Glutamate Receptor Antibodies in Autoimmune Central Nervous System Disease: Basic Mechanisms, Clinical Features, and Antibody Detection

Part of the Methods in Molecular Biology book series (MIMB, volume 1941)


Immune-mediated inflammation of the brain has been recognized for more than 50 years, although the initial descriptions were mainly thought to be secondary to an underlying neoplasm. Some of these paraneoplastic encephalitides express serum antibodies, but these were not thought to be pathogenic but instead have a T-cell-mediated pathophysiology. Over the last two decades, several pathogenic antibodies against neuronal surface antigens have been described in autoimmune encephalitis, which are amenable to immunotherapy. Several of these antibodies are directed against glutamate receptors (GluRs). NMDAR encephalitis (NMDARE) is the most common of these antibodies, and patients often present with psychosis, hallucinations, and reduced consciousness. Patients often progress on to develop confusion, seizures, movement disorders, autonomic instability, and respiratory depression. Although initially described as exclusively occurring secondary to ovarian teratoma (and later other tumors), non-paraneoplastic forms are increasingly common, and other triggers like viral infections are now well recognized. AMPAR encephalitis is relatively less common than NMDARE but is more likely to paraneoplastic. AMPAR antibodies typically cause limbic encephalitis, with patients presenting with confusion, disorientation, memory loss, and often seizures. The syndromes associated with the metabotropic receptor antibodies are much rarer and often can be paraneoplastic—mGluR1 (cerebellar degeneration) and mGluR5 (Ophelia syndrome) being the ones described in literature.

With the advance in molecular biology techniques, it is now possible to detect these antibodies using cell-based assays with high sensitivity and specificity, especially when coupled with brain tissue immunohistochemistry and binding to live cell-based neurons. The rapid and reliable identification of these antibodies aids in the timely treatment (either in the form of identifying/removing the underlying tumor or instituting immunomodulatory therapy) and has significantly improved clinical outcome in this otherwise devastating group of conditions.

Key words

Glutamate receptor Autoimmune encephalitis Paraneoplastic Neuronal surface antibodies Neuropsychiatric disorder NMDAR AMPAR mGluR1 mGluR5 KAR Transfected cell-based assay Pathogenic markers 


  1. 1.
    Florey E (1954) An inhibitory and an excitatory factor of mammalian central nervous system, and their action of a single sensory neuron. Arch Int Physiol 62:33–53PubMedGoogle Scholar
  2. 2.
    Kuffler SW (1954) Mechanisms of activation and motor control of stretch receptors in lobster and crayfish. J Neurophysiol 17:558–574PubMedCrossRefGoogle Scholar
  3. 3.
    Nicoll RA, Malenka RC (1995) Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377(6545):115–118PubMedCrossRefGoogle Scholar
  4. 4.
    Rousseaux CG (2008) A review of glutamate receptors I: current understanding of their biology. J Toxicol Pathol 21:25–51CrossRefGoogle Scholar
  5. 5.
    Karim AR, Jacob S (2012) Immunological markers in neurological disorders. Ann Clin Biochem 49:29–43PubMedCrossRefGoogle Scholar
  6. 6.
    Levite M (2014) Glutamate receptor antibodies in neurological diseases. J Neural Transm 121:1029–1075CrossRefGoogle Scholar
  7. 7.
    Rose CR, Felix L, Zeug A et al (2018) Astroglial glutamate signaling and uptake in the hippocampus. Front Mol Neurosci 17(10):451CrossRefGoogle Scholar
  8. 8.
    Krnjevir K, Phillis JW (1963) Actions of certain amines on cerebral cortical neurones. Br J Pharmacol Chemother 20:471–490CrossRefGoogle Scholar
  9. 9.
    Krnjevic K, Phillis JW (1963) Iontophoretic studies of neurones in the mammalian cerebral cortex. J Physiol 165:274–304PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Watkins JC, Evans RH (1981) Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol 21:165–204PubMedCrossRefGoogle Scholar
  11. 11.
