癫痫的免疫性病因研究进展_Journal of Epilepsy

Authors：

赵腾 ,  林卫红

吉林大学第一医院神经内科（长春 130021）;

Corresponding author：

林卫红, Email: linweihong321@126.com

Keywords：

癫痫; 免疫性病因; 继发于自身免疫性脑炎的急性症状性发作; 自身免疫相关癫痫

DOI：

10.7507/2096-0247.20200085

Video：

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Abstract Full text Figures/Tables Video References Cited by

国际抗癫痫联盟（ILAE）于 2017 年提出了癫痫的六大病因，其中免疫性病因是目前研究的热点。系统性自身免疫性疾病、神经系统自身免疫性疾病、自身免疫性脑炎（Autoimmune encephalitis，AE）与癫痫的关系均十分密切。其中，AE 与癫痫的关系尤为复杂。从癫痫的概念及AE的特点出发，ILAE 提出了“继发于自身免疫性脑炎的急性症状性发作”及“自身免疫相关癫痫”这两个概念，可以更好地从发病机制及临床特点来认识 AE 与癫痫的关系，为后续的研究理清了思路。

Citation： 赵腾, 林卫红. 癫痫的免疫性病因研究进展. Journal of Epilepsy, 2020, 6(6): 516-522. doi: 10.7507/2096-0247.20200085 Copy

