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
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Paraneoplastic neurological syndromes (PNSs) are clinical manifestations of spontaneous antitumour immune responses against neuronal proteins expressed by tumour cells.
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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.
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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.
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Patients with cancer types that are frequently associated with PNSs might be at an increased risk of developing PNSs when treated with ICIs.
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Future research should focus on the identification of patients with cancer who are at risk of developing PNSs when treated with ICIs.
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References
Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).
Graus, F. et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J. Neurol. Neurosurg. Psychiatry 75, 1135–1140 (2004).
Gozzard, P. et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: a prospective study. Neurology 85, 235–239 (2015).
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).
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).
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).
June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).
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).
Neelapu, S. S. et al. Chimeric antigen receptor T cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).
Postow, M. A. & Hellmann, M. D. Adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 1165 (2018).
Yshii, L. M. et al. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain 139, 2923–2934 (2016).
Graus, F. et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 124, 1138–1148 (2001).
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).
Titulaer, M. J. et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force. Eur. J. Neurol. 18, 19–e13 (2011).
Rojas, I. et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 55, 713–715 (2000).
Sabater, L. et al. SOX1 antibodies are markers of paraneoplastic Lambert Eaton myasthenic syndrome. Neurology 70, 924–928 (2008).
van Sonderen, A. et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 87, 1449–1456 (2016).
Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
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).
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).
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).
Dalmau, J. et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 127, 1831–1844 (2004).
Pittock, S. J., Lucchinetti, C. F. & Lennon, V. A. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann. Neurol. 53, 580–587 (2003).
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).
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).
Graus, F. et al. Syndrome and outcome of antibody-negative limbic encephalitis. Eur. J. Neurol. 25, 1011–1016 (2018).
Alamowitch, S. et al. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain 120, 923–928 (1997).
Gultekin, H. S. et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumor association in 50 patients. Brain 123, 1481–1494 (2000).
Shams’ili, S. et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126, 1409–1418 (2003).
Sabater, L. et al. Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer. PLOS ONE 8, e60438 (2013).
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).
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).
Molinuevo, J. L. et al. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann. Neurol. 44, 976–980 (1998).
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).
Koike, H. & Sobue, G. Paraneoplastic neuropathy. Handb. Clin. Neurol. 115, 713–726 (2013).
Chinn, J. S. & Schuffler, M. D. Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology 95, 1279–1286 (1988).
Vernino, S. et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855 (2000).
Henson, R. A., Hoffman, H. L. & Urich, H. Encephalomyelitis with carcinoma. Brain 88, 449–464 (1965).
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).
Yu, Z. et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann. Neurol. 49, 146–154 (2001).
Caviness, J. N., Forsyth, P. A., Layton, D. D. & McPhee, T. J. The movement disorder of adult opsoclonus. Mov. Disord. 10, 22–27 (1995).
Bataller, L., Graus, F., Saiz, A. & Vilchez, J. J. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 124, 437–443 (2001).
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).
Anderson, N. E. et al. Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine (Baltimore) 67, 100–109 (1988).
Armangue, T. et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann. Neurol. 75, 435–441 (2014).
Berridge, G. et al. Glutamate receptor delta2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome. Neurology 91, e714–e723 (2018).
Fukuoka, T. et al. Anti-glutamate receptor delta2 antibody-positive migrating focal encephalitis. Clin. Neurol. Neurosurg. 114, 1351–1354 (2012).
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).
Pranzatelli, M. R. & Tate, E. D. Trends and tenets in relapsing and progressive opsoclonus-myoclonus syndrome. Brain Dev. 38, 439–448 (2016).
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).
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).
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).
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).
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).
D’Alessandro, V. et al. Molecular analysis of the HuD gene in neuroendocrine lung cancers. Lung Cancer 67, 69–75 (2010).
Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014).
Small, M. et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol. 135, 569–579 (2018).
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).
Hillary, R. P. et al. Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies. J. Neuroimmunol. 315, 28–32 (2018).
de Graaf, M. T. et al. HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes. J. Neuroimmunol. 226, 147–149 (2010).
Carpentier, A. F. et al. DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. Clin. Cancer Res. 4, 2819–2824 (1998).
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).
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).
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).
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).
Bernal, F. et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 103, 509–515 (2002).
Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).
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).
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).
Mollman, J. E., Hogan, W. M., Glover, D. J. & McCluskey, L. F. Unusual presentation of cis-platinum neuropathy. Neurology 38, 488–490 (1988).
Cuzzubbo, S. et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur. J. Cancer 73, 1–8 (2017).
Fellner, A. et al. Neurologic complications of immune checkpoint inhibitors. J. Neurooncol. 137, 601–609 (2018).
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).
Kolb, N. A. et al. Neuromuscular complications of immune checkpoint inhibitor therapy. Muscle Nerve 58, 10–22 (2018).
Pakkala, S. & Owonikoko, T. K. Immune checkpoint inhibitors in small cell lung cancer. J. Thorac Dis. 10, S460–s467 (2018).
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).
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).
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).
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).
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).
Arino, H. et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 72, 874–881 (2015).
Williams, T. J. et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 73, 928–933 (2016).
Makarious, D., Horwood, K. & Coward, J. I. G. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur. J. Cancer 82, 128–136 (2017).
Suzuki, S. et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 89, 1127–1134 (2017).
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).
Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018).
Berzero, G. et al. Early intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with onconeural antibodies. J. Neurol. Neurosurg. Psychiatry 89, 798–792 (2018).
Keime-Guibert, F. et al. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology 53, 1719–1723 (1999).
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).
Shams’ili, S. et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J. Neurol. 253, 16–20 (2006).
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).
Hottinger, A. F. et al. Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 5, e439 (2018).
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).
Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Gadoth, A. et al. Microtubule-associated protein 1B: novel paraneoplastic biomarker. Ann. Neurol. 81, 266–277 (2017).
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).
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).
Werner, C. et al. Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. Brain 139, 365–379 (2016).
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).
Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
Hoftberger, R. et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 84, 2403–2412 (2015).
Hoftberger, R. et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81, 1500–1506 (2013).
Spatola, M. et al. Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 90, e1964–e1972 (2018).
Bost, C. et al. Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies. J. Neurol. 265, 2190–2200 (2018).
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).
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).
Saiz, A. et al. Anti-Hu-associated brainstem encephalitis. J. Neurol. Neurosurg. Psychiatry 80, 404–407 (2009).
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).
Vigliani, M. C. et al. Chorea and related movement disorders of paraneoplastic origin: the PNS EuroNetwork experience. J. Neurol. 258, 2058–2068 (2011).
Murinson, B. B. & Guarnaccia, J. B. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71, 1955–1958 (2008).
Flanagan, E. P. et al. Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 76, 2089–2095 (2011).
Sepulveda, M. et al. Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies. Mult. Scler. 24, 1753–1759 (2017).
Verschueren, A. et al. Paraneoplastic subacute lower motor neuron syndrome associated with solid cancer. J. Neurol. Sci. 358, 413–416 (2015).
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).
Dubey, D. et al. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology 90, e103–e110 (2018).
Antoine, J. C. & Camdessanche, J. P. Paraneoplastic neuropathies. Curr. Opin. Neurol. 30, 513–520 (2017).
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).
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).
Salam, S., Lavin, T. & Turan, A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep. 2016, bcr2016215012 (2016).
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).
Kawamura, R. et al. Acute cerebellar ataxia induced by nivolumab. Intern. Med. 56, 3357–3359 (2017).
Shah, S. et al. Nivolumab-induced autoimmune encephalitis in two patients with lung adenocarcinoma. Case Rep. Neurol. Med. 2018, 2548528 (2018).
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).
Appelbaum, J. et al. Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report. J. Immunother. Cancer 6, 82 (2018).
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).
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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.).
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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.
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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.
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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
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