    Mayer ML, Westbrook GL (1987) The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 28(3):197–276PubMedCrossRefGoogle Scholar
  12. 12.
    Collingridge GL, Lester RA (1989) Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 41:143–210PubMedGoogle Scholar
  13. 13.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39PubMedCrossRefGoogle Scholar
  14. 14.
    Chapman PF, Kairiss EW, Keenan CL et al (1990) Long-term synaptic potentiation in the amygdala. Synapse 6:271–278PubMedCrossRefGoogle Scholar
  15. 15.
    Bruno V, Copani A, Battaglia G et al (1994) Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death. Eur J Pharmacol 256(1):109–112PubMedCrossRefGoogle Scholar
  16. 16.
    Monyer H, Sprengel R, Schoepfer R et al (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256(5060):1217–1221PubMedCrossRefGoogle Scholar
  17. 17.
    Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108PubMedCrossRefGoogle Scholar
  18. 18.
    Nakanishi S, Masu M (1994) Molecular diversity and functions of glutamate receptors. Annu Rev Biophys Biomol Struct 23:319–348PubMedCrossRefGoogle Scholar
  19. 19.
    Dingledine R, Borges K, Bowie D et al (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–61PubMedGoogle Scholar
  20. 20.
    Asztély F, Gustafsson B (1996) Ionotropic glutamate receptors. Their possible role in the expression of hippocampal synaptic plasticity. Mol Neurobiol 12:1–11PubMedCrossRefGoogle Scholar
  21. 21.
    Miller S, Kesslak JP, Romano C et al (1995) Roles of metabotropic glutamate receptors in brain plasticity and pathology. Ann N Y Acad Sci 757:460–474PubMedCrossRefGoogle Scholar
  22. 22.
    Ozawa S, Kamiya H, Tsuzuki K (1998) Glutamate receptors in the mammalian nervous system. Prog Neurobiol 54(5):581–618PubMedCrossRefGoogle Scholar
  23. 23.
    Cunningham MD, Ferkany JW, Enna SJ (1994) Excitatory amino acid receptors: a gallery of new targets for pharmacological intervention. Life Sci 54(3):135–148PubMedCrossRefGoogle Scholar
  24. 24.
    Shannon HE, Sawyer BD (1989) Glutamate receptors of the N-methyl-D-aspartate subtype in the myenteric plexus of the guinea pig ileum. J Pharmacol Exp Ther 251:518–523PubMedGoogle Scholar
  25. 25.
    Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237PubMedCrossRefGoogle Scholar
  26. 26.
    Bowie D (2008) Ionotropic glutamate receptors & CNS disorders. CNS Neurol Disord Drug Targets 7:129–143PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Mayer ML (2011) Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation. Curr Opin Neurobiol 21(2):283–290PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Mayer ML (2011) Emerging models of glutamate receptor ion channel structure and function. Structure 19(10):1370–1380PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sobolevsky AI (2015) Structure and gating of tetrameric glutamate receptors. J Physiol 5931:29–38CrossRefGoogle Scholar
  30. 30.
    Lynch DR, Rattelle A, Dong YN et al (2018) Anti-NMDA receptor encephalitis: clinical features and basic mechanisms. Adv Pharmacol 82:235–260PubMedCrossRefGoogle Scholar
  31. 31.
    Regan MC, Romero-Hernandez A, Furukawa H (2015) A structural biology perspective on NMDA receptor pharmacology and function. Curr Opin Struct Biol 33:68–75PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Traynelis SF, Wollmuth LP, Mcbain CJ et al (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Zhu S, Paoletti P (2015) Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol 20:14–23PubMedCrossRefGoogle Scholar
  34. 34.
    Monyer H, Sprengel R, Schoepfer R et al (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221PubMedCrossRefGoogle Scholar
  35. 35.
    Karakas E, Simorowski N, Furukawa H (2009) Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J 28:3910–3920PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Dalmau J, Geis C, Graus F (2017) Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 97:839–887PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gleichman AJ, Spruce LA, Dalmau J et al (2012) Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J Neurosci 32:11082–11094PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Herron CE, Lester RA, Coan EJCG (1986) Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature 322(6076):265–268PubMedCrossRefGoogle Scholar
  39. 39.
