, Volume 16, Issue 3, pp 685–702 | Cite as

Autoimmune Epilepsy

  • Khalil S. Husari
  • Divyanshu DubeyEmail author
Current Perspectives


The field of autoimmune epilepsy has evolved substantially in the last few decades with discovery of several neural autoantibodies and improved mechanistic understanding of these immune-mediated syndromes. A considerable proportion of patients with epilepsy of unknown etiology have been demonstrated to have an autoimmune cause. The majority of the patients with autoimmune epilepsy usually present with new-onset refractory seizures along with subacute progressive cognitive decline and behavioral or psychiatric dysfunction. Neural specific antibodies commonly associated with autoimmune epilepsy include leucine-rich glioma-inactivated protein 1 (LGI1), N-methyl-d-aspartate receptor (NMDA-R), and glutamic acid decarboxylase 65 (GAD65) IgG. Diagnosis of these cases depends on the identification of the clinical syndrome and ancillary studies including autoantibody evaluation. Predictive models (Antibody Prevalence in Epilepsy and Encephalopathy [APE2] and Response to Immunotherapy in Epilepsy and Encephalopathy [RITE2] scores) based on clinical features and initial neurological assessment may be utilized for selection of cases for autoimmune epilepsy evaluation and management. In this article, we will review the recent advances in autoimmune epilepsy and provide diagnostic and therapeutic algorithms for epilepsies with suspected autoimmune etiology.

