Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지
DOI QR코드

DOI QR Code

Autoimmune encephalitis and epilepsy: evolving definition and clinical spectrum

  • Seo, Joo Hee (Comprehensive Epilepsy Center, AdventHealth for Children) ;
  • Lee, Yun-Jin (Comprehensive Epilepsy Center, AdventHealth for Children) ;
  • Lee, Ki Hyeong (Comprehensive Epilepsy Center, AdventHealth for Children) ;
  • Gireesh, Elakkat (Comprehensive Epilepsy Center, AdventHealth for Children) ;
  • Skinner, Holly (Comprehensive Epilepsy Center, AdventHealth for Children) ;
  • Westerveld, Michael (Comprehensive Epilepsy Center, AdventHealth for Children)
  • Received : 2019.05.30
  • Accepted : 2019.08.13
  • Published : 2020.08.15
Download PDF
⟨ Previous Next ⟩

Abstract

Advances in autoimmune encephalitis studies in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to the disorder. The disorder or syndrome has been linked to a wide variety of pathologic processes associated with the neuron-specific autoantibodies targeting intracellular and plasma membrane antigens. However, current criteria for autoimmune encephalitis are quite dependent on antibody testing and responses to immunotherapy, which might delay the diagnosis. This form of encephalitis can involve the multifaceted presentation of seizures and unexpected behavioral changes. The spectrum of neuropsychiatric symptoms in children is less definitive than that in adults, and the incorporation of clinical, immunological, electrophysiological, and neuroradiological results is critical to the diagnostic approach. In this review, we document the clinical and immunologic characteristics of autoimmune encephalitis known to date, with the goal of helping clinicians in differential diagnosis and to provide prompt and effective treatment.

