Skip to main content

Advertisement

SpringerLink
Log in

Paraneoplastic disorders of the nervous system

  • Neurological Update
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

This article on paraneoplastic neurologic disorders provides an update on the diagnostic approach, utility and pitfalls of autoantibody testing and emerging settings in which these disorders are encountered. Recognition of the clinical and neuroimaging features accompanying paraneoplastic neurologic disorders is crucial to select those at highest risk who need neural antibody testing and screening for cancer. Cursory knowledge of the antibody assay methodology being ordered is important as the false positive rate varies by the technique utilized for detection. Antibodies can generally be stratified by the location of the target antigen (intraceullar versus cell-surface/synaptic) which informs frequency of cancer association, treatment response and prognosis. The therapeutic approach generally involves detection of the underlying cancer and combinations of oncologic treatments and immunosuppressant medications. The occurrence of paraneoplastic autoimmune neurologic disorders in novel settings, such as with immune checkpoint inhibitor use, has improved understanding of their pathogenesis and increased the likelihood neurologists will encounter such patients in their practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12(2):157–165. https://doi.org/10.1016/S1474-4422(12)70310-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Armangue T, Spatola M, Vlagea A, Mattozzi S, Carceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Gimenez L, Corral-Corral I, Montejo C, Toledo M, Bataller L, Secondi G, Arino H, Martinez-Hernandez E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J, Spanish Herpes Simplex Encephalitis Study G (2018) Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol 17(9):760–772. https://doi.org/10.1016/S1474-4422(18)30244-8

    Article  PubMed  PubMed Central  Google Scholar 

  3. Flanagan EP (2020) Paraneoplastic disorders of the nervous system. Continuum (Minneap Minn) 26(6):1602–1628. https://doi.org/10.1212/CON.0000000000000941

    Article  Google Scholar 

  4. Graus F, Dalmau J (2019) Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat Rev Clin Oncol 16(9):535–548. https://doi.org/10.1038/s41571-019-0194-4

    Article  CAS  PubMed  Google Scholar 

  5. Hara M, Arino H, Petit-Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, Schreurs MW, Rosenfeld MR, Graus F, Dalmau J (2017) DPPX antibody-associated encephalitis: main syndrome and antibody effects. Neurology 88(14):1340–1348. https://doi.org/10.1212/WNL.0000000000003796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tobin WO, Lennon VA, Komorowski L, Probst C, Clardy SL, Aksamit AJ, Appendino JP, Lucchinetti CF, Matsumoto JY, Pittock SJ, Sandroni P, Tippmann-Peikert M, Wirrell EC, McKeon A (2014) DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 83(20):1797–1803. https://doi.org/10.1212/WNL.0000000000000991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Escudero D, Guasp M, Arino H, Gaig C, Martinez-Hernandez E, Dalmau J, Graus F (2017) Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology 89(14):1471–1475. https://doi.org/10.1212/WNL.0000000000004541

    Article  PubMed  PubMed Central  Google Scholar 

  8. Budhram A, Britton JW, Liebo GB, Dubey D, Zekeridou A, Flanagan EP, McKeon A, Pittock SJ, Braksick SA, Zalewski NL (2020) Use of diffusion-weighted imaging to distinguish seizure-related change from limbic encephalitis. J Neurol 267(11):3337–3342. https://doi.org/10.1007/s00415-020-10007-1

    Article  PubMed  Google Scholar 

  9. Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, Julia Benique MR, Benson L, Gorman M, Felipe A, Caparo Oblitas RL, Rosenfeld MR, Graus F, Dalmau J (2017) Investigations in GABAA receptor antibody-associated encephalitis. Neurology 88(11):1012–1020. https://doi.org/10.1212/WNL.0000000000003713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Flanagan EP, Hinson SR, Lennon VA, Fang B, Aksamit AJ, Morris PP, Basal E, Honorat JA, Alfugham NB, Linnoila JJ, Weinshenker BG, Pittock SJ, McKeon A (2017) Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol 81(2):298–309. https://doi.org/10.1002/ana.24881

    Article  CAS  PubMed  Google Scholar 

  11. Vogrig A, Muniz-Castrillo S, Joubert B, Picard G, Rogemond V, Marchal C, Chiappa AM, Chanson E, Skowron F, Leblanc A, Ducray F, Honnorat J (2020) Central nervous system complications associated with immune checkpoint inhibitors. J Neurol Neurosurg Psychiatry 91(7):772–778. https://doi.org/10.1136/jnnp-2020-323055

    Article  PubMed  Google Scholar 

  12. Vernino S, Tuite P, Adler CH, Meschia JF, Boeve BF, Boasberg P, Parisi JE, Lennon VA (2002) Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 51(5):625–630. https://doi.org/10.1002/ana.10178

    Article  PubMed  Google Scholar 

  13. Zekeridou A, Kryzer T, Guo Y, Hassan A, Lennon V, Lucchinetti CF, Pittock S, McKeon A (2019) Phosphodiesterase 10A IgG: a novel biomarker of paraneoplastic neurologic autoimmunity. Neurology 93(8):e815–e822. https://doi.org/10.1212/WNL.0000000000007971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Flanagan EP, Kotsenas AL, Britton JW, McKeon A, Watson RE, Klein CJ, Boeve BF, Lowe V, Ahlskog JE, Shin C, Boes CJ, Crum BA, Laughlin RS, Pittock SJ (2015) Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm 2(6):e161. https://doi.org/10.1212/NXI.0000000000000161

    Article  PubMed  PubMed Central  Google Scholar 

  15. Thompson J, Bi M, Murchison AG, Makuch M, Bien CG, Chu K, Farooque P, Gelfand JM, Geschwind MD, Hirsch LJ, Somerville E, Lang B, Vincent A, Leite MI, Waters P, Irani SR, Faciobrachial Dystonic Seizures Study G (2018) The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 141(2):348–356. https://doi.org/10.1093/brain/awx323

    Article  PubMed  Google Scholar 

  16. Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR (2004) Clinical analysis of anti-Ma2-associated encephalitis. Brain 127(Pt 8):1831–1844. https://doi.org/10.1093/brain/awh203

    Article  PubMed  Google Scholar 

  17. Salvarani C, Brown RD Jr, Christianson TJH, Huston J 3rd, Ansell SM, Giannini C, Hunder GG (2018) Primary central nervous system vasculitis associated with lymphoma. Neurology 90(10):e847–e855. https://doi.org/10.1212/WNL.0000000000005062

    Article  PubMed  Google Scholar 

  18. Graus F, Arino H, Dalmau J (2014) Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas. Blood 123(21):3230–3238. https://doi.org/10.1182/blood-2014-03-537506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Madhavan AA, Carr CM, Morris PP, Flanagan EP, Kotsenas AL, Hunt CH, Eckel LJ, Lindell EP, Diehn FE (2020) Imaging review of paraneoplastic neurologic syndromes. Am J Neuroradiol 41(12):2176–2187. https://doi.org/10.3174/ajnr.A6815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dubey D, Wilson MR, Clarkson B, Giannini C, Gandhi M, Cheville J, Lennon VA, Eggers S, Devine MF, Mandel-Brehm C, Kryzer T, Hinson SR, Khazaie K, Hales C, Kattah J, Pavelko KD, Andrews P, Eaton JE, Jitprapaikulsan J, Mills JR, Flanagan EP, Zekeridou A, Leibovich B, Fryer J, Torre M, Kaufman C, Thoreson JB, Sagen J, Linnoila JJ, DeRisi JL, Howe CL, McKeon A, Pittock SJ (2020) Expanded Clinical Phenotype, Oncological Associations, and immunopathologic insights of paraneoplastic kelch-like protein-11 encephalitis. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020.2231

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mandel-Brehm C, Dubey D, Kryzer TJ, O’Donovan BD, Tran B, Vazquez SE, Sample HA, Zorn KC, Khan LM, Bledsoe IO, McKeon A, Pleasure SJ, Lennon VA, DeRisi JL, Wilson MR, Pittock SJ (2019) Kelch-like protein 11 antibodies in seminoma-associated paraneoplastic encephalitis. N Engl J Med 381(1):47–54. https://doi.org/10.1056/NEJMoa1816721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Madhavan A, Carr CM, Krecke KN, Wood CP, McKeon A, Dubey D (2021) Association between paraneoplastic rhombencephalitis and hypertrophic olivary degeneration. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2020-325569

    Article  PubMed  Google Scholar 

  23. Hutchinson M, Waters P, McHugh J, Gorman G, O’Riordan S, Connolly S, Hager H, Yu P, Becker CM, Vincent A (2008) Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 71(16):1291–1292. https://doi.org/10.1212/01.wnl.0000327606.50322.f0

    Article  CAS  PubMed  Google Scholar 

  24. Flanagan EP, McKeon A, Lennon VA, Kearns J, Weinshenker BG, Krecke KN, Matiello M, Keegan BM, Mokri B, Aksamit AJ, Pittock SJ (2011) Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 76(24):2089–2095. https://doi.org/10.1212/WNL.0b013e31821f468f

    Article  CAS  PubMed  Google Scholar 

  25. Diehn FE, Krecke KN (2021) Neuroimaging of spinal cord and cauda equina disorders. Continuum (Minneap Minn) 27(1):225–263. https://doi.org/10.1212/CON.0000000000000926

    Article  Google Scholar 

  26. Pittock SJ, Lennon VA (2008) Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol 65(5):629–632. https://doi.org/10.1001/archneur.65.5.629

    Article  PubMed  Google Scholar 

  27. Probasco JC, Solnes L, Nalluri A, Cohen J, Jones KM, Zan E, Javadi MS, Venkatesan A (2017) Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 4(4):e352. https://doi.org/10.1212/NXI.0000000000000352

    Article  PubMed  PubMed Central  Google Scholar 

  28. Probasco JC, Solnes L, Nalluri A, Cohen J, Jones KM, Zan E, Javadi MS, Venkatesan A (2018) Decreased occipital lobe metabolism by FDG-PET/CT: an anti-NMDA receptor encephalitis biomarker. Neurol Neuroimmunol Neuroinflamm 5(1):e413. https://doi.org/10.1212/NXI.0000000000000413

    Article  PubMed  Google Scholar 

  29. Linnoila JJ (2018) Imaging in autoimmune neurology. Semin Neurol 38(3):371–378. https://doi.org/10.1055/s-0038-1660476

    Article  PubMed  Google Scholar 

  30. McKeon A, Apiwattanakul M, Lachance DH, Lennon VA, Mandrekar JN, Boeve BF, Mullan B, Mokri B, Britton JW, Drubach DA, Pittock SJ (2010) Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 67(3):322–329. https://doi.org/10.1001/archneurol.2009.336

    Article  PubMed  Google Scholar 

  31. Budhram A, Dubey D, Sechi E, Flanagan EP, Yang L, Bhayana V, McKeon A, Pittock SJ, Mills JR (2020) Neural antibody testing in patients with suspected autoimmune encephalitis. Clin Chem. https://doi.org/10.1093/clinchem/hvaa254

    Article  PubMed  Google Scholar 

  32. Ruiz-Garcia R, Martinez-Hernandez E, Saiz A, Dalmau J, Graus F (2020) The diagnostic value of onconeural antibodies depends on how they are tested. Front Immunol 11:1482. https://doi.org/10.3389/fimmu.2020.01482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dechelotte B, Muniz-Castrillo S, Joubert B, Vogrig A, Picard G, Rogemond V, Pinto AL, Lombard C, Desestret V, Fabien N, Honnorat J (2020) Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000701

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lang K, Pruss H (2017) Frequencies of neuronal autoantibodies in healthy controls: estimation of disease specificity. Neurol Neuroimmunol Neuroinflamm 4(5):e386. https://doi.org/10.1212/NXI.0000000000000386

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zekeridou A, Lennon VA (2019) Neurologic autoimmunity in the era of checkpoint inhibitor cancer immunotherapy. Mayo Clin Proc 94(9):1865–1878. https://doi.org/10.1016/j.mayocp.2019.02.003

    Article  PubMed  Google Scholar 

  36. Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, Liewluck T, Hammack JE, Sandroni P, Finnes H, Mauermann ML (2017) Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 74(10):1216–1222. https://doi.org/10.1001/jamaneurol.2017.1912

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liewluck T, Kao JC, Mauermann ML (2018) PD-1 Inhibitor-associated myopathies: emerging Immune-mediated myopathies. J Immunother 41(4):208–211. https://doi.org/10.1097/CJI.0000000000000196

    Article  CAS  PubMed  Google Scholar 

  38. Sechi E, Markovic SN, McKeon A, Dubey D, Liewluck T, Lennon VA, Lopez-Chiriboga AS, Klein CJ, Mauermann M, Pittock SJ, Flanagan EP, Zekeridou A (2020) Neurologic autoimmunity and immune checkpoint inhibitors: autoantibody profiles and outcomes. Neurology 95(17):e2442–e2452. https://doi.org/10.1212/WNL.0000000000010632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dubey D, David WS, Amato AA, Reynolds KL, Clement NF, Chute DF, Cohen JV, Lawrence DP, Mooradian MJ, Sullivan RJ, Guidon AC (2019) Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies. Neurology 93(11):e1093–e1103. https://doi.org/10.1212/WNL.0000000000008091

    Article  CAS  PubMed  Google Scholar 

  40. Safa H, Johnson DH, Trinh VA, Rodgers TE, Lin H, Suarez-Almazor ME, Fa’ak F, Saberian C, Yee C, Davies MA, Tummala S, Woodman K, Abdel-Wahab N, Diab A (2019) Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J Immunother Cancer 7(1):319. https://doi.org/10.1186/s40425-019-0774-y

    Article  PubMed  PubMed Central  Google Scholar 

  41. Vogrig A, Muniz-Castrillo S, Joubert B, Picard G, Rogemond V, Skowron F, Egri M, Desestret V, Tilikete C, Psimaras D, Ducray F, Honnorat J (2020) Cranial nerve disorders associated with immune checkpoint inhibitors. Neurology. https://doi.org/10.1212/WNL.0000000000011340

    Article  PubMed  Google Scholar 

  42. Vogrig A, Muniz-Castrillo S, Honnorat J (2020) Value of onconeural antibodies in checkpoint inhibitor-related toxicities. Ann Neurol 88(1):199–200. https://doi.org/10.1002/ana.25764

    Article  PubMed  Google Scholar 

  43. Vogrig A, Muniz-Castrillo S, Desestret V, Joubert B, Honnorat J (2020) Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors. Ther Adv Neurol Disord 13:1756286420932797. https://doi.org/10.1177/1756286420932797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gerdes LA, Held K, Beltran E, Berking C, Prinz JC, Junker A, Tietze JK, Ertl-Wagner B, Straube A, Kumpfel T, Dornmair K, Hohlfeld R (2016) CTLA4 as immunological checkpoint in the development of multiple sclerosis. Ann Neurol 80(2):294–300. https://doi.org/10.1002/ana.24715

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA

    Eoin P. Flanagan

Authors
  1. Eoin P. Flanagan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eoin P. Flanagan.

Ethics declarations

Conflicts of interest

The author states that there is no conflict of interest.

Ethical approval

Dr. Flanagan is a site principal investigator in a randomized placebo-controlled clinical trial of Inebilizumab (A CD19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio. He receives no personal compensation and just receives reimbursement for the research activities related to the trial.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Flanagan, E.P. Paraneoplastic disorders of the nervous system. J Neurol 268, 4899–4907 (2021). https://doi.org/10.1007/s00415-021-10570-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-021-10570-1

Keywords

Search

Navigation