INFECTION (ML SOLBRIG, SECTION EDITOR) Autoimmune Encephalitis and Its Relation to Infection Arun Venkatesan & David R. Benavides # Springer Science+Business Media New York 2015 Abstract Encephalitis, an inflammatory condition of the brain that results in substantial morbidity and mortality, has numerous causes. Over the past decade, it has become increas- ingly recognized that autoimmune conditions contribute sig- nificantly to the spectrum of encephalitis causes. Clinical sus- picion 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 recog- nized 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 infec- tious 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. Keywords Autoimmune encephalopathy . CNS autoimmunity . Anti-NMDA receptor antibodies . FIRES . Rasmussen’ s syndrome . Molecular mimicry Introduction Encephalitis refers to inflammation of the brain parenchyma with associated neurologic dysfunction and is usually defined on the basis of selected clinical, laboratory, and neuroimaging features [1–7]. Clinical signs and symptoms typically include a combination of fever, confusion, amnesia, personality changes, paralysis, seizures, language dysfunction, and auto- nomic dysfunction. Although the true incidence of encephali- tis is challenging to determine, recent estimates have sug- gested an incidence of 5–10 cases per 100,000 people per year [8, 9]. The causes of encephalitis are myriad and include in- fectious and autoimmune etiologies. While infectious enceph- alitis can be caused by numerous microorganisms including bacteria, fungi, and parasites, viruses are by far the most com- monly identified pathogens [4, 10, 11]. Regarding autoim- mune causes, it has long been recognized that certain cancers can rarely be associated with neurologic dysfunction and ev- idence of brain inflammation; these paraneoplastic conditions, in which tumor antigens drive central nervous system (CNS) autoimmunity, include syndromes such as anti-Hu-associated limbic encephalitis [12]. More recently, however, there has been an increased appreciation of the contribution of addition- al autoimmune etiologies to encephalitis. This has been spurred by the discovery of a growing list of neuronal cell surface proteins, including NMDA receptors, α-amino-3-hy- droxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep- tors, gamma-aminobutyric acid (GABA) A receptors, leu- cine-rich, glioma-inactivated protein 1 (LGI1), and contactin- associated protein-like 2 (CASPR2), which can serve as tar- gets for CNS autoimmunity with resultant encephalitis [13]. Early identification of such syndromes is important, since au- toimmune encephalitis is associated with significant morbidity and mortality [14, 15•] although potentially treatable [2, 16]. Here, we review the link between infection and autoim- mune encephalitis, with emphasis on three conditions with This article is part of the Topical Collection on Infection A. Venkatesan (*) : D. R. Benavides Johns Hopkins Encephalitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD 21287, USA e-mail: avenkat2@jhmi.edu Curr Neurol Neurosci Rep (2015) 15:3 DOI 10.1007/s11910-015-0529-1