Keywords

References

  1. Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013;57:1114-28. https://doi.org/10.1093/cid/cit458
  2. Varley J, Taylor J, Irani SR. Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy. Neuropharmacology 2018;132:71-82. https://doi.org/10.1016/j.neuropharm.2017.04.046
  3. Quek AM, Britton JW, McKeon A, So E, Lennon VA, Shin C, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582-93. https://doi.org/10.1001/archneurol.2011.2985
  4. Toledano M, Britton JW, McKeon A, Shin C, Lennon VA, Quek AM, et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014;82:1578-86. https://doi.org/10.1212/WNL.0000000000000383
  5. Esposito S, Principi N, Calabresi P, Rigante D. An evolving redefinition of autoimmune encephalitis. Autoimmun Rev 2019;18:155-63. https://doi.org/10.1016/j.autrev.2018.08.009
  6. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404. https://doi.org/10.1016/S1474-4422(15)00401-9
  7. Toledano M, Pittock SJ. Autoimmune epilepsy. Semin Neurol 2015;35:245-58. https://doi.org/10.1055/s-0035-1552625
  8. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135-40. https://doi.org/10.1136/jnnp.2003.034447
  9. Irani SR. 'Moonlighting' surface antigens: a paradigm for autoantibody pathogenicity in neurology? Brain 2016;139(Pt 2):304-6. https://doi.org/10.1093/brain/awv364
  10. Dalmau J, Rosenfeld MR. Autoimmune encephalitis update. Neuro Oncol 2014;16:771-8. https://doi.org/10.1093/neuonc/nou030
  11. Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157-65. https://doi.org/10.1016/S1474-4422(12)70310-1
  12. Eker A, Saka E, Dalmau J, Kurne A, Bilen C, Ozen H, et al. Testicular teratoma and anti-N-methyl-D-aspartate receptor-associated encephalitis. J Neurol Neurosurg Psychiatry 2008;79:1082-3. https://doi.org/10.1136/jnnp.2008.147611
  13. Leypoldt F, Wandinger KP. Paraneoplastic neurological syndromes. Clin Exp Immunol 2014;175:336-48. https://doi.org/10.1111/cei.12185
  14. Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol 1999;59:279-98. https://doi.org/10.1016/S0301-0082(99)00007-6
  15. MacDonald JF, Jackson MF, Beazely MA. Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit Rev Neurobiol 2006;18:71-84. https://doi.org/10.1615/CritRevNeurobiol.v18.i1-2.80
  16. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001;11:327-35. https://doi.org/10.1016/S0959-4388(00)00215-4
  17. Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866-75. https://doi.org/10.1523/JNEUROSCI.0167-10.2010
  18. Armangue T, Titulaer MJ, Malaga I, Bataller L, Gabilondo I, Graus F, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;162:850-6.e2. https://doi.org/10.1016/j.jpeds.2012.10.011
  19. Goldberg EM, Titulaer M, de Blank PM, Sievert A, Ryan N. Anti-Nmethyl-D-aspartate receptor-mediated encephalitis in infants and toddlers: case report and review of the literature. Pediatr Neurol 2014;50:181-4. https://doi.org/10.1016/j.pediatrneurol.2013.10.002
  20. Zhang L, Wu MQ, Hao ZL, Chiang SM, Shuang K, Lin MT, et al. Clinical characteristics, treatments, and outcomes of patients with anti-N-methyld-aspartate receptor encephalitis: A systematic review of reported cases. Epilepsy Behav 2017;68:57-65. https://doi.org/10.1016/j.yebeh.2016.12.019
  21. Viaccoz A, Desestret V, Ducray F, Picard G, Cavillon G, Rogemond V, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 2014;82:556-63. https://doi.org/10.1212/WNL.0000000000000126
  22. Zhang Y, Liu G, Jiang MD, Li LP, Su YY. Analysis of electroencephalogram characteristics of anti-NMDA receptor encephalitis patients in China. Clin Neurophysiol 2017;128:1227-33. 3. https://doi.org/10.1016/j.clinph.2017.04.015
  23. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012;79:1094-100. https://doi.org/10.1212/WNL.0b013e3182698cd8
  24. Bacchi S, Franke K, Wewegama D, Needham E, Patel S, Menon D. et al. Magnetic resonance imaging and positron emission tomography in anti-NMDA receptor encephalitis: A systematic review. J Clin Neurosci 2018;52:54-9. https://doi.org/10.1016/j.jocn.2018.03.026
  25. Pruss H, Dalmau J, Harms L, Holtje M, Ahnert-Hilger G, Borowski K, et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 2010;75:1735-9. https://doi.org/10.1212/WNL.0b013e3181fc2a06
  26. Suppiej A, Nosadini M, Zuliani L, Pelizza MF, Toldo I, Bertossi C, et al. Plasma exchange in pediatric anti-NMDAR encephalitis: a systematic review. Brain Dev 2016;38:613-22. https://doi.org/10.1016/j.braindev.2016.01.009
  27. Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 2010;107:3799-804. https://doi.org/10.1073/pnas.0914537107
  28. Ohkawa T, Fukata Y, Yamasaki M, Miyazaki T, Yokoi N, Takashima H, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161-74. https://doi.org/10.1523/JNEUROSCI.3506-13.2013
  29. Petit-Pedrol M, Sell J, Planaguma J, Mannara F, Radosevic M, Haselmann H, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144-59.
  30. Arino H, Armangue T, Petit-Pedrol M, Sabater L, Martinez-Hernandez E, Hara M, et al. Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome. Neurology 2016;87:759-65. https://doi.org/10.1212/WNL.0000000000003009
  31. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892-900. https://doi.org/10.1002/ana.22307
  32. Thompson J, Bi M, Murchison AG, Makuch M, Bien CG, Chu K, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348-56. https://doi.org/10.1093/brain/awx323
  33. Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P, et al. Motor cortex and hippocampus are the two main cortical targets in LGI1- antibody encephalitis. Brain 2016;139(Pt 4):1079-93. https://doi.org/10.1093/brain/aww012
  34. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, 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. https://doi.org/10.1093/brain/awq213
  35. Irani SR, Gelfand JM, Bettcher BM, Singhal NS, Geschwind MD. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibodyassociated encephalopathy. JAMA Neurol 2014;71:896-900. https://doi.org/10.1001/jamaneurol.2014.463
  36. Finke C, Pruss H, Heine J, Reuter S, Kopp UA, Wegner F, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74:50-9. https://doi.org/10.1001/jamaneurol.2016.4226
  37. Lancaster E, Huijbers MG, Bar V, Boronat A, Wong A, Martinez-Hernandez E, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011;69:303-11. https://doi.org/10.1002/ana.22297
  38. Joubert B, Saint-Martin M, Noraz N, Picard G, Rogemond V, Ducray F, et al. Characterization of a subtype of autoimmune encephalitis with anticontactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures. JAMA Neurol 2016;73:1115-24. https://doi.org/10.1001/jamaneurol.2016.1585
  39. van Sonderen A, Arino H, Petit-Pedrol M, Leypoldt F, Kortvelyessy P, Wandinger KP, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology 2016;87:521-8. https://doi.org/10.1212/WNL.0000000000002917
  40. Maat P, de Beukelaar JW, Jansen C, Schuur M, van Duijn CM, van Coevorden MH, et al. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease. Neurol Neuroimmunol Neuroinflamm 2015;2:e178. https://doi.org/10.1212/NXI.0000000000000178
  41. Klein CJ, Lennon VA, Aston PA, McKeon A, O'Toole O, Quek A, et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70:229-34. https://doi.org/10.1001/jamaneurol.2013.592
  42. Lilleker JB, Jones MS, Mohanraj R. VGKC complex antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure 2013;22:776-9. https://doi.org/10.1016/j.seizure.2013.06.004
  43. Pon NC, Houck KM, Muscal E, Idicula SA. Voltage-gated potassium channel antibody autoimmune encephalopathy presenting with isolated psychosis in an adolescent. J Psychiatr Pract 2017;23:441-5. https://doi.org/10.1097/PRA.0000000000000265
  44. Benarroch EE. GABAB receptors: structure, functions, and clinical implications. Neurology 2012;78:578-84. https://doi.org/10.1212/WNL.0b013e318247cd03
  45. Petit-Pedrol M, Armangue T, Peng X, Bataller L, Cellucci T, Davis R, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276-86. https://doi.org/10.1016/S1474-4422(13)70299-0
  46. Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, et al. Investigations in GABAA receptor antibodyassociated encephalitis. Neurology 2017;88:1012-20. https://doi.org/10.1212/wnl.0000000000003713
  47. Nikolaus M, Knierim E, Meisel C, Kreye J, Pruss H, Schnabel D, et al. Severe GABAA receptor encephalitis without seizures: a paediatric case successfully treated with early immunomodulation. Eur J Paediatr Neurol 2018;22:558-62. https://doi.org/10.1016/j.ejpn.2018.01.002
  48. Hoftberger R, Titulaer MJ, Sabater L, Dome B, Rozsas A, Hegedus B, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81:1500-6. https://doi.org/10.1212/WNL.0b013e3182a9585f
  49. Kruer MC, Hoeftberger R, Lim KY, Coryell JC, Svoboda MD, Woltjer RL, et al. Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of ${\gamma}$-aminobutyric acid type B receptor autoimmunity. JAMA Neurol 2014;71:620-3. https://doi.org/10.1001/jamaneurol.2013.4786
  50. Lai M, Hughes EG, Peng X, Zhou L, Gleichman AJ, Shu H, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65:424-34. https://doi.org/10.1002/ana.21589
  51. Hoftberger R, van Sonderen A, Leypoldt F, Houghton D, Geschwind M, Gelfand J, et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 2015;84:2403-12. https://doi.org/10.1212/WNL.0000000000001682
  52. Zeilhofer HU, Wildner H, Yevenes GE. Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 2012;92:193-235. https://doi.org/10.1152/physrev.00043.2010
  53. Thomas RH, Chung SK, Wood SE, Cushion TD, Drew CJ, Hammond CL, et al. Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay. Brain 2013;136(Pt 10):3085-95. https://doi.org/10.1093/brain/awt207
  54. Iizuka T, Leite MI, Lang B, Waters P, Urano Y, Miyakawa S, et al. Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations. J Neurol 2012;259:1566-73. https://doi.org/10.1007/s00415-011-6377-2
  55. Carvajal-Gonzalez A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014;137(Pt 8):2178-92. https://doi.org/10.1093/brain/awu142
  56. Kanaani J, Cianciaruso C, Phelps EA, Pasquier M, Brioudes E, Billestrup N, et al. Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons. PLoS One 2015;10:e0117130. https://doi.org/10.1371/journal.pone.0117130
  57. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist 2007;13:261-71. https://doi.org/10.1097/nrl.0b013e31813e34a5
  58. Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 2010;67:470-8. https://doi.org/10.1002/ana.21917
  59. Ben Achour N, Ben Younes T, Rebai I, Ben Ahmed M, Kraoua I, Ben Youssef-Turki I. Severe dysautonomia as a main feature of anti-GAD encephalitis: report of a paediatric case and literature review. Eur J Paediatr Neurol 2018;22:548-51. https://doi.org/10.1016/j.ejpn.2018.01.004
  60. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011;10:759-72. https://doi.org/10.1016/S1474-4422(11)70096-5
  61. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003;78:1363-8. https://doi.org/10.4065/78.11.1363
  62. Perucca P, Dubeau F, Gotman J. Intracranial electroencephalographic seizure-onset patterns: effect of underlying pathology. Brain 2014;137(Pt 1):183-96. https://doi.org/10.1093/brain/awt299
  63. Hacohen Y, Wright S, Waters P, Agrawal S, Carr L, Cross H, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry 2013;84:748-55. https://doi.org/10.1136/jnnp-2012-303807
  64. Escudero D, Guasp M, Arino H, Gaig C, Martinez-Hernandez E, Dalmau J, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology 2017;89:1471-5. https://doi.org/10.1212/wnl.0000000000004541
  65. Darnell RB, Posner JB. A new cause of limbic encephalopathy. Brain 2005;128(Pt 8):1745-6. https://doi.org/10.1093/brain/awh592
  66. Bascic-Kes V, Kes P, Zavoreo I, Lisak M, Zadro L, Coric L, et al. Guidelines for the use of intravenous immunoglobulin in the treatment of neurologic diseases. Acta Clin Croat 2012;51:673-83.
  67. Dogan Onugoren M, Golombeck KS, Bien C, Abu-Tair M, Brand M, Bulla-Hellwig M, et al. Immunoadsorption therapy in autoimmune encephalitides. Neurol Neuroimmunol Neuroinflamm 2016;3:e207. https://doi.org/10.1212/NXI.0000000000000207
  68. Platt MP, Agalliu D, Cutforth T. Hello from the other side: how autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis. Front Immunol 2017;8:442. https://doi.org/10.3389/fimmu.2017.00442

Cited by

  1. Commentary on "Autoimmune encephalitis and epilepsy: evolving definition and clinical spectrum" vol.63, pp.8, 2020, https://doi.org/10.3345/cep.2020.00353
  2. Characteristics and Prognosis of Autoimmune Encephalitis in the East of China: A Multi-Center Study vol.12, 2020, https://doi.org/10.3389/fneur.2021.642078
  3. Anti-Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Encephalitis: A Review vol.12, 2021, https://doi.org/10.3389/fimmu.2021.652820
  4. Association between autoimmune encephalitis and epilepsy: Systematic review and meta-analysis vol.91, 2020, https://doi.org/10.1016/j.seizure.2021.07.005