Autoimmune encephalitis with negative anti-neuronal antibodies – clinical characteristics and available methods of antibody detection

Czech version

Authors: H. Mojžíšová ¹; M. Elišák ¹; ; J. Hanzalová ^1,2; M. Petržalka ¹; P. Marusič ¹
Authors‘ workplace: Neurologická klinika, 2. LF UK a FN Motol, Praha ¹; Ústav imunologie, 2. LF UK a FN Motol, Praha ²
Published in: Cesk Slov Neurol N 2020; 83/116(3): 251-256
Category: Review Article
doi: https://doi.org/10.14735/amcsnn2020251

Overview

Autoimmune encephalitis is a relatively recently recognized clinical unit. Diagnosis is based on clinical manifestations of the disease, and can be further confirmed by positivity of specific anti-neuronal antibodies. In spite of the fact that there are new types of antibodies discovered almost every year, there are still patients who manifest with clinical signs of autoimmune encephalitis, and yet do not test positive on anti-neuronal antibody assay testing. The reasons for this can be as follows: 1) specific antibodies for these cases might not have been discovered yet; 2) methods used for their detection are not sensitive enough; or 3) humoral immunity does not play a major role in the autoimmune response in a particular case. The absence of anti-neuronal antibodies to confirm the diagnosis of autoimmune encephalitis complicates clinical diagnosis. Recognition and early identification of the group of patients with negativity of anti-neuronal antibodies is crucial, because prompt initiation of immunotherapy is associated with a better outcome.

Keywords:

autoimmune encephalitis – anti-neuronal antibodies – limbic encephalitis

Sources

1. Johnson RT. Acute encephalitis. Clin Infect Dis 1996; 23 (2): 219–224. doi: 10.1093/clinids/23.2.219.

2. Gubala A, Warrilow D. Many encephalitis cases still a medical mystery. Aust N Z J Public Health 2018; 42 (1): 106–107. doi: 10.1111/1753-6405.12740.

3. George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000–2010. PLoS One 2014; 9 (9): e104169. doi: 10.1371/journal.pone.0104169.

4. Granerod J, Cousens S, Davies NW et al. New estimates of incidence of encephalitis in England. Emerg Infect Dis 2013; 19 (9): 1455–1462. doi: 10.3201/eid1909.130064.

5. Singh TD, Fugate JE, Rabinstein AA. The spectrum of acute encephalitis: causes, management, and predictors of outcome. Neurology 2015; 84 (4): 359–366. doi: 10.1212/WNL.0000000000001190.

6. Pillai SC, Hacohen Y, Tantis E et al. Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome. Pediatrics 2015; 135 (4): 974–984. doi: 10.1542/peds.2014-2702.

7. Granerod J, Ambrose HE, Davies NW et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010; 10 (12): 835–844. doi: 10.1016/S1473-3099 (10) 70222-X.

8. Solimena M, Folli F, Aparisi R et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322 (22): 1555–1560. doi: 10.1056/NEJM199005313222202.

9. Rosenfeld MR, Eichen JG, Wade DF et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50 (3): 339–348. doi: 10.1002/ana.1288.

10. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003; 53 (5): 580–587. doi: 10.1002/ana.10518.

11. Pittock SJ, Lucchinetti CF, Parisi JE et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005; 58 (1): 96–107. doi: 10.1002/ana.20529.

12. Graus F, Titulaer MJ, Balu R et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15 (4): 391–404. doi: 10.1016/S1474-4422 (15) 00401-9.

13. Gresa-Arribas N, Titulaer MJ, Torrents A et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13 (2): 167–177. doi: 10.1016/S1474-4422 (13) 70282-5.

14. Ricken G, Schwaiger C, De Simoni D et al. Detection Methods for autoantibodies in suspected autoimmune encephalitis. Front Neurol 2018; 9: 841. doi: 10.3389/fneur.2018.00841.

15. Höftberger R, Dalmau J, Graus F. Clinical neuropathology practice guide 5-2012: updated guideline for the diagnosis of antineuronal antibodies. Clin Neuropathol 2012; 31 (5): 337–341. doi: 10.5414/NP300545.

16. Graus F, Delattre JY, Antoine JC et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75 (8): 1135–1140. doi: 10.1136/jnnp.2003.034447.

17. Tampoia M, Zucano A, Antico A et al. Diagnostic accuracy of different immunological methods for the detection of antineuronal antibodies in paraneoplastic neurological syndromes. Immunol Invest 2010; 39 (2): 186–195. doi: 10.3109/08820130903513431.

18. Storsein A, Monstad SE, Haugen M et al. Onconeural antibodies: improved detection and clinical correlations. J Neuroimmunol 2011; 232 (1–2): 166–170. doi: 10.1016/j.jneuroim.2010.10.009.

19. Dalmau JG, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017; 97 (2): 839–887. doi: 10.1152/physrev.00010.2016.

20. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018; 378 (9): 840–851. doi: 10.1056/NEJMra1708712.

21. Meinck H, Faber L, Morgenthaler N et al. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J Neurol Neurosurg Psychiatry 2001; 71 (1): 100–103. doi: 10.1136/jnnp.71.1.100.

22. Saiz A, Blanco Y, Sabater L et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008; 131 (10): 2553–2563. doi: 10.1093/brain/awn183.

23. Bien CG. Contactin-associated protein-like 2 antibodies: tackling the issue of syndrome diversity. JAMA Neurol 2016; 73 (9): 1058–1059. doi: 10.1001/jamaneurol.2016.1739.

24. Bien CG, Mirzadjanova Z, Baumgartner C et al. Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome. Eur J Neurol 2017; 24 (1): 175–186. doi: 10.1111/ene.13180.

25. Armangue T, Santamaria J, Dalmau J. When a serum test overrides the clinical assessment. Neurology 2015; 84 (13): 1379–1381. doi: 10.1212/WNL.0000000000001425.

26. Zandi MS, Paterson RW, Ellul MA et al. Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry 2015; 86 (7): 708–713. doi: 10.1136/jnnp-2014-308736.

27. Bien CG, Vincent A, Barnett MH et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012; 135 (5): 1622–1638. doi: 10.1093/brain/awv32.

28. van Sonderen A, Thijs RD, Coenders EC et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 2016; 4; 87 (14): 1449–1456. doi: 10.1212/WNL.0000000000003173.

29. Prüss H, Dalmau J, Harms L et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 2010; 75 (19): 1735–1739. doi: 10.1212/WNL.0b013e3181fc2a06.

30. Zandi MS, Irani SR, Lang B et al. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 2011; 258 (4): 686–688. doi: 10.1007/s00415-010-5788-9.

31. Steiner J, Walter M, Glanz W et al. Increased prevalence of diverse N -methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N -methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 2013; 70 (3): 271–278. doi: 10.1001/2013.jamapsychiatry.86.

32. Gono T, Kawaguchi Y, Kaneko H et al. Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology 2011; 50 (9): 1578–1585. doi: 10.1093/rheumatology/keq408.

33. Mackay G, Ahmad K, Stone J et al. NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease. J Neurol 2012; 259 (9): 1979–1981. doi: 10.1007/s00415-012-6489-3.

34. de Witte LD, Hoffmann C, van Mierlo HC et al. Absence of N-methyl-D-aspartate receptor IgG autoantibodies in schizophrenia: the importance of cross-validation studies. JAMA Psychiatry 2015; 72 (7): 731–733. doi: 10.1001/jamapsychiatry.2015.0526.

35. Hara M, Martinez-Hernandez E, Ariño H et al. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology 2018; 90 (16): e1386–e1394. doi: 10.1212/WNL.0000000000005329.

36. McCracken L, Zhang J, Greene M et al. Improving the antibody-based evaluation of autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 2017; 4 (6): e404. doi: 10.1212/NXI.0000000000000404.

37. Gaig C, Graus F, Compta Y et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017; 88 (18): 1736–1743. doi: 10.1212/WNL.0000000000003887.

38. Sabater L, Gaig C, Gelpi E et al. 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 2014; 13 (6): 575–586. doi: 10.1016/S1474-4422 (14) 70051-1.

39. Gelpi E, Hoftberger R, Graus F et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016; 132 (4): 531–543. doi: 10.1007/s00401-016-1591-8.

40. Sabater L, Planagumà J, Dalmau J et al. Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J Neuroinflam 2016; 13 (1): 226. doi: 10.1186/s12974-016-0689-1.

41. Basal E, Zalewski N, Kryzer T et al. Paraneoplastic neuronal intermediate filament autoimmunity. Neurology 2018; 91 (18): e1677–e1689. doi: 10.1212/WNL.0000000000006435.

42. Fang B, McKeon A, Hinson SR et al. Autoimmune glial fibrillary acidic protein astrocytopathy a novel meningoencephalomyelitis. JAMA Neurol 2016; 73 (11): 1297–1307. doi: 10.1001/jamaneurol.2016.2549.

43. Long Y, Liang J, Xu H et al. Autoimmune glial fibrillary acidic protein astrocytopathy in Chinese patients: a retrospective study. Eur J Neurol 2018; 25 (3): 477–483. doi: 10.1111/ene.13531.

44. Iorio R, Damato V, Evoli A et al. Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients. J Neurol Neurosurg Psychiatry 2018; 89 (2): 138–146. doi: 10.1136/jnnp-2017-316583.

45. Prüss H, Höltje M, Maier N et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology 2012; 78 (22): 1743–1753. doi: 10.1212/WNL.0b013e318258300d.

46. Hacohen Y, Wright S, Waters P 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 (7): 748–755. doi: 10.1136/jnnp-2012-303807.

47. Graus F, Escudero D, Oleaga L et al. Syndrome and outcome of antibody-negative limbic encephalitis. Eur J Neurol 2018; 25 (8): 1011–1016. doi: 10.1111/ene.13661.

48. Graus F, Saiz A, Lai J et al. Neuronal surface antigen antibodies in limbic encephalitis. Neurology 2008; 71 (12): 930–936. doi: 10.1212/01.wnl.0000325917.48466.55.

49. Krýsl D, Elišák M. Autoimunitní encefalitidy. Cesk Slov Neurol N 2015; 78/111 (1): 7–23. doi: 10.14735/ amcsnn20151.