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2.	Ong MS, Kohane IS, Cai T, et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol, 2014, 7l(5): 569-574.
3.	Man Amanat, Roland D Thijs, Mona Salehi, et al. Seizures as a clinical manifestation in somatic autoimmune disorders. Seizure, 2019, 64: 59-64.
4.	Devinsky O, Schein A, Najjar S. Epilepsy associated with systemic autoimmune disorders. Epilepsy Curr, 2013, 13(2): 62-68.
5.	Eriksson K, Peltola J, Keranen T, et al. High prevalence of antiphospholipid antibodies in children with epilepsy: A controlled study of 50 cases. Epilepsy Res, 2001, 46(2): 129-137.
6.	Watad A, Tiosano S, Bragazzi NL, et al. Epilepsy among systemic lupus erythematosus patients: insights from a large database analysis. Neuroepidemiology, 2018, 50(1-2): 1-6.
7.	Chan PC, Yu CH, Yeh KW, et al. Comorbidities of pediatric s ystemic lupus erythematosus: a 6-year nationwide population-based study. J Microbiol Immunol Infect, 2016, 49(2): 257-263.
8.	Hanly JG. Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol, 2014, 10(6): 338-347.
9.	Duarte-Delgado NP, Vasquez G, Ortiz-Reyes B L. Blood-brain barrier disruption and neuroinflammation as pathophysiological mechanisms of the diffuse manifestations of neuropsychiatric systemic lupus erythematosus. Autoimmun Rev, 2019, 18(4): 426-432.
10.	Bialas AR, Presuney J, Das A, et al. Microglia-dependent synapse loss in type I interferon -mediated lupus. Nature, 2017, 5(7659): 539-543.
11.	Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol, 2014, 10(10): 579-596.
12.	Zardi EM, Giorgi C, Zardi DM. Diagnostic approach to neuropsychiatric lupus erythematosus: what should we do? Postgrad Med, 2018, 130(6): 536-547.
13.	Yoneda M, Fujii A, Ito A, et al. High prevalence of serum autoantibodies against the amino terminal of α-enolase in Hashimoto's encephalopathy. Journal of Neuroimmunology, 2007, 185(1): 195-200.
14.	Graham BR, Shiff N, Nour M, et al. Hashimoto Encephalopathy presenting with stroke-like episodes in an adolescent female: a case report and literature review. Pediatr Neurol, 2016, 59: 62-70.
15.	Montagna G, Imperiali M, Agazzi P, et al. Hashimoto’s encephalopathy: a rare proteiform disorder. Autoimmun Rev, 2016, 15(5): 466-476.
16.	Ajjan RA, Weetman AP. The pathogenesis of hashimoto's thyroiditis: Further developments in our understanding. Hormone and Metabolic Research, 2015, 47(10): 702-710.
17.	Ong MS, Kohane IS, Cai T, et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol, 2014, 71(5): 569-574.
18.	Rom AL, Wu CS, Olsen J, et al. Parental rheumatoid arthritis and childhood e pilepsy: a nationwide cohort study. Neurology, 2016, 87(12): 2510-2516.
19.	Loya-de la Cerda DG, Avilés-Solís JC, Delgado-Montemayor MJ, et al. Isolated rheumatoid arthritis-associated cerebral vasculitis: a diagnostic challenge. Joint Bone Spine, 2013, 80: 88-90.
20.	Bourgeois P, Rivest J, Bocti C. Rheumatoid meningitis presenting with stroke-like episodes. Neurology, 2014, 82(17): 1564-1565.
21.	Lorenzoni PJ, Ducci RD, Tensini TS, et al. Treatment of epilepsy in patients with myasthenia gravis: Is really harder than it looks? J Clin Neurosci, 2017, 44: 353-356.
22.	Uzawa A, Kawaguchi N, Himuro K, et al. Serum cytokine and chemokine profiles in patients with myasthenia gravis. Clin Exp Immunol, 2014, 176(2): 232-237.
23.	Williams GH, Nosik WA, Hunter JA. Convulsions as manifestation of multiple sclerosis. JAMA, 1952, 150(10): 990-992.
24.	Gasparini S, Ferlazzo E, Ascoli M, et al. Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and metaanalysis. Neurol Sci, 2017, 38: 399-406.
25.	Benjaminsen E, Myhr KM, Alstadhaug KB. The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland county, Norway. Seizure, 2017, 52: 131-135.
26.	Calabrese M, Castellaro M, Bertoldo A, et al. Epilepsy in multiple sclerosis: the role of temporal lobe damage. Mult Scler, 2017, 23: 473-482.
27.	Vincent A, Crino PB. Systemic and neurologic autoimmune disorders associated with seizures or epilepsy. Epilepsia, 2011, 52(1): 12-17.
28.	Nakano H, Tanaka M, Kinoshita M, et al. Epileptic seizures in Japanese patients with multiple sclerosis and neuromyelitis optica. Epilepsy Res, 2013, 104: 175-180.
29.	Hubbard JA, Szu JI, Binder DK. The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res Bull, 2018, 136(1): 118-129.
