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Paraneoplastic Neurological Disorders

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Central Nervous System Metastases

Abstract

Paraneoplastic syndromes are rare disorders that occur remote from a malignant neoplasm or metastases and can affect any organ system (Tarin D, Cancer Metastasis Rev, 32:707–721, 2013). Well-described paraneoplastic disorders include cancer cachexia, hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, and Lambert-Eaton myasthenic syndrome (Pelosof LC, Gerber DE, Mayo Clin Proc, 85:838–854, 2010). Collectively, paraneoplastic syndromes can affect up to 70% of cancer patients, with neurological paraneoplastic disorders affecting approximately 0.01–0.2%, though this is likely an underestimate (Dalmau J, Rosenfeld MR, Lancet Neurol, 7:327–340, 2008). In general, paraneoplastic disorders are the result of two main process: (1) synthesis and secretion of cytokines, hormones, or bioactive molecules and (2) immune reactions to tumor-related antigens (Pelosof LC, Gerber DE, Mayo Clin Proc, 85:838–854, 2010). Paraneoplastic neurological disorders (PNDs) predominately affect the nervous system and are almost all the product of an immune response to onconeural antigens of tumors that cross-react with the nervous system (Iorio R, Lennon VA, Immunol Rev, 248:104–121, 2012). PNDs are often the first sign of an asymptomatic or occult cancer and/or cancer relapse (Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Eur J Neurol, 18:19-e3, 2011). Neurological immune-related adverse events (nirAEs) following immune checkpoint inhibitor (ICI) treatment for cancer are similar in many respects to PNDs (Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, Eur J Cancer, 73:1–8, 2017). Given the expanding use of ICI in the treatment of a variety of cancers and since PNDs can present at diagnosis, treatment, and relapse of cancer, it is crucial for both neurologists and oncologists to be familiar with the presentation and pathophysiology of PNDs. This chapter will review the presentation of PNDs, their association with specific autoantibodies and cancers, treatment, pathogenesis, and similarities with nirAEs following ICI therapy for cancer.

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References

  1. Mckeon A. Paraneoplastic and other autoimmune disorders of the central nervous system. Neurohospitalist. 2013;3(2):53–64.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force. Eur J Neurol. 2011;18(1):19–e3.

    Article  CAS  PubMed  Google Scholar 

  3. Iorio R, Lennon VA. Neural antigen-specific autoimmune disorders. Immunol Rev. 2012;248(1):104–21.

    Article  PubMed  Google Scholar 

  4. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–40.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85(9):838–54.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Didelot A, Honnorat JÔ. Paraneoplastic disorders of the central and peripheral nervous systems. Handb Clin Neurol. 2014;121:1159–79.

    Article  PubMed  Google Scholar 

  7. Wells EM, Dalmau J. Paraneoplastic neurologic disorders in children. Curr Neurol Neurosci Rep. 2011;11(2):187–94.

    Article  PubMed  Google Scholar 

  8. Gozzard P, Woodhall M, Chapman C, Nibber A, Waters P, Vincent A, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma. Neurology. 2015;85(3):235–9.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med [Internet]. 2003;349(16):1543–54.

    Article  CAS  Google Scholar 

  10. Graus F, Dalmau J, Reñé R, Tora M, Malats N, Verschuuren JJ, et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol. 1997;15(8):2866–72.

    Article  CAS  PubMed  Google Scholar 

  11. Linnoila J, Pittock SJ. Autoantibody-associated central nervous system neurologic disorders. Semin Neurol. 2016;36(4):382–96.

    Article  PubMed  Google Scholar 

  12. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol. 1992;141(4):881–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Darnell JC, Albert ML, Darnell RB. cdr2, A target antigen of naturally occurring human tumor immunity, is widely expressed in gynecological tumors. Cancer Res. 2000;60(8):2136–9.

    CAS  PubMed  Google Scholar 

  14. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56(5):715–9.

    Article  CAS  PubMed  Google Scholar 

  16. Venkatraman A, Opal P. Paraneoplastic cerebellar degeneration with anti-Yo antibodies – a review. Ann Clin Transl Neurol. 2016;3(8):655–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shams’Ili S, Grefkens J, De Leeuw B, Van den Bent M, Hooijkaas H, Van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003;126(6):1409–18.

    Article  PubMed  Google Scholar 

  18. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992;42(10):1931–7.

    Article  CAS  PubMed  Google Scholar 

  19. Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985;35(4):538–43.

    Article  CAS  PubMed  Google Scholar 

  20. McKeon A, Pittock SJ. Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol. 2011;122(4):381–400.

    Article  CAS  PubMed  Google Scholar 

  21. Albert ML, Darnell RB. Paraneoplastic neurological degenerations: keys to tumour immunity. Nat Rev Cancer. 2004;4:36–44.

    Article  CAS  PubMed  Google Scholar 

  22. Kazarian M, Laird-Offringa IA. Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer. 2011;10:33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Darnell RB, Roberts WK. Neuroimmunology of the paraneoplastic neurological degenerations. Curr Opin Immunol. 2004;16(5):616–22.

    Article  PubMed  CAS  Google Scholar 

  24. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med. 1998;4(11):1321–4.

    Article  CAS  PubMed  Google Scholar 

  25. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol. 2000;47(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  26. Iorio R, Smitt PS. Paraneoplastic cerebellar degeneration. In: Essentials of cerebellum and cerebellar disorders: a primer for graduate students. Cham: Springer; 2016. p. 587–93.

    Chapter  Google Scholar 

  27. Graus F, Illa I, Agusti M, Ribalta T, Cruz-Sanchez F, Juarez C. Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a Guinea pig model. J Neurol Sci. 1991;106(1):82–7.

    Article  CAS  PubMed  Google Scholar 

  28. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Anda V, Ennon AL, Homas T, Ryzer JK, Uy G, Riesmann EG, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med. 1995;30(17):5866–75.

    Google Scholar 

  31. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol. 2009;9:449–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Meriney SD, Tarr TB, Ojala KS, Wu M, Li Y, Lacomis D, et al. Lambert–Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads. Ann N Y Acad Sci. 2018;1421(1):73–81.

    Article  CAS  Google Scholar 

  33. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Malviya M, Barman S, Golombeck KS, Planagumà J, Mannara F, Strutz-Seebohm N, et al. NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody. Ann Clin Transl Neurol. 2017;4(11):768–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim TJ, Lee ST, Moon J, Sunwoo JS, Byun JI, Lim JA, et al. Anti-LGI1 encephalitis is associated with unique HLA subtypes. Ann Neurol. 2017;81(2):183–92.

    Article  CAS  PubMed  Google Scholar 

  36. Binks S, Varley J, Lee W, Makuch M, Elliott K, Gelfand JM, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain. 2018;141(8):2263–71.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Klein CJ, Lennon VA, Aston PA, McKeon A, O’Toole O, Quek A, et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013;70(2):229–34.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Horta ES, Lennon VA, Lachance DH, Jenkins SM, Smith CY, McKeon A, et al. Neural autoantibody clusters aid diagnosis of cancer. Clin Cancer Res. 2014;20(14):3862–9.

    Article  CAS  PubMed  Google Scholar 

  39. Bernal F, Shams’Ili S, Rojas I, Sanchez-Valle R, Saiz A, Dalmau J, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin’s disease. Neurology. 2003;60(2):230–4.

    Article  CAS  PubMed  Google Scholar 

  40. Sabater L, Höftberger R, Boronat A, Saiz A. Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer. PLoS One. 2013;8(3):e60438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Verschnuren J, Chuang L, Rosenblum MK, Lieberman F, Pryor A, Posner JB, et al. Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo-associated paraneoplastic cerebellar degeneration. Acta Neuropathol. 1996;91(5):519–25.

    Article  Google Scholar 

  42. Jones AL, Flanagan EP, Pittock SJ, Mandrekar JN, Eggers SD, Ahlskog JE, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 2015;72(11):1304–12.

    Article  PubMed  Google Scholar 

  43. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Paterson RW, Takada LT, Geschwind MD. Diagnosis and treatment of rapidly progressive dementias. Neurol Clin Pract. 2012;2(3):187–200.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Probasco JC, Solnes L, Nalluri A, Cohen J, Jones KM, Zan E, et al. Decreased occipital lobe metabolism by FDG-PET/CT. Neurol Neuroimmunol Neuroinflamm. 2018;5(1):e413.

    Article  PubMed  Google Scholar 

  46. Lancaster E, Dalmau J. Neuronal autoantigens-pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8(7):380–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alamowitch S, Graus F, Uchuya M, Reñé R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain. 1997;120(6):923–8.

    Article  PubMed  Google Scholar 

  48. Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760–72.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Chalk CH, Windebank AJ, Kimmel DW, Mcmanis PG. The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci/J Can des Sci Neurol. 1992;19(3):346–51.

    Article  CAS  Google Scholar 

  50. Gazic B, Pisem J, Dolenc-Groselj L, Popovic M. Paraneoplastic encephalomyelitis/sensory motor peripheral neuropathy – an autopsy case study. Folia Neuropathol. 2005;43(2):113–7.

    PubMed  Google Scholar 

  51. Camdessanché JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain. 2009;132(7):1723–33.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tarin D. Update on clinical and mechanistic aspects of paraneoplastic syndromes. Cancer Metastasis Rev. 2013;32:707–21.

    Article  CAS  PubMed  Google Scholar 

  53. Oh S-Y, Kim J-S, Dieterich M. Update on opsoclonus–myoclonus syndrome in adults. J Neurol [Internet]. 2018;266(6):1541–8. [Cited 2018 Dec 5]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/30483882

    Article  Google Scholar 

  54. Titulaer MJ, Lang B, Verschuuren JJGM. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098–107.

    Article  PubMed  Google Scholar 

  55. McKeon A, Apiwattanakul M, Lachance DH, Lennon VA, Mandrekar JN, Boeve BF, et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010;67(3):322–9.

    Article  PubMed  Google Scholar 

  56. Hassel JC. Ipilimumab plus nivolumab for advanced melanoma. Lancet Oncol. 2016;17(11):1471–2.

    Article  PubMed  Google Scholar 

  57. Jain P, Jain C, Velcheti V. Role of immune-checkpoint inhibitors in lung cancer. Ther Adv Respir Dis. 2018;12:1–13.

    Article  CAS  Google Scholar 

  58. 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.

    Article  CAS  PubMed  Google Scholar 

  59. Hottinger AF. Neurologic complications of immune checkpoint inhibitors. Curr Opin Neurol. 2016;29(6):806–12.

    Article  CAS  PubMed  Google Scholar 

  60. Astaras C, de Micheli R, Moura B, Hundsberger T, Hottinger AF. Neurological adverse events associated with immune checkpoint inhibitors: diagnosis and management. Curr Neurol Neurosci Rep. 2018;18(1):1–9.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Monica Weaver Buckley & John C. Probasco

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  1. Monica Weaver Buckley
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  2. John C. Probasco
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Correspondence to John C. Probasco .

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Editors and Affiliations

  1. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, Director - Brain Metastases Program, New York, NY, USA

    Rohan Ramakrishna

  2. Department of Neurology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Rajiv S. Magge

  3. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Ali A. Baaj

  4. Department of Radiation Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Jonathan P.S. Knisely

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Buckley, M.W., Probasco, J.C. (2020). Paraneoplastic Neurological Disorders. In: Ramakrishna, R., Magge, R., Baaj, A., Knisely, J. (eds) Central Nervous System Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-42958-4_13

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  • DOI: https://doi.org/10.1007/978-3-030-42958-4_13

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