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Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis

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Abstract

Objective

To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs).

Methods

Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis.

Results

We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55–85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1–30), the recurrent seizures’ phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6–65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years).

Conclusion

Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

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References

  1. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404

    Article  PubMed Central  PubMed  Google Scholar 

  2. Rosenfeld MR, Dalmau J (2011) Anti–NMDA-Receptor Encephalitis and Other Synaptic Autoimmune Disorders. Curr Treat Options Neurol 13:324–332

    Article  PubMed Central  PubMed  Google Scholar 

  3. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR et al (2011) Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 69:892–900

    Article  PubMed  Google Scholar 

  5. Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P et al (2016) Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain 139:1079–1093

    Article  PubMed  Google Scholar 

  6. Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J et al (2010) Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9:67–76

    Article  CAS  PubMed  Google Scholar 

  7. Benarroch EE (2012) GABAB receptors: structure, functions, and clinical implications. Neurology 78:578–584

    Article  CAS  PubMed  Google Scholar 

  8. Höftberger R, Titulaer MJ, Sabater L, Dome B, Rózsás A, Hegedus B et al (2013) Encephalitis and GABAB receptor antibodies. Neurology 81:1500–1506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Boronat A, Sabater L, Saiz A, Dalmau J, Graus F (2011) GABAB receptor antibodies in limbic encephalitis and anti-GAD–associated neurologic disorders. Neurology 76:795–800

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Onugoren MD, Deuretzbacher D, Haensch CA, Hagedorn HJ, Halve S, Isenmann S et al (2015) Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry 86:965–972

    Article  Google Scholar 

  11. Jeffery OJ, Lennon VA, Pittock SJ, Gregory JK, Britton JW, McKeon A (2013) GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 81:882–887

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Hainsworth JB, Shishido A, Theeler BJ, Carroll CG, Fasano RE (2014) Treatment responsive GABA(B)-receptor limbic encephalitis presenting as new-onset super-refractory status epilepticus (NORSE) in a deployed US soldier. Epileptic Disord 16:486–493

    PubMed  Google Scholar 

  13. Qiao S, Zhang Y-X, Zhang B-J, Lu R-Y, Lai Q-L, Chen L-H et al (2017) Clinical, imaging, and follow-up observations of patients with anti-GABAB receptor encephalitis. Int J Neurosci 127:379–385

    Article  CAS  PubMed  Google Scholar 

  14. Mundiyanapurath S, Jarius S, Probst C, Stöcker W, Wildemann B, Bösel J (2013) GABA-B-receptor antibodies in paraneoplastic brainstem encephalitis. J Neuroimmunol 259:88–91

    Article  CAS  PubMed  Google Scholar 

  15. Jarius S, Steinmeyer F, Knobel A, Streitberger K, Hotter B, Horn S et al (2013) GABAB receptor antibodies in paraneoplastic cerebellar ataxia. J Neuroimmunol 256:94–96

    Article  CAS  PubMed  Google Scholar 

  16. DeFelipe-Mimbrera A, Masjuan J, Corral Í, Villar LM, Graus F, García-Barragán N (2014) Opsoclonus–myoclonus syndrome and limbic encephalitis associated with GABAB receptor antibodies in CSF. J Neuroimmunol 272:91–93

    Article  CAS  PubMed  Google Scholar 

  17. Quinn TJ, Dawson J, Walters MR, Lees KR (2009) Reliability of the modified rankin scale. Stroke 40:3393–3395

    Article  PubMed  Google Scholar 

  18. Golombeck KS, Bönte K, Mönig C, van Loo KM, Hartwig M, Schwindt W et al (2016) Evidence of a pathogenic role for CD8 + T cells in anti-GABAB receptor limbic encephalitis. Neurol Neuroimmunol Neuroinflamm 3:e232

    Article  PubMed Central  PubMed  Google Scholar 

  19. Vigot R, Barbieri S, Bräuner-Osborne H, Turecek R, Shigemoto R, Zhang Y-P et al (2006) Differential compartmentalization and distinct functions of GABA B receptor variants. Neuron 50:589–601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Brown JT, Davies CH, Randall AD (2007) Synaptic activation of GABAB receptors regulates neuronal network activity and entrainment. Eur J Neurosci 25:2982–2990

    Article  PubMed  Google Scholar 

  21. Schuler V, Lüscher C, Blanchet C, Klix N, Sansig G, Klebs K et al (2001) Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 31:47–58

    Article  CAS  PubMed  Google Scholar 

  22. Prosser HM, Gill CH, Hirst WD, Grau E, Robbins M, Calver A et al (2001) Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol Cell Neurosci 17:1059–1070

    Article  CAS  PubMed  Google Scholar 

  23. Jurado-Parras MT, Delgado-García JM, Sánchez-Campusano R, Gassmann M, Bettler B, Gruart A (2016) Presynaptic GABAB receptors regulate hippocampal synapses during associative learning in behaving mice. PLoS One 11:e0148800

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Vienne J, Bettler B, Franken P, Tafti M (2010) Differential effects of GABAB receptor subtypes, γ-hydroxybutyric acid, and baclofen on eeg activity and sleep regulation. J Neurosci 30:14194–14204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gambardella A, Manna I, Labate A, Chifari R, La Russa A, Serra P et al (2003) GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy. Neurology 60:560–563

    Article  CAS  PubMed  Google Scholar 

  26. Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF (2004) Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology 29:1050–1062

    Article  CAS  PubMed  Google Scholar 

  27. Heaney CF, Kinney JW (2016) Role of GABA B receptors in learning and memory and neurological disorders. Neurosci Biobehav Rev 63:1–28

    Article  CAS  PubMed  Google Scholar 

  28. Ng AS, Kramer J, Centurion A, Dalmau J, Huang E, Cotter JA, Geschwind MD (2015) Clinico-pathological correlation in adenylate kinase 5 autoimmune limbic encephalitis. J Neuroimmunol 287:31–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Do L-D, Chanson E, Desestret V, Joubert B, Ducray F, Brugière S et al (2017) Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies. Neurology 88:514–524

    Article  CAS  PubMed  Google Scholar 

  30. Voltz R, Dalmau J, Posner JB, Rosenfeld MR (1998) T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 51(4):1146–1150

    Article  CAS  PubMed  Google Scholar 

  31. Graus F, Saiz A, Lai M, Bruna J, López F, Sabater L et al (2008) Neuronal surface antigen antibodies in limbic encephalitis. Neurology 71(12):9306

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Doctors Wang (Foch, Paris), Flament (Tours), Khederchah (Tours), Blonski (Nancy), Boudabous (Avicenne, Paris), Bouariche (Cherbourg), Charef (Argenteuil), Droy (Colmar), Marchal (Bordeaux), Bourdain (Foch, Paris), Ahle (Colmar), Behr (Strasbourg), Toko (Arras), Derache (Caen), Paulus (Besançon), Sauvee (Nancy), Tortel (Colmar), Hopes (Nancy), and Bernardy (Bayonne) for clinical data collection. We gratefully acknowledge Philip Robinson for English language editing (Direction de la Recherche Clinique, Hospices civils de Lyon). This study was supported by research grants from ANR (ANR-14-CE15-0001-MECANO), the Fondation pour la recherche sur le cerveau (FRC-Neurodon2014), and CSL Behring France, FRM (Fondation pour la recherche médicale) DQ20170336751.

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Authors and Affiliations

  1. French Reference Center on Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Neuro-Oncologie, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69677, Bron Cedex, France

    Aurélien Maureille, Bastien Joubert, Géraldine Picard, Véronique Rogemond, Anne-Laurie Pinto, Laure Thomas, François Ducray, Dimitri Psimaras, Giulia Berzero, Jean-Christophe Antoine, Virginie Desestret & Jérôme Honnorat

  2. Memory clinic, CHRU Lille, Lille, France

    Aurélien Maureille

  3. Service d’anatomopathologie, Hospices civils de Lyon, Lyon, France

    Tanguy Fenouil

  4. Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, 69372, Lyon, France

    François Ducray, Virginie Desestret & Jérôme Honnorat

  5. Service de Neurobiologie, Hospices civils de Lyon, Lyon, France

    Isabelle Quadrio

  6. Service de Neurologie, CHU de Saint-Etienne, Saint-Etienne, France

    Jean-Christophe Antoine

  7. Service de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, APHP, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, UMR S975, CNRS, UMR 7225, Paris, France

    Dimitri Psimaras & Giulia Berzero

Authors
  1. Aurélien Maureille
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  2. Tanguy Fenouil
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  3. Bastien Joubert
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  4. Géraldine Picard
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  6. Anne-Laurie Pinto
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  7. Laure Thomas
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  8. François Ducray
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  9. Isabelle Quadrio
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  10. Dimitri Psimaras
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  11. Giulia Berzero
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  12. Jean-Christophe Antoine
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  13. Virginie Desestret
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  14. Jérôme Honnorat
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Contributions

AM: analysis and interpretation of the data, drafting the manuscript for intellectual contents. TF: analysis and interpretation of the data. BJ: analysis and interpretation of the data, revising the manuscript for intellectual content. GP: analysis of the data. VR: analysis of the data. A-LP: analysis of the data. FD: analysis of the data and critical revision of the manuscript for intellectual content. IQ: analysis of the data. DP: analysis of the data and critical revision of the manuscript for intellectual content. J-CA: critical revision of the manuscript for intellectual content. J-YD: critical revision of the manuscript for intellectual content. VD: analysis and interpretation of the data and critical revision of the manuscript for intellectual content. JH: design and conceptualization of the study, critical revision of manuscript for intellectual content, and study supervision.

Corresponding author

Correspondence to Jérôme Honnorat.

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Conflicts of interest

All authors report no conflicts of interest. The principal author, Jerome Honnorat, takes full responsibility for the data, the analyses and interpretation, and the conduct of the research; He has full access to all of the data; and he has the right to publish any and all data separate and apart from any sponsor. It also exists in no financial or other relationships that might lead to a perceived conflict of interest.

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Maureille, A., Fenouil, T., Joubert, B. et al. Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis. J Neurol 266, 195–206 (2019). https://doi.org/10.1007/s00415-018-9132-0

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  • DOI: https://doi.org/10.1007/s00415-018-9132-0

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