Acute Neurological Complications of Brain Tumors and Immune Therapies, a Guideline for the Neuro-hospitalist


Purpose of Review

Patients with brain tumors presenting to the emergency room with acute neurologic complications may warrant urgent investigations and emergent management. As the neuro-hospitalist will likely encounter this complex patient population, an understanding of the acute neurologic issues will have value.

Recent Findings

We discuss updated information and management regarding various acute neurologic complications among neuro-oncology patients and neurologic complications of immunotherapy.


Understanding of the acute neurologic complications associated with central nervous system tumors and with common contemporary cancer treatments will facilitate the neuro-hospitalist management of these patient populations. While there are aspects analogous to the diagnosis and management in the non-oncologic population, a number of unique features discussed in this review should be considered.

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Central nervous system


Radiation therapy


Stroke-like migraine attacks after radiation therapy


Intracerebral hemorrhage


Modified Rankin score


(American Heart Association)/ASA (American Stroke Association)


Direct oral anticoagulants


Low molecular weight heparin


Vascular endothelial growth factor


Platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke


Mechanistic target of rapamycin


Mitogen-activated protein kinases


Dysembryoplastic neuroepithelial tumors


Isocitrate dehydrogenase


Long-term epilepsy-associated tumors




Multidrug resistance gene


Intracranial pressure


Cerebrospinal fluid


Blood-brain barrier


Magnetic resonance imaging


Posterior reversible encephalopathy syndrome


Peripheral nervous system


Immune checkpoint inhibitors


Chimeric antigen receptor


Programmed death1


Programmed death ligand 1


Cytotoxic T lymphocyte-associated protein 4


Adverse events


Cytokine release syndrome


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    • Lukas RV, Taylor JW, Kurz SC, Mohile NA. Clinical neuro-oncology for the neurologist. Neurology Clincial Practice. 2019. Useful review which compliments this manuscript.

  2. 2.

    Karlinska AG, Gromadzka G, Karlinski MA, Czlonkowska A. The activity of malignancy may determine stroke pattern in cancer patients. J Stroke Cerebrovasc Dis. 2015;24(4):778-83.

    Article  PubMed  Google Scholar 

  3. 3.

    Guo YJ, Chang MH, Chen PL, Lee YS, Chang YC, Liao YC. Predictive value of plasma (D)-dimer levels for cancer-related stroke: a 3-year retrospective study. J Stroke Cerebrovasc Dis. 2014;23(4):e249-54.

    Article  PubMed  Google Scholar 

  4. 4.

    Zoller B, Ji J, Sundquist J, Sundquist K. Risk of haemorrhagic and ischaemic stroke in patients with cancer: a nationwide follow-up study from Sweden. Eur J Cancer. 2012;48(12):1875-83.

    Article  PubMed  Google Scholar 

  5. 5.

    Kneihsl M, Enzinger C, Wunsch G, Khalil M, Culea V, Urbanic-Purkart T, et al. Poor short-term outcome in patients with ischaemic stroke and active cancer. J Neurol. 2016;263(1):150-6.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology. 2004;62(11):2025-30.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Stefan O, Vera N, Otto B, Heinz L, Wolfgang G. Stroke in cancer patients: a risk factor analysis. J Neuro-Oncol. 2009;94(2):221-6.

    Article  Google Scholar 

  8. 8.

    Kreisl TN, Toothaker T, Karimi S, DeAngelis LM. Ischemic stroke in patients with primary brain tumors. Neurology. 2008;70(24):2314-20.

    Article  PubMed  Google Scholar 

  9. 9.

    Katz JM, Segal AZ. Incidence and etiology of cerebrovascular disease in patients with malignancy. Curr Atheroscler Rep. 2005;7(4):280-8.

    Article  PubMed  Google Scholar 

  10. 10.

    Dearborn JL, Urrutia VC, Zeiler SR. Stroke and cancer- a complicated relationship. J Neurol Transl Neurosci. 2014;2(1):1039.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Anghel G, Petrinato G, Severino A, Remotti D, Insabato L, De Renzo A, et al. Intravascular B-cell lymphoma: report of two cases with different clinical presentation but rapid central nervous system involvement. Leuk Lymphoma. 2003;44(8):1353-9.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Parikh NS, Burch JE, Kamel H, DeAngelis LM, Navi BB. Recurrent thromboembolic events after ischemic stroke in patients with primary brain tumors. J Stroke Cerebrovasc Dis. 2017;26(10):2396-403.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kayser-Gatchalian MC, Kayser K. Thrombosis and intracranial tumors. J Neurol. 1975;209(3):217-24.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Nemerson Y. Tissue factor and hemostasis. Blood. 1988;71(1):1-8.

    CAS  Article  Google Scholar 

  15. 15.

    Boffa MC, Jackman RW, Peyri N, Boffa JF, George B. Thrombomodulin in the central nervous system. Nouv Rev Fr Hematol. 1991;33(6):423-9.

    CAS  PubMed  Google Scholar 

  16. 16.

    Unruh D, Schwarze SR, Khoury L, Thomas C, Wu M, Chen L, et al. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol. 2016;132(6):917-30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Unruh D, Mirkov S, Wray B, Drumm M, Lamano J, Li YD, et al. Methylation-dependent tissue factor suppression contributes to the reduced malignancy of IDH1-mutant gliomas. Clin Cancer Res. 2019;25(2):747-59.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Grisold W, Oberndorfer S, Struhal W. Stroke and cancer: a review. Acta Neurol Scand. 2009;119(1):1-16.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Cheng SW, Wu LL, Ting AC, Lau H, Lam LK, Wei WI. Irradiation-induced extracranial carotid stenosis in patients with head and neck malignancies. Am J Surg. 1999;178(4):323-8.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Stewart FA, Hoving S, Russell NS. Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients. Radiat Res. 2010;174(6):865-9.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA. Cerebrovascular disease in childhood cancer survivors: a children’s oncology group report. Neurology. 2009;73(22):1906-13.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Murthy SB, Moradiya Y, Shah S, Shastri A, Bershad EM, Suarez JI. In-hospital outcomes of thrombolysis for acute ischemic stroke in patients with primary brain tumors. J Clin Neurosci. 2015;22(3):474-8.

    Article  PubMed  Google Scholar 

  23. 23.

    Fonkem E, Lok E, Robison D, Gautam S, Wong ET. The natural history of intravascular lymphomatosis. Cancer Med. 2014;3(4):1010-24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cutting S, Wettengel M, Conners JJ, Ouyang B, Busl K. Three-month outcomes are poor in stroke patients with cancer despite acute stroke treatment. J Stroke Cerebrovasc Dis. 2017;26(4):809-15.

    Article  PubMed  Google Scholar 

  25. 25.

    •• Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. Updated guidelines for management of acute stroke.

  26. 26.

    Zander T, Maynar J, Lopez-Zarraga F, Herrera R, Timiraos-Fernandez JJ, Saraceni A, et al. Mechanical thrombectomy in patients with tumour-related ischaemic stroke. Interv Neuroradiol. 2016;22(6):705-8.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Merkler AE, Marcus JR, Gupta A, Kishore SA, Leifer D, Patsalides A, et al. Endovascular therapy for acute stroke in patients with cancer. Neurohospitalist. 2014;4(3):133-5.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Noje C, Cohen K, Jordan LC. Hemorrhagic and ischemic stroke in children with cancer. Pediatr Neurol. 2013;49(4):237-42.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Carrilho Romeiro A, Valadas A, Marques J. Acute ischemic stroke on cancer patients, a distinct etiology? A case-control study. Acta Med Port. 2015;28(5):613-8.

    Article  PubMed  Google Scholar 

  30. 30.

