Autoimmune Encephalitis

  • Arun VenkatesanEmail author
  • John C. Probasco


Acute encephalitis is a rapidly progressive encephalopathy due to brain inflammation. Historically, the most frequently identified causes of acute encephalitis have been infectious, though recently an increasing number of autoimmune encephalitides have been described. While autoimmune encephalitis can occur in the setting of a tumor, infections such as herpes simplex encephalitis can also serve as a trigger. The clinical presentation, along with neuroimaging and cerebrospinal fluid studies, are vital in making the diagnosis of autoimmune encephalitis and in distinguishing it from infectious encephalitis and from other causes of encephalopathy. First line treatments include corticosteroids, intravenous immunoglobulin, and plasma exchange, while second line agents include targeted or broad spectrum immunosuppressive agents. Long-term outcomes following autoimmune encephalitis are poorly characterized and persistent neurocognitive symptoms are likely underrecognized.


Autoimmune encephalitis Treatment Diagnostics 


  1. 1.
    Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57:1114–28.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998–2010. Neurology. 2014;82:443–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349:1543–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7:327–40.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tarin D. Update on clinical and mechanistic aspects of paraneoplastic syndromes. Cancer Metastasis Rev. 2013;32:707–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391–404.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18:19–e13.CrossRefPubMedGoogle Scholar
  8. 8.
    Frontera JA. Metabolic encephalopathies in the critical care unit. Continuum. 2012;18:611–39.PubMedGoogle Scholar
  9. 9.
    McKeon A. Paraneoplastic and other autoimmune disorders of the central nervous system. Neurohospitalist. 2013;3:53–64.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–65.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86:1683–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Arino H, Armangue T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology. 2016;87:759–65.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Johnson N, Henry C, Fessler AJ, Dalmau J. Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus. Neurology. 2010;75:1480–2.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Savard M, Irani SR, Guillemette A, et al. Creutzfeldt-Jakob disease-like periodic sharp wave complexes in voltage-gated potassium channel-complex antibodies encephalitis: a case report. J Clin Neurophysiol. 2016;33:e1–4.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Probasco JC, Solnes L, Nalluri A, et al. Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm. 2017;4:e352.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Solnes LB, Jones KM, Rowe SP, et al. Diagnostic value of 18F-FDG PET/CT versus MRI in the setting of antibody specific autoimmune encephalitis. J Nucl Med. 2017;58:1307–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Leypoldt F, Buchert R, Kleiter I, et al. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry. 2012;83:681–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yuan J, Guan H, Zhou X, et al. Changing brain metabolism patterns in patients with ANMDARE: serial 18F-FDG PET/CT findings. Clin Nucl Med. 2016;41:366–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    McKeon A, Pittock SJ. Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol. 2011;122:381–400.CrossRefPubMedGoogle Scholar
  23. 23.
    Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56:715–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Kim B, Yoo P, Sutherland T, et al. LGI1 antibody encephalopathy overlapping with sporadic Creutzfeldt-Jakob disease. Neurol Neuroimmunol Neuroinflamm. 2016;3:e248.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rossi M, Mead S, Collinge J, Rudge P, Vincent A. Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. 2015;86:692–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Sköldenberg B, Aurelius E, Hjalmarsson A, et al. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. 2006;253:163–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–11.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Venkatesan A, Benavides DR. Autoimmune encephalitis and its relation to infection. Curr Neurol Neurosci Rep. 2015;15(3):3.CrossRefPubMedGoogle Scholar
  29. 29.
    van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, de Graaff E, Sillevis Smitt PA, Hoogenraad CC. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13:167–77.CrossRefPubMedGoogle Scholar
  31. 31.
    Ramberger M, Peschl P, Schanda K, et al. Comparison of diagnostic accuracy of microscopy and flow cytometry in evaluating N-methyl-D-aspartate receptor antibodies in serum using a live cell-based assay. PLoS One. 2015;10:e0122037.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9:67–76.CrossRefPubMedGoogle Scholar
  33. 33.
    Höftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology. 2015;84:2403–12.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: a practical approach. Neurol Clin Pract. 2014;4:206–15.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol. 2016;12:1–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Varley J, Taylor J, Irani SR. Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy. Neuropharmacology. 2017;132:71–82.CrossRefPubMedGoogle Scholar
  37. 37.
    Didelot A, Honnorat J. Paraneoplastic disorders of the central and peripheral nervous systems. Handb Clin Neurol. 2014;121:1159–79.CrossRefPubMedGoogle Scholar
  38. 38.
    Byun JI, Lee ST, Jung KH, et al. Effect of immunotherapy on seizure outcome in patients with autoimmune encephalitis: a prospective observational registry study. PLoS One. 2016;11:e0146455.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gabilondo I, Saiz A, Galán L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011;77:996–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.CrossRefPubMedGoogle Scholar
  41. 41.
    Lee W-J, Lee S-T, Moon J, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics. 2016;13:824–32.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Scheibe F, Prüss H, Mengel AM, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88:366–70.CrossRefPubMedGoogle Scholar
  43. 43.
    Michael BD, Griffiths MJ, Granerod J, et al. The Interleukin-1 balance during encephalitis is associated with clinical severity, blood-brain barrier permeability, neuroimaging changes, and disease outcome. J Infect Dis. 2016;213:1651–60.CrossRefPubMedGoogle Scholar
  44. 44.
    Novroski AR, Baldwin KJ. Chronic autoimmune meningoencephalitis and periodic fever syndrome treated with Anakinra. Case Rep Neurol. 2017;9:91–7.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10:835–44.CrossRefPubMedGoogle Scholar
  46. 46.
    Singh TD, Fugate JE, Rabinstein AA. The spectrum of acute encephalitis: causes, management, and predictors of outcome. Neurology. 2015;84:359–66.CrossRefPubMedGoogle Scholar
  47. 47.
    Larman HB, Zhao Z, Laserson U, et al. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol. 2011;29:535–41.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhu J, Larman HB, Gao G, et al. Protein interaction discovery using parallel analysis of translated ORFs (PLATO). Nat Biotechnol. 2013;31:331–4.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Pearson RM, Casey LM, Hughes KR, Miller SD, Shea LD. In vivo reprogramming of immune cells: technologies for induction of antigen-specific tolerance. Adv Drug Deliv Rev. 2017;114:240–55.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Luo X, Miller SD, Shea LD. Immune tolerance for autoimmune disease and cell transplantation. Annu Rev Biomed Eng. 2016;18:181–205.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305–34.CrossRefPubMedGoogle Scholar
  52. 52.
    Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90:720–4.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gross G, Eshhar Z. Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB J. 1992;6:3370–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353:179–84.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tradtrantip L, Zhang H, Saadoun S, et al. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol. 2012;71:314–22.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kreye J, Wenke NK, Chayka M, et al. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain. 2016;139:2641–52.CrossRefPubMedGoogle Scholar
  57. 57.
    Granerod J, Davies NW, Ramanuj PP, Easton A, Brown DW, Thomas SL. Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study. J Neurol. 2017;264:407–15.CrossRefPubMedGoogle Scholar
  58. 58.
    Gaspard N, Foreman BP, Alvarez V, et al. New-onset refractory status epilepticus: Etiology, clinical features, and outcome. Neurology. 2015;85:1604–13.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Feyissa AM, Lopez Chiriboga AS, Britton JW. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm. 2017;4:e353.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Finke C, Pruss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with Leucine-rich, Glioma-inactivated 1 antibodies. JAMA Neurol. 2017;74:50–9.PubMedGoogle Scholar
  61. 61.
    Lejuste F, Thomas L, Picard G, et al. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e280.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sacks O, Shulman M. Steroid dementia: an overlooked diagnosis? Neurology. 2005;64:707–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Kowski AB, Weissinger F, Gaus V, Fidzinski P, Losch F, Holtkamp M. Specific adverse effects of antiepileptic drugs—a true-to-life monotherapy study. Epilepsy Behav. 2016;54:150–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Iorio R, Lennon VA. Neural antigen-specific autoimmune disorders. Immunol Rev. 2012;248:104–21.CrossRefPubMedGoogle Scholar
  65. 65.
    McKeon A. Immunotherapeutics for autoimmune encephalopathies and dementias. Curr Treat Options Neurol. 2013;15:723–37.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Johns Hopkins Encephalitis Center, Division of Neuroimmunology and Neuroinfectious Diseases, Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations