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Diagnosis and treatment-related issues of autoimmune epilepsy


Due to elevated frequency of autoimmune epilepsy cases, the issues related to reliable clinical and laboratory-instrumental criteria for establishing the disease etiology become relevant. Differentiated assessment of autoantibody markers allows to choose the most effective tactics for managing patients. The article presents the criteria for assessing autoimmune epilepsy as well as diagnostic scales, features related to clinical picture and response to therapy based on the type of synthesized autoantibodies. Therapeutic lines and targets for immunomodulatory and antiepileptic drugs used in autoimmune epilepsy are detailed, the knowledge of which along with clinical and laboratory data collectively allow to determine effective and safe therapy algorithm.

About the Authors

O. S. Shilkina
Voino-Yasenetsky Krasnoyarsk State Medical University
Russian Federation

Olga S. Shilkina – MD, PhD, Neurologist, Neurological Center of Epileptology, Neurogenetics and Brain Research, University Clinic

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

E. E. Timechko
Voino-Yasenetsky Krasnoyarsk State Medical University
Russian Federation

Elena E. Timechko – Junior Researcher, Laboratory of Medical Genetics, Center of Collective Usage “Molecular and Cellular Technologies”

WoS ResearcherID: CAF-2677-2022

1 Partizan Zheleznyak Str., Krasnoyarsk 660022

D. V. Dmitrenko
Voino-Yasenetsky Krasnoyarsk State Medical University
Russian Federation

Diana V. Dmitrenko – Dr. Med. Sc., Chief of Chair of Medical Genetics and Clinical Neurophysiology, Institute of Professional Education

WoS ResearcherID: H-7787-2016

1 Partizan Zheleznyak Str., Krasnoyarsk 660022


1. Jang Y., Kim D.W., Yang K.I., et al. Clinical approach to autoimmune epilepsy. J Clin Neurol. 2020; 16 (4): 519–29.

2. Scheffer I.E., Berkovic S., Capovilla G., et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017; 58 (4): 512–21.

3. Steriade C., Britton J., Dale R.C., et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmuneassociated epilepsy: conceptual definitions. Epilepsia. 2020; 61 (7): 1341–51.

4. Toledano M., Britton J.W., McKeon A., et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology. 2014; 82 (18): 1578–86.

5. Graus F., Titulaer M.J., Balu R., et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15 (4): 391–404.

6. Shilkina О.S., Kantimirova E.A., Usoltseva A.A., et al. Autoimmune epilepsy. Epilepsia i paroksizmalʹnye sostoania / Epilepsy and Paroxysmal Conditions. 2022; 14 (1): 74–90 (in Russ.).

7. Fang Z., Yang Y., Chen X., et al. Advances in autoimmune epilepsy associated with antibodies, their potential pathogenic molecular mechanisms, and current recommended immunotherapies. Front Immunol. 2017; 8: 395.

8. Taraschenko O., Fox H.S., Pittock S.J., et al. A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis. Epilepsia. 2019; 60 (3): 452–63.

9. von Podewils F., Suesse M., Geithner J., et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia. 2017; 58 (9): 1542–50.

10. Elisak M., Krysl D., Hanzalova J., et al. The prevalence of neural antibodies in temporal lobe epilepsy and the clinical characteristics of seropositive patients. Seizure. 2018; 63: 1–6.

11. Nóbrega A.W. Jr., Gregory C.P., Schlindwein-Zanini R., et al. Mesial temporal lobe epilepsy with hippocampal sclerosis is infrequently associated with neuronal autoantibodies. Epilepsia. 2018; 59 (9): e152–6.

12. Ismail F.S., Spatola M., Woermann F.G., et al. Diagnostic challenges in patients with temporal lobe seizures and features of autoimmune limbic encephalitis. Eur J Neurol. 2022; 29 (5): 1303–10. https://doi. org/10.1111/ene.15026.

13. Yavuz E.N.V., Altındağ E., Tüzün E., Baykan B. Do the neurologists recognize autoimmune epilepsy well enough? What is the effect of the pandemic on this matter? Neurol Sci. 2022; 43 (8): 5029–37.

14. Panina Yu.S., Dmitrenko D.V., Sapronova M.R. Clinical case of early diagnosis of autoimmune epilepsy. Doctor.Ru. 2019; 1: 10–3 (in Russ.).

15. Irani S.R., Michell A.W., Lang B., et al. Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol. 2011; 69 (5): 892–900.

16. Lv R.J., Ren H.T., Guan H.Z., et al. Seizure semiology: an important clinical clue to the diagnosis of autoimmune epilepsy. Ann Clin Transl Neurol. 2018; 5 (2): 208–15.

17. Chen B., López Chiriboga A.S., Sirven J.I., Feyissa A.M. Autoimmune encephalitise related seizures and epilepsy: diagnostic and therapeutic approaches. Mayo Clin Proc. 2021; 96 (8): 2029–39.

18. Gaspard N., Foreman B.P., Alvarez V., et al. New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology. 2015; 85 (18): 1604–13.

19. Irani S.R., Stagg C.J., Schott J.M., 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): 3151–62.

20. Granerod J., Ambrose H.E., Davies N.W., et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010; 10 (12): 835–44.

21. de Bruijn M.A.A.M., Bastiaansen A.E.M., Mojzisova H., et al. Antibodies contributing to focal epilepsy signs and symptoms score. Ann Neurol. 2021; 89 (4): 698–710.

22. Muñoz-Lopetegi A., de Bruijn M.A.A.M., Boukhrissi S., et al. Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020; 7 (3): e696.

23. Pittock S.J., Yoshikawa H., Ahlskog J.E., et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc. 2006; 81 (9): 1207–14.

24. Falip M., Rodriguez-Bel L., Castañer S., et al. Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies. Acta Neurol Scand. 2018; 137 (2): 272–6.

25. Mattozzi S., Sabater L., Escudero D., et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020; 94 (2): e217–24.

26. McKeon A., Tracy J.A. GAD65 neurological autoimmunity. Muscle Nerve. 2017; 56 (1): 15–27.

27. van Sonderen A., Schreurs M.W., de Bruijn M.A., et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016; 86 (18): 1692–9.

28. Michael S., Waters P., Irani S.R. Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Pract Neurol. 2020; 20 (5): 377–84.

29. Lang B., Makuch M., Moloney T., et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry. 2017; 88 (4): 353–61.

30. Ding S., Gong J., Lin J., et al. Validation of predictive models for autoimmune encephalitis-related antibodies to cell-surface proteins expressed in neurons: a retrospective study based in a hospital. Front Neurol. 2021; 12: 601761.

31. Dubey D., Pittock S.J., McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia. 2019; 60 (2): 367–9.

32. Hara M., Martinez-Hernandez E., Ariño H., et al. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology. 2018; 90 (16): e1386–94.

33. Iizuka T., Yoshii S., Kan S., et al. Reversible brain atrophy in anti-NMDA receptor encephalitis: a long-term observational study. J Neurol. 2010; 257 (10): 1686–91.

34. Finke C., Prüss 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 (1): 50–9.

35. Spatola M., Petit-Pedrol M., Simabukuro M.M., et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology. 2017; 88 (11): 1012–20.

36. Baumgartner A., Rauer S., Masder I., Meyer P.T. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody. J Neurol. 2013; 260: 2744–53.

37. Thompson J., Bi M., Murchison A.G., et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018; 141 (2): 348–56.

38. Quek A.M., Britton J.W., McKeon A., et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol. 2012; 69 (5): 582–93.

39. Sapolsky R.M., McEwen B.S., Rainbow T.C. Quantitative autoradiography of [3H] corticosterone receptors in rat brain. Brain Res. 1983; 271 (2): 331–4.

40. Al Amrani F., Dudley R., Bello-Espinosa L.E., et al. Intravenous immunoglobulin as a treatment for intractable epilepsy secondary to focal cortical dysplasia: a meta-analysis. Pediatr Neurol. 2017; 76: 79– 81.

41. Sunwoo J.S. Corticosteroid treatment in autoimmune encephalitis. J Neurocrit Care. 2017; 10 (2): 60–8.

42. Vandevyver S., Dejager L., Tuckermann J., Libert C. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology. 2013; 154 (3): 993–1007.

43. Mahata B., Zhang X., Kolodziejczyk A.A., et al. Single-cell RNA sequencing reveals T helper cells synthesizing steroids de novo to contribute to immune homeostasis. Cell Rep. 2014; 7 (4): 1130–42.