Key Words

Autoimmune limbic encephalitis Diagnosis Epilepsy Immunotherapy 



  1. 1.
    Ong, M.S., et al., Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol, 2014. 71(5): p. 569–74.Google Scholar
  2. 2.
    Brodie, M.J., et al., The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? Epileptic Disord, 2018. 20(2): p. 77–87.Google Scholar
  3. 3.
    Dubey, D., S.J. Pittock, and A. McKeon, Antibody Prevalence in Epilepsy and Encephalopathy score: Increased specificity and applicability. Epilepsia, 2019. 60(2): p. 367–369.Google Scholar
  4. 4.
    Dubey, D., et al., Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA Neurol, 2017. 74(4): p. 397–402.Google Scholar
  5. 5.
    Scheffer, I.E., et al., ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017. 58(4): p. 512–521.Google Scholar
  6. 6.
    Granata, T. and F. Andermann, Rasmussen encephalitis. Handb Clin Neurol, 2013. 111: p. 511–9.Google Scholar
  7. 7.
    Britton, J., Autoimmune epilepsy. Handb Clin Neurol, 2016. 133: p. 219–45.Google Scholar
  8. 8.
    Dalmau, J. and F. Graus, Antibody-Mediated Encephalitis. N Engl J Med, 2018. 378(9): p. 840–851.Google Scholar
  9. 9.
    Larman, H.B., et al., Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol, 2011. 29(6): 535–41.Google Scholar
  10. 10.
    Scharf, M., et al., A Spectrum of Neural Autoantigens, Newly Identified by Histo-Immunoprecipitation, Mass Spectrometry, and Recombinant Cell-Based Indirect Immunofluorescence. Front Immunol, 2018. 9: p. 1447.Google Scholar
  11. 11.
    Schubert, R.D. and M.R. Wilson, A tale of two approaches: how metagenomics and proteomics are shaping the future of encephalitis diagnostics. Curr Opin Neurol, 2015. 28(3): p. 283–7.Google Scholar
  12. 12.
    Sun, H., G.Y. Chen, and S.Q. Yao, Recent advances in microarray technologies for proteomics. Chem Biol, 2013. 20(5): p. 685–99.Google Scholar
  13. 13.
    Toledano, M., et al., Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology, 2014. 82(18): p. 1578–86.Google Scholar
  14. 14.
    Dubey, D., et al., Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol, 2018. 83(1): p. 166–177.Google Scholar
  15. 15.
    Dubey, D., M. Toledano, and A. McKeon, Clinical presentation of autoimmune and viral encephalitides. Curr Opin Crit Care, 2018. 24(2): p. 80–90.Google Scholar
  16. 16.
    Graus, F., et al., Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 2004. 75(8): p. 1135–40.Google Scholar
  17. 17.
    Dubey, D., et al., Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia, 2017. 58(7): 1181–1189.Google Scholar
  18. 18.
    Brenner, T., et al., Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia, 2013. 54(6): p. 1028–35.Google Scholar
  19. 19.
    Abramovici, S. and A. Bagic, Epidemiology of epilepsy. Handb Clin Neurol, 2016. 138: 159–71.Google Scholar
  20. 20.
    Wright, S., et al., Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. Epilepsia, 2016. 57(5): p. 823–31.Google Scholar
  21. 21.
    Suleiman, J., et al., Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies. Epilepsia, 2013. 54(12): p. 2091–100.Google Scholar
  22. 22.
    Bauer, J., et al., Innate and adaptive immunity in human epilepsies. Epilepsia, 2017. 58 Suppl 3: p. 57–68.Google Scholar
  23. 23.
    Fujinami, R.S., et al., Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev, 2006. 19(1): p. 80–94.Google Scholar
  24. 24.
    Armangue, T., 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):760-772.Google Scholar
  25. 25.
    Ohkawa, T., et al., Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci, 2013. 33(46): p. 18161–74.Google Scholar
  26. 26.
    Aysit-Altuncu, N., et al., Effect of LGI1 antibody-positive IgG on hippocampal neuron survival: a preliminary study. Neuroreport, 2018. 29(11): p. 932–938.Google Scholar
  27. 27.
    Hughes, E.G., et al., Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci, 2010. 30(17): 5866–75.Google Scholar
  28. 28.
    Gresa-Arribas, N., et al., Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol, 2014. 13(2): p. 167–77.Google Scholar
  29. 29.
    Albert, M.L., et al., Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med, 1998. 4(11): p. 1321–4.Google Scholar
  30. 30.
    Flanagan, E. P., et al., (2017), Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis of 102 patients. Ann Neurol., 81:298–309.Google Scholar
  31. 31.
    Liimatainen, S., et al., Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia, 2010. 51(5): p. 760–7.Google Scholar
  32. 32.
    Daif, A., et al., Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav, 2018. 80: p. 331–336.Google Scholar
  33. 33.
    Dubey, D., et al., Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol, 2018. 323: p. 62–72.Google Scholar
  34. 34.
    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, 2013. 12(2): p. 157–65.Google Scholar
  35. 35.
    Dalmau, J., C. Geis, and F. Graus, Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System. Physiol Rev, 2017. 97(2): p. 839–887.Google Scholar
  36. 36.
    Quek, A.M.L. and O. O’Toole, Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management. Semin Neurol, 2018. 38(3): p. 290–302.Google Scholar
  37. 37.
    Dalmau, J., et al., Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol, 2007. 61(1): p. 25–36.Google Scholar
  38. 38.
