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01-03-2021 | Epilepsy | Original Communication

Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data

Authors: Anna Rada, Robert Birnbacher, Claudio Gobbi, Martin Kurthen, Albert Ludolph, Markus Naumann, Ulrike Neirich, Tim J. von Oertzen, Gerhard Ransmayr, Matthias Riepe, Mareike Schimmel, Oliver Schwartz, Rainer Surges, Christian G. Bien

Published in: Journal of Neurology | Issue 3/2021

Abstract

Background

Clinicians have questioned whether any disorder involving seizures and neural antibodies should be called “(auto)immune epilepsy.” The concept of “acute symptomatic seizures” may be more applicable in cases with antibodies against neural cell surface antigens. We aimed at determining the probability of achieving seizure-freedom, the use of anti-seizure medication (ASM), and immunotherapy in patients with either constellation. As a potential pathophysiological correlate, we analyzed antibody titer courses.

Methods

Retrospective cohort study of 39 patients with seizures and neural antibodies, follow-up ≥ 3 years.

Results

Patients had surface antibodies against the N-methyl-d-aspartate receptor (NMDAR, n = 6), leucine-rich glioma inactivated protein 1 (LGI1, n = 11), contactin-associated protein-2 (CASPR2, n = 8), or antibodies against the intracellular antigens glutamic acid decarboxylase 65 kDa (GAD65, n = 13) or Ma2 (n = 1). Patients with surface antibodies reached first seizure-freedom (88% vs. 7%, P < 0.001) and terminal seizure-freedom (80% vs. 7%, P < 0.001) more frequently. The time to first and terminal seizure-freedom and the time to freedom from ASM were shorter in the surface antibody group (Kaplan–Meier curves: P < 0.0001 for first seizure-freedom; P < 0.0001 for terminal seizure-freedom; P = 0.0042 for terminal ASM-freedom). Maximum ASM defined daily doses were higher in the groups with intracellular antibodies. Seizure-freedom was achieved after additional immunotherapy, not always accompanied by increased ASM doses. Titers of surface antibodies but not intracellular antibodies decreased over time.

Conclusion

Seizures with surface antibodies should mostly be considered acute symptomatic and transient and not indicative of epilepsy. This has consequences for ASM prescription and social restrictions. Antibody titers correlate with clinical courses.

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Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA (2010) Recommendation for a definition of acute symptomatic seizure. Epilepsia 51:671–675. https://doi.org/10.1111/j.1528-1167.2009.02285.xCrossRefPubMed

Bien CG, Bien CI, Dogan Onugoren M, De Simoni D, Eigler V, Haensch CA, Holtkamp M, Ismail FS, Kurthen M, Melzer N, Mayer K, von Podewils F, Rauschka H, Rossetti AO, Schabitz WR, Simova O, Witt K, Hoftberger R, May TW (2020) Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome. J Neurol 267:2101–2114. https://doi.org/10.1007/s00415-020-09814-3CrossRefPubMedPubMedCentral

Bien CG, Holtkamp M (2017) "Autoimmune epilepsy": encephalitis with autoantibodies for epileptologists. Epilepsy Curr 17:134–141. https://doi.org/10.5698/1535-7511.17.3.134CrossRefPubMedPubMedCentral

Bien CG, Mirzadjanova Z, Baumgartner C, Onugoren MD, Grunwald T, Holtkamp M, Isenmann S, Kermer P, Melzer N, Naumann M, Riepe M, Schabitz WR, von Oertzen TJ, von Podewils F, Rauschka H, May TW (2017) Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome. Eur J Neurol 24:175–186. https://doi.org/10.1111/ene.13180CrossRefPubMed

Bien CG, Urbach H, Schramm J, Soeder BM, Becker AJ, Voltz R, Vincent A, Elger CE (2007) Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 69:1236–1244. https://doi.org/10.1212/01.wnl.0000276946.08412.efCrossRefPubMed

Bien CG, Vincent A, Barnett MH, Becker AJ, Blümcke I, Graus F, Jellinger KA, Reuss DE, Ribalta T, Schlegel J, Sutton I, Lassmann H, Bauer J (2012) Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135:1622–1638. https://doi.org/10.1093/brain/aws082CrossRefPubMed

Byun JI, Lee ST, Jung KH, Sunwoo JS, Moon J, Lim JA, Lee DY, Shin YW, Kim TJ, Lee KJ, Lee WJ, Lee HS, Jun J, Kim DY, Kim MY, Kim H, Kim HJ, Suh HI, Lee Y, Kim DW, Jeong JH, Choi WC, Bae DW, Shin JW, Jeon D, Park KI, Jung KY, Chu K, Lee SK (2016) Effect of immunotherapy on seizure outcome in patients with autoimmune encephalitis: a prospective observational registry study. PLoS ONE 11:e0146455. https://doi.org/10.1371/journal.pone.0146455CrossRefPubMedPubMedCentral

Carreño M, Bien CG, Asadi-Pooya AA, Sperling M, Marusic P, Elisak M, Pimentel J, Wehner T, Mohanraj R, Uranga J, Gomez-Ibanez A, Villanueva V, Gil F, Donaire A, Bargallo N, Rumia J, Roldan P, Setoain X, Pintor L, Boget T, Bailles E, Falip M, Aparicio J, Dalmau J, Graus F (2017) Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies. Epilepsy Res 129:101–105. https://doi.org/10.1016/j.eplepsyres.2016.12.010CrossRefPubMed

Daif A, Lukas RV, Issa NP, Javed A, VanHaerents S, Reder AT, Tao JX, Warnke P, Rose S, Towle VL, Wu S (2018) Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav 80:331–336. https://doi.org/10.1016/j.yebeh.2018.01.021CrossRefPubMed

10.

Dalmau J, Graus F (2018) Antibody-mediated encephalitis. N Engl J Med 378:840–851. https://doi.org/10.1056/NEJMra1708712CrossRefPubMed

11.

Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR (2004) Clinical analysis of anti-Ma2-associated encephalitis. Brain 127:1831–1844. https://doi.org/10.1093/brain/awh203CrossRefPubMed

12.

Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10:63–74. https://doi.org/10.1016/S1474-4422(10)70253-2CrossRefPubMedPubMedCentral

13.

de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, Bastiaansen AEM, Schreurs MWJ, Rouhl RPW, van Donselaar CA, Majoie M, Neuteboom RF, Sillevis Smitt PAE, Thijs RD, Titulaer MJ (2019) Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 92:e2185–e2196. https://doi.org/10.1212/WNL.0000000000007475CrossRefPubMedPubMedCentral

14.

Di Giacomo R, Deleo F, Pastori C, Didato G, Andreetta F, Del Sole A, de Curtis M, Villani F (2019) Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis. J Neuroimmunol 337:577063. https://doi.org/10.1016/j.jneuroim.2019.577063CrossRefPubMed

15.

Dogan Onugoren M, Golombeck KS, Bien C, Abu-Tair M, Brand M, Bulla-Hellwig M, Lohmann H, Munstermann D, Pavenstadt H, Tholking G, Valentin R, Wiendl H, Melzer N, Bien CG (2016) Immunoadsorption therapy in autoimmune encephalitides. Neurol Neuroimmunol Neuroinflamm 3:e207. https://doi.org/10.1212/NXI.0000000000000207CrossRefPubMedPubMedCentral

16.

Driver & Vehicle Licensing Agency (2020) Assessing fitness to drive—a guide for medical professionals. https://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medical-professionals. Accessed on 05.04.2020

17.

Falip M, Rodriguez-Bel L, Castañer S, Sala-Padró J, Miro J, Jaraba S, Casasnovas C, Morandeira F, Berdejo J, Carreño M (2019) Hippocampus and insula are targets in epileptic patients with glutamic acid decarboxylase antibodies. Front Neurol 9:1143. https://doi.org/10.3389/fneur.2018.01143CrossRefPubMedPubMedCentral

18.

Feyissa AM, Lamb C, Pittock SJ, Gadoth A, McKeon A, Klein CJ, Britton JW (2018) Antiepileptic drug therapy in autoimmune epilepsy associated with antibodies targeting the leucine-rich glioma-inactivated protein 1. Epilepsia Open 3:348–356. https://doi.10.1002/epi4.12226CrossRefPubMedPubMedCentral

19.

Feyissa AM, Lopez Chiriboga AS, Britton JW (2017) Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm 4:e353. https://doi.org/10.1212/NXI.0000000000000353CrossRefPubMedPubMedCentral

20.

Finke C, Kopp UA, Scheel M, Pech LM, Soemmer C, Schlichting J, Leypoldt F, Brandt AU, Wuerfel J, Probst C, Ploner CJ, Pruss H, Paul F (2013) Functional and structural brain changes in anti-N-methyl-d-aspartate receptor encephalitis. Ann Neurol 74:284–296. https://doi.org/10.1002/ana.23932CrossRefPubMed

21.

Finke C, Prüss H, Heine J, Reuter S, Kopp UA, Wegner F, Then Bergh F, Koch S, Jansen O, Münte T, Deuschl G, Ruprecht K, Stöcker W, Wandinger KP, Paul F, Bartsch T (2017) Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 74:50–59. https://doi.org/10.1001/jamaneurol.2016.4226CrossRefPubMed

22.

Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55:475–482. https://doi.org/10.1111/epi.12550CrossRefPubMed

23.

Fisher RS, van Emde BW, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472. https://doi.org/10.1111/j.0013-9580.2005.66104.xCrossRefPubMed

24.

Geis C, Planaguma J, Carreño M, Graus F, Dalmau J (2019) Autoimmune seizures and epilepsy. J Clin Invest 129:926–940. https://doi.org/10.1172/JCI125178CrossRefPubMedPubMedCentral

25.

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 (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404. https://doi.org/10.1016/S1474-4422(15)00401-9CrossRefPubMedPubMedCentral

26.

Graus F, Vega F, Delattre JY, Bonaventura I, Rene R, Arbaiza D, Tolosa E (1992) Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies. Neurology 42:536–540. https://doi.org/10.1212/WNL.42.3.536CrossRefPubMed

27.

Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R, Rosenfeld MR, Lynch D, Graus F, Dalmau J (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13:167–177. https://doi.org/10.1016/S1474-4422(13)70282-5CrossRefPubMed

28.

Hesdorffer DC, Benn EK, Cascino GD, Hauser WA (2009) Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia 50:1102–1108. https://doi.org/10.1111/j.1528-1167.2008.01945.xCrossRefPubMed

29.

Iorio R, Assenza G, Tombini M, Colicchio G, Della Marca G, Benvenga A, Damato V, Rossini PM, Vollono C, Plantone D (2015) The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy. Eur J Neurol 22:70–78. https://doi.org/10.1111/ene.12529CrossRefPubMed

30.

Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese MA, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A (2010) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133:1655–1667. https://doi.org/10.1093/brain/awq113CrossRefPubMedPubMedCentral

31.

Irani SR, Bien CG, Lang B (2011) Autoimmune epilepsies. Curr Opin Neurol 24:146–153. https://doi.org/10.1097/WCO.0b013e3283446f05CrossRefPubMed

32.

Joubert B, Saint-Martin M, Noraz N, Picard G, Rogemond V, Ducray F, Desestret V, Psimaras D, Delattre JY, Antoine JC, Honnorat J (2016) Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures. JAMA Neurol 73:1115–1124. https://doi.org/10.1001/jamaneurol.2016.1585CrossRefPubMed

33.

Lee WJ, Lee ST, Byun JI, Sunwoo JS, Kim TJ, Lim JA, Moon J, Lee HS, Shin YW, Lee KJ, Kim S, Jung KH, Jung KY, Chu K, Lee SK (2016) Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology 86:1683–1691. https://doi.org/10.1212/WNL.0000000000002635CrossRefPubMed

34.

Liu X, Yan B, Wang R, Li C, Chen C, Zhou D, Hong Z (2017) Seizure outcomes in patients with anti-NMDAR encephalitis: a follow-up study. Epilepsia 58:2104–2111. https://doi.org/10.1111/epi.13929CrossRefPubMed

35.

Mäkelä K-M, Hietaharju A, Brander A, Peltola J (2018) Clinical management of epilepsy with glutamic acid decarboxylase antibody positivity: the interplay between immunotherapy and anti-epileptic drugs. Front Neurol 9:579. https://doi.org/10.3389/fneur.2018.00579CrossRefPubMedPubMedCentral

36.

Malter MP, Frisch C, Zeitler H, Surges R, Urbach H, Helmstaedter C, Elger CE, Bien CG (2015) Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure 30:57–63. https://doi.org/10.1016/j.seizure.2015.05.017CrossRefPubMed

37.

Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478. https://doi.org/10.1002/ana.21917CrossRefPubMed

38.

Muñoz-Lopetegi A, de Bruijn MA, Boukhrissi S, Bastiaansen AE, Nagtzaam MM, Hulsenboom ES, Boon AJ, Neuteboom RF, de Vries JM, Sillevis Smitt PA, Schreurs MW, Titulaer MJ (2020) Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm 7:e696. https://doi.org/10.1212/NXI.0000000000000696CrossRefPubMedPubMedCentral

39.