44. Schwab I., Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013; 13 (3): 176–89.

45. Jang Y., Lee S.T., Kim T.J., et al. High albumin level is a predictor of favorable response to immunotherapy in autoimmune encephalitis. Sci Rep. 2018; 8: 1012.

46. Shin Y.W., Lee S.T., Park K.I., et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2018; 11: 1756285617722347.

47. Lee W.J., Lee S.T., Byun J.I., et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016; 86 (18): 1683–91.

48. Johnson P.W., Glennie M.J. Rituximab: mechanisms and applications. Br J Cancer. 2001; 85 (11): 1619–23.

49. Martin S.T., Cardwell S.M., Nailor M.D., Gabardi S. Hepatitis B reactivation and rituximab: a new boxed warning and considerations for solid organ transplantation. Am J Transplant. 2014; 14 (4): 788–96.

50. Lee W.J., Lee S.T., Moon J., et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics. 2016; 13 (4): 824–32.

51. Shetty A., Hanson R., Korsten P., et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther. 2014; 8: 349– 64.

52. Emadi A., Jones R.J., Brodsky R.A. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009; 6 (11): 638–47.

53. Jang Y., Woo K.A., Lee S.T., et al. Cerebral autoinflammatory disease treated with anakinra. Ann Clin Transl Neurol. 2018; 5 (11): 1428–33.

54. Kenney-Jung D.L., Vezzani A., Kahoud R.J., et al. Febrile infectionrelated epilepsy syndrome treated with anakinra. Ann Neurol. 2016; 80 (6): 939–45.

55. Mertens M., Singh J.A. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009; 36 (6): 1118–25.

56. Shin Y.W., Lee S.T., Kim T.J., et al. Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis. Ann Clin Transl Neurol. 2018; 5 (5): 598–605.

57. Meister S., Schubert U., Neubert K., et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 2007; 67 (4): 1783–92.

58. Johnson P.J., McFarlane I.G., Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995; 333 (15): 958–63.

59. Iaccarino L., Rampudda M., Canova M., et al. Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases? Autoimmun Rev. 2007; 6 (3): 190–5.

60. Ginzler E.M., Aranow C. Mycophenolate mofetil in lupus nephritis. Lupus. 2005; 14 (1): 59–64.

61. Titulaer M.J., 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 (2): 157–65.

62. McGinty R.N., Handel A., Moloney T., et al. Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies. J Neurol Neurosurg Psychiatry. 2021; 92 (3): 291–4.

63. Dubey D., Britton J., McKeon A., et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol. 2020; 87 (2): 313–23.

64. Irani S.R., Gelfand J.M., Bettcher B.M., et al. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy. JAMA Neurol. 2014; 71 (7): 896–900.

65. Xu X., Lu Q., Huang Y., et al. Anti-NMDAR encephalitis: a single-center, longitudinal study in China. Neurol Neuroimmunol Neuroinflamm. 2020; 7 (1): e633.

66. Gofton T.E., Gaspard N., Hocker S.E., et al. New onset refractory status epilepticus research: what is on the horizon? Neurology. 2019; 92 (17): 802–10.

67. Jun J.S., Lee S.T., Kim R., et al. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol. 2018; 84 (6): 940–5.

68. Sakuma H., Tanuma N., Kuki I., et al. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus. J Neurol Neurosurg Psychiatry. 2015; 86 (7): 820–2.

69. Feyissa A.M., López Chiriboga A.S., Britton J.W. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm. 2017; 4 (4): e353.

70. Vogrig A., Joubert B., André-Obadia N., et al. Seizure specificities in patients with antibodymediated autoimmune encephalitis. Epilepsia. 2019; 60 (8): 1508–25.

71. de Bruijn M.A.A.M., van Sonderen A., van Coevorden-Hameete M.H., et al. Evaluation of seizure treatment in antiLGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology. 2019; 92 (19): e2185–96.


For citations:

Shilkina O.S., Timechko E.E., Dmitrenko D.V. Diagnosis and treatment-related issues of autoimmune epilepsy. Epilepsy and paroxysmal conditions. 2023;15(2):135–147. (In Russ.)

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ISSN 2077-8333 (Print)
ISSN 2311-4088 (Online)