    Titulaer, M.J., et al., Late-onset anti-NMDA receptor encephalitis. Neurology, 2013. 81(12): 1058–63.Google Scholar
  39. 39.
    Mueller, S.H., et al., Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol, 2018. 83(4): p. 863–869.Google Scholar
  40. 40.
    Sebastian Lopez-Chiriboga, A., et al., LGI1 and CASPR2 Neurological Autoimmunity in Children. Ann Neurol, 2018. 84(3):473-480Google Scholar
  41. 41.
    Irani, S.R., et al., Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol, 2011. 69(5): p. 892–900.Google Scholar
  42. 42.
    Gadoth, A., et al., Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol, 2017. 82(1): 79–92.Google Scholar
  43. 43.
    Lilleker, J.B., et al., The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology, 2016. 87(17): 1848–1849.Google Scholar
  44. 44.
    van Sonderen, A., et al., The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology, 2016. 86(18): p. 1692–9.Google Scholar
  45. 45.
    Lai, M., et al., AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol, 2009. 65(4): p. 424–34.Google Scholar
  46. 46.
    Haselmann, H., et al., Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron, 2018. 100(1):91-105.e9Google Scholar
  47. 47.
    Hoftberger, R., et al., Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology, 2015. 84(24): p. 2403–12.Google Scholar
  48. 48.
    Joubert, B., et al., Clinical Spectrum of Encephalitis Associated With Antibodies Against the alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor: Case Series and Review of the Literature. JAMA Neurol, 2015. 72(10): p. 1163–9.Google Scholar
  49. 49.
    Boronat, A., et al., Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol, 2013. 73(1): p. 120–8.Google Scholar
  50. 50.
    Carr, I., The Ophelia syndrome: memory loss in Hodgkin’s disease. Lancet, 1982. 1(8276): p. 844–5.Google Scholar
  51. 51.
    Lancaster, E., et al., Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology, 2011. 77(18): 1698–701.Google Scholar
  52. 52.
    Spatola, M., et al., Encephalitis with mGluR5 antibodies: Symptoms and antibody effects. Neurology, 2018. 90(22): p. e1964-e1972.Google Scholar
  53. 53.
    Pittock, S.J., et al., Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc, 2006. 81(9): p. 1207–14.Google Scholar
  54. 54.
    Peltola, J., et al., Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology, 2000. 55(1): p. 46–50.Google Scholar
  55. 55.
    Lilleker, J.B., V. Biswas, and R. Mohanraj, Glutamic acid decarboxylase (GAD) antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure, 2014. 23(8): p. 598–602.Google Scholar
  56. 56.
    Roberts, W.K., et al., Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells. J Clin Invest, 2009. 119(7): 2042–51.Google Scholar
  57. 57.
    Rudzinski, L.A., et al., Extratemporal EEG and MRI findings in ANNA-1 (anti-Hu) encephalitis. Epilepsy Res, 2011. 95(3): p. 255–62.Google Scholar
  58. 58.
    Pittock, S.J., C.F. Lucchinetti, and V.A. Lennon, Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol, 2003. 53(5): p. 580–7.Google Scholar
  59. 59.
    Dalmau, J., et al., Clinical analysis of anti-Ma2-associated encephalitis. Brain, 2004. 127(Pt 8): 1831–44.Google Scholar
  60. 60.
    Voltz, R., et al., A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med, 1999. 340(23): p. 1788–95.Google Scholar
  61. 61.
    Yu, Z., et al., CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol, 2001. 49(2): p. 146–54.Google Scholar
  62. 62.
    Dubey, D., et al., Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology, 2018. 90(2): p. e103-e110.Google Scholar
  63. 63.
    Vernino, S., et al., Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol, 2002. 51(5): p. 625–30.Google Scholar
  64. 64.
    Quek, A.M., et al., Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol, 2012. 69(5): p. 582–93.Google Scholar
  65. 65.
    Bien, C.G., et al., Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain, 2005. 128(Pt 3): p. 454–71.Google Scholar
  66. 66.
    Longaretti, F., et al., Evolution of the EEG in children with Rasmussen’s syndrome. Epilepsia, 2012. 53(9): p. 1539–45.Google Scholar
  67. 67.
    Bien, C.G., et al., Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia, 2013. 54(3): p. 543–50.Google Scholar
  68. 68.
    Vining, E.P., et al., Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996. Pediatrics, 1997. 100(2 Pt 1): p. 163–71.Google Scholar
  69. 69.
    Gaspard, N., et al., New-onset refractory status epilepticus: Etiology, clinical features, and outcome. Neurology, 2015. 85(18): p. 1604–13.Google Scholar
  70. 70.
    Gaspard, N., et al., New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia, 2018. 59(4): p. 745–752.Google Scholar
  71. 71.
    Kaplan, P.W. and R. Sutter, Electroencephalography of autoimmune limbic encephalopathy. J Clin Neurophysiol, 2013. 30(5): p. 490–504.Google Scholar
  72. 72.
    Schmitt, S.E., et al., Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology, 2012. 79(11): p. 1094–100.Google Scholar
  73. 73.
    Baykan, B., et al., Delta Brush Pattern Is Not Unique to NMDAR Encephalitis: Evaluation of Two Independent Long-Term EEG Cohorts. Clin EEG Neurosci, 2018. 49(4): p. 278–284.Google Scholar
  74. 74.
    Aurangzeb, S., et al., LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures. Seizure, 2017. 50: p. 14–17.Google Scholar
  75. 75.
    Graus, F., et al., A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol, 2016. 15(4): p. 391–404.Google Scholar
  76. 76.
    Escudero, D., et al., Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology, 2017. 89(14): p. 1471–1475.Google Scholar
  77. 77.
    Dubey, D., et al., The spectrum of autoimmune encephalopathies. J Neuroimmunol, 2015. 287: p. 93–7.Google Scholar
  78. 78.
    Malter, M.P., et al., Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement. Epilepsia, 2016. 57(9): p. 1485–94.Google Scholar
  79. 79.
    Finke, C., et al., Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol, 2013. 74(2): 284–96.Google Scholar
  80. 80.
    Solnes, L.B., et al., Diagnostic Value of (18)F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis. J Nucl Med, 2017. 58(8): p. 1307–1313.Google Scholar
  81. 81.
    Probasco, J.C., et al., Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker. Neurol Neuroimmunol Neuroinflamm, 2018. 5(1): e413.Google Scholar
  82. 82.
    Ohta, K., et al., Perfusion IMP-SPECT shows reversible abnormalities in GABA(B) receptor antibody associated encephalitis with normal MRI. Brain Behav, 2011. 1(2): 70–2.Google Scholar
  83. 83.
    Guerin, J., et al., Autoimmune epilepsy: findings on MRI and FDG-PET. Br J Radiol, 2019. 92(1093): p. 20170869.Google Scholar
  84. 84.
    Heine, J., et al., Imaging of autoimmune encephalitis--Relevance for clinical practice and hippocampal function. Neuroscience, 2015. 309: p. 68–83.Google Scholar
  85. 85.
    Irani, S.R. and A. Vincent, Voltage-gated potassium channel-complex autoimmunity and associated clinical syndromes. Handb Clin Neurol, 2016. 133: p. 185–97.Google Scholar
  86. 86.
    Flanagan, E.P., et al., Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm, 2015. 2(6): p. e161.Google Scholar
  87. 87.
    Shin, Y.W., et al., VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol, 2013. 265(1–2): p. 75–81.Google Scholar
  88. 88.
    Fredriksen, J.R., et al., MRI findings in glutamic acid decarboxylase associated autoimmune epilepsy. Neuroradiology, 2018. 60(3): p. 239–245.Google Scholar
  89. 89.
    Spatola, M., et al., Investigations in GABAA receptor antibody-associated encephalitis. Neurology, 2017. 88(11): 1012–1020.Google Scholar
  90. 90.
    Dogan Onugoren, M., et al., Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry, 2015. 86(9): 965–72.Google Scholar
  91. 91.
    Hoftberger, R., et al., Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology, 2013. 81(17): p. 1500–6.Google Scholar
  92. 92.
    Do, L.D., et al., Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies. Neurology, 2017. 88(6): 514–524.Google Scholar
  93. 93.
    Pittock, S.J. and J. Palace, Paraneoplastic and idiopathic autoimmune neurologic disorders: approach to diagnosis and treatment: Handb Clin Neurol, 2016. 133: p. 165–83.Google Scholar
  94. 94.
    Irani, S.R., et al., Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain, 2013. 136(Pt 10): p. 3151–62.Google Scholar
  95. 95.
    Byun, J.I., et al., Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study. PLoS One, 2016. 11(1): p. e0146455.Google Scholar
  96. 96.
    Thompson, J., et al., The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain, 2018. 141(2): 348–356.Google Scholar
  97. 97.
    Scheibe, F., et al., Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology, 2017. 88(4): p. 366–370.Google Scholar
  98. 98.
    Kishimoto, T., IL-6: from its discovery to clinical applications. Int Immunol, 2010. 22(5): p. 347–52.Google Scholar
  99. 99.
    Abbott, B.P., et al., GW170104: Observation of a 50-Solar-Mass Binary Black Hole Coalescence at Redshift 0.2. Phys Rev Lett, 2017. 118(22): p. 221101.Google Scholar
  100. 100.
    Jun, J.S., et al., Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol, 2018. 84(6): p. 940–945.Google Scholar
  101. 101.
    Lee, W.J., et al., Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study. Neurotherapeutics, 2016. 13(4): p. 824–832.Google Scholar
  102. 102.
    Abou-Khalil, B.W., Antiepileptic Drugs. Continuum (Minneap Minn), 2016. 22(1 Epilepsy): p. 132–56.Google Scholar
  103. 103.
    Feyissa, A.M., A.S. Lopez Chiriboga, and J.W. Britton, Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm, 2017. 4(4): p. e353.Google Scholar
  104. 104.
    Beghi, E. and S. Shorvon, Antiepileptic drugs and the immune system. Epilepsia, 2011. 52 Suppl 3: p. 40–4.Google Scholar
  105. 105.
    Carreno, M., et al., Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies. Epilepsy Res, 2017. 129: p. 101–105.Google Scholar
  106. 106.
    Malter, M.P., et al., Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure, 2015. 30: p. 57–63.Google Scholar
  107. 107.
    Gadoth, A., et al., Elevated LGI1-IgG CSF index predicts worse neurological outcome. Ann Clin Transl Neurol, 2018. 5(5): p. 646–650.Google Scholar
  108. 108.
    Balu, R., et al., A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology, 2019. 92(3): p. e244-e252.Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Comprehensive Epilepsy Center, Department of NeurologyJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of Neurology and Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA

Personalised recommendations