    Kupper J, Ascher P, Neytont J (1996) Probing the pore region of recombinant N-methyl-D-aspartate channels using external and internal magnesium block. Proc Natl Acad Sci U S A 93(16):8648–8653PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Forrest D, Yuzaki M, Soares HD et al (1994) Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 13:325–338PubMedCrossRefGoogle Scholar
  41. 41.
    Partin KM, Fleck MW, Mayer ML (1996) AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by Cyclothiazide, Aniracetam, and Thiocyanate. J Neurosci 16(21):6634–6647PubMedCrossRefGoogle Scholar
  42. 42.
    Parsons CG, Zong X, Lux HD (1993) Whole cell and single channel analysis of the kinetics of glycine-sensitive N-methyl-D-aspartate receptor desensitization. Br J Pharmacol 109(1):213–221PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Chávez AE, Singer JH, Diamond JS (2006) Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature 443(7112):705–708PubMedCrossRefGoogle Scholar
  44. 44.
    Sommer B, Keinänen K, Verdoorn TA et al (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249(4976):1580–1585PubMedCrossRefGoogle Scholar
  45. 45.
    Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643PubMedCrossRefGoogle Scholar
  46. 46.
    Rosenmund C, Stern-Bach Y, Stevens CF (1998) The tetrameric structure of a glutamate receptor channel. Science 280:1596–1599PubMedCrossRefGoogle Scholar
  47. 47.
    Mayer ML (2005) Glutamate receptor ion channels. Curr Opin Neurobiol 15:282–288PubMedCrossRefGoogle Scholar
  48. 48.
    Palmer CL, Cotton L, Henley JM (2005) The molecular pharmacology and cell biology of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev 57(2):253–277PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Geiger JR, Melcher T, Koh DS et al (1995) Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15(1):193–204PubMedCrossRefGoogle Scholar
  50. 50.
    Sans N, Vissel B, Petralia RS et al (2003) Aberrant formation of glutamate receptor complexes in hippocampal neurons of mice lacking the GluR2 AMPA receptor subunit. J Neurosci 23(28):9367–9373PubMedCrossRefGoogle Scholar
  51. 51.
    Wenthold RJ, Petralia RS, Niedzielski AS (1996) Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J Neurosci 16(6):1982–1989PubMedCrossRefGoogle Scholar
  52. 52.
    Sprengel R (2006) Role of AMPA receptors in synaptic plasticity. Cell Tissue Res 326(2):447–455PubMedCrossRefGoogle Scholar
  53. 53.
    Vignes M, Bleakman D, Lodge D et al (1997) The synaptic activation of the GluR5 subtype of kainate receptor in area CA3 of the rat hippocampus. Neuropharmacology 36:1477–1481PubMedCrossRefGoogle Scholar
  54. 54.
    Lerma J, Paternain AV, Rodriguez A et al (2001) Molecular physiology of Kainate receptors. Physiol Rev 81(3):971–998PubMedCrossRefGoogle Scholar
  55. 55.
    Collingridge GL, Olsen RW, Peters J et al (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology 56(1):2–5PubMedCrossRefGoogle Scholar
  56. 56.
    Keinänen K, Wisden W, Sommer B et al (1990) A family of AMPA-selective glutamate receptors. Science 249:556–560PubMedCrossRefGoogle Scholar
  57. 57.
    Lerma J (2006) Kainate receptor physiology. Curr Opin Pharmacol 6:89–97PubMedCrossRefGoogle Scholar
  58. 58.
    Chittajallu R, Braithwaite SP, Clarke VR et al (1999) Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol Sci 20:26–35PubMedCrossRefGoogle Scholar
  59. 59.
    Ohashi H, Maruyama T, Higashi-Matsumoto H et al (2002) A novel binding assay for metabotropic glutamate receptors using [3H] L-quisqualic acid and recombinant receptors. Z Naturforsch C 57:348–355PubMedCrossRefGoogle Scholar
  60. 60.
    Hinoi E, Ogita K, Takeuchi Y et al (2001) Characterization with [3H]quisqualate of group I metabotropic glutamate receptor subtype in rat central and peripheral excitable tissues. Neurochem Int 38:277–285PubMedCrossRefGoogle Scholar
  61. 61.
    Chu Z, Hablitz JJ (2000) Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons. Brain Res 879:88–92PubMedCrossRefGoogle Scholar
  62. 62.
    Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Schoepp DD (1994) Novel functions for subtypes of metabotropic glutamate receptors. Neurochem Int 24:439–449PubMedCrossRefGoogle Scholar
  64. 64.
    Narahashi T, Arakawa O, Brunner EA et al (1992) Modulation of GABA receptor-channel complex by alcohols and general anesthetics. Adv Biochem Psychopharmacol 47:325–334PubMedGoogle Scholar
  65. 65.
    Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 75:889–907PubMedCrossRefGoogle Scholar
  66. 66.
    Kew JNC, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology 179:4–29PubMedCrossRefGoogle Scholar
  67. 67.
    Crisp SJ, Kullmann DM, Vincent A (2016) Autoimmune synaptopathies. Nat Rev Neurosci 17:103–117PubMedCrossRefGoogle Scholar
  68. 68.
    Darnell RB, Posner JB (2003) Paraneoplastic syndromes involving the nervous system. N Engl J Med 349(16):1543–1554PubMedCrossRefGoogle Scholar
  69. 69.
    Drachman DB, Angus CW, Adams RN et al (1978) Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med 298:1116–1122PubMedCrossRefGoogle Scholar
  70. 70.
    Drachman DB, Adams RN, Josifek LF et al (1982) Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 307:769–775PubMedCrossRefGoogle Scholar
  71. 71.
    Nagel A, Engel AG, Lang B et al (1988) Lambert-Eaton myasthenic syndrome IgG depletes presynaptic membrane active zone particles by antigenic modulation. Ann Neurol 24:552–558PubMedCrossRefGoogle Scholar
  72. 72.
    Waterman SA, Lang B, Newsom-Davis J (1997) Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 42:147–156PubMedCrossRefGoogle Scholar
  73. 73.
    Casper J (1928) Subacute cortical cerebellar degeneration associated with carcinoma. Zbl ges Neurol Psychiat 53:854Google Scholar
  74. 74.
    Brain WR, Daniel PM, Greenfield JG (1951) Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry 14(2):59–75PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Corsellis JA, Goldberg GJ, Norton AR (1968) “Limbic encephalitis” and its association with carcinoma. Brain 91(3):481–496PubMedCrossRefGoogle Scholar
  76. 76.
    Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 35:538–543PubMedCrossRefGoogle Scholar
  77. 77.
    Dalmau J, Rosenfeld MR (2008) Paraneoplastic syndromes of the CNS. Lancet Neurol 7(4):327–340PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Moscato EH, Jain A, Peng X et al (2010) Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies. Eur J Neurosci 32(2):298–309PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Buckley C, Oger J, Clover L et al (2001) Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 50:73–78PubMedCrossRefGoogle Scholar
  80. 80.
    Vincent A, Buckley C, Schott JM et al (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701–712PubMedCrossRefGoogle Scholar
  81. 81.
    Irani SR, Alexander S, Waters P et al (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(9):2734–2748PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Vitaliani R, Mason W, Ances B et al (2005) Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 58(4):594–604PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ances BM, Vitaliani R, Taylor RA et al (2005) Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128:1764–1777PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Gable MS, Gavali S, Radner A et al (2009) Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis 28:1421–1429PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Dalmau J, Tüzün E, Wu H et al (2007) Paraneoplastic anti- N -methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lai M, Hughes EG, Peng X et al (2009) AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 65:424–434PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Höftberger R, Titulaer MJ, Sabater L et al (2013) Encephalitis and GABA B receptor antibodies novel findings in a new case series of 20 patients. Neurology 81(17):1500–1506PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Jeffery OJ, Lennon VA, Pittock SJ et al (2013) GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 81:882–887PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lancaster E, Lai M, Peng X et al (2010) Antibodies to the GABA B receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9(1):67–76PubMedCrossRefGoogle Scholar
  90. 90.