    Navi BB, Reichman JS, Berlin D, Reiner AS, Panageas KS, Segal AZ, et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology. 2010;74(6):494-501.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost. 2010;8(2):221-7.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Donato J, Campigotto F, Uhlmann EJ, Coletti E, Neuberg D, Weber GM, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015;126(4):494-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Horstman H, Gruhl J, Smith L, Ganti AK, Shonka NA. Safety of long-term anticoagulation in patients with brain metastases. Med Oncol. 2018;35(4):43.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Carney BJ, Uhlmann EJ, Puligandla M, Mantia C, Weber GM, Neuberg DS, et al. Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors. J Thromb Haemost. 2019;17(1):72-6.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Lieu AS, Hwang SL, Howng SL, Chai CY. Brain tumors with hemorrhage. J Formos Med Assoc. 1999;98(5):365-7.

    CAS  PubMed  Google Scholar 

  36. 36.

    Lin RJ, Green DL, Shah GL. Therapeutic anticoagulation in patients with primary brain tumors or secondary brain metastasis. Oncologist. 2018;23(4):468-73.

    Article  PubMed  Google Scholar 

  37. 37.

    • Mantia C, Uhlmann EJ, Puligandla M, Weber GM, Neuberg D, Zwicker JI. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood. 2017;129(25):3379-85. Useful study to predict ICH in glioma patients receiving anticoagulation.

  38. 38.

    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709-22.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699-708.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Auer TA, Renovanz M, Marini F, Brockmann MA, Tanyildizi Y. Ischemic stroke and intracranial hemorrhage in patients with recurrent glioblastoma multiforme, treated with bevacizumab. J Neuro-Oncol. 2017;133(3):571-9.

    CAS  Article  Google Scholar 

  41. 41.

    Di Minno MN, Ageno W, Dentali F. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment. J Thromb Haemost. 2014;12(12):2136-8.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Velander AJ, DeAngelis LM, Navi BB. Intracranial hemorrhage in patients with cancer. Curr Atheroscler Rep. 2012;14(4):373-81.

    Article  PubMed  Google Scholar 

  43. 43.

    Zwicker JI, Karp Leaf R, Carrier M. A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation. J Thromb Haemost. 2016;14(9):1736-40.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 2007;6(5):421-30.

    Article  PubMed  Google Scholar 

  45. 45.

    Englot DJ, Berger MS, Barbaro NM, Chang EF. Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. J Neurosurg. 2011;115(2):240-4.

    Article  PubMed  Google Scholar 

  46. 46.

    Lee JW, Wen PY, Hurwitz S, Black P, Kesari S, Drappatz J, et al. Morphological characteristics of brain tumors causing seizures. Arch Neurol. 2010;67(3):336-42.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Chang EF, Christie C, Sullivan JE, Garcia PA, Tihan T, Gupta N, et al. Seizure control outcomes after resection of dysembryoplastic neuroepithelial tumor in 50 patients. J Neurosurg Pediatr. 2010;5(1):123-30.

    Article  PubMed  Google Scholar 

  48. 48.

    Southwell DG, Garcia PA, Berger MS, Barbaro NM, Chang EF. Long-term seizure control outcomes after resection of gangliogliomas. Neurosurgery 2012;70(6):1406-1413; discussion 13-4.

  49. 49.

    Chang EF, Potts MB, Keles GE, Lamborn KR, Chang SM, Barbaro NM, et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg. 2008;108(2):227-35.

    Article  PubMed  Google Scholar 

  50. 50.

    You G, Sha ZY, Yan W, Zhang W, Wang YZ, Li SW, et al. Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas: a clinicopathological study. Neuro-Oncology. 2012;14(2):230-41.

    Article  PubMed  Google Scholar 

  51. 51.

    Kerkhof M, Vecht CJ. Seizure characteristics and prognostic factors of gliomas. Epilepsia. 2013;54(Suppl 9):12-7.

    Article  PubMed  Google Scholar 

  52. 52.

    Toledo M, Sarria-Estrada S, Quintana M, Maldonado X, Martinez-Ricarte F, Rodon J, et al. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res. 2017;130:1-6.

    Article  PubMed  Google Scholar 

  53. 53.

    Wirsching HG, Morel C, Gmur C, Neidert MC, Baumann CR, Valavanis A, et al. Predicting outcome of epilepsy after meningioma resection. Neuro-Oncology. 2016;18(7):1002-10.