30.	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(2): 157-165.
31.	Annette Baumgartner, Sebastian Rauer, Tilman Hottenrott. Admission diagnoses of patients later diagnosed with autoimmune encephalitis. Journal of Neurology, 2019, 266(1): 124-132.
32.	Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol, 2016, 15(4): 391-404.
33.	Keiko Tanaka, Meiko Kawamura, Kenji Sakimura, et al. Significance of autoantibodies in autoimmune encephalitis in relation to antigen localization: an outline of frequently reported autoantibodies with a non-systematic review. Int. J Mol Sci, 2020, 21: 4941.
34.	de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evalua- tion of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology, 2019, 92(19): e2185-2196.
35.	Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest, 2019, 129(3): 926-940.
36.	Claude Steriade, Jeffrey Britton, Russell C. Dale, et al Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune‐associated epilepsy: Conceptual definitions. Epilepsia, 2020, 61(7): 1341-1351.
37.	Gaspard N, Foreman BP, Alvarez V, et al. New-onsetrefractory status epilepticus: Etiology, clinical features, andoutcome. Neurology, 2015, 85(18): 1604-1613.
38.	Fedele L, Newcombe J, Topf M, et al. Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun, 2018, 9(1): 957.
39.	Lynch DR, Rattelle A, Dong YN, et al. Anti-NMDA receptor encephalitis: clinical features and basic mechanisms. Adv Pharmacol, 2018, 82(2): 235-260.
40.	Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbicencephalitis previously attributed to potassium channels: a case series. Lancet Neurol, 2010, 9(8): 776-785.
41.	van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology, 2016, 87(5): 521-528.
42.	Seagar M, Russier M, Caillard O, et al. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proc Natl Acad Sci USA, 2017, 114(29): 7719-7724.
43.	Iyer RS, Ramakrishnan TCR, Karunakaran, et al. Faciobrachial dystonic seizures result from fronto-temporo-basalganglial network involvement. Epilepsy Behav Case Rep, 2017, 8(1): 47-50.
44.	Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol, 2018, 83(1): 40-51.
45.	Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitiswith refractory seizures, status epilepticus, and antibodies to the GABA_A receptor: a case series, characterizeation of the antigen, and analysis of the effects of antibodies. Lancet Neurol, 2014, 13(3): 276-286.
46.	Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABA_A receptor antibody-associated encephalitis. Neurology, 2017, 88(11): 1012-1020.
47.	Mckay JH, Dimberg EL, Lopez CA. A systematic review of gamma-am inobutyric acid receptor type B autoimmunity. Neurol Neurochir Pol, 2019, 53(1): 1-7.
48.	Osvaldo Laurido-Soto, Matthew R Brier, Laura E Simon, et al. Patient charac-teristics and outcome associations in AMPA receptor encephalitis. Journal of Neurology, 2019, 266(2): 450-460.
49.	Adotevi NK, Leitch B. Synaptic changes in AMPA receptor subunit expression in cortical parvalbumin interneurons in the stargazer model of absence epilepsy. Front Mol Neurosci, 2017, 10: 434.
50.	Tohid H. Anti glutamic acid decarboxylase antibody positive neurological syndromes. Neurosci, 2016, 21(3): 215-222.
51.	Bastien Joubert, Aude Belbezier, Julie Haesebaert, et al. Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies. Journal of Neurology, 2020, 267(7): 2083-2089.
52.	Lilleker, J. B., V. Biswas, and R. Mohanraj Glutamic acid decarboxylase (GAD) antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure, 2014, 23(8): 598-602.
53.	Khalil S. Husari1, Divyanshu Dubey. Autoimmune Epilepsy Neurotherap eutics, 2019, 16(3): 685-702.
54.	余年, 狄晴. 正确认识自身免疫性癫痫与自身免疫性脑炎的关系. 中华神经科杂志, 2020, 53(2): 152-156.
55.	Dash D, Pandey S. Movement disorders associated with neuronal antibodies. Acta Neurol Scand, 2019, 139(2): 106-117.
56.	CG Bien, T Granata, C Antozzi, et al. Pathogenesis, diagnosis and treatment of rasmussen encephalitis: a european consensus statement. Brain, 2005, 128(3): 54.
57.	Marianna Spatola, Josep Dalmau. Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Current Opinion in Neurology, 2017, 30(1): 104-106.
58.	Tilman Schneider-Hohendorf, Hema Mohan, Christian G Bien, et al. CD8⁺T cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nature Communications, 2016, 7(1): 153.

1. Levite M. Autoimmune epilepsy. Nat Immunol, 2002, 3(6): 500.
2. Ong MS, Kohane IS, Cai T, et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol, 2014, 7l(5): 569-574.
3. Man Amanat, Roland D Thijs, Mona Salehi, et al. Seizures as a clinical manifestation in somatic autoimmune disorders. Seizure, 2019, 64: 59-64.
4. Devinsky O, Schein A, Najjar S. Epilepsy associated with systemic autoimmune disorders. Epilepsy Curr, 2013, 13(2): 62-68.
5. Eriksson K, Peltola J, Keranen T, et al. High prevalence of antiphospholipid antibodies in children with epilepsy: A controlled study of 50 cases. Epilepsy Res, 2001, 46(2): 129-137.
6. Watad A, Tiosano S, Bragazzi NL, et al. Epilepsy among systemic lupus erythematosus patients: insights from a large database analysis. Neuroepidemiology, 2018, 50(1-2): 1-6.
7. Chan PC, Yu CH, Yeh KW, et al. Comorbidities of pediatric s ystemic lupus erythematosus: a 6-year nationwide population-based study. J Microbiol Immunol Infect, 2016, 49(2): 257-263.
8. Hanly JG. Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol, 2014, 10(6): 338-347.
9. Duarte-Delgado NP, Vasquez G, Ortiz-Reyes B L. Blood-brain barrier disruption and neuroinflammation as pathophysiological mechanisms of the diffuse manifestations of neuropsychiatric systemic lupus erythematosus. Autoimmun Rev, 2019, 18(4): 426-432.
10. Bialas AR, Presuney J, Das A, et al. Microglia-dependent synapse loss in type I interferon -mediated lupus. Nature, 2017, 5(7659): 539-543.
11. Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol, 2014, 10(10): 579-596.
12. Zardi EM, Giorgi C, Zardi DM. Diagnostic approach to neuropsychiatric lupus erythematosus: what should we do? Postgrad Med, 2018, 130(6): 536-547.
13. Yoneda M, Fujii A, Ito A, et al. High prevalence of serum autoantibodies against the amino terminal of α-enolase in Hashimoto's encephalopathy. Journal of Neuroimmunology, 2007, 185(1): 195-200.
14. Graham BR, Shiff N, Nour M, et al. Hashimoto Encephalopathy presenting with stroke-like episodes in an adolescent female: a case report and literature review. Pediatr Neurol, 2016, 59: 62-70.
15. Montagna G, Imperiali M, Agazzi P, et al. Hashimoto’s encephalopathy: a rare proteiform disorder. Autoimmun Rev, 2016, 15(5): 466-476.
16. Ajjan RA, Weetman AP. The pathogenesis of hashimoto's thyroiditis: Further developments in our understanding. Hormone and Metabolic Research, 2015, 47(10): 702-710.
17. Ong MS, Kohane IS, Cai T, et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol, 2014, 71(5): 569-574.
18. Rom AL, Wu CS, Olsen J, et al. Parental rheumatoid arthritis and childhood e pilepsy: a nationwide cohort study. Neurology, 2016, 87(12): 2510-2516.
19. Loya-de la Cerda DG, Avilés-Solís JC, Delgado-Montemayor MJ, et al. Isolated rheumatoid arthritis-associated cerebral vasculitis: a diagnostic challenge. Joint Bone Spine, 2013, 80: 88-90.
20. Bourgeois P, Rivest J, Bocti C. Rheumatoid meningitis presenting with stroke-like episodes. Neurology, 2014, 82(17): 1564-1565.
21. Lorenzoni PJ, Ducci RD, Tensini TS, et al. Treatment of epilepsy in patients with myasthenia gravis: Is really harder than it looks? J Clin Neurosci, 2017, 44: 353-356.
22. Uzawa A, Kawaguchi N, Himuro K, et al. Serum cytokine and chemokine profiles in patients with myasthenia gravis. Clin Exp Immunol, 2014, 176(2): 232-237.
23. Williams GH, Nosik WA, Hunter JA. Convulsions as manifestation of multiple sclerosis. JAMA, 1952, 150(10): 990-992.
24. Gasparini S, Ferlazzo E, Ascoli M, et al. Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and metaanalysis. Neurol Sci, 2017, 38: 399-406.
25. Benjaminsen E, Myhr KM, Alstadhaug KB. The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland county, Norway. Seizure, 2017, 52: 131-135.
26. Calabrese M, Castellaro M, Bertoldo A, et al. Epilepsy in multiple sclerosis: the role of temporal lobe damage. Mult Scler, 2017, 23: 473-482.
27. Vincent A, Crino PB. Systemic and neurologic autoimmune disorders associated with seizures or epilepsy. Epilepsia, 2011, 52(1): 12-17.
28. Nakano H, Tanaka M, Kinoshita M, et al. Epileptic seizures in Japanese patients with multiple sclerosis and neuromyelitis optica. Epilepsy Res, 2013, 104: 175-180.
29. Hubbard JA, Szu JI, Binder DK. The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res Bull, 2018, 136(1): 118-129.
30. 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(2): 157-165.
31. Annette Baumgartner, Sebastian Rauer, Tilman Hottenrott. Admission diagnoses of patients later diagnosed with autoimmune encephalitis. Journal of Neurology, 2019, 266(1): 124-132.
32. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol, 2016, 15(4): 391-404.
33. Keiko Tanaka, Meiko Kawamura, Kenji Sakimura, et al. Significance of autoantibodies in autoimmune encephalitis in relation to antigen localization: an outline of frequently reported autoantibodies with a non-systematic review. Int. J Mol Sci, 2020, 21: 4941.
34. de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evalua- tion of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology, 2019, 92(19): e2185-2196.
35. Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest, 2019, 129(3): 926-940.
36. Claude Steriade, Jeffrey Britton, Russell C. Dale, et al Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune‐associated epilepsy: Conceptual definitions. Epilepsia, 2020, 61(7): 1341-1351.
37. Gaspard N, Foreman BP, Alvarez V, et al. New-onsetrefractory status epilepticus: Etiology, clinical features, andoutcome. Neurology, 2015, 85(18): 1604-1613.
38. Fedele L, Newcombe J, Topf M, et al. Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun, 2018, 9(1): 957.
39. Lynch DR, Rattelle A, Dong YN, et al. Anti-NMDA receptor encephalitis: clinical features and basic mechanisms. Adv Pharmacol, 2018, 82(2): 235-260.
40. Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbicencephalitis previously attributed to potassium channels: a case series. Lancet Neurol, 2010, 9(8): 776-785.
41. van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology, 2016, 87(5): 521-528.
42. Seagar M, Russier M, Caillard O, et al. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proc Natl Acad Sci USA, 2017, 114(29): 7719-7724.
43. Iyer RS, Ramakrishnan TCR, Karunakaran, et al. Faciobrachial dystonic seizures result from fronto-temporo-basalganglial network involvement. Epilepsy Behav Case Rep, 2017, 8(1): 47-50.
44. Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol, 2018, 83(1): 40-51.
45. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitiswith refractory seizures, status epilepticus, and antibodies to the GABA_A receptor: a case series, characterizeation of the antigen, and analysis of the effects of antibodies. Lancet Neurol, 2014, 13(3): 276-286.
46. Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABA_A receptor antibody-associated encephalitis. Neurology, 2017, 88(11): 1012-1020.
47. Mckay JH, Dimberg EL, Lopez CA. A systematic review of gamma-am inobutyric acid receptor type B autoimmunity. Neurol Neurochir Pol, 2019, 53(1): 1-7.
48. Osvaldo Laurido-Soto, Matthew R Brier, Laura E Simon, et al. Patient charac-teristics and outcome associations in AMPA receptor encephalitis. Journal of Neurology, 2019, 266(2): 450-460.
49. Adotevi NK, Leitch B. Synaptic changes in AMPA receptor subunit expression in cortical parvalbumin interneurons in the stargazer model of absence epilepsy. Front Mol Neurosci, 2017, 10: 434.
50. Tohid H. Anti glutamic acid decarboxylase antibody positive neurological syndromes. Neurosci, 2016, 21(3): 215-222.
51. Bastien Joubert, Aude Belbezier, Julie Haesebaert, et al. Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies. Journal of Neurology, 2020, 267(7): 2083-2089.
52. Lilleker, J. B., V. Biswas, and R. Mohanraj Glutamic acid decarboxylase (GAD) antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure, 2014, 23(8): 598-602.
53. Khalil S. Husari1, Divyanshu Dubey. Autoimmune Epilepsy Neurotherap eutics, 2019, 16(3): 685-702.
54. 余年, 狄晴. 正确认识自身免疫性癫痫与自身免疫性脑炎的关系. 中华神经科杂志, 2020, 53(2): 152-156.
55. Dash D, Pandey S. Movement disorders associated with neuronal antibodies. Acta Neurol Scand, 2019, 139(2): 106-117.
56. CG Bien, T Granata, C Antozzi, et al. Pathogenesis, diagnosis and treatment of rasmussen encephalitis: a european consensus statement. Brain, 2005, 128(3): 54.
57. Marianna Spatola, Josep Dalmau. Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Current Opinion in Neurology, 2017, 30(1): 104-106.
58. Tilman Schneider-Hohendorf, Hema Mohan, Christian G Bien, et al. CD8⁺T cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nature Communications, 2016, 7(1): 153.

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