    Petit-Pedrol M, Armangue T, Peng X et al (2014) Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABA A receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 13(3):276–286PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Carvajal-Gonzá Lez A, Leite MI, Waters P et al (2014) Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 137:2178–2192CrossRefGoogle Scholar
  92. 92.
    Martinez-Hernandez E, Ariño H, McKeon A et al (2016) Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurol 73:714–720PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Lancaster E, Martinez-Hernandez E, Titulaer MJ et al (2011) Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 77(18):1698–1701PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sabater L, Gaig C, Gelpi E et al (2014) A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 13:575–586PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gelpi E, Höftberger R, Graus F et al (2016) Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 132:531–543PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Marignier R, Chenevier F, Rogemond V et al (2010) Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease? Arch Neurol 67:627–630PubMedCrossRefGoogle Scholar
  97. 97.
    Smitt PS, Kinoshita A, De Leeuw B et al (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342:21–27CrossRefGoogle Scholar
  98. 98.
    Dale RC, Merheb V, Pillai S et al (2012) Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 135:3453–3468PubMedCrossRefGoogle Scholar
  99. 99.
    Boronat A, Gelfand JM, Gresa-Arribas N et al (2013) Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 73:120–128PubMedCrossRefGoogle Scholar
  100. 100.
    Cheng MH, Fan U, Grewal N et al (2010) Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N Engl J Med 362:764–766PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Meager A, Peterson P, Willcox N (2008) Hypothetical review: thymic aberrations and type-I interferons; attempts to deduce autoimmunizing mechanisms from unexpected clues in monogenic and paraneoplastic syndromes. Clin Exp Immunol 154:141–151PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Shelly S, Agmon-Levin N, Altman A et al (2011) Thymoma and autoimmunity. Cell Mol Immunol 8:199–202PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Leypoldt F, Wandinger KP, Bien CG et al (2013) Autoimmune encephalitis. Eur Neurol Rev 8(1):31–37PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y et al (2011) Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77(6):589–593PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Binks S, Varley J, Lee W et al (2018) Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain. PubMedCentralCrossRefPubMedGoogle Scholar
  106. 106.
    Jones HF, Mohammad SS, Reed PW et al (2017) Anti- N -methyl- d -aspartate receptor encephalitis in Māori and Pacific Island children in New Zealand. Dev Med Child Neurol 59:719–724PubMedCrossRefGoogle Scholar
  107. 107.
    Mueller SH, Färber A, Prüss H et al (2018) Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol 83:863–869PubMedCrossRefGoogle Scholar
  108. 108.
    Graus F, Delattre JY, Antoine JC et al (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75:1135–1140PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Tüzün E, Zhou L, Baehring JM et al (2009) Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol 118:737–743PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Makuch M, Wilson R, Al-Diwani A et al (2018) N-methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 83:553–561PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Dalmau J, Gleichman AJ, Hughes EG et al (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Armangue T, Leypoldt F, Málaga I et al (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75:317–323PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Armangue T, Titulaer MJ, Málaga I et al (2013) Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 162:850–856.e2PubMedCrossRefGoogle Scholar
  114. 114.
    Prüss H, Finke C, Höltje M et al (2012) N-methyl- D -aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 72:902–911PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Schabitz W-R, Rogalewski A, Hagemeister C et al (2014) VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology 83:2309–2311PubMedCrossRefGoogle Scholar
  116. 116.
    Gable MS, Gavali S, Radner A et al (2009) Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis 28:1421–1429PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Salovin A, Glanzman J, Roslin K et al (2018) Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol neuroinflamm 5:e458PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Dalmau J (2016) NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: the 2016 Cotzias lecture. Neurology 87(23):2471–2482PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Titulaer MJ, McCracken L, Gabilondo I et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Granerod J, Ambrose HE, Davies NW et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10:835–844PubMedCrossRefGoogle Scholar
  121. 121.
    Gresa-Arribas N, Titulaer MJ, Torrents A et al (2014) Diagnosis and significance of antibody titers in anti-NMDA receptor encephalitis, a retrospective study. Lancet Neurol 13(2):167–177PubMedCrossRefGoogle Scholar
  122. 122.
    Kreye J, Wenke NK, Chayka M et al (2016) Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 139:2641–2652PubMedCrossRefGoogle Scholar
  123. 123.
    Gable MS, Sheriff H, Dalmau J et al (2012) The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California encephalitis project. Clin Infect Dis 54(7):899–904PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Dalmau J, Lancaster E, Martinez-Hernandez E et al (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10:63–74PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Titulaer MJ, McCracken L, Gabilondo I et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Zandi MS, Irani SR, Lang B et al (2011) Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 258:686–688PubMedCrossRefGoogle Scholar
  127. 127.
    Kleinig TJ, Thompson PD, Matar W et al (2008) The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord 23:1256–1261PubMedCrossRefGoogle Scholar
  128. 128.
    Gresa-Arribas N, Titulaer MJ, Torrents A et al (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13:167–177PubMedCrossRefGoogle Scholar
  129. 129.
    Hill KE, Clawson SA, Rose JW et al (2009) Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics. J Neuroinflammation 6:31PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Hacohen Y, Zuberi S, Vincent A et al (2015) Neuromyelitis optica in a child with Aicardi-Goutières syndrome. Neurology 85(4):381–383PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Schmitt SE, Pargeon K, Frechette ES et al (2012) Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 79(11):1094–1100PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Abbas A, Garg A, Jain R et al (2016) Extreme delta brushes and BIRDs in the EEG of anti-NMDA-receptor encephalitis. Pract Neurol 16(4):326–327PubMedCrossRefGoogle Scholar
  133. 133.
    Baykan B, Gungor Tuncer O, Vanli-Yavuz EN et al (2018) Delta brush pattern is not unique to NMDAR encephalitis: evaluation of two independent long-term EEG cohorts. Clin EEG Neurosci 49:278–284PubMedCrossRefGoogle Scholar
  134. 134.
    Leypoldt F, Buchert R, Kleiter I et al (2012) Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry 83:681–686PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Steiner J, Walter M, Glanz W et al (2013) Increased prevalence of diverse N -methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia. JAMA Psychiat 70:271CrossRefGoogle Scholar
  136. 136.
    Busse S, Busse M, Brix B et al (2014) Seroprevalence of N-methyl-D-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients. Eur Arch Psychiatry Clin Neurosci 264:545–550PubMedCrossRefGoogle Scholar
  137. 137.
    Zerche M, Weissenborn K, Ott C et al (2015) Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke 46:1180–1186PubMedCrossRefGoogle Scholar
  138. 138.
    Doss S, Wandinger K-P, Hyman BT et al (2014) High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types. Ann Clin Transl Neurol 1:822–832PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Dahm L, Ott C, Steiner J et al (2014) Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 76:82–94PubMedCrossRefGoogle Scholar
  140. 140.
    Gastaldi M, Thouin A, Franciotta D et al (2017) Pitfalls in the detection of N -methyl- d -aspartate-receptor (NMDA-R) antibodies. Clin Biochem 50:354–355PubMedCrossRefGoogle Scholar
  141. 141.
    Zandi MS, Paterson RW, Ellul MA et al (2015) Clinical relevance of serum antibodies to extracellular N -methyl-d-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry 86:708–713PubMedCrossRefGoogle Scholar
  142. 142.
    Hara M, Martinez-Hernandez E, Ariño H et al (2018) Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology 90(16):e1386–e1394PubMedCrossRefGoogle Scholar
  143. 143.
    Hansen H-C, Klingbeil C, Dalmau J et al (2013) Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis. JAMA Neurol 70:117–119PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Viaccoz A, Desestret V, Ducray F et al (2014) Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 82:556–563PubMedCrossRefGoogle Scholar
  145. 145.
    Lapteva L, Nowak M, Yarboro CH et al (2006) Anti–N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum 54:2505–2514PubMedCrossRefGoogle Scholar
  146. 146.
    Fragoso-Loyo H, Cabiedes J, Orozco-Narváez A et al (2008) Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLoS One 3:e3347PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Harrison MJ, Ravdin LD, Lockshin MD (2006) Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum 54:2515–2522PubMedCrossRefGoogle Scholar
  148. 148.
    Steup-Beekman G, Steens S, van Buchem M et al (2007) Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 16:329–334PubMedCrossRefGoogle Scholar
  149. 149.
    Graus F, Dalmau J (2014) Neuronal antibodies in Creutzfeldt-Jakob disease—reply. JAMA Neurol 71:514–515PubMedCrossRefGoogle Scholar
  150. 150.
    De Bruijn MA, Titulaer MJ (2016) Anti-NMDAR encephalitis and other glutamate and GABA receptor antibody encephalopathies. Handb Clin Neurol 133:199–217PubMedCrossRefGoogle Scholar
  151. 151.
    Höftberger R, van Sonderen A, Leypoldt F et al (2015) Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 84:2403–2412PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Peng X, Hughes EG, Moscato EH et al (2015) Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies. Ann Neurol 77:381–398PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Rogers SW, Andrews PI, Gahring LC et al (1994) Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 265:648–651CrossRefGoogle Scholar
  154. 154.
    Mat A, Adler H, Merwick A et al (2013) Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF. Neurology 80:1349–1350PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Spatola M, Sabater L, Planaguma J et al (2018) Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 90:e1964–e1972PubMedCrossRefGoogle Scholar
  156. 156.
    Carr I (1982) The Ophelia syndrome: memory loss in Hodgkin’s disease. Lancet 319:844–845CrossRefGoogle Scholar
  157. 157.
    Graus F, Rosenfeld MR, Saiz A et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Irani SR, Bera K, Waters P et al (2010) N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133:1655–1667PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    McCracken L, Zhang J, Greene M et al (2017) Improving the antibody-based evaluation of autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 4(6):e404PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Graus F, Saiz A, Dalmau J (2010) Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257:509–517PubMedCrossRefGoogle Scholar
  161. 161.
    Karim A, Egner W, Patel D et al (2016) International consensus: paraneoplastic neurological antibodies—are we there yet? J Clin Exp Neuroimmunol 1(1).
  162. 162.
    Lancaster E, Dalmau J (2012) Neuronal autoantigens-pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8(7):380–390PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Wandinger K-P, Klingbeil C, Gneiss C et al (2011) Neue serologische Marker zur Differentialdiagnose der Autoimmun-Enzephalitis/New serological markers for the differential diagnosis of autoimmune limbic encephalitis. J Lab Med 35:329–342Google Scholar
  164. 164.
    Qin W, Beck LH, Zeng C et al (2011) Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol 22:1137–1143PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Leypoldt F, Wandinger KP (2014) Paraneoplastic neurological syndromes. Clin Exp Immunol 175:336–348PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    McKeon A, Pittock SJ, Lennon VA (2011) CSF complements serum for evaluations paraneoplastic antibodies and NMO-IgG. Neurology 76(12):1108–1110PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Hachiya Y, Uruha A, Kasai-Yoshida E et al (2013) Rituximab ameliorates anti-N-methyl-D-aspartate receptor encephalitis by removal of short-lived plasmablasts. J Neuroimmunol 265:128–130PubMedCrossRefGoogle Scholar
  168. 168.
    Jeong IH, Park B, Kim S-H et al (2016) Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints. Mult Scler 22:329–339PubMedCrossRefGoogle Scholar
  169. 169.
    Mealy MA, Wingerchuk DM, Palace J et al (2014) Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 71:324–330PubMedCrossRefGoogle Scholar
  170. 170.
    Tanyi JL, Marsh EB, Dalmau J et al (2012) Reversible paraneoplastic encephalitis in three patients with ovarian neoplasms. Acta Obstet Gynecol Scand 91:630–634PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologyUniversity Hospitals Birmingham NHS Foundation TrustBirminghamUK
  2. 2.Department of NeuroimmunologyUniversity of BirminghamBirminghamUK

Personalised recommendations