Immunomediated Encephalitis: New Diagnoses on the Neurology–Psychiatry Interface

Abstract

Immune-mediated encephalitis is a real diagnostic challenge. Initially, patients present with subacute behavioral alterations, evolving over months, being attributed to purely psychiatric mechanisms, as well as neurological symptoms that often go unnoticed by professionals who are not neurologists. The etiologies behind these diseases are represented by paraneoplastic syndromes (including occult tumors) as well as viral infections, in both cases constituting true immunological triggers with exposure of antigens that will lead to a cross-immunological response directed at healthy structures of the nervous system. In the current review, we present the different clinical scenarios which differ based on antibodies against membrane receptors described so far, emphasizing the relevance of an early diagnosis for a smaller impact on prognosis.

Resumo

As encefalites imunomediadas constituem-se em um verdadeiro desafio diagnóstico. Inicialmente, os pacientes apresentam alterações comportamentais de caráter subagudo, com meses de evolução, sendo atribuídos a mecanismos puramente psiquiátricos, bem como sintomas neurológicos que passam muitas vezes despercebidos por profissionais não neurologistas. As etiologias por trás destas doenças são representadas por síndromes paraneoplásicas (incluindo tumores ocultos) bem como por infecções virais, em ambos os casos constituindo verdadeiros gatilhos imunológicos com exposição de antígenos que desencadeará uma resposta imunológica cruzada direcionada a estruturas saudáveis do sistema nervoso. Nesta revisão, apresentamos os diversos cenários clínicos diferenciados pelos anticorpos contra receptores de membrana descritos até o momento, enfatizando a relevância de um diagnóstico precoce para um menor impacto nos prognósticos.

Keywords

encephalitis - autoimmune encephalitis - antibody-mediated encephalitis - limbic encephalitis

Palavras-chave

encefalite - encefalites autoimune - encefalite mediada por anticorpos - encefalite límbica

Publikationsverlauf

Eingereicht: 10. September 2023

Angenommen: 23. Oktober 2024

Artikel online veröffentlicht:
31. Januar 2025

• References

• 1 Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med 2018; 378 (09) 840-851
• 2 Dutra LA, Abrantes F, Toso FF, Pedroso JL, Barsottini OGP, Hoftberger R. Autoimmune encephalitis: a review of diagnosis and treatment. Arq Neuropsiquiatr 2018; 76 (01) 41-49
• 3 Granerod J, Ambrose HE, Davies NW. et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. 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
• 4 Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. 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 2012; 54 (07) 899-904
• 5 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003; 349 (16) 1543-1554
• 6 Hughes EG, Peng X, Gleichman AJ. et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010; 30 (17) 5866-5875
• 7 Kreye J, Wenke NK, Chayka M. et al. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 2016; 139 (Pt 10): 2641-2652
• 8 Ohkawa T, Fukata Y, Yamasaki M. et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013; 33 (46) 18161-18174
• 9 Bien CG, Vincent A, Barnett MH. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012; 135 (Pt 5): 1622-1638
• 10 Dahm L, Ott C, Steiner J. et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 2014; 76 (01) 82-94
• 11 Dalmau J, Tüzün E, Wu HY. et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61 (01) 25-36
• 12 Lancaster E, Huijbers MG, Bar V. et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011; 69 (02) 303-311
• 13 van Sonderen A, Thijs RD, Coenders EC. et al. Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up. Neurology 2016; 87 (14) 1449-1456
• 14 Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77 (02) 179-189
• 15 Höftberger R, van Sonderen A, Leypoldt F. et al. Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology 2015; 84 (24) 2403-2412
• 16 van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 2017; 13 (05) 290-301
• 17 Irani SR, Pettingill P, Kleopa KA. et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012; 72 (02) 241-255
• 18 Petit-Pedrol M, Armangue T, Peng X. 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 (03) 276-286
• 19 Ohkawa T, Satake S, Yokoi N. et al. Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis. J Neurosci 2014; 34 (24) 8151-8163
• 20 Piepgras J, Höltje M, Michel K. et al. Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons. Neurology 2015; 85 (10) 890-897
• 21 Tobin WO, Lennon VA, Komorowski L. et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 2014; 83 (20) 1797-1803
• 22 Hutchinson M, Waters P, McHugh J. et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71 (16) 1291-1292
• 23 Martinez-Hernandez E, Sepulveda M, Rostásy K. et al. Antibodies to aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor α1 subunit in patients with isolated optic neuritis. JAMA Neurol 2015; 72 (02) 187-193
• 24 Ariño H, Höftberger R, Gresa-Arribas N. et al. paraneoplastic neurological Syndromes and Glutamic acid Decarboxylase Antibodies. JAMA Neurol 2015; 72 (08) 874-881
• 25 Gaig C, Graus F, Compta Y. et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017; 88 (18) 1736-1743
• 26 Gelpi E, Höftberger R, Graus F. et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016; 132 (04) 531-543
• 27 Lopez-Chiriboga AS, Komorowski L, Kümpfel T. et al. Metabotropic glutamate receptor type 1 autoimmunity: Clinical features and treatment outcomes. Neurology 2016; 86 (11) 1009-1013
• 28 Lancaster E, Martinez-Hernandez E, Titulaer MJ. et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011; 77 (18) 1698-1701
• 29 Titulaer MJ, McCracken L, Gabilondo I. 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 (02) 157-165
• 30 Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7 (04) 327-340