Journal of Neurology

, Volume 261, Issue 9, pp 1695–1705 | Cite as

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity

  • M. P. MalterEmail author
  • C. Frisch
  • J. C. Schoene-Bake
  • C. Helmstaedter
  • K. P. Wandinger
  • W. Stoecker
  • H. Urbach
  • R. Surges
  • C. E. Elger
  • A. V. Vincent
  • C. G. Bien
Original Communication


In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab+ patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab+ patients, but in none of the CASPR-2-Ab+ or LGI/CASPR-2-Ab patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab+ patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab+-LE.


Limbic encephalitis VGKC LGI1 Autoimmune epilepsy 



The authors would like to thank Dr. Bethan Lang and Ms. Linda Clover, Nuffield Department of Clinical Neurosciences, for Ab determinations.

Conflicts of interest

MPM received payments for congress participation, travel expenses, lecture and manuscript preparation from UCB and EISAI.

CF reports no disclosure.

JCSB was funded by grants from Transregio SFB TR3 (Projects A1 and A8) and as part of the Gerok programme (BONFOR commission, University of Bonn). He received payments for travel expenses from Desitin.

CH was funded by grants from Transregio SFB TR3 A1, BMBF and DFG, he received payments for board membership, consultancy, lectures, manuscript preparation and royalties from UCB Pharma, Desitin, VIAMED GmbH, EISAI, Glaxo Smith Kline.

KPW is a full-time employee of and hold stock in EUROIMMUN AG.

WS is a full-time employee of and hold stock in EUROIMMUN AG.

HU reports no disclosure.

RS has received support for congress participation and speaker fees from EISAI and had a consultancy agreement with UCB.

CEE received honoraria for consultancy, expert testimony and lectures from UCB Pharma, Desitin and Pfizer. He is an employee of the Life and Brain Institute Bonn.

AV and the University of Oxford hold patents and receive royalties and payments for antibody testing. AV receives funding from Euroimmun AG and has consultancy agreement with Athena Diagnostics.

CGB served on a scientific advisory board of UCB and EISAI, Germany, undertook industry-funded travel with support of Eisai, UCB, Desitin and Grifols (all Germany), and obtained honoraria for speaking engagements from Eisai, UCB, GlaxoSmithKline and Desitin (all Germany). As part of his present position, he performs serum and cerebrospinal fluid tests for antibodies as those described in the text; for this, his employer charges fees from external senders.

Ethical standard

Studies have been approved by the ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.

Supplementary material

415_2014_7408_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 kb)


  1. 1.
    Barajas RF, Collins DE, Cha S, Geschwind MD (2010) Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 51:473–477PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Bien CG, Scheffer IE (2011) Autoantibodies and epilepsy. Epilepsia 52(Suppl 3):18–22CrossRefPubMedGoogle Scholar
  3. 3.
    Bien CG, Schulze-Bonhage A, Deckert M, Urbach HC, Grunwald T, Schaller C, Elger CE (2000) Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy. Neurology 55:1823–1828CrossRefPubMedGoogle Scholar
  4. 4.
    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 69:1236–1244CrossRefPubMedGoogle Scholar
  5. 5.
    Brierley JB, Corsellis JAN, Hierons R, Nevin S (1960) Subacute encephalitis of later adult life mainly affecting the limbic areas. Brain 83:357–368CrossRefGoogle Scholar
  6. 6.
    Corsellis JA, Goldberg GJ, Norton AR (1968) “Limbic encephalitis” and its association with carcinoma. Brain 91:481–496CrossRefPubMedGoogle Scholar
  7. 7.
    Engel J Jr, Van Ness PC, Rasmussen TB, Ojemann LM (1993) Outcome with respect to epileptic seizures. In: Engel J Jr (ed) Surgical treatment of the Epilepsies. Raven Press, New York, pp 609–621Google Scholar
  8. 8.
    Frisch C, Malter MP, Elger CE, Helmstaedter C (2013) Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis. Eur J Neurol 20:1297–1304CrossRefPubMedGoogle Scholar
  9. 9.
    Haberlandt E, Bast T, Ebner A, Holthausen H, Kluger G, Kravljanac R, Kroll-Seger J, Kurlemann G, Makowski C, Rostasy K, Tuschen-Hofstatter E, Weber G, Vincent A, Bien CG (2011) Limbic encephalitis in children and adolescents. Arch Dis Child 96:186–191CrossRefPubMedGoogle Scholar
  10. 10.
    Hart IK, Waters C, Vincent A, Newland C, Beeson D, Pongs O, Morris C, Newsom-Davis J (1997) Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia. Ann Neurol 41:238–246CrossRefPubMedGoogle Scholar
  11. 11.
    Helmstaedter C, Lendt M, Lux S (2000) VLMT: verbaler Lern- und Merkfaehigkeitstest. Testhandbuch, HogrefeGoogle Scholar
  12. 12.
    Helmstaedter C, Pohl C, Elger CE (1991) Eine modifizierte version des diagnostikums fuer cerebralschaeden (DCS) zur diagnostik raeumlich-visueller Gedaechtnisdefizite bei Patienten mit Temporallappenepilepsie. In: Scheffner D (ed) Epilepsie 90. Einhorn-Presse, Reinbek, pp 272–279Google Scholar
  13. 13.
    Hoppe C, Fliessbach K, Schlegel U, Elger CE, Helmstaedter C (2009) NeuroCog FX: computerized screening of cognitive functions in patients with epilepsy. Epilepsy Behav 16:298–310CrossRefPubMedGoogle Scholar
  14. 14.
    Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) 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 133:2734–2748PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Irani SR, Bien CG, Lang B (2011) Autoimmune epilepsies. Curr Opin Neurol 24:146–153CrossRefPubMedGoogle Scholar
  16. 16.
    Irani SR, Buckley C, Vincent A, Cockerell OC, Rudge P, Johnson MR, Smith S (2008) Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 71:1647–1648CrossRefPubMedGoogle Scholar
  17. 17.
    Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, Schott JM, Armstrong RJ, Zagami AS, Bleasel A, Somerville ER, Smith SM, Vincent A (2011) Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 69:892–900CrossRefPubMedGoogle Scholar
  18. 18.
    Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, Zuliani L, Watanabe O, Lang B, Buckley C, Vincent A (2012) Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 72:241–255CrossRefPubMedGoogle Scholar
  19. 19.
    Irani SR, Stagg CJ, Schott JM, Rosenthal CR, Schneider SA, Pettingill P, Pettingill R, Waters P, Thomas A, Voets NL, Cardoso MJ, Cash DM, Manning EN, Lang B, Smith SJ, Vincent A, Johnson MR (2013) Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 136:3151–3162CrossRefPubMedGoogle Scholar
  20. 20.
    Klein CJ, Lennon VA, Aston PA, McKeon A, O’Toole O, Quek A, Pittock SJ (2013) Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 70:229–234PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, Cowell JK, Dalmau J (2010) Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 9:776–785PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Langhoff E, Ladefoged J (1983) Relative immunosuppressive potency of various corticosteroids measured in vitro. Eur J Clin Pharmacol 25:459–462CrossRefPubMedGoogle Scholar
  23. 23.
    Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478CrossRefPubMedGoogle Scholar
  24. 24.
    Mathern GW, Babb TL, Vickrey BG, Melendez M, Pretorius JK (1995) The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain 118(Pt 1):105–118CrossRefPubMedGoogle Scholar
  25. 25.
    McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, Shoenfeld Y, Vincent A, Palace J, Lang B (2005) Serum antibodies in epilepsy and seizure-associated disorders. Neurology 65:1730–1736CrossRefPubMedGoogle Scholar
  26. 26.
    Paterson RW, Zandi MS, Armstrong R, Vincent A, Schott JM (2013) Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry 85(6):625–630PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Quek AM, Britton JW, McKeon A, So E, Lennon VA, Shin C, Klein CJ, 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(5):582–593PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Reiber H (1998) Cerebrospinal fluid–physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler 4:99–107CrossRefPubMedGoogle Scholar
  29. 29.
    Reid JM, Foley P, Willison HJ (2009) Voltage-gated potassium channel-associated limbic encephalitis in the West of Scotland: case reports and literature review. Scott Med J 54:27–31CrossRefPubMedGoogle Scholar
  30. 30.
    Shillito P, Molenaar PC, Vincent A, Leys K, Zheng W, van den Berg RJ, Plomp JJ, van Kempen GT, Chauplannaz G, Wintzen AR et al (1995) Acquired neuromyotonia: evidence for autoantibodies directed against K + channels of peripheral nerves. Ann Neurol 38:714–722CrossRefPubMedGoogle Scholar
  31. 31.
    Shin YW, Lee ST, Shin JW, Moon J, Lim JA, Byun JI, Kim TJ, Lee KJ, Kim YS, Park KI, Jung KH, Lee SK, Chu K (2013) VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 265:75–81CrossRefPubMedGoogle Scholar
  32. 32.
    Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S (2004) Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62:1177–1182CrossRefPubMedGoogle Scholar
  33. 33.
    Urbach H (2005) Imaging of the epilepsies. Eur Radiol 15:494–500CrossRefPubMedGoogle Scholar
  34. 34.
    Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, Clover L, Parkinson A, Bien CG, Omer S, Lang B, Rossor MN, Palace J (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701–712CrossRefPubMedGoogle Scholar
  35. 35.
    Wong SH, Saunders MD, Larner AJ, Das K, Hart IK (2010) An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis. J Neurol Neurosurg Psychiatry 81:1167–1169CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • M. P. Malter
    • 1
    • 7
    Email author
  • C. Frisch
    • 1
  • J. C. Schoene-Bake
    • 1
    • 6
  • C. Helmstaedter
    • 1
  • K. P. Wandinger
    • 2
  • W. Stoecker
    • 2
  • H. Urbach
    • 3
  • R. Surges
    • 1
  • C. E. Elger
    • 1
  • A. V. Vincent
    • 4
  • C. G. Bien
    • 1
    • 5
  1. 1.Department of EpileptologyUniversity of Bonn Medical CenterBonnGermany
  2. 2.Institute of Experimental ImmunologyAffiliated to Euroimmun AG LuebeckLuebeckGermany
  3. 3.Department of NeuroradiologyUniversity of Freiburg Medical CenterFreiburgGermany
  4. 4.Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of OxfordOxfordUK
  5. 5.Epilepsy Centre Bethel, Krankenhaus MaraBielefeldGermany
  6. 6.Department of PediatricsBraunschweig City HospitalsBrunswickGermany
  7. 7.Department of NeurologyMarien-Krankenhaus Bergisch GladbachBergisch GladbachGermany

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