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:

Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors

Abstract

Paraneoplastic neurological syndromes (PNSs) comprise a group of disorders that can affect any part of the nervous system in patients with cancer and frequently result from autoimmune responses triggered by the ectopic expression of neuronal proteins in cancer cells. These disorders are rare, although the introduction of immune-checkpoint inhibitors (ICIs) into cancer treatment algorithms has renewed interest in PNSs. ICIs are associated with a considerably increased incidence of immunological toxicities compared with traditional anticancer therapies, including neurological immune-related adverse effects (nirAEs) that can manifest as PNSs. Theoretically, the use of ICIs might increase the risk of PNSs, in particular, in patients with the types of cancer that are most frequently associated with these disorders (such as small-cell lung cancer), emphasizing the importance of their prompt diagnosis and treatment to prevent irreversible neurological deficits. To facilitate the recognition of these disorders in the context of immune-checkpoint inhibition, we provide an overview of PNSs, including the main syndromes, types of neuronal autoantibodies and associated immunological mechanisms. We also review the scenarios in which nirAEs fulfil the criteria for PNSs and examine their frequency and clinical presentations. Finally, we provide recommendations for the prevention and management of PNSs that can occur during ICI therapy.

Key points

  • Paraneoplastic neurological syndromes (PNSs) are clinical manifestations of spontaneous antitumour immune responses against neuronal proteins expressed by tumour cells.

  • The enhanced immunity resulting from anticancer treatment with immune-checkpoint inhibitors (ICIs) is associated with a range of neurological immune-related adverse effects, some of which are PNSs.

  • The diagnosis of PNSs is aided by the recognition of distinct clinical syndromes and/or the presence of autoantibodies to intracellular (onconeural) antigens or a subset of neuronal cell surface synaptic proteins.

  • Patients with cancer types that are frequently associated with PNSs might be at an increased risk of developing PNSs when treated with ICIs.

  • Future research should focus on the identification of patients with cancer who are at risk of developing PNSs when treated with ICIs.

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

Fig. 1: Proposed mechanisms of PNSs as nirAEs of ICIs.

Similar content being viewed by others

References

  1. Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).

    CAS  PubMed  Google Scholar 

  2. Graus, F. et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J. Neurol. Neurosurg. Psychiatry 75, 1135–1140 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Gozzard, P. et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: a prospective study. Neurology 85, 235–239 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Drlicek, M. et al. Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J. Neurol. 244, 85–89 (1997).

    CAS  PubMed  Google Scholar 

  5. Monstad, S. E., Knudsen, A., Salvesen, H. B., Aarseth, J. H. & Vedeler, C. A. Onconeural antibodies in sera from patients with various types of tumours. Cancer Immunol. Immunother. 58, 1795–1800 (2009).

    CAS  PubMed  Google Scholar 

  6. Mayes, P. A., Hance, K. W. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug Discov. 17, 509–527 (2018).

    CAS  PubMed  Google Scholar 

  7. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    CAS  PubMed  Google Scholar 

  8. Yshii, L. M., Hohlfeld, R. & Liblau, R. S. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nat. Rev. Neurol. 13, 755–763 (2017).

    CAS  PubMed  Google Scholar 

  9. Neelapu, S. S. et al. Chimeric antigen receptor T cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    CAS  PubMed  Google Scholar 

  10. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  PubMed  Google Scholar 

  11. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    CAS  PubMed  Google Scholar 

  12. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Postow, M. A. & Hellmann, M. D. Adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 1165 (2018).

    PubMed  Google Scholar 

  14. Yshii, L. M. et al. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain 139, 2923–2934 (2016).

    PubMed  Google Scholar 

  15. Graus, F. et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 124, 1138–1148 (2001).

    CAS  PubMed  Google Scholar 

  16. Titulaer, M. J. et al. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J. Clin. Oncol. 26, 4276–4281 (2008).

    PubMed  Google Scholar 

  17. Titulaer, M. J. et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force. Eur. J. Neurol. 18, 19–e13 (2011).

    CAS  PubMed  Google Scholar 

  18. Rojas, I. et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 55, 713–715 (2000).

    CAS  PubMed  Google Scholar 

  19. Sabater, L. et al. SOX1 antibodies are markers of paraneoplastic Lambert Eaton myasthenic syndrome. Neurology 70, 924–928 (2008).

    CAS  PubMed  Google Scholar 

  20. van Sonderen, A. et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 87, 1449–1456 (2016).

    PubMed  Google Scholar 

  21. Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. Dalmau, J., Geis, C. & Graus, F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol. Rev. 97, 839–887 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Peterson, K., Rosenblum, M. K., Kotanides, H. & Posner, J. B. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 42, 1931–1937 (1992).

    CAS  PubMed  Google Scholar 

  24. de Graaff, E. et al. Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann. Neurol. 71, 815–824 (2012).

    PubMed  Google Scholar 

  25. Dalmau, J. et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 127, 1831–1844 (2004).

    PubMed  Google Scholar 

  26. Pittock, S. J., Lucchinetti, C. F. & Lennon, V. A. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann. Neurol. 53, 580–587 (2003).

    CAS  PubMed  Google Scholar 

  27. Titulaer, M. J. et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J. Clin. Oncol. 27, 4260–4267 (2009).

    CAS  PubMed  Google Scholar 

  28. Graus, F. et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J. Clin. Oncol. 15, 2866–2872 (1997).

    CAS  PubMed  Google Scholar 

  29. Graus, F. et al. Syndrome and outcome of antibody-negative limbic encephalitis. Eur. J. Neurol. 25, 1011–1016 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Alamowitch, S. et al. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain 120, 923–928 (1997).

    PubMed  Google Scholar 

  31. Gultekin, H. S. et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumor association in 50 patients. Brain 123, 1481–1494 (2000).

    PubMed  Google Scholar 

  32. Shams’ili, S. et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126, 1409–1418 (2003).

    PubMed  Google Scholar 

  33. Sabater, L. et al. Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer. PLOS ONE 8, e60438 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wanschitz, J., Hainfellner, J. A., Kristoferitsch, W., Drlicek, M. & Budka, H. Ganglionitis in paraneoplastic subacute sensory neuronopathy: a morphologic study. Neurology 49, 1156–1159 (1997).

    CAS  PubMed  Google Scholar 

  35. Camdessanche, J. P. et al. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 125, 166–175 (2002).

    PubMed  Google Scholar 

  36. Molinuevo, J. L. et al. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann. Neurol. 44, 976–980 (1998).

    CAS  PubMed  Google Scholar 

  37. Keime-Guibert, F. et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J. Neurol. Neurosurg. Psychiatry 68, 479–482 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Koike, H. & Sobue, G. Paraneoplastic neuropathy. Handb. Clin. Neurol. 115, 713–726 (2013).

    PubMed  Google Scholar 

  39. Chinn, J. S. & Schuffler, M. D. Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology 95, 1279–1286 (1988).

    CAS  PubMed  Google Scholar 

  40. Vernino, S. et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855 (2000).

    CAS  PubMed  Google Scholar 

  41. Henson, R. A., Hoffman, H. L. & Urich, H. Encephalomyelitis with carcinoma. Brain 88, 449–464 (1965).

    CAS  PubMed  Google Scholar 

  42. Dalmau, J., Graus, F., Rosenblum, M. K. & Posner, J. B. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 71, 59–72 (1992).

    CAS  Google Scholar 

  43. Yu, Z. et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann. Neurol. 49, 146–154 (2001).

    CAS  PubMed  Google Scholar 

  44. Caviness, J. N., Forsyth, P. A., Layton, D. D. & McPhee, T. J. The movement disorder of adult opsoclonus. Mov. Disord. 10, 22–27 (1995).

    CAS  PubMed  Google Scholar 

  45. Bataller, L., Graus, F., Saiz, A. & Vilchez, J. J. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 124, 437–443 (2001).

    CAS  PubMed  Google Scholar 

  46. Pranzatelli, M. R., Tate, E. D. & McGee, N. R. Demographic, clinical, and immunologic features of 389 children with opsoclonus-myoclonus syndrome: a cross-sectional study. Front. Neurol. 8, 468 (2017).

    PubMed  PubMed Central  Google Scholar 

  47. Anderson, N. E. et al. Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine (Baltimore) 67, 100–109 (1988).

    CAS  Google Scholar 

  48. Armangue, T. et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann. Neurol. 75, 435–441 (2014).

    PubMed  Google Scholar 

  49. Berridge, G. et al. Glutamate receptor delta2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome. Neurology 91, e714–e723 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Fukuoka, T. et al. Anti-glutamate receptor delta2 antibody-positive migrating focal encephalitis. Clin. Neurol. Neurosurg. 114, 1351–1354 (2012).

    PubMed  Google Scholar 

  51. Shiihara, T., Kato, M., Konno, A., Takahashi, Y. & Hayasaka, K. Acute cerebellar ataxia and consecutive cerebellitis produced by glutamate receptor delta2 autoantibody. Brain Dev. 29, 254–256 (2007).

    PubMed  Google Scholar 

  52. Pranzatelli, M. R. & Tate, E. D. Trends and tenets in relapsing and progressive opsoclonus-myoclonus syndrome. Brain Dev. 38, 439–448 (2016).

    PubMed  Google Scholar 

  53. Weizman, D. A. & Leong, W. L. Anti-Ri antibody opsoclonus-myoclonus syndrome and breast cancer: a case report and a review of the literature. J. Surg. Oncol. 87, 143–145 (2004).

    PubMed  Google Scholar 

  54. Vincent, A., Lang, B. & Newsom-Davis, J. Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci. 12, 496–502 (1989).

    CAS  PubMed  Google Scholar 

  55. O’Neill, J. H., Murray, N. M. & Newsom-Davis, J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 111, 577–596 (1988).

    PubMed  Google Scholar 

  56. Motomura, M. et al. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J. Neurol. Sci. 147, 35–42 (1997).

    CAS  PubMed  Google Scholar 

  57. Titulaer, M. J. et al. Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. J. Clin. Oncol. 29, 902–908 (2011).

    PubMed  Google Scholar 

  58. D’Alessandro, V. et al. Molecular analysis of the HuD gene in neuroendocrine lung cancers. Lung Cancer 67, 69–75 (2010).

    PubMed  Google Scholar 

  59. Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014).

    CAS  PubMed  Google Scholar 

  60. Small, M. et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol. 135, 569–579 (2018).

    CAS  PubMed  Google Scholar 

  61. Pignolet, B. S., Gebauer, C. M. & Liblau, R. S. Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies: a beneficial antitumor immune response going awry. Oncoimmunology 2, e27384 (2013).

    PubMed  PubMed Central  Google Scholar 

  62. Hillary, R. P. et al. Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies. J. Neuroimmunol. 315, 28–32 (2018).

    CAS  PubMed  Google Scholar 

  63. de Graaf, M. T. et al. HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes. J. Neuroimmunol. 226, 147–149 (2010).

    PubMed  Google Scholar 

  64. Carpentier, A. F. et al. DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. Clin. Cancer Res. 4, 2819–2824 (1998).

    CAS  PubMed  Google Scholar 

  65. Blachere, N. E. et al. T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation. Eur. J. Immunol. 44, 3240–3251 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Monstad, S. E. et al. Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J. Clin. Oncol. 22, 795–800 (2004).

    CAS  PubMed  Google Scholar 

  67. Gozzard, P., Chapman, C., Vincent, A., Lang, B. & Maddison, P. Novel humoral prognostic markers in small-cell lung carcinoma: a prospective study. PLOS ONE 10, e0143558 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. de Jongste, A. H. et al. Three sensitive assays do not provide evidence for circulating HuD-specific T cells in the blood of patients with paraneoplastic neurological syndromes with anti-Hu antibodies. Neuro-oncology. 14, 841–848 (2012).

    PubMed  PubMed Central  Google Scholar 

  69. Bernal, F. et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 103, 509–515 (2002).

    CAS  PubMed  Google Scholar 

  70. Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    PubMed  Google Scholar 

  71. Ohara, S., Iijima, N., Hayashida, K., Oide, T. & Katai, S. Autopsy case of opsoclonus-myoclonus-ataxia and cerebellar cognitive affective syndrome associated with small cell carcinoma of the lung. Mov. Disord. 22, 1320–1324 (2007).

    PubMed  Google Scholar 

  72. Martinez-Hernandez, E. et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77, 589–593 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Mollman, J. E., Hogan, W. M., Glover, D. J. & McCluskey, L. F. Unusual presentation of cis-platinum neuropathy. Neurology 38, 488–490 (1988).

    CAS  PubMed  Google Scholar 

  74. Cuzzubbo, S. et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur. J. Cancer 73, 1–8 (2017).

    CAS  PubMed  Google Scholar 

  75. Fellner, A. et al. Neurologic complications of immune checkpoint inhibitors. J. Neurooncol. 137, 601–609 (2018).

    CAS  PubMed  Google Scholar 

  76. Astaras, C., de Micheli, R., Moura, B., Hundsberger, T. & Hottinger, A. F. Neurological adverse events associated with immune checkpoint inhibitors: diagnosis and management. Curr. Neurol. Neurosci. Rep. 18, 3 (2018).

    PubMed  Google Scholar 

  77. Kolb, N. A. et al. Neuromuscular complications of immune checkpoint inhibitor therapy. Muscle Nerve 58, 10–22 (2018).

    Google Scholar 

  78. Pakkala, S. & Owonikoko, T. K. Immune checkpoint inhibitors in small cell lung cancer. J. Thorac Dis. 10, S460–s467 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Gadducci, A. & Guerrieri, M. E. Immune checkpoint inhibitors in gynecological cancers: update of literature and perspectives of clinical research. Anticancer Res. 37, 5955–5965 (2017).

    CAS  PubMed  Google Scholar 

  80. Reck, M. et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J. Clin. Oncol. 34, 3740–3748 (2016).

    CAS  PubMed  Google Scholar 

  81. Antonia, S. J. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 17, 883–895 (2016).

    CAS  PubMed  Google Scholar 

  82. Papadopoulos, K. P. et al. Anti-Hu-associated autoimmune limbic encephalitis in a patient with PD-1 inhibitor-responsive myxoid chondrosarcoma. Oncologist 23, 118–120 (2018).

    PubMed  Google Scholar 

  83. Matsuoka, H. et al. Nivolumab-induced limbic encephalitis with anti-Hu antibody in a patient with advanced pleomorphic carcinoma of the lung. Clin. Lung Cancer 19, e597–e599 (2018).

    PubMed  Google Scholar 

  84. Arino, H. et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 72, 874–881 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. Williams, T. J. et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 73, 928–933 (2016).

    PubMed  Google Scholar 

  86. Makarious, D., Horwood, K. & Coward, J. I. G. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur. J. Cancer 82, 128–136 (2017).

    CAS  PubMed  Google Scholar 

  87. Suzuki, S. et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 89, 1127–1134 (2017).

    CAS  PubMed  Google Scholar 

  88. Brahmer, J. R. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 36, 1714–1768 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018).

    PubMed  Google Scholar 

  90. Berzero, G. et al. Early intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with onconeural antibodies. J. Neurol. Neurosurg. Psychiatry 89, 798–792 (2018).

    Google Scholar 

  91. Keime-Guibert, F. et al. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology 53, 1719–1723 (1999).

    CAS  PubMed  Google Scholar 

  92. Horvat, T. Z. et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J. Clin. Oncol. 33, 3193–3198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Shams’ili, S. et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J. Neurol. 253, 16–20 (2006).

    PubMed  Google Scholar 

  94. Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hottinger, A. F. et al. Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 5, e439 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. Leonardi, G. C. et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J. Clin. Oncol. 36, 1905–1912 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016).

    PubMed  Google Scholar 

  98. Mammen, A. L. et al. Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann. Rheum. Dis. 78, 150–152 (2019).

    CAS  PubMed  Google Scholar 

  99. Hu, Y. et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J. Hematol. Oncol. 9, 70 (2016).

    PubMed  PubMed Central  Google Scholar 

  100. Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Sterner, R. M. et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 133, 697–709 (2019).

    CAS  PubMed  Google Scholar 

  102. Heery, C. R. et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 18, 587–598 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Patel, M. R. et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 19, 51–64 (2018).

    CAS  PubMed  Google Scholar 

  104. Antonia, S. et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 17, 299–308 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bronicki, L. M. & Jasmin, B. J. Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction. RNA 19, 1019–1037 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gure, A. O. et al. Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer. Proc. Natl Acad. Sci. USA 97, 4198–4203 (2000).

    CAS  PubMed  Google Scholar 

  107. Gadoth, A. et al. Microtubule-associated protein 1B: novel paraneoplastic biomarker. Ann. Neurol. 81, 266–277 (2017).

    CAS  PubMed  Google Scholar 

  108. Darnell, J. C., Albert, M. L. & Darnell, R. B. Cdr2, a target antigen of naturally occuring human tumor immunity, is widely expressed in gynecological tumors. Cancer Res. 60, 2136–2139 (2000).

    CAS  PubMed  Google Scholar 

  109. Buckanovich, R. J., Posner, J. B. & Darnell, R. B. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11, 657–672 (1993).

    CAS  PubMed  Google Scholar 

  110. Werner, C. et al. Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. Brain 139, 365–379 (2016).

    PubMed  Google Scholar 

  111. Dalmau, J. et al. Antibodies against Ma1-Ma5 define distinct paraneoplastic neurologic syndromes associated with limbic, brainstem, or cerebellar dysfunction. Neurology 52, 197–198 (1999).

    Google Scholar 

  112. Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hoftberger, R. et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 84, 2403–2412 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Hoftberger, R. et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81, 1500–1506 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Spatola, M. et al. Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 90, e1964–e1972 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Bost, C. et al. Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies. J. Neurol. 265, 2190–2200 (2018).

    CAS  PubMed  Google Scholar 

  117. Shavit, Y. B., Graus, F., Probst, A., Rene, R. & Steck, A. J. Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann. Neurol. 45, 255–258 (1999).

    CAS  PubMed  Google Scholar 

  118. Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R. & Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63–74 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Saiz, A. et al. Anti-Hu-associated brainstem encephalitis. J. Neurol. Neurosurg. Psychiatry 80, 404–407 (2009).

    CAS  PubMed  Google Scholar 

  120. Sutton, I. J., Barnett, M. H., Watson, J. D., Ell, J. J. & Dalmau, J. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J. Neurol. 249, 1597–1598 (2002).

    CAS  PubMed  Google Scholar 

  121. Vigliani, M. C. et al. Chorea and related movement disorders of paraneoplastic origin: the PNS EuroNetwork experience. J. Neurol. 258, 2058–2068 (2011).

    PubMed  Google Scholar 

  122. Murinson, B. B. & Guarnaccia, J. B. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71, 1955–1958 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Flanagan, E. P. et al. Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 76, 2089–2095 (2011).

    CAS  PubMed  Google Scholar 

  124. Sepulveda, M. et al. Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies. Mult. Scler. 24, 1753–1759 (2017).

    PubMed  Google Scholar 

  125. Verschueren, A. et al. Paraneoplastic subacute lower motor neuron syndrome associated with solid cancer. J. Neurol. Sci. 358, 413–416 (2015).

    PubMed  Google Scholar 

  126. Flanagan, E. P., Sandroni, P., Pittock, S. J., Inwards, D. J. & Jones, L. K. Jr. Paraneoplastic lower motor neuronopathy associated with Hodgkin lymphoma. Muscle Nerve 46, 823–827 (2012).

    PubMed  Google Scholar 

  127. Dubey, D. et al. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology 90, e103–e110 (2018).

    CAS  PubMed  Google Scholar 

  128. Antoine, J. C. & Camdessanche, J. P. Paraneoplastic neuropathies. Curr. Opin. Neurol. 30, 513–520 (2017).

    CAS  PubMed  Google Scholar 

  129. Rana, S. S., Ramanathan, R. S., Small, G. & Adamovich, B. Paraneoplastic Isaacs’ syndrome: a case series and review of the literature. J. Clin. Neuromuscul. Dis. 13, 228–233 (2012).

    PubMed  Google Scholar 

  130. Bhatia, S., Huber, B. R., Upton, M. P. & Thompson, J. A. Inflammatory enteric neuropathy with severe constipation after ipilimumab treatment for melanoma: a case report. J. Immunother. 32, 203–205 (2009).

    PubMed  Google Scholar 

  131. Salam, S., Lavin, T. & Turan, A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep. 2016, bcr2016215012 (2016).

    PubMed  PubMed Central  Google Scholar 

  132. Brown, M. P., Hissaria, P., Hsieh, A. H., Kneebone, C. & Vallat, W. Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody secondary to pembrolizumab therapy. J. Neuroimmunol. 305, 16–18 (2017).

    CAS  PubMed  Google Scholar 

  133. Kawamura, R. et al. Acute cerebellar ataxia induced by nivolumab. Intern. Med. 56, 3357–3359 (2017).

    PubMed  PubMed Central  Google Scholar 

  134. Shah, S. et al. Nivolumab-induced autoimmune encephalitis in two patients with lung adenocarcinoma. Case Rep. Neurol. Med. 2018, 2548528 (2018).

    PubMed  PubMed Central  Google Scholar 

  135. Kopecky, J. et al. Nivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report. J. Med. Case Rep. 12, 262–269 (2018).

    PubMed  PubMed Central  Google Scholar 

  136. Appelbaum, J. et al. Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report. J. Immunother. Cancer 6, 82 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Maller, B., Peguero, E. & Tanvetyanon, T. Ipilimumab/nivolumab-related ppsoclonus-myoclonus-ataxia syndrome variant in a patient with malignant pleural mesothelioma. J. Immunother. 41, 411–412 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported in part by grants from the Instituto Carlos III–FEDER (FIS 15/00377 to F.G.; FIS 17/00234 and PIE 16/00014 to J.D.), the NIH (RO1NS077851 to J.D.) and Fundació Privada CELLEX (J.D.).

Reviewer information

Nature Reviews Clinical Oncology thanks J. Honnorat, R. Liblau and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

Authors

Contributions

Both authors made equal contributions to all stages of the preparation of this manuscript.

Corresponding author

Correspondence to Josep Dalmau.

Ethics declarations

Competing interests

F.G. holds a patent licensed to Euroimmun for the use of IgLON5 in an autoantibody test, for which he receives royalties, and receives honoraria from MedLink Neurology for his role as an associate editor. J.D. holds patents licensed to Athena Diagnostics for the use of Ma2 in an autoantibody test and licensed to Euroimmun for the use of N-methyl-d-aspartate receptor (NMDAR), GABA type B receptor (GABABR), DPPX, GABAAR and IgLON5 in autoantibody tests, for which he receives royalties, and he receives honoraria from Neurology: Neuroimmunology & Neuroinflammation for his role as an editor.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Graus, F., Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat Rev Clin Oncol 16, 535–548 (2019). https://doi.org/10.1038/s41571-019-0194-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0194-4

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer