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Typical clinical and imaging manifestations of encephalitis with anti-γ-aminobutyric acid B receptor antibodies: clinical experience and a literature review

  • Zhihua Si
  • Aihua Wang
  • Jinzhi Liu
  • Zixian Zhang
  • Ke HuEmail author
Original Article
  • 20 Downloads

Abstract

Objective

To explore the clinical, imaging, and electroencephalogram (EEG) findings, as well as the treatment and prognosis of five patients with anti-γ-aminobutyric acid B receptor (GABABR) encephalitis and review the current literature to gain a deeper understanding and improve the clinical diagnostic ability of the disease.

Methods

Clinical data such as blood examination, imaging, computed tomography (CT), EEG, and magnetic resonance imaging (MRI) findings from five patients with anti-GABABR encephalitis were retrospectively analyzed.

Results

Based on the imaging data, autoimmune encephalitis with anti-GABABR antibodies displayed subacute onset of episodic memory loss, seizures, and confusion, in addition to signal changes in the medial temporal lobe and/or hippocampus. Anti-GABABR antibodies were found in blood and cerebrospinal fluid (CSF) in all five patients, although the CSF leukocyte count and the levels of protein, sugar, and chloride showed no obvious abnormalities. On MRI, only two patients presented with abnormal signals in the medial temporal lobe and/or hippocampus. The EEG showed a slow wave rhythm in all five patients. After treatment with methylprednisolone pulse therapy combined with antiepileptic treatment, all five patients recovered well, without any complications.

Conclusions

Autoimmune encephalitis with anti-GABABR antibodies may be a severe and refractory disease. Anti-GABABR antibodies tested in CSF and serum play a crucial role in the definitive diagnosis and treatment of autoimmune encephalitis. Early treatment is of vital importance to avoid serious complications and neurological sequelae.

Keywords

Anti-GABABR antibodies Autoimmune encephalitis Seizure Early diagnosis Autoantibodies 