    Article  PubMed  Google Scholar 

  54. 54.

    Lieu AS, Howng SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res. 2000;38(1):45-52.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Englot DJ, Magill ST, Han SJ, Chang EF, Berger MS, McDermott MW. Seizures in supratentorial meningioma: a systematic review and meta-analysis. J Neurosurg. 2016;124(6):1552-61.

    Article  PubMed  Google Scholar 

  56. 56.

    Lynam LM, Lyons MK, Drazkowski JF, Sirven JI, Noe KH, Zimmerman RS, et al. Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review. Clin Neurol Neurosurg. 2007;109(7):634-8.

    Article  PubMed  Google Scholar 

  57. 57.

    Skardelly M, Brendle E, Noell S, Behling F, Wuttke TV, Schittenhelm J, et al. Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: a retrospective observational single center study. Ann Neurol. 2015;78(6):917-28.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Riva M. Brain tumoral epilepsy: a review. Neurol Sci. 2005;26(1):s40-s2.

    Article  PubMed  Google Scholar 

  59. 59.

    Oberndorfer S, Schmal T, Lahrmann H, Urbanits S, Lindner K, Grisold W. The frequency of seizures in patients with primary brain tumors or cerebral metastases. An evaluation from the Ludwig Boltzmann Institute of Neuro-Oncology and the Department of Neurology, Kaiser Franz Josef hospital, Vienna. Wien Klin Wochenschr. 2002;114(21-22):911-6.

    PubMed  Google Scholar 

  60. 60.

    Hwang SL, Lin CL, Lee KS, Lieu AS, Kuo TH, Chang CZ, et al. Factors influencing seizures in adult patients with supratentorial astrocytic tumors. Acta Neurochir. 2004;146(6):589-94: discussion 94.

    Article  PubMed  Google Scholar 

  61. 61.

    Koh HY, Kim SH, Jang J, Kim H, Han S, Lim JS, et al. BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat Med. 2018;24(11):1662-8.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Zhang YX, Shen CH, Guo Y, Zheng Y, Zhu JM, Ding Y, et al. BRAF V600E mutation in epilepsy-associated glioneuronal tumors: prevalence and correlation with clinical features in a Chinese population. Seizure. 2017;45:102-6.

    Article  PubMed  Google Scholar 

  63. 63.

    Liu J, Reeves C, Michalak Z, Coppola A, Diehl B, Sisodiya SM, et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. 2014;2:71.

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Pernice HF, Schieweck R, Kiebler MA, Popper B. mTOR and MAPK: from localized translation control to epilepsy. BMC Neurosci. 2016;17(1):73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Delev D, Daka K, Heynckes S, Gaebelein A, Franco P, Pfeifer D, et al. Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course. Sci Rep. 2020;10(1):96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Prabowo AS, Iyer AM, Veersema TJ, Anink JJ, Schouten-van Meeteren AY, Spliet WG, et al. BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. Brain Pathol. 2014;24(1):52-66.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Chen H, Judkins J, Thomas C, Wu M, Khoury L, Benjamin CG, et al. Mutant IDH1 and seizures in patients with glioma. Neurology. 2017;88(19):1805-13.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Luyken C, Blumcke I, Fimmers R, Urbach H, Elger CE, Wiestler OD, et al. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia. 2003;44(6):822-30.

    Article  PubMed  Google Scholar 

  69. 69.

    Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol. 2012;13(9):e375-82.

    Article  PubMed  Google Scholar 

  70. 70.

    Armstrong TS, Grant R, Gilbert MR, Lee JW, Norden AD. Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy. Neuro-Oncology. 2016;18(6):779-89.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Ruda R, Trevisan E, Soffietti R. Epilepsy and brain tumors. Curr Opin Oncol. 2010;22(6):611-20.

    Article  PubMed  Google Scholar 

  72. 72.

    Sperling MR, Ko J. Seizures and brain tumors. Semin Oncol. 2006;33(3):333-41.

    Article  PubMed  Google Scholar 

  73. 73.

    Roelcke U, Boxheimer L, Fathi AR, Schwyzer L, Ortega M, Berberat J, et al. Cortical hemosiderin is associated with seizures in patients with newly diagnosed malignant brain tumors. J Neuro-Oncol. 2013;115(3):463-8.

    CAS  Article  Google Scholar 

  74. 74.

    Greenberg SM, Vonsattel JP, Stakes JW, Gruber M, Finklestein SP. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology. 1993;43(10):2073-9.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Biffi A, Rattani A, Anderson CD, Ayres AM, Gurol EM, Greenberg SM, et al. Delayed seizures after intracerebral haemorrhage. Brain. 2016;139(Pt 10):2694-705.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Telfeian AE, Philips MF, Crino PB, Judy KD. Postoperative epilepsy in patients undergoing craniotomy for glioblastoma multiforme. J Exp Clin Cancer Res. 2001;20(1):5-10.

    CAS  PubMed  Google Scholar 

  77. 77.

    Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2000;54(10):1886-93.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Yap KY, Chui WK, Chan A. Drug interactions between chemotherapeutic regimens and antiepileptics. Clin Ther. 2008;30(8):1385-407.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Bourg V, Lebrun C, Chichmanian RM, Thomas P, Frenay M. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann Oncol. 2001;12(2):217-9.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011;77(12):1156-64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Gattis WA, May DB. Possible interaction involving phenytoin, dexamethasone, and antineoplastic agents: a case report and review. Ann Pharmacother. 1996;30(5):520-6.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Levin VA, Stearns J, Byrd A, Finn A, Weinkam RJ. The effect of phenobarbital pretreatment on the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea (PCNU), and on the plasma pharmacokinetics and biotransformation of BCNU. J Pharmacol Exp Ther 1979;208(1):1-6.

  83. 83.

    Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J, et al. Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to brain tumor therapy central nervous system consortium. J Clin Oncol. 1997;15(9):3121-8.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Neef C, de Voogd-van der Straaten I. An interaction between cytostatic and anticonvulsant drugs. Clin Pharmacol Ther. 1988;43(4):372-5.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Brickell K, Porter D, Thompson P. Phenytoin toxicity due to fluoropyrimidines (5FU/capecitabine): three case reports. Br J Cancer. 2003;89(4):615-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    van Breemen MS, Rijsman RM, Taphoorn MJ, Walchenbach R, Zwinkels H, Vecht CJ. Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol. 2009;256(9):1519-26.

    Article  PubMed  Google Scholar 

  87. 87.

    Rosati A, Buttolo L, Stefini R, Todeschini A, Cenzato M, Padovani A. Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch Neurol. 2010;67(3):343-6.

    Article  PubMed  Google Scholar 

  88. 88.

    Villanueva V, Saiz-Diaz R, Toledo M, Piera A, Mauri JA, Rodriguez-Uranga JJ, et al. NEOPLASM study: real-life use of lacosamide in patients with brain tumor-related epilepsy. Epilepsy Behav. 2016;65:25-32.

    Article  PubMed  Google Scholar 

  89. 89.

    Maschio M, Dinapoli L, Saveriano F, Pompili A, Carapella CM, Vidiri A, et al. Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report. Acta Neurol Scand. 2009;120(3):210-2.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Ohgami M, Kaburagi T, Kurosawa A, Homma M. Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer. Lung Cancer. 2016;101:9-10.

    Article  PubMed  Google Scholar 

  91. 91.

    Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348(15):1442-8.

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Régina A, Demeule M, Laplante A, Jodoin J, Dagenais C, Berthelet F, et al. Multidrug resistance in brain tumors: roles of the blood-brain barrier. Cancer Metastasis Rev. 2001;20(1):13-25.

    Article  PubMed  Google Scholar 

  93. 93.

    Aronica E, Gorter JA, Jansen GH, van Veelen CW, van Rijen PC, Leenstra S, et al. Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors. Neuroscience. 2003;118(2):417-29.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Loscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002;301(1):7-14.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Koekkoek JA, Dirven L, Heimans JJ, Postma TJ, Vos MJ, Reijneveld JC, et al. Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide. J Neuro-Oncol. 2016;126(2):347-54.

    CAS  Article  Google Scholar 

  96. 96.

    Ruda R, Magliola U, Bertero L, Trevisan E, Bosa C, Mantovani C, et al. Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro-Oncology. 2013;15(12):1739-49.

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801-11.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Avila EK, Chamberlain M, Schiff D, Reijneveld JC, Armstrong TS, Ruda R, et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. Neuro-Oncology. 2017;19(1):12-21.

    Article  PubMed  Google Scholar 

  99. 99.

    Zaatreh MM, Firlik KS, Spencer DD, Spencer SS. Temporal lobe tumoral epilepsy: characteristics and predictors of surgical outcome. Neurology. 2003;61(5):636-41.

    Article  PubMed  Google Scholar 

  100. 100.

    Benifla M, Otsubo H, Ochi A, Weiss SK, Donner EJ, Shroff M, Chuang S, Hawkins C, Drake JM, Elliott I, Smith ML, Snead III OC, Rutka JT Temporal lobe surgery for intractable epilepsy in children: an analysis of outcomes in 126 children. Neurosurgery 2006;59(6):1203-1213; discussion 13-4.

  101. 101.

    van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985-90.

    Article  PubMed  Google Scholar 

  102. 102.

    Boiardi A, Salmaggi A, Eoli M, Lamperti E, Silvani A. Headache in brain tumours: a symptom to reappraise critically. Neurol Sci. 2004;25(Suppl 3):S143-7.

    Article  PubMed  Google Scholar 

  103. 103.

    Fokstuen T, Wilking N, Rutqvist LE, Wolke J, Liedberg A, Signomklao T, et al. Radiation therapy in the management of brain metastases from breast cancer. Breast Cancer Res Treat. 2000;62(3):211-6.

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Carella RJ, Gelber R, Hendrickson F, Berry HC, Cooper JS. Value of radiation therapy in the management of patients with cerebral metastases from malignant melanoma: radiation therapy oncology group brain metastases study I and II. Cancer. 1980;45(4):679-83.<679::aid-cncr2820450410>;2-j.

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Sierko E, Hempel D, Zuzda K, Wojtukiewicz MZ. Personalized radiation therapy in cancer pain management. Cancers (Basel). 2019;11(3).

  106. 106.

    El Shafie RA, Bohm K, Weber D, Lang K, Schlaich F, Adeberg S, et al. Palliative radiotherapy for leptomeningeal carcinomatosis-analysis of outcome, prognostic factors, and symptom response. Front Oncol. 2018;8:641.

    Article  PubMed  Google Scholar 

  107. 107.

    Saito T, Tomitaka E, Toya R, Matsuyama T, Ninomura S, Watakabe T, et al. A neuropathic pain component as a predictor of improvement in pain interference after radiotherapy for painful tumors: a secondary analysis of a prospective observational study. Clin Transl Radiat Oncol. 2018;12:34-9.

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Rocha-Filho PA. Post-craniotomy headache: a clinical view with a focus on the persistent form. Headache. 2015;55(5):733-8.

    Article  PubMed  Google Scholar 

  109. 109.

    Zheng Q, Yang L, Tan LM, Qin LX, Wang CY, Zhang HN. Stroke-like migraine attacks after radiation therapy syndrome. Chin Med J. 2015;128(15):2097-101.

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Kamiya-Matsuoka C, Cachia D, Olar A, Armstrong TS, Gilbert MR. Primary brain tumors and posterior reversible encephalopathy syndrome. Neurooncol Pract. 2014;1(4):184-90.

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Singh V, Sinha A, Prakash N. Ondansetron-induced migraine-type headache. Can J Anaesth. 2010;57(9):872-3.

    Article  PubMed  Google Scholar 

  112. 112.

    Bevacizumab package insert.

  113. 113.

    Ondansetron FDA package insert.

  114. 114.

    Thakkar JP, Kumthekar P, Dixit KS, Stupp R, Lukas RV. Leptomeningeal metastasis from solid tumors. J Neurol Sci. 2020;411:116706.

    Article  PubMed  Google Scholar 

  115. 115.

    Jha SK. Cerebral edema and its management. Med J Armed Forces India. 2003;59(4):326-31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC. Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors. Neurosurgery 1999;44(4):732-740; discussion 40-1.,.

  117. 117.

    Ryan R, Booth S, Price S. Corticosteroid-use in primary and secondary brain tumour patients: a review. J Neuro-Oncol. 2012;106(3):449-59.

    CAS  Article  Google Scholar 

  118. 118.

    Lukas RV, Stupp R, Gondi V, Raizer JJ. Primary central nervous system lymphoma-PART 1: epidemiology, diagnosis, staging, and prognosis. Oncology (Williston Park). 2018;32(1):17-22.

    Google Scholar 

  119. 119.

    Lukas RV, Riedell P, Horowitz PM, Pytel P, Kamson DO. Diagnostic evaluation in primary CNS lymphoma. Neurologist. 2018;23(2):53-4.

    Article  PubMed  Google Scholar 

  120. 120.

    Irvin W, MacDonald G, Smith JK, Kim WY. Dexamethasone-induced posterior reversible encephalopathy syndrome. J Clin Oncol. 2007;25(17):2484-6.

    Article  PubMed  Google Scholar 

  121. 121.

    Sutyawan WE, Widiastuti IAP, Ryalino C. Steroid induced cataract in Langerhans cell histiocytosis patient. Open Access Maced J Med Sci. 2019;7(6):1025-8.

    Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123.

    • Lim-Fat MJ, Bi WL, Lo J, Lee EQ, Ahluwalia MS, Batchelor TT et al. Letter: When less is more: dexamethasone dosing for brain tumors. Neurosurgery. 2019;85(3):E607-E6E8. .Useful expert opinion regarding management of steroids in brain tumor patients.

  124. 124.

    Galicich JH, French LA, Melby JC. Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet. 1961;81:46-53.

    CAS  PubMed  Google Scholar 

  125. 125.

    Aulakh R, Singh S. Strategies for minimizing corticosteroid toxicity: a review. Indian J Pediatr. 2008;75(10):1067-73.

    Article  PubMed  Google Scholar 

  126. 126.

    Kostaras X, Cusano F, Kline GA, Roa W, Easaw J. Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol. 2014;21(3):e493-503.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Lukas RV, Wainwright DA, Ladomersky E, Sachdev S, Sonabend AM, Stupp R. Newly diagnosed glioblastoma: a review on clinical management. Oncology (Williston Park). 2019;33(3):91-100.

    Google Scholar 

  128. 128.

    Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, et al. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(4):1222-38.

    Article  PubMed  Google Scholar 

  129. 129.

    Giglio P, Gilbert MR. Neurologic complications of cancer and its treatment. Curr Oncol Rep. 2010;12(1):50-9.

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Chi DBA, Delattre J-Y. Neurologic complications of radiation therapy. New Jersey. 2008.

  131. 131.

    Le EM, Loghin ME. Posterior reversible encephalopathy syndrome: a neurologic phenomenon in cancer patients. Curr Oncol Rep. 2014;16(5):383.

    Article  PubMed  Google Scholar 

  132. 132.

    Verstappen CC, Heimans JJ, Hoekman K, Postma TJ. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs. 2003;63(15):1549-63.

  133. 133.

    Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol. 2009;63(5):761-7.

  134. 134.

    Newton HB. Neurological complications of chemotherapy to the central nervous system. Handb Clin Neurol. 2012;105:903-16.

  135. 135.

    Peddi PF, Peddi S, Santos ES, Morgensztern D. Central nervous system toxicities of chemotherapeutic agents. Expert Rev Anticancer Ther. 2014;14(7):857-63.

  136. 136.

    Fellner A, Makranz C, Lotem M, Bokstein F, Taliansky A, Rosenberg S, et al. Neurologic complications of immune checkpoint inhibitors. J Neuro-Oncol. 2018;137(3):601-9.

    CAS  Article  Google Scholar 

  137. 137.

    • Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B, et al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J ImmunoTher Cancer. 2019;7(1):134. study highlighling neurotoxicity with immune therapies.

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138.

    •• Rubin DB, Danish HH, Ali AB, Li K, LaRose S, Monk AD et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142(5):1334-48. Useful study reporting neurotoxicity of CAR-T cell therapy.

  139. 139.

    Zukas AM, Schiff D. Neurological complications of new chemotherapy agents. Neuro-Oncology. 2018;20(1):24-36.

    CAS  Article  PubMed  Google Scholar 

  140. 140.

    Sharma A LG, Porter A, Grill MF, Rosenthal A, Brown CE, Swanson K, Mrugala MM. CAR-T cell therapy in neuro-oncology: applications and toxicity. Neuroimmunol Neuroinflammation 2018.

  141. 141.

    Lukas RV, Wainwright DA, Horbinski CM, Iwamoto FM, Sonabend AM. Immunotherapy against gliomas: is the breakthrough near? Drugs. 2019;79(17):1839-48.

    CAS  Article  PubMed  Google Scholar 

  142. 142.

    Arrieta VA, Iwamoto F, Lukas RV, Sachdev S, Rabadan R, Sonabend AM. Can patient selection and neoadjuvant administration resuscitate PD-1 inhibitors for glioblastoma? J Neurosurg. 2019;132:1-6.

    Article  Google Scholar 

  143. 143.

    Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1-8.

    CAS  Article  PubMed  Google Scholar 

  144. 144.

    Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist. 2017;22(6):709-18.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Wang DY, Salem J-E, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncology. 2018;4(12):1721-8.

    Article  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Mancone S, Lycan T, Ahmed T, Topaloglu U, Dothard A, Petty WJ, et al. Severe neurologic complications of immune checkpoint inhibitors: a single-center review. J Neurol. 2018;265(7):1636-42.

    CAS  Article  PubMed  Google Scholar 

  147. 147.

    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-17.

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Migliorini D, Dietrich PY, Stupp R, Linette GP, Posey AD Jr, June CH. CAR T-cell therapies in glioblastoma: a first look. Clin Cancer Res. 2018;24(3):535-40.

    CAS  Article  PubMed  Google Scholar 

  149. 149.

    •• Perrinjaquet C, Desbaillets N, Hottinger AF. Neurotoxicity associated with cancer immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy. Curr Opin Neurol. 2019;32(3):500-10. Useful review regarding management of CAR-T cell therapy.

  150. 150.

    Rubinstein JD, Nelson AS, Krupski C, O'Brien W, Taylor JM, Badgett TC, et al. Chimeric antigen receptor T-cell therapy in patients with neurologic comorbidities. Pediatr Blood Cancer. 2020;67(4):e28199.

    Article  PubMed  Google Scholar 

  151. 151.

    Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958-71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Conception/design: Jigisha Thakkar, Rimas Lukas

Collection and/or assembly of data: Jigisha Thakkar, Rimas Lukas

Data analysis and interpretation: Jigisha Thakkar, Rimas Lukas

Manuscript writing and editing: Jigisha Thakkar, Rimas Lukas, Vikram Prabhu

Table creation: Jigisha Thakkar, Rimas Lukas

Final approval of manuscript: Jigisha Thakkar, Rimas Lukas, Vikram Prabhu, Stasia Rouse

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Correspondence to Jigisha P. Thakkar.

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Conflict of Interest

Jigisha Thakkar: No conflict of interest

Vikram Prabhu: No conflict of interest

Stasia Rouse: No conflict of interest

Rimas Lukas: BMS research support (drug only), Novocure Speakers bureau and advisory board, Honoraria for medical editing for Medlink Neurology and EBSCO. Received funding from P50CA221747

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Thakkar, J.P., Prabhu, V.C., Rouse, S. et al. Acute Neurological Complications of Brain Tumors and Immune Therapies, a Guideline for the Neuro-hospitalist. Curr Neurol Neurosci Rep 20, 32 (2020).

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  • Neurotoxicity
  • Brain tumors
  • Immunotherapies
  • Brain metastases
  • CART-T cell
  • Neurologic complications