Quek AM, Britton JW, McKeon A, So E, Lennon VA, Shin C, Klein C, Watson RE Jr, Kotsenas AL, Lagerlund TD, Cascino GD, Worrell GA, Wirrell EC, Nickels KC, Aksamit AJ, Noe KH, Pittock SJ (2012) Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 69:582–593. https://doi.org/10.1001/archneurol.2011.2985CrossRefPubMedPubMedCentral

40.

Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL (2017) ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 58:512–521. https://doi.org/10.1111/epi.13709CrossRefPubMedPubMedCentral

41.

Schimmel M, Frühwald MC, Bien CG (2018) Limbic encephalitis with LGI1 antibodies in a 14-year-old boy. Eur J Paediatr Neurol 22:190–193. https://doi.org/10.1016/j.ejpn.2017.08.004CrossRefPubMed

42.

Serafini A, Lukas RV, VanHaerents S, Warnke P, Tao JX, Rose S, Wu S (2016) Paraneoplastic epilepsy. Epilepsy Behav 61:51–58. https://doi.org/10.1016/j.yebeh.2016.04.046CrossRefPubMed

43.

Spatola M, Dalmau J (2017) Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Curr Opin Neurol 30:345–353. https://doi.org/10.1097/WCO.0000000000000449CrossRefPubMedPubMedCentral

44.

Steriade C, Britton J, Dale RC, Gadoth A, Irani SR, Linnoila J, McKeon A, Shao XQ, Venegas V, Bien CG (2020) Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 61:1341–1351. https://doi.org/10.1111/epi.16571CrossRefPubMed

45.

Steriade C, Moosa ANV, Hantus S, Prayson RA, Alexopoulos A, Rae-Grant A (2018) Electroclinical features of seizures associated with autoimmune encephalitis. Seizure 60:198–204. https://doi.org/10.1016/j.seizure.2018.06.021CrossRefPubMed

46.

Thompson J, Bi M, Murchison AG, Makuch M, Bien CG, Chu K, Farooque P, Gelfand JM, Geschwind MD, Hirsch LJ, Somerville E, Lang B, Vincent A, Leite MI, Waters P, Irani SR (2018) The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 141:348–356. https://doi.org/10.1093/brain/awx323CrossRefPubMed

47.

Toledano M, Britton JW, McKeon A, Shin C, Lennon VA, Quek AM, So E, Worrell GA, Cascino GD, Klein CJ, Lagerlund TD, Wirrell EC, Nickels KC, Pittock SJ (2014) Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 82:1578–1586. https://doi.org/10.1212/WNL.0000000000000383CrossRefPubMedPubMedCentral

48.

van Sonderen A, Arino H, Petit-Pedrol M, Leypoldt F, Körtvélyessy P, Wandinger KP, Lancaster E, Wirtz PW, Schreurs MW, Sillevis Smitt PA, Graus F, Dalmau J, Titulaer MJ (2016) The clinical spectrum of Caspr2 antibody-associated disease. Neurology 87:521–528. https://doi.org/10.1212/WNL.0000000000002917CrossRefPubMedPubMedCentral

49.

van Sonderen A, Thijs RD, Coenders EC, Jiskoot LC, Sanchez E, de Bruijn MA, van Coevorden-Hameete MH, Wirtz PW, Schreurs MW, Sillevis Smitt PA, Titulaer MJ (2016) Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 87:1449–1456. https://doi.org/10.1212/WNL.0000000000003173CrossRefPubMed

50.

Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, Pardo CA, Vincent A, Mathern GW, Cross JH (2014) Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 13:195–205. https://doi.org/10.1016/S1474-4422(13)70260-6CrossRefPubMedPubMedCentral

Title: Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data
Authors: Anna Rada
Robert Birnbacher
Claudio Gobbi
Martin Kurthen
Albert Ludolph
Markus Naumann
Ulrike Neirich
Tim J. von Oertzen
Gerhard Ransmayr
Matthias Riepe
Mareike Schimmel
Oliver Schwartz
Rainer Surges
Christian G. Bien
Publication date: 01-03-2021
Publisher: Springer Berlin Heidelberg
Keywords: Epilepsy
Autoimmune Encephalitis
Published in: Journal of Neurology / Issue 3/2021
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-020-10250-6

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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