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Current Neurology and Neuroscience Reports

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01-05-2013 | Epilepsy (CW Bazil, Section Editor)

Antibodies in Epilepsy

Author: Cynthia M. Correll

Published in: Current Neurology and Neuroscience Reports | Issue 5/2013

Abstract

Antibody mediated limbic encephalitis is an increasingly recognized cause of seizures in cryptogenic epilepsy. Autoimmune encephalitis and epilepsy have been linked to both neuronal intracellular antibodies (GAD65, ANNA-1, and Ma) and neuronal cell surface antibodies (VGKC complex, NMDAR, AMPA, GABA-B, and GluR5). This article outlines the latest data on these various antibodies with a focus on their association with acute seizures in limbic encephalitis and likely increased risk for chronic epilepsy. There is mounting evidence that these antibodies may play a role in acute onset and chronic seizures in the general epilepsy population without manifesting typical limbic encephalitis symptoms. This review will discuss the data supporting early recognition and treatment options, beyond typical antiepileptic medications, necessary to improve outcomes in this epilepsy subgroup.

Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.PubMedCrossRef

Iorio R, Lennon V. Neural antigen-specific autoimmune disorders. Immunol Rev. 2012;248:104–21.PubMedCrossRef

Bien CG, Schulz-Bonhage A, Deckert M, et al. Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy. Neurology. 2000;55:1823–8.PubMedCrossRef

Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings, and tumor association in 50 patients. Brain. 2000;123:1481–94.PubMedCrossRef

Vincent A, Irani SR, Lang B. The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr Opin Neurol. 2010;23:144–50.PubMedCrossRef

Bien CG, Scheffer IE. Autoantibodies and epilepsy. Epilepsia. 2011;52(3):18–22.PubMedCrossRef

Zuliani L, Graus F, Giometto B, et al. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry. 2012;83:638–45.PubMedCrossRef

Irani SR, Bien CG, Lang B. Autoimmune epilepsies. Curr Opin Neurol. 2011;24:146–53.PubMedCrossRef

Graus F, Saiz A, Lai M, et al. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology. 2008;71:930–6.PubMedCrossRef

10.

Alamowitch S, Graus F, Uchuya M, et al. Limbic encephalitis and small cell lung cancer: clinical and immunological features. Brain. 1997;120:923–8.PubMedCrossRef

11.

Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124:1138–48.PubMedCrossRef

12.

Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–7.PubMedCrossRef

13.

Dalmau J, Graus F, Rosenblum MK, et al. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine. 1992;71:59–72.PubMedCrossRef

14.

Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol. 2001;50:339–48.PubMedCrossRef

15.

Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain. 2004;127:1831–44.PubMedCrossRef

16.

Mata S, Muscas GC, Naldi I, et al. Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J Neuroimmunol. 2008;199(1–2):155–9.PubMedCrossRef

17.

Blanc F, Ruppert E, Kleitz C, et al. Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? J Neurol Sci. 2009;287:69–71.PubMedCrossRef

18.

Malter MP, Helmstaedter C, Urbach H. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol. 2010;67:470–8.PubMedCrossRef

19.

Majoie HJM, de Baets M, Renier W, et al. Antibodies to voltage-gated potassium and calcium channels in epilepsy. Epilepsy Res. 2006;71:135–41.PubMedCrossRef

20.

Vincent A, Buckley C, Schott J, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127:701–12.PubMedCrossRef

21.

•• Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9:776–85. This study of 57 patients with limbic encephalitis attributed to voltage-gated potassium channels demonstrated that the antibodies were actually binding to Lgi1 and CASPR2 antigens, proteins associated with the VGKC complex.PubMedCrossRef

22.

Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133:2734–48.PubMedCrossRef

23.

Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25–36.PubMedCrossRef

24.

Sansing LH, Tüzün E, Ko MW, Baccon J, Lynch DR, Dalmau J. A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol. 2007;3(5):291–6.PubMedCrossRef

25.

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.PubMedCrossRef

26.

Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133:1655–67.PubMedCrossRef

27.

Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.PubMedCrossRef

28.

•• Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcomes in patients with anti-NMDA receptor encephalitis: an observation cohort study. Lancet Neurol. 2013;12:157–65. This observation cohort study of immunotherapy outcomes on 501 patients with NMDAR encephalitis found that 81 % of patients had improvement with good outcome at 2 years. Predictors of good outcome included early initiation of treatment and initiation of second line therapy (rituximab and/or cyclophosphamide).PubMedCrossRef

29.

Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65:424–34.PubMedCrossRef

30.

Bataller L, Galiano R, Garcia-Escrig M, et al. Reversible paraneoplastic limbic encephalitis associated with antibodies to the AMPA receptor. Neurology. 2010;74:265–7.PubMedCrossRef

31.

• Lancaster E, Lai M, Hughes E. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterization of the antigen. Lancet Neurol. 2010;9:67–76. This study of 15 patients with limbic encephalitis was the first to identify GABA-B antibodies as a cause of this disorder. All 15 patients with GABA-B antibody encephalitis developed seizures with 13 of the patients noted to have seizures as their presenting symptom.PubMedCrossRef

32.

Boronat A, Sabater L, Saiz A, et al. GABAB receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology. 2011;76:795–800.PubMedCrossRef

33.

Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology. 2011;77:1698–701.PubMedCrossRef

34.

•• Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69:892–900. This case series described 29 patients with faciobrachial dystonic seizures. Lgi1 antibodies were found in 89 % of the patients. This seizure type showed a much poorer response to antiepileptic medications compared with immunotherapy.PubMedCrossRef

35.

Irani SR, Vincent A. NMDA receptor antibody encephalitis. Curr Neurol Neurosci Rep. 2011;11:298–304.PubMedCrossRef

36.

Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.PubMedCrossRef

37.

Dalmau J. Status epilepticus due to paraneoplastic and nonparaneoplastic encephalitides. Epilepsia. 2009;50 Suppl. 12:58–60.PubMedCrossRef

38.

Graus F, Boronat A, Xifro X, et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology. 2010;74:857–9.PubMedCrossRef

39.

Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. 2002;23:145–51.PubMedCrossRef

40.

Giometto B, Nicolao P, Macucci M, et al. Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies. Lancet. 1998;352:457.PubMedCrossRef

41.

Peltola J, Kulmala P, Isojarvi J, et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology. 2000;55(1):46–50.PubMedCrossRef

42.

Errichiello L, Perruolo G, Pascarella A, et al. Autoantibodies to glutamic acid decarboxylase (GAD) in focal and generalized epilepsy: a study on 233 patients. J Neuroimmunol. 2009;211(1–2):120–3.PubMedCrossRef

43.

Errichiello L, Striano S, Zara F, et al. Temporal lobe epilepsy and anti-glutamic acid decarboxylase autoimmunity. Neurol Sci. 2011;32:547–50.PubMedCrossRef

44.

Liimatainen S, Peltola M, Sabater L, et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia. 2010;51(5):760–7.PubMedCrossRef

45.

• Falip M, Carreno M, Miro J, et al. Prevalence and immunological spectrum of temporal lobe epilepsy with glutamic acid decarboxylase antibodies. Eur J Neurol. 2012;19:827–33. This study examined the prevalence of GAD65 antibodies in 42 patients with adult onset temporal lobe epilepsy, 19 with known etiology and 23 with unknown etiology. GAD65 antibodies were present in 21 % of the patients (8.7 % high titers) with unknown etiology of their epilepsy.PubMedCrossRef

46.

Porta-Etessam J, Ruiz-Morales J, Millan JM, et al. Epilepsia partialis continua and frontal features as a debut of anti-Hu paraneo- plastic encephalomyelitis with focal frontal encephalitis. Eur J Neurol. 2001;8:359–60.PubMedCrossRef

47.

Shavit YB, Graus F, Probst A, et al. Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann Neurol. 1999;45:255–8.PubMedCrossRef

48.

Rudzinskia LA, Pittockb SJ, McKeon A, et al. Extratemporal EEG and MRI findings in ANNA-1 (anti-Hu) encephalitis. Epilepsy Res. 2011;95:255–62.CrossRef

49.

McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, et al. Serum antibodies in epilepsy and seizure-associated disorders. Neurology. 2005;65:1730–6.PubMedCrossRef

50.

Niehusmann P, Dalmau J, Rudlowski C, et al. Diagnostic value of N-methyl-D-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol. 2009;66(4):458–64.PubMedCrossRef

51.

Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 2007;10:529–38.PubMedCrossRef

52.

Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, Anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry. 2000;68(4):479–82.PubMedCrossRef

53.

Battaler L, Kleopa KA, Wu GF, et al. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry. 2007;78:381–5.CrossRef

54.

Gabilondo I, Saiz A, Galán L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011;77:996–9.PubMedCrossRef

55.

Irani SR, Buckley C, Vincent A, et al. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology. 2008;71:1647–8.PubMedCrossRef

56.

Kaymakamzade B, Kansu T, Tan E, et al. LGI1 related limbic encephalitis and response to immunosuppressive therapy. J Neurol. 2011;258:2075–7.PubMedCrossRef

57.

•• Quek AM, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol. 2012;69(5):582–93. This case series of 32 patients with autoimmune antibody-mediated epilepsy treated with immunotherapy reported an improvement rate of 81 %, with 18 patients becoming seizure free. Patients who showed improvement had a significantly shorter time to therapy initiation than patients who did not respond to therapy, at 4 months and 22 months respectively.PubMedCrossRef

58.

Scheid R, Lincke T, Voltz R, et al. Serial 18F-fluoro-2-deoxy-D-glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis. Arch Neurol. 2004;61:1785–9.PubMedCrossRef

59.

Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(8):1764–77.PubMedCrossRef

60.

Fauser S, Talazko J, Wagner K, et al. FDG-PET and MRI in potassium channel antibody-associated non-paraneoplastic limbic encephalitis: correlation with clinical course and neuropsychology. Acta Neurol Scand. 2005;111:338–43.PubMedCrossRef

61.

Urbach H, Soeder BM, Jeub M, et al. Serial MRI of limbic encephalitis. Neuroradiology. 2006;48:380–6.PubMedCrossRef

62.

Bien CG, Urbach H, Schramm J, et al. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology. 2007;69:1236–44.PubMedCrossRef

63.

Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumors in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18:19–27.PubMedCrossRef

Title: Antibodies in Epilepsy
Author: Cynthia M. Correll
Publication date: 01-05-2013
Publisher: Current Science Inc.
Published in: Current Neurology and Neuroscience Reports / Issue 5/2013
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-013-0348-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Antibodies in Epilepsy

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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