Notes

Funding information

This study was supported by grants from by Science and Technology Development Program of Shandong Province, China (No. 2011GGB14095), Medicine and Health Science Technology Development Program of Shandong Province, China (No. 2011HD009), Traditional Chinese Medicine Science and Technology Development Program of Shandong Province, China (2011-194, 2017-163), Natural Science Foundation of Shandong Province, China (No.Y2007C168, No. ZR2011HL020, No. ZR2012HL28, No. ZR2016HP23), and Key Science and Technology Program of Jinan City, China (201704113).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy 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(4):391–404CrossRefGoogle Scholar
  2. 2.
    Sarkis RA, Nehme R, Chemali ZN (2014) Neuropsychiatric and seizure outcomes in nonparaneoplastic autoimmune limbic encephalitis. Epilepsy Behav 39:21–25CrossRefGoogle Scholar
  3. 3.
    Irani SR, Vincent A (2011) Autoimmune encephalitis -- new awareness, challenging questions. Discov Med 11(60):449–458PubMedGoogle Scholar
  4. 4.
    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(1):e0146455CrossRefGoogle Scholar
  5. 5.
    Bost C, Pascual O, Honnorat J (2016) Autoimmune encephalitis in psychiatric institutions: current perspectives. Neuropsychiatr Dis Treat 12:2775–2787CrossRefGoogle Scholar
  6. 6.
    Möhler H, Fritschy JM (1999) GABAB receptors make it to the top--as dimers. Trends Pharmacol Sci 20(3):87–89CrossRefGoogle Scholar
  7. 7.
    Marshall FH, Jones KA, Kaupmann K, Bettler B (1999) GABAB receptors - the first 7TM heterodimers. Trends Pharmacol Sci 20(10):396–399CrossRefGoogle Scholar
  8. 8.
    Jensen AA, Mosbacher J, Elg S, Lingenhoehl K, Lohmann T, Johansen TN, Abrahamsen B, Mattsson JP, Lehmann A, Bettler B, Bräuner-Osborne H (2002) The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors. Mol Pharmacol 61(6):1377–1384CrossRefGoogle Scholar
  9. 9.
    Ohkawa T, Satake S, Yokoi N, Miyazaki Y, Ohshita T, Sobue G, Takashima H, Watanabe O, Fukata Y, Fukata M (2014) Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis. J Neurosci 34(24):8151–8163CrossRefGoogle Scholar
  10. 10.
    González RP, Hudson AL, Basáez ME, Miranda CM (2016) Autoimmune encephalitis induced by antibodies against GABA-A receptor. Rev Med Chil 144(11):1491–1493CrossRefGoogle Scholar
  11. 11.
    Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, Friedman D, Skeen MB, Grisold W, Kimura A, Ohta K, Iizuka T, Guzman M, Graus F, Moss SJ, Balice-Gordon R, Dalmau J (2010) Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9(1):67–76CrossRefGoogle Scholar
  12. 12.
    Hoftberger R, Titulaer MJ, Sabater L, Dome B, Rozsas A, Hegedus B, Hoda MA, Laszlo V, Ankersmit HJ, Harms L, Boyero S, de Felipe A, Saiz A, Dalmau J, Graus F (2013) Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81(17):1500–1506CrossRefGoogle Scholar
  13. 13.
    Jeffery OJ, Lennon VA, Pittock SJ, Gregory JK, Britton JW, McKeon A (2013) GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 81(10):882–887CrossRefGoogle Scholar
  14. 14.
    Irani SR, Bien CG, Lang B (2011) Autoimmune epilepsies. Curr Opin Neurol 24(2):146–153CrossRefGoogle Scholar
  15. 15.
    Fassbender C, Klingel R, Kohler W (2017) Immunoadsorption for autoimmune encephalitis. Atheroscler Suppl 30:257–263CrossRefGoogle Scholar
  16. 16.
    Sibbe M, Kulik A (2016) GABAergic regulation of adult hippocampal neurogenesis. Mol NeurobiolGoogle Scholar
  17. 17.
    Collingridge GL, Isaac JT, Wang YT (2004) Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5(12):952–962CrossRefGoogle Scholar
  18. 18.
    Prosser HM, Gill CH, Hirst WD, Grau E, Robbins M, Calver A, Soffin EM, Farmer CE, Lanneau C, Gray J, Schenck E, Warmerdam BS, Clapham C, Reavill C, Rogers DC, Stean T, Upton N, Humphreys K, Randall A, Geppert M, Davies CH, Pangalos MN (2001) Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol Cell Neurosci 17(6):1059–1070CrossRefGoogle Scholar
  19. 19.
    Ramanathan S, Mohammad SS, Brilot F, Dale RC (2014) Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci 21(5):722–730CrossRefGoogle Scholar
  20. 20.
    Lancaster E, Martinez-Hernandez E, Dalmau J (2011) Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77(2):179–189CrossRefGoogle Scholar
  21. 21.
    Billinton A, Ige AO, Wise A, White JH, Disney GH, Marshall FH, Waldvogel HJ, Faull RLM, Emson PC (2000) GABA(B) receptor heterodimer-component localisation in human brain. Brain Res Mol Brain Res 77(1):111–124CrossRefGoogle Scholar
  22. 22.
    Lujan R, Shigemoto R (2006) Localization of metabotropic GABA receptor subunits GABAB1 and GABAB2 relative to synaptic sites in the rat developing cerebellum. Eur J Neurosci 23(6):1479–1490CrossRefGoogle Scholar
  23. 23.
    Randall A, Huda S, Jacob A, Larner AJ (2018) Autoimmune encephalitis (NMDAR antibody) in a patient receiving chronic post-transplant immunosuppression. Pract Neurol 18:320–322CrossRefGoogle Scholar
  24. 24.
    Benarroch EE (2012) GABAB receptors: structure, functions, and clinical implications. Neurology 78(8):578–584CrossRefGoogle Scholar
  25. 25.
    Guan HZ, Ren HT, Yang XZ, Lu Q, Peng B, Zhu YC, Shao XQ, Hu YQ, Zhou D, Cui LY (2015) Limbic encephalitis associated with anti-gamma-aminobutyric acid B receptor antibodies: a case series from China. Chin Med J 128(22):3023–3028CrossRefGoogle Scholar
  26. 26.
    Aoki E, Semba R, Kashiwamata S (1986) New candidates for GABAergic neurons in the rat cerebellum: an immunocytochemical study with anti-GABA antibody. Neurosci Lett 68(3):267–271CrossRefGoogle Scholar
  27. 27.
    Gamrani H, Onteniente B, Seguela P, Geffard M, Calas A (1986) Gamma-aminobutyric acid-immunoreactivity in the rat hippocampus. A light and electron microscopic study with anti-GABA antibodies. Brain Res 364(1):30–38CrossRefGoogle Scholar
  28. 28.
    Bressers AA, Goto NA, Piepers S, Regelink JC (2016) Autoimmune encephalitis due to mantle cell lymphoma. Ned Tijdschr Geneeskd 160(0):D394Google Scholar
  29. 29.
    Martinelli GP, Holstein GR, Pasik P, Cohen B (1992) Monoclonal antibodies for ultrastructural visualization of L-baclofen-sensitive GABAB receptor sites. Neuroscience 46(1):23–33CrossRefGoogle Scholar
  30. 30.
    Goldberg TN, Cellucci MF (2017) New onset insomnia in a pediatric patient: a case of anti-NMDA receptor encephalitis. Case Rep Pediatr 2017:4083785PubMedPubMedCentralGoogle Scholar
  31. 31.
    Marques IB, Teotónio R, Cunha C, Bento C, Sales F (2014) Anti-NMDA receptor encephalitis presenting with total insomnia--a case report. J Neurol Sci 336(1–2):276–280CrossRefGoogle Scholar
  32. 32.
    Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NKV, Dalmau J (2003) Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol 53(3):347–353CrossRefGoogle Scholar
  33. 33.
    Jarius S, Steinmeyer F, Knobel A, Streitberger K, Hotter B, Horn S, Heuer H, Schreiber SJ, Wilhelm T, Trefzer U, Wildemann B, Ruprecht K (2013) GABAB receptor antibodies in paraneoplastic cerebellar ataxia. J Neuroimmunol 256(1–2):94–96CrossRefGoogle Scholar
  34. 34.
    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(1–2):91–93CrossRefGoogle Scholar
  35. 35.
    Simabukuro MM (2015) Autoimmune encephalitis and anti-GAD/GABA-A receptor antibodies. Epileptic Disord 17(1):97PubMedGoogle Scholar
  36. 36.
    Dogan Onugoren M, Deuretzbacher D, Haensch CA, Hagedorn HJ, Halve S, Isenmann S, Kramme C, Lohner H, Melzer N, Monotti R, Presslauer S, Schäbitz WR, Steffanoni S, Stoeck K, Strittmatter M, Stögbauer F, Trinka E, von Oertzen TJ, Wiendl H, Woermann FG, Bien CG (2015) Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry 86(9):965–972CrossRefGoogle Scholar
  37. 37.
    Magoul R, Onteniente B, Geffard M, Calas A (1987) Anatomical distribution and ultrastructural organization of the GABAergic system in the rat spinal cord. An immunocytochemical study using anti-GABA antibodies. Neuroscience 20(3):1001–1009CrossRefGoogle Scholar
  38. 38.
    Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, Engberg G, Erhardt S, Schwieler L, Orhan F, Malmqvist A, Hedberg M, Farde L, Cervenka S, Flyckt L, Collste K, Ikonen P, Piehl F, Agartz I, Cervenka S, Collste K, Victorsson P, Sellgren CM, Flyckt L, Erhardt S, Engberg G (2018) CSF GABA is reduced in first-episode psychosis and associates to symptom severity. Mol Psychiatry 23(5):1244–1250CrossRefGoogle Scholar
  39. 39.
    Su M, Xu D, Tian R (2015) (18)F-FDG PET/CT and MRI findings in a patient with anti-GABA(B) receptor encephalitis. Clin Nucl Med 40(6):515–517CrossRefGoogle Scholar
  40. 40.
    Morbelli S, Arbizu J, Booij J, Chen MK, Chetelat G, Cross DJ, Djekidel M, Drzezga A, Ekmekcioglu O, Garibotto V, Hesse S, Ishii K, Jafari L, Lammertsma AA, Law I, Mathews D, Minoshima S, Mosci K, Pagani M, Pappata S, Silverman DH, Signore A, Van De Giessen E, Villemagne V, Barthel H; European Association of Nuclear Medicine (EANM) and of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) (2016) The need of standardization and of large clinical studies in an emerging indication of [18F]FDG PET: the autoimmune encephalitis. Eur J Nucl Med Mol Imaging 44(3):353–357Google Scholar
  41. 41.
    Stingl C, Cardinale K, Van Mater H (2018) An update on the treatment of pediatric autoimmune encephalitis. Curr Treatm Opt Rheumatol 4(1):14–28CrossRefGoogle Scholar
  42. 42.
    Shin YW, Lee ST, Park KI, Jung KH, Jung KY, Lee SK, Chu K (2018) Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord 11:1756285617722347PubMedGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  • Zhihua Si
    • 1
  • Aihua Wang
    • 1
  • Jinzhi Liu
    • 1
  • Zixian Zhang
    • 2
  • Ke Hu
    • 3
    Email author
  1. 1.Department of NeurologyShandong Provincial Qianfoshan Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.Department of NeurologyZaozhuang Municopal HospitalZaozhuangChina
  3. 3.Department of EmergencyShandong Provincial Qianfoshan Hospital Affiliated to Shandong UniversityJinanChina

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