Autoimmune Encephalitis and Its Relation to Infection
- 2.2k Downloads
Encephalitis, an inflammatory condition of the brain that results in substantial morbidity and mortality, has numerous causes. Over the past decade, it has become increasingly recognized that autoimmune conditions contribute significantly to the spectrum of encephalitis causes. Clinical suspicion and early diagnosis of autoimmune etiologies are of particular importance due to the need for early institution of immune suppressive therapies to improve outcome. Emerging clinical observations suggest that the most commonly recognized cause of antibody-mediated autoimmune encephalitis, anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, may in some cases be triggered by herpes virus infection. Other conditions such as Rasmussen’s encephalitis (RE) and febrile infection-related epilepsy syndrome (FIRES) have also been posited to be autoimmune conditions triggered by infectious agents. This review focuses on emerging concepts in central nervous system autoimmunity and addresses clinical and mechanistic findings linking autoimmune encephalitis and infections. Particular consideration will be given to anti-NMDA receptor encephalitis and its relation to herpes simplex encephalitis.
KeywordsAutoimmune encephalopathy CNS autoimmunity Anti-NMDA receptor antibodies FIRES Rasmussen’s syndrome Molecular mimicry
David R. Benavides is supported by NINDS T32 training grant in neuroimmunology and neurological infectious disease (T32NS069351).
Arun Venkatesan receives support from the National Institutes of Health, Maryland Stem Cell Research Fund, and Accelerated Cure Project for Multiple Sclerosis.
Compliance with Ethics Guidelines
Conflict of Interest
Arun Venkatesan and David R. Benavides declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.Sejvar JJ, Kohl KS, Bilynsky R, Blumberg D, Cvetkovich T, Galama J, et al. Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2007;25:5771–92.CrossRefPubMedGoogle Scholar
- 8.Granerod J, Cousens S, Davies NW, Crowcroft NS, Thomas SL. New estimates of incidence of encephalitis in England. In: Emerg Infect Dis [Internet]. Edited by; 2013;19(9). http://dx.doi.org/10.3201/eid1909.130064.
- 15.•Titulaer MJ, McCracken L, Gabilondo I, Armangué 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. A large observational study of 577 patients, including 211 pediatric patients, with anti-NMDAR antibodies provides data on response to therapy, longitudinal outcomes, and prognostic factors.Google Scholar
- 24.Alves-Leon SV, Veluttini-Pimentel ML, Gouveia ME, Malfetano FR, Gaspareto EL, Alvarenga MP, et al. Acute disseminated encephalomyelitis: clinical features, HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602, and HLA DPA1*0301 allelic association study. Arq Neuropsiquiatr. 2009;67:643–51.CrossRefPubMedGoogle Scholar
- 25.Shwetank, Date OS, Kim KS, Manjunath R. Infection of human endothelial cells by Japanese encephalitis virus: increased expression and release of soluble HLA-E. PLoS One. 2013;8(11):e79197.Google Scholar
- 26.Clarke P, Leser JS, Bowen RA, Tyler KL. Virus-induced transcriptional changes in the brain include the differential expression of genes associated with interferon, apoptosis, interleukin 17 receptor A, and glutamate signaling as well as flavivirus-specific upregulation of tRNA synthetases. MBio. 2014;5:e00902–14.CrossRefPubMedCentralPubMedGoogle Scholar
- 33.Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, et al. N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133:1655–67.CrossRefPubMedCentralPubMedGoogle Scholar
- 35.••Prüss H, Finke C, Höltje M, Hofmann J, Klingbeil C, Probst C, et al. N-methyl-d-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–11. This is the first report of anti-NMDAR antibodies in patients with herpes simplex encephalitis with retrospective analysis of 44 patients with proven HSE, 13 of which were found to have anti-NMDAR in the course of HSE.CrossRefPubMedCentralPubMedGoogle Scholar
- 40.Bektaş O, Tanyel T, Kocabaş BA, Fitöz S, Ince E, Deda G. Anti-N-methyl-d-aspartate receptor encephalitis that developed after herpes encephalitis: a case report and literature review. Neuropediatrics. 2014;45(6):396–401.Google Scholar
- 42.Armangue T, Titulaer MJ, Málaga I, Bataller L, Gabilondo I, Graus F, Dalmau J, Group SA-N-m-D-ARNEW: pediatric anti-N-methyl-d-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162:850–856:e852.Google Scholar
- 43.••Armangue T, Leypoldt F, Málaga I, Raspall-Chaure M, Marti I, Nichter C, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75:317–23. This series of patients with “relapsing post-HSE” and well-characterized serum and CSF contributes to our understanding of the timing and nature of the interaction between HSE, NMDAR antibodies, and a post-HSE immune syndrome.CrossRefPubMedCentralPubMedGoogle Scholar
- 45.•Gleichman AJ, Spruce LA, Dalmau J, Seeholzer SH, Lynch DR. Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J Neurosci. 2012;32:11082–94. The N368/G369 region of GluN1 is identified as crucial for anti-NMDAR antibody immunoreactivity, and it is shown that antibody binding alters receptor function by increasing open channel time.CrossRefPubMedCentralPubMedGoogle Scholar
- 46.Planagumà J, Leypoldt F, Mannara F, Gutiérrez-Cuesta J, Martín-García E, Aguilar E, Titulaer MJ, Petit-Pedrol M, Jain A, Balice-Gordon R,Lakadamyali M, Graus F, Maldonado R, Dalmau J. Human N-methyl-d-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015;138(Pt 1):94–109.Google Scholar
- 48.•Moscato EH, Peng X, Jain A, Parsons TD, Dalmau J, Balice-Gordon RJ. Acute mechanisms underlying antibody effects in anti-N-methyl-d-aspartate receptor encephalitis. Ann Neurol. 2014;76:108–19. Using dissociated neuronal culture, the authors provide biochemical and electrophysiological evidence of antibody-mediated downregulation of surface NMDARs independent of NMDAR activity, and show evidence of homeostatic synaptic plasticity mechanisms with a decrease in inhibitory synapse density onto excitatory hippocampal neurons.CrossRefPubMedCentralPubMedGoogle Scholar
- 49.•Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain. 2012;135:1606–21. High-resolution nanoparticle imaging and live imaging is used to shed light on cellular and molecular mechanisms of anti-NMDAR autoantibody pathogenic mechanisms, implicating dysfunction of NMDAR-EphB2R interactions in the trafficking abnormalities of synaptic and extrasynaptic NMDAR.Google Scholar
- 50.Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci. 2014;1–21.Google Scholar
- 58.Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, et al. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol. 2002;131:179–85.CrossRefPubMedGoogle Scholar
- 64.••Owens GC, Huynh MN, Chang JW, McArthur DL, Hickey MJ, Vinters HV, et al. Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J Neuroinflammation. 2013;10:56. Brain tissue from patients with RE subjected to quantitative PCR was found to express high levels of Th1-associated genes in the early symptomatic phase of disease, suggesting a role for the Th1 immune response in the pathogenesis of RE.CrossRefPubMedCentralPubMedGoogle Scholar
- 70.Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676–85.Google Scholar
- 72.••Kramer U, Chi CS, Lin KL, Specchio N, Sahin M, Olson H, et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia. 2011;52:1956–65. This retrospective multicenter study identified the largest group of children to date who fit criteria for FIRES. The clinical presentations, results of serologic and CSF testing, and neuroimaging results are comprehensively presented.CrossRefPubMedGoogle Scholar
- 74.van Baalen A, Häusler M, Plecko-Startinig B, Strautmanis J, Vlaho S, Gebhardt B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics. 2012;43:209–16.CrossRefPubMedGoogle Scholar