Autoimmune Encephalitis

European Neurological Review, 2013;8(1):31-7 DOI: http://doi.org/10.17925/ENR.2013.08.01.31

Abstract:

The term autoimmune encephalitis is used to describe a group of disorders characterised by symptoms of limbic and extra-limbic dysfunction occurring in association with antibodies against synaptic antigens and proteins localised on the neuronal cell surface. in recent years there has been a rapidly expanding knowledge of these syndromes resulting in a shift in clinical paradigms and new insights into pathogenic mechanisms. Since many patients respond well to immunosuppressive treatment, the recognition of these disorders is of utmost importance. in general, there are no brain-imaging modalities or biomarkers specific of these disorders other than the demonstration of the neuronal antibodies. a disease classification based on these antibodies provides information on prognosis and paraneoplastic aetiology. This article focuses on recent clinical advances, newly characterised antibodies and treatment approaches to these disorders.
Keywords: Encephalitis, limbic encephalitis, stiff-person-syndrome, basal ganglia encephalitis, anti-NMda-receptor encephalitis, synaptic autoimmunity, neuronal surface antigen antibody, GaBa(b) receptor antibody, aMPa receptor antibody, glycine receptor antibody, dopamine d2 receptor encephalitis, VGKc complex antibody, SREaT, hashimoto encephalopathy
Disclosure: Frank leypoldt has received speakers honoraria from Grifols and scientific funding from Euroimmun. christian G Bien served on the scientific advisory boards of UCB and Eisai (both Germany), undertook industry-funded travel with support of Eisai, UCB and desitin (all Germany) and obtained honoraria for speaking engagements from Eisai, UCB and desitin (all Germany). as part of his present position, he performs serum and cerebrospinal fluid tests for antibodies as those described in the text; for this, his employer charges fees from external senders. Josep dalmau receives royalties from athena diagnostics for a patent for the use of Ma2 as an autoantibody test and licensing fees from Euroimmun for a patent for the use of NMdaR as an autoantibody test. dalmau’s contribution to this work was supported by the Nih grants Ro1NS077851, Ro1Mh094741; Spanish FiS Pi11/01780 and Fundació la Marató TV3. Klaus-Peter Wandinger has no conflicts of interest to declare.
Received: January 10, 2013 Accepted February 05, 2013
Correspondence: Frank leypoldt, Josep dalmau’s lab, institut d’investigacions Biomèdiques august Pi i Sunyer (idiBaPS), university of Barcelona, Rosselló 149-153, 08036 Barcelona, Spain. E: f.leypoldt@uke.de

The first type of autoimmune limbic encephalitis, reported in 1968, was a paraneoplastic disorder occurring in association with small-cell lung cancer (SCLC).1 Until 2001, it was believed that ‘limbic encephalitis’ almost always associated with cancer and had a poor outcome. In 2001, a form of immunotherapy-responsive limbic encephalitis with IgG antibodies initially considered against voltage gated potassium channels (VGKC) was described.2,3 Four years later, antibodies against other cell surface neuronal antigens with intense immunostaining of the hippocampal neuropil, were detected in several patients with different forms of immunotherapy-responsive encephalitis.4 Indeed, one of these patients was a young woman with ovarian teratoma who developed prominent psychiatric symptoms and coma. Further studies with serum and cerebrospinal fluid (CSF) of this patient and several additional patients with a remarkably similar immunotherapy-responsive syndrome resulted in the characterisation of the antigen as the NR1 subunit of the N-methyl- D-aspartic acid receptor (NMDA-receptor).5 In quick succession, further neuronal cell surface antigens were characterised in patient cohorts with autoimmune encephalitis. They included the α-amino-3-hydroxy- 5-methyl-4-isoxazol-propionic acid receptor (AMPA-receptor),6 γ-aminobