Autoimmune Encephalitis: Paraneoplastic Syndromes

  • Serge Weis
  • Michael Sonnberger
  • Andreas Dunzinger
  • Eva Voglmayr
  • Martin Aichholzer
  • Raimund Kleiser
  • Peter Strasser


Paraneoplastic disorders are caused by cancer but not by a direct result of cancer invasion of the affected tissue or organ. Neurologic signs and symptoms result from either direct or indirect damage to the nervous system. Autoimmune encephalitis (AE) is a diverse group of neuropsychiatric disorders associated with systemic autoimmune disorders, CNS autoimmune disorders, and paraneoplastic syndromes. AE is mediated by antibodies (Abs) directed against membrane receptors (e.g., N-methyl d-aspartate receptors) and ion channel-associated CNS proteins (e.g., voltage-gated potassium channels).

During the last two decades, a variety of disorders have been clinically recognized and the causing autoantibody identified. Autoimmune encephalitides include limbic encephalitis (LE), paraneoplastic limbic encephalitis (PLE), NMDA-R encephalitis, voltage-gated potassium antibody syndromes (LGI1, contactin-associated protein like (CASPR2)), Morvan syndrome, AMPAR (GluR1, GluR2) antibody syndrome, glycine receptor antibody syndrome, dopamine 2 receptor antibody syndrome (D2RA), GABA receptor Ab syndrome, metabotropic glutamate receptor antibody syndrome, and IgLON5 Ab syndrome.

Radiologically, these disorders show initial edema, later atrophy of affected region (limbic encephalitis, rhombencephalitis). Imaging without pathological findings does not exclude paraneoplastic syndromes.

Histologically, variable loss of neurons in the hippocampal formation is seen. Gliomesenchymal nodules, neuronal damage, softening of the tissue, and perivascular lymphocytic infiltrates are seen.

Paraneoplastic encephalitis results from immune responses against intraneuronal proteins, ectopic expression of neuronal proteins triggers immune response misdirected against the nervous system, antigens released by apoptotic tumor cells are taken up and processed by antigen-presenting cells at the regional lymph node, presented to the immune system eliciting an anti-tumor immune response, prominent cytotoxic T-cell responses, and neuronal degeneration via perforin or granzyme-related mechanisms.

In autoimmune encephalitis, antibodies access cell surface targets and alter their structure and function by cross-linking and internalization of the receptors leading to a functional blocking of receptors. Priming B-cell immune responses lead to production of autoantibodies with functional and reversible rather than structural and irreversible neuronal alteration. Predisposition to autoimmunity results from genetic susceptibility (HLA associations with LGI1 and IgLON5 antibodies).

Treatment consists in finding and treating the cancer. Immunity suppression of predominantly T-cell suppression with corticosteroids, cyclophosphamide, tacrolimus, stem cell transplantation and of predominantly B-cell suppression with plasma exchange, intravenous immunoglobulin (IVIG), or antibodies (e.g., rituximab). Control of symptoms (ataxia, stiff muscle, weakness, pain, cognitive dysfunction, and seizures). Outcome is variable depending on the underlying mechanisms, i.e., intracellular-onconeural (10–30% of patients with mild response, infrequent relapses, usually monophasic and irreversible), intracellular-synaptic (about 60% of patients have partial improvement, infrequent relapses, symptoms may fluctuate), and cell surface or synaptic receptor (substantial or full recoveries).

Selected References

  1. Armangue T, Leypoldt F, Dalmau J (2014) Autoimmune encephalitis as differential diagnosis of infectious encephalitis. Curr Opin Neurol 27(3):361–368. Scholar
  2. Bauer J, Bien CG (2016) Neuropathology of autoimmune encephalitides. Handb Clin Neurol 133:107–120. Scholar
  3. Bruggemann N, Wandinger KP, Gaig C, Sprenger A, Junghanns K, Helmchen C, Munchau A (2016) Dystonia, lower limb stiffness, and upward gaze palsy in a patient with IgLON5 antibodies. Mov Disord 31(5):762–764. Scholar
  4. Chastain EM, Miller SD (2012) Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease. Immunol Rev 245(1):227–238. Scholar
  5. Corrigan JJ, Crisp SJ, Kullmann DM, Vincent A (2016) Autoimmune synaptopathies. Nat Rev Neurosci 17(2):103–117. Scholar
  6. Dale RC, Merheb V, Pillai S, Wang D, Cantrill L, Murphy TK, Ben-Pazi H, Varadkar S, Aumann TD, Horne MK, Church AJ, Fath T, Brilot F (2012) Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 135(Pt 11):3453–3468. Scholar
  7. Dalmau J, Rosenfeld MR (2014) Autoimmune encephalitis update. Neuro Oncol 16(6):771–778. Scholar
  8. Dalmau J, Geis C, Graus F (2017) Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 97(2):839–887. Scholar
  9. Darnell RB, Posner JB (2011) Paraneoplastic syndromes. Oxford University Press, OxfordGoogle Scholar
  10. Davidson A, Diamond B (2014) General features of autoimmune disease. In: Rose NR, Mackay IR (eds) The autoimmune diseases, 5th edn. Elsevier, Amsterdam, pp 19–37Google Scholar
  11. Dubey D, Blackburn K, Greenberg B, Stuve O, Vernino S (2016) Diagnostic and therapeutic strategies for management of autoimmune encephalopathies. Expert Rev Neurother 16(8):937–949. Scholar
  12. Fukata M, Yokoi N, Fukata Y (2017) Neurobiology of autoimmune encephalitis. Curr Opin Neurobiol 48:1–8. Scholar
  13. Gaspard N (2016) Autoimmune epilepsy. Continuum 22(1 Epilepsy):227–245. Scholar
  14. Gastaldi M, Thouin A, Vincent A (2016) Antibody-mediated autoimmune encephalopathies and immunotherapies. Neurotherapeutics 13(1):147–162. Scholar
  15. Gelpi E, Hoftberger R, Graus F, Ling H, Holton JL, Dawson T, Popovic M, Pretnar-Oblak J, Hogl B, Schmutzhard E, Poewe W, Ricken G, Santamaria J, Dalmau J, Budka H, Revesz T, Kovacs GG (2016) Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 132(4):531–543. Scholar
  16. Graus F, Dalmau J (2012) Paraneoplastic neurological syndromes. Curr Opin Neurol 25(6):795–801. Scholar
  17. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler C, Verschuuren JJ, Vincent A, Voltz R (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75(8):1135–1140. Scholar
  18. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016a) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15(4):391–404. Scholar
  19. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016b) A clinical approach to diagnosis of autoimmune encephalitis. Am J Neuroradiol 15(4):391–404. Scholar
  20. Griffith B, Haitao R, Yingmai Y, Yan H, Fei H, Xia L, Honglin H, Chaiyan L, Stocker W, Liying C, Hongzhi G (2016) Chorea and parkinsonism associated with autoantibodies to IgLON5 and responsive to immunotherapy. J Neuroimmunol 300:9–10. Scholar
  21. Heine J, Pruss H, Bartsch T, Ploner CJ, Paul F, Finke C (2015) Imaging of autoimmune encephalitis—relevance for clinical practice and hippocampal function. Neuroscience 309:68–83. Scholar
  22. Hogl B, Heidbreder A, Santamaria J, Graus F, Poewe W (2015) IgLON5 autoimmunity and abnormal behaviours during sleep. Lancet 385(9977):1590. Scholar
  23. Iorio R, Lennon VA (2012) Neural antigen-specific autoimmune disorders. Immunol Rev 248(1):104–121. Scholar
  24. Kalman B (2017) Autoimmune encephalitides: a broadening field of treatable conditions. Am J Neuroradiol 22(1):1–13. Scholar
  25. Kawakami N (2016) In vivo imaging in autoimmune diseases in the central nervous system. Allergol Int 65(3):235–242. Scholar
  26. Kelley BP, Patel SC (2017) Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. Am J Neuroradiol 38(6):1070–1078. Scholar
  27. Lancaster E (2016) The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol 12(1):1–13. Scholar
  28. Lancaster E, Dalmau J (2012) Neuronal autoantigens—pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8(7):380–390. Scholar
  29. Leypoldt F, Armangue T, Dalmau J (2015) Autoimmune encephalopathies. Ann N Y Acad Sci 1338:94–114. Scholar
  30. Linnoila J, Pittock SJ (2016) Autoantibody-associated central nervous system neurologic disorders. Semin Neurol 36(4):382–396. Scholar
  31. Linnoila JJ, Rosenfeld MR, Dalmau J (2014) Neuronal surface antibody-mediated autoimmune encephalitis. Semin Neurol 34(4):458–466. Scholar
  32. Mangesius S, Sprenger F, Hoftberger R, Seppi K, Reindl M, Poewe W (2017) IgLON5 autoimmunity tested negative in patients with progressive supranuclear palsy and corticobasal syndrome. Parkinsonism Relat Disord 38:102–103. Scholar
  33. Marin HL, McKeon A (2016) Autoimmune encephalopathies and dementias. Continuum 22(2 Dementia):538–558. Scholar
  34. McKeon A, Pittock SJ (2011) Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol 122(4):381–400. Scholar
  35. Mitsias PD, Pittock SJ, Vincent A (2016) Introduction to autoimmune neurology. Handb Clin Neurol 133:3–14. Scholar
  36. Pittock SJ, Vincent A (2016) Introduction to autoimmune neurology. Handb Clin Neurol. 133:3-14.
  37. Ramanathan S, Mohammad SS, Brilot F, Dale RC (2014) Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci 21(5):722–730. Scholar
  38. Rose NR, Mackay IR (2014) The autoimmune diseases, 5th edn. Elsevier-Academic Press, AmsterdamGoogle Scholar
  39. Rosenfeld MR, Dalmau JO (2012) Paraneoplastic disorders of the CNS and autoimmune synaptic encephalitis. Continuum 18(2):366–383. Scholar
  40. Sabater L, Gaig C, Gelpi E, Bataller L, Lewerenz J, Torres-Vega E, Contreras A, Giometto B, Compta Y, Embid C, Vilaseca I, Iranzo A, Santamaria J, Dalmau J, Graus F (2014) A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 13(6):575–586. Scholar
  41. Sabater L, Planaguma J, Dalmau J, Graus F (2016) Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J Neuroinflammation 13(1):226. Scholar
  42. Schroder JB, Melzer N, Ruck T, Heidbreder A, Kleffner I, Dittrich R, Muhle P, Warnecke T, Dziewas R (2017) Isolated dysphagia as initial sign of anti-IgLON5 syndrome. Neurol Neuroimmunol Neuroinflamm 4(1):e302. Scholar
  43. Shoenfeld Y, Meroni PL, Gershwin ME (2014) Autoantibodies, 3rd edn. Elsevier, AmsterdamGoogle Scholar
  44. Simabukuro MM, Sabater L, Adoni T, Cury RG, Haddad MS, Moreira CH, Oliveira L, Boaventura M, Alves RC, Azevedo Soster L, Nitrini R, Gaig C, Santamaria J, Dalmau J, Graus F (2015) Sleep disorder, chorea, and dementia associated with IgLON5 antibodies. Neurol Neuroimmunol Neuroinflamm 2(4):e136. Scholar
  45. van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ (2017) The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 13(5):290–301. Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Serge Weis
    • 1
  • Michael Sonnberger
    • 2
  • Andreas Dunzinger
    • 3
  • Eva Voglmayr
    • 2
  • Martin Aichholzer
    • 4
  • Raimund Kleiser
    • 2
  • Peter Strasser
    • 5
  1. 1.Division of Neuropathology, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  2. 2.Department of Neuroradiology, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  3. 3.Department of Neuro-Nuclear Medicine, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  4. 4.Department of Neurosurgery, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  5. 5.PMU University Institute for Medical & Chemical Laboratory DiagnosticsSalzburgAustria

Personalised recommendations