Hu positive limbic encephalitis in a patient with neuroblastoma. Pediatr Blood Cancer, 58(3), 472–474. Scholar
  36. 36.
    Fisher, P. G., Wechsler, D. S., & Singer, H. S. (1994). Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome. Pediatr Neurol, 10(4), 309–312. Scholar
  37. 37.
    Wilfong, A. A., Parke, J. T., & McCrary, J. A. (1992). Opsoclonus-myoclonus with Beckwith-Wiedemann syndrome and hepatoblastoma. Pediatr Neurol, 8(1), 77–79. Scholar
  38. 38.
    Swart, J. F., De Kraker, J., & Van der Lely, N. (2002). Metaiodobenzylguanidine total-body scintigraphy required for revealing occult neuroblastoma in opsoclonus-myoclonus syndrome. Eur J Pediatr, 161(5), 255–258. Scholar
  39. 39.
    McGarvey, C. K., Applegate, K., Lee, N. D., & Sokol, D. K. (2006). False-positive metaiodobenzylguanidine scan for neuroblastoma in a child with opsoclonus-myoclonus syndrome treated with adrenocorticotropic hormone (ACTH). J Child Neurol, 21(7), 606–610. Scholar
  40. 40.
    Brunklaus, A., Pohl, K., Zuberi, S. M., & De Sousa, C. (2012). Investigating neuroblastoma in childhood opsoclonus-myoclonus syndrome. Arch Dis Child. Scholar
  41. 41.
    Baizabal-Carvallo, J. F., Stocco, A., Muscal, E., & Jankovic, J. (2013). The spectrum of movement disorders in children with anti-NMDA receptor encephalitis. Mov Disord, 28(4), 543–547. Scholar
  42. 42.
    Mohammad, S. S., Fung, V. S. C., Grattan-Smith, P., Gill, D., Pillai, S., Ramanathan, S., et al. (2014). Movement disorders in children with anti-NMDAR encephalitis and other autoimmune encephalopathies. Mov Disord, 29(12), 1539–1542. Scholar
  43. 43.
    Yeshokumar, A. K., Sun, L. R., Klein, J. L., Baranano, K. W., & Pardo, C. A. (2016). Gait disturbance as the presenting symptom in young children with anti-NMDA receptor encephalitis. Pediatrics, 138(3), e20160901. Scholar
  44. 44.
    Darnell, R. B. (2007). NMDA receptor as a target in paraneoplastic encephalitis. Ann Neurol, 61(1), 3–4. Scholar
  45. 45.
    Dalmau, J., Tüzün, E., Wu, H., & Masjuan, J. (2007). Paraneoplastic anti–N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol, 61(1), 25–36.CrossRefGoogle Scholar
  46. 46.
    Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., & Lynch, D. R. (2008). Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol, 7(12), 1091–1098. Scholar
  47. 47.
    Kunstreich, M., Kreth, J. H., Oommen, P. T., Schaper, J., Karenfort, M., Aktas, O., Tibussek, D., Distelmaier, F., Borkhardt, A., & Kuhlen, M. (2017). Paraneoplastic limbic encephalitis with SOX1 and PCA2 antibodies and relapsing neurological symptoms in an adolescent with Hodgkin lymphoma. Eur J Paediatr Neurol, 21(4), 661–665. Scholar
  48. 48.
    Chan, D. W. S., Thomas, T., Lim, M., Ling, S., Woodhall, M., & Vincent, A. (2017). Focal status epilepticus and progressive dyskinesia: a novel phenotype for glycine receptor antibody-mediated neurological disease in children. Eur J Paediatr Neurol, 21(2), 414–417. Scholar
  49. 49.
    Spatola, M., Sabater, L., Planagumà, J., Martínez-Hernandez, E., Armangué, T., Prüss, H., Iizuka, T., Caparó Oblitas, R. L., Antoine, J. C., Li, R., Heaney, N., Tubridy, N., Munteis Olivas, E., Rosenfeld, M. R., Graus, F., & Dalmau, J. (2018). Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology, 90(22), e1964–e1972. Scholar
  50. 50.
    Rudock R, Helis J, & Mar SS (2017). Anti-glutamic acid decarboxylase limbic encephalitis. In Pediatric demyelinating diseases of the central nervous system and their mimics (pp. 67–73). Springer International Publishing. doi: Scholar
  51. 51.
    Gresa-Arribas, N., Titulaer, M. J., Torrents, A., Aguilar, E., McCracken, L., Leypoldt, F., Gleichman, A. J., Balice-Gordon, R., Rosenfeld, M. R., Lynch, D., Graus, F., & Dalmau, J. (2014). Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol, 13(2), 167–177. Scholar
  52. 52.
    Rosenfeld, M. R., & Dalmau, J. (2011). Anti-NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol, 13(3), 324–332. Scholar
  53. 53.
    Gungor, S., Kilic, B., Arslan, M., Ozgen, U., & Dalmau, J. (2017). Hodgkin’s lymphoma associated with paraneoplastic cerebellar degeneration in children: a case report and review of the literature. Childs Nerv Syst, 33(3), 509–512. Scholar
  54. 54.
    Nakamura, T., Morimoto, N., Goto, F., Shioda, Y., Hoshino, H., Kubota, M., & Taiji, H. (2012). Langerhans cell histiocytosis with disequilibrium. Auris Nasus Larynx, 39(6), 627–630. Scholar
  55. 55.
    Emir, S., Tezer Kutluk, M., Göğüş, S., & Büyükpamukçu, M. (2000). Paraneoplastic cerebellar degeneration and horner syndrome: association of two uncommon findings in a child with hodgkin disease. Am J Pediatr Hematol/Oncol, 22(2), 158–161. Scholar
  56. 56.
    Greenlee, J. E. (2013). Treatment of paraneoplastic cerebellar degeneration. Curr Treat Options Neurol, 15(2), 185–200. Scholar
  57. 57.
    Ojeda, V. J., & Ojeda, V. J. (1984). Necrotizing myelopathy associated with malignancy. a clinicopathologic study of two cases and literature review. Cancer, 53(5), 1115–1123.<1115::aid-cncr2820530517>;2-w.CrossRefPubMedGoogle Scholar
  58. 58.
    Pittock, S. J., & Lennon, V. A. (2008). Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol, 65(5), 629–632. Scholar
  59. 59.
    de Buys Roessingh, A. S., Loriot, M. H., Wiesenauer, C., & Lallier, M. (2009). Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma. J Pediatr Surg, 44(8), E5–E7. Scholar
  60. 60.
    Sun, L. R., & Cooper, S. (2018). Neurological complications of the treatment of pediatric neoplastic disorders. Pediatr Neurol, 85, 33–42. Scholar
  61. 61.
    Küper, M., & Timmann, D. (2013). Cerebellar mutism. Brain Lang, 127(3), 327–333. Scholar
  62. 62.
    Neil, E. C., Hanmantgad, S., & Khakoo, Y. (2016). Neurological complications of pediatric cancer. J Child Neurol, 31(12), 1412–1420. Scholar
  63. 63.
    Newton HB (2012). Neurological complications of chemotherapy to the central nervous system. In Handbook of clinical neurology (Vol. 105, pp. 903–916). Elsevier B.V. doi: Scholar
  64. 64.
    Staff, N. P, Grisold, A., Grisold, W., & Windebank, A. J. (2017). Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol, 81(6), 772–781. Scholar
  65. 65.
    Schiff, D., Wen, P. Y., & van den Bent, M. J. (2009). Neurological adverse effects caused by cytotoxic and targeted therapies. Nat Rev Clin Oncol, 6(10), 596–603. Scholar
  66. 66.
    Wick, W., Hertenstein, A., & Platten, M. (2016). Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol, 17(12), e529–e541. Scholar
  67. 67.
    Cordelli, D. M., Masetti, R., Zama, D., Toni, F., Castelli, I., Ricci, E., Franzoni, E., & Pession, A. (2017). Central nervous system complications in children receiving chemotherapy or hematopoietic stem cell transplantation. Front Pediatr, 5, 105. Scholar
  68. 68.
    Carson KR, Newsome SD, Kim EJ, Wagner-Johnston ND, Von Geldern G, Moskowitz CH, … Bennett CL (2014). Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer, 120(16), 2464–2471. doi: Scholar
  69. 69.
    Toxicology and Environmental Health Information Program (TEHIP). (2019). TOXNET. National Library of Medicine. Retrieved November 26, 2019, from Accessed 12/2/2019.
  70. 70.
    Aspesberro, F., Milewski, L. S., & Brogan, T. V. (2014). Acute central nervous system complications in pediatric hematopoietic stem cell patients. J Pediatr Intensive Care, 3, 169–181. Scholar
  71. 71.
    Tibussek D, Natesirinilkul R, Sun LR, Wasserman, B. A., Brandao LR, deVeber G, … deVeber G (2016). Severe cerebral vasospasm and childhood arterial ischemic stroke after intrathecal cytarabine. Pediatrics, 137(2), e20152143–e20152143. doi: Scholar
  72. 72.
    Sait, S., & Modak, S. (2017). Anti-GD2 immunotherapy for neuroblastoma. Expert Rev Anticancer Ther, 17(10), 889–904. Scholar
  73. 73.
    Han, R., Yang, Y. M., Dietrich, J., Luebke, A., Mayer-Pröschel, M., & Noble, M. (2008). Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol, 7(4), 12. Scholar
  74. 74.
    Ewins, K., Malone, A., Phelan, E., Webb, D., McHugh, J. C., & Smith, O. (2017). Nelarabine-induced peripheral and central neurotoxicity: can sequential MRI brain imaging help to define its natural history? Br J Haematol, 179(2), 294–297. Scholar
  75. 75.
    Judge, C., Moheb, N., & Melinosky, C. (2019). Nilotinib-associated demyelinating disease. Neurology, 92(Suppl 15), P2.2–P093.Google Scholar
  76. 76.
    Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, … Widemann BC (2016). Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Eng J Med, 375(26), 2550–2560. doi: Scholar
  77. 77.
    Grace, R. F., Dahlberg, S. E., Neuberg, D., Sallan, S. E., Connors, J. M., Neufeld, E. J., Deangelo, D. J., & Silverman, L. B. (2011). The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol, 152(4), 452–459. Scholar
  78. 78.
    Mitchell LG, Andrew M, Abshire T, Halton J, Anderson R, Cherrick I, … Way C (2003). A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with l-asparaginase: results of the Prophylactic antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) study. Cancer, 97(2), 508–516. doi: Scholar
  79. 79.
    Caruso, V., Iacoviello, L., Di Castelnuovo, A., Storti, S., Mariani, G., De Gaetano, G., & Donati, M. B. (2006). Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. Scholar
  80. 80.
    Greiner J, Schrappe M, Claviez A, Zimmermann M, Niemeyer C, Kolb R, … Möricke A (2019). THROMBOTECT – a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica, 104(4), 756–765. doi: Scholar
  81. 81.
    Malhotra, P., Jain, S., & Kapoor, G. (2018). Symptomatic cerebral sinovenous thrombosis associated with l-asparaginase in children with acute lymphoblastic leukemia: a single institution experience over 17 years. J Pediatr Hematol Oncol, 40(7), e450–e453. Scholar
  82. 82.
    Nicolao, P., & Giometto, B. (2003). Neurological toxicity of ifosfamide. Oncology, 65(Suppl 2), 11–16. Scholar
  83. 83.
    Taupin, D., Racela, R., & Friedman, D. (2014). Ifosfamide chemotherapy and nonconvulsive status epilepticus: case report and review of the literature. Clin EEG Neurosci, 45(3), 222–225. Scholar
  84. 84.
    Bhojwani, D., Sabin, N. D., Pei, D., Yang, J. J., Khan, R. B., Panetta, J. C., Krull, K. R., Inaba, H., Rubnitz, J. E., Metzger, M. L., Howard, S. C., Ribeiro, R. C., Cheng, C., Reddick, W. E., Jeha, S., Sandlund, J. T., Evans, W. E., Pui, C. H., & Relling, M. V. (2014). Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol, 32(9), 949–959. Scholar
  85. 85.
    Inaba, H., Khan, R. B., Laningham, F. H., Crews, K. R., Pui, C. H., & Daw, N. C. (2008). Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol, 19(1), 178–184. Scholar
  86. 86.
    Cheung, Y. T., Sabin, N. D., Reddick, W. E., Bhojwani, D., Liu, W., Brinkman, T. M., Glass, J. O., Hwang, S. N., Srivastava, D., Pui, C. H., Robison, L. L., Hudson, M. M., & Krull, K. R. (2016). Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis. Lancet Haematol, 3(10), 456–466. Scholar
  87. 87.
    Koh, S., Nelson, M. D., Kovanlikaya, A., & Chen, L. S. (1999). Anterior lumbosacral radiculopathy after intrathecal methotrexate treatment. Pediatr Neurol, 21(2), 576–578. Scholar
  88. 88.
    Junna, M. R., & Rabinstein, A. A. (2007). Tacrolimus induced leukoencephalopathy presenting with status epilepticus and prolonged coma. J Neurol Neurosurg Psychiatry, 78(12), 1410–1411. Scholar
  89. 89.
    Antoine, J. C., & Camdessanché, J. P. (2007). Peripheral nervous system involvement in patients with cancer. Lancet Neurol, 6(1), 75–86. Scholar
  90. 90.
    Tang, J.-H., Tian, J.-M., Sheng, M., Hu, S.-Y., Li, Y., Zhang, L.-Y., Gu, Q., & Wang, Q. (2016). Study of posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia after induction chemotherapy. J Child Neurol, 31(3), 279–284. Scholar
  91. 91.
    Landi, D. B., Thompson, E. M., & Ashley, D. M. (2018). Immunotherapy for pediatric brain tumors. Neuroimmunol Neuroinflamm, 5, 29. Scholar
  92. 92.
    Kabir, T. F., Chauhan, A., Anthony, L., & Hildebrandt, G. C. (2018). Immune checkpoint inhibitors in pediatric solid tumors: status in 2018. Ochsner J, 18(4), 370–376. Scholar
  93. 93.
    AlHarbi M, Mobark NA, AlMubarak L, Aljelaify R, AlSaeed M, Almutairi A, … Abedalthagafi M (2018). Durable response to nivolumab in a pediatric patient with refractory glioblastoma and constitutional biallelic mismatch repair deficiency Saudi human genome project View project medulloblastoma View project, 23(12), 1401–1406. doi: Scholar
  94. 94.
    Gorsi H, Malicki DM, Barsan, V, Tumblin M, Yeh-Nayre L, Milburn M, … Crawford JR (2019). Nivolumab in the treatment of recurrent or refractory pediatric brain tumors: a single institutional experience. J Pediatr Hematol/Oncol, 41(4), e235–241. doi: Scholar
  95. 95.
    Wang, S. S., Bandopadhayay, P., & Jenkins, M. R. (2019). Towards immunotherapy for pediatric brain tumors. Trends Immunol, 40(8), 748–761. Scholar
  96. 96.
    Williams TJ, Benavides DR, Patrice, K A, Dalmau JO, De Ávila AL R, Le DT, … Mowry EM (2016). Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol, 73(8), 928–933. doi: Scholar
  97. 97.
    Zekeridou, A., & Lennon, V. A. (2019). Neurologic autoimmunity in the era of checkpoint inhibitor cancer immunotherapy. Mayo Clin Proc, 94(9), 1865–1878. Scholar
  98. 98.
    Dalakas, M. C. (2018). Neurological complications of immune checkpoint inhibitors: what happens when you ‘take the brakes off’ the immune system. Ther Adv Neurol Disord, 11, 1756286418799864. Scholar
  99. 99.
    Brudno, J. N., & Kochenderfer, J. N. (2019). Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev, 34, 45–55. Scholar
  100. 100.
    Gust, J., Hay KA, Hanafi L A, Li D, Myerson D, Gonzalez-Cuyar LF, … Turtle CJ (2017). Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov doi: Scholar
  101. 101.
    Hay, K. A. (2018). Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy. Br J Haematol. Scholar
  102. 102.
    Santomasso BD, Park JH, Salloum D, Riviere, I., Flynn J, Mead E, … Brentjens RJ (2018). Clinical and biological correlates of neurotoxicity associated with car t-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. doi: Scholar
  103. 103.
    Willis, M. D., & Robertson, N. P. (2019). Neurotoxicity of novel cancer immunotherapies. J Neurol, 266, 2087–2089. Scholar
  104. 104.
    Gust, J., Taraseviciute, A., & Turtle, C. J. (2018). Neurotoxicity associated with CD19-targeted CAR-T cell therapies. CNS Drugs, 32(12), 1091–1101. Scholar
  105. 105.
    Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, … Pazdur R (2018). FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. The Oncologist, 23(8), 943–947. doi: Scholar
  106. 106.
    Reynolds, M. R., Haydon, D. H., Caird, J., & Leonard, J. R. (2016). Radiation-induced moyamoya syndrome after proton beam therapy in the pediatric patient: a case series. Pediatr Neurosurg, 51(6), 297–301. Scholar
  107. 107.
    Meadows, A. T., Massari, D. J., Fergusson, J., Gordon, J., Littman, P., & Moss, K. (1981). Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet, 2(8254), 1015–1018. Scholar
  108. 108.
    Amirjamshidi, A., & Abbassioun, K. (2000). Radiation-induced tumors of the central nervous system occurring in childhood and adolescence. Childs Nerv Syst, 16(7), 390–397. Scholar
  109. 109.
    Gastelum, E., Sear, K., Hills, N., Roddy, E., Randazzo, D., Chettout, N., Hess, C., Cotter, J., Haas-Kogan, D. A., Fullerton, H., & Mueller, S. (2015). Rates and characteristics of radiographically detected intracerebral cavernous malformations after cranial radiation therapy in pediatric cancer patients. J Child Neurol, 30(7), 842–849. Scholar
  110. 110.
    Strenger, V., Sovinz, P., Lackner, H., Dornbusch, H. J., Lingitz, H., Eder, H. G., Moser, A., & Urban, C. (2008). Intracerebral cavernous hemangioma after cranial irradiation in childhood: incidence and risk factors. Strahlenther Onkol, 184(5), 276–280. Scholar
  111. 111.
    Lew, S. M., Morgan, J. N., Psaty, E., Lefton, D. R., Allen, J. C., & Abbott, R. (2006). Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma. J Neurosurg, 104(Suppl 2), 103–107. Scholar
  112. 112.
    Sciubba, D. M., Gallia, G. L., Recinos, P., Garonzik, I. M., & Clatterbuck, R. E. (2006). Intracranial aneurysm following radiation therapy during childhood for a brain tumor: case report and review of the literature. J Neurosurg, 105(2), 134–139. Scholar
  113. 113.
    Fan, E. P., Heiber, G., Gerard, E. E., & Schuele, S. (2018). Stroke-like migraine attacks after radiation therapy: a misnomer? Epilepsia, 59(1), 259–268. Scholar
  114. 114.
    Wai, K., Balabanski, A., Chia, N., & Kleinig, T. (2017). Reversible hemispheric hypoperfusion in two cases of SMART syndrome. J Clin Neurosci, 43, 146–148. Scholar
  115. 115.
    Stubblefield, M. D. (2017). Neuromuscular complications of radiation therapy. Muscle Nerve, 56(6), 1031–1040. Scholar
  116. 116.
    Neglia, J. P., Robison, L. L., Stovall, M., Liu, Y., Packer, R. J., Hammond, S., Yasui, Y., Kasper, C. E., Mertens, A. C., Donaldson, S. S., Meadows, A. T., & Inskip, P. D. (2006). New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst, 98(21), 1528–1537. Scholar
  117. 117.
    Schmidt-Hieber, M., Silling, G., Schalk, E., Heinz, W., Panse, J., Penack, O., Christopeit, M., Buchheidt, D., Meyding-Lamadé, U., Hähnel, S., Wolf, H. H., Ruhnke, M., Schwartz, S., & Maschmeyer, G. (2016). CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)-guidelines of the infectious DiseasesWorking party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Ann Oncol, 27(7), 1207–1225. Scholar
  118. 118.
    Schoettler, M., Duncan, C., & Lehmann, L. (2019). Severe, persistent neurotoxicity after transplant-associated thrombotic microangiopathy in a pediatric patient despite treatment with eculizumab. Pediatr Transplant, 23(3), e13381. Scholar
  119. 119.
    Callahan, M. J., MacDougall, R. D., Bixby, S. D., Voss, S. D., Robertson, R. L., & Cravero, J. P. (2018). Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations. Pediatr Radiol, 48(1), 21–30. Scholar
  120. 120.
    Tekes, A., Senglaub, S. S., Ahn, E. S., Huisman, T. A. G. M., & Jackson, E. M. (2018). Ultrafast brain MRI can be used for indications beyond shunted hydrocephalus in pediatric patients. Am J Neuroradiol, 39(8), 1515–1518. Scholar
  121. 121.
    Tuma, R., & DeAngelis, L. M. (2000). Altered mental status in patients with cancer. Arch Neurol, 57(12), 1727–1731. Scholar
  122. 122.
    Khan, R. B., Hunt, D. L., Boop, F. A., Sanford, R. A., Merchant, T. E., Gajjar, A., & Kun, L. E. (2005). Seizures in children with primary brain tumors: Incidence and long-term outcome. Epilepsy Res, 64(3), 85–91. Scholar
  123. 123.
    Ibrahim, K., & Appleton, R. E. (2004). Seizures as the presenting symptom of brain tumours in children. Seizure, 13(2), 108–112. Scholar
  124. 124.
    Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, … Cairncross JG (2000). Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the quality standards Subcommittee of the American Academy of neurology. Neurology, 54(10), 1886–1893. doi: Scholar
  125. 125.
    Hardesty, D. A., Sanborn, M. R., Parker, W. E., & Storm, P. B. (2011). Perioperative seizure incidence and risk factors in 223 pediatric brain tumor patients without prior seizures: clinical article. J Neurosurg Pediatr. Scholar
  126. 126.
    Patsalos, P. N., & St. Louis, E. K. (2018). The epilepsy prescriber’s guide to antiepileptic drugs (3rd ed.). Cambridge: Cambridge University Press. Scholar
  127. 127.
    The Childhood Brain Tumor Consortium. (1991). The epidemiology of headache among children with brain tumor. Headache in children with brain tumors. J Neuro-Oncol, 10(1), 31–46. Scholar
  128. 128.
    Kirby, S., & Purdy, R. A. (2007). Headache and brain tumors. Curr Neurol Neurosci Rep, 7(2), 110–116. Scholar
  129. 129.
    Demaree, C. J., Soliz, J. M., & Gebhardt, R. (2016). Cancer seeding risk from an epidural blood patch in patients with leukemia or lymphoma. Pain Med, 18(4), 218. Scholar
  130. 130.
    Rusch, R., Schulta, C., Hughes, L., & Withycombe, J. S. (2014). Evidence-based practice recommendations to prevent/manage post-lumbar puncture headaches in pediatric patients receiving intrathecal chemotherapy. J Pediatr Oncol Nurs, 31(4), 230–238. Scholar
  131. 131.
    Lee, L. C.-Y., Sennett, M., & Erickson, J. M. (2007). Prevention and management of post–lumbar puncture headache in pediatric oncology patients. J Pediatr Oncol Nurs, 24(4), 200–207. Scholar
  132. 132.
    Kranick, S. M., Campen, C. J., Kasner, S. E., Kessler, S. K., Zimmerman, R. A., Lustig, R. A., Phillips, P. C., Beslow, L. A., Ichord, R., & Fisher, M. J. (2013). Headache as a risk factor for neurovascular events in pediatric brain tumor patients. Neurology, 80(16), 1452–1456. Scholar
  133. 133.
    Black, D., Bartleson, J., Bell, M., & Lachance, D. (2006). SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia, 26(9), 1137–1142. Scholar
  134. 134.
    Sporns PB, Sträter R, Minnerup, J, Wiendl H, Hanning U, Chapot R, … Kemmling A (2019). Feasibility, safety, and outcome of endovascular recanalization in childhood stroke: the Save ChildS Study. JAMA Neurol. doi:
  135. 135.
    Bigi, S., Dulcey, A., Gralla, J., Bernasconi, C., Melliger, A., Datta, A. N., Arnold, M., Kaesmacher, J., Fluss, J., Hackenberg, A., Maier, O., Weber, J., Poloni, C., Fischer, U., & Steinlin, M. (2018). Feasibility, safety, and outcome of recanalization treatment in childhood stroke. Ann Neurol, 83(6), 1125–1132. Scholar
  136. 136.
    Amlie-Lefond, C., & Wainwright, M. S. (2019). Organizing for acute arterial ischemic stroke in children. Stroke, 50(12), 3662–3668. Scholar
  137. 137.
    Furuhata, M., Aihara, Y., Eguchi, S., Horiba, A., Tanaka, M., Komori, T., & Okada, Y. (2014). Pediatric medulloblastoma presenting as cerebellar hemorrhage: a case report. No shinkei geka. Neurol Surg, 42(6), 545–551.Google Scholar
  138. 138.
    Wilson, M. P., Johnson, E. S., Hawkins, C., Atkins, K., Alshaya, W., & Pugh, J. A. (2016). Hemorrhagic presentations of cerebellar pilocytic astrocytomas in children resulting in death: report of 2 cases. J Neurosurg Pediatr, 17(4), 446–452. Scholar
  139. 139.
    Packer, R. J., Rorke, L. B., Lange, B. J., Siegel, K. R., & Evans, A. E. (1985). Cerebrovascular accidents in children with cancer. Pediatrics, 76(2), 194–201.PubMedGoogle Scholar
  140. 140.
    Bajzar, L., Chan, A. K., Massicotte, M. P., & Mitchell, L. G. (2006). Thrombosis in children with malignancy. Curr Opin Pediatr, 18(1), 1–9. Scholar
  141. 141.
    Herrlinger, U., Schabet, M., Bitzer, M., Petersen, D., & Krauseneck, P. (1999). Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neuro-Oncol, 43(3), 219–226. Scholar
  142. 142.
    Bühring, U., Herrlinger, U., Krings, T., Thiex, R., Weller, M., & Küker, W. (2001). MRI features of primary central nervous system lymphomas at presentation. Neurology, 57(3), 393–396. Scholar
  143. 143.
    Bjornard, K. L., Leventaki, V., Nichols, K. E., Sandlund, J. T., Prockop, S., & Ehrhardt, M. J. (2018). Two-year-old female with EBV-positive diffuse large B-cell lymphoma and subsequent CNS involvement with neurolymphomatosis. Pediatr Blood Cancer, 65(12), e27415. Scholar
  144. 144.
    Grisariu S, Avni B, Batchelor T T, Bent MJ van den, Bokstein F, Schiff, D, … Siegal T (2010). Neurolymphomatosis: an international primary CNS lymphoma collaborative group report. Blood, 115(24), 5005–5011. doi: Scholar
  145. 145.
    Grisold, W., Cavaletti, G., & Windebank, A. J. (2012). Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-Oncology, 14(suppl 4), v45–v54. Scholar
  146. 146.
    Ness, K. K., Hudson, M. M., Pui, C. H., Green, D. M., Krull, K. R., Huang, T. T., Robison, L. L., & Morris, E. B. (2012). Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses. Cancer, 118(3), 828–838. Scholar
  147. 147.
    Chu, S. H., Lee, Y. J., Lee, E. S., Geng, Y., Wang, X. S., & Cleeland, C. S. (2015). Current use of drugs affecting the central nervous system for chemotherapy-induced peripheral neuropathy in cancer patients: A systematic review. Support Care Cancer, 23(2), 513–524. Scholar
  148. 148.
    Hou, S., Huh, B., Kim, H. K., Kim, K. H., & Abdi, S. (2018). Treatment of chemotherapy-induced peripheral neuropathy: systematic review and recommendations. Pain Physician, 21(6), 571–592.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of NeurologyJohns Hopkins HospitalBaltimoreUSA

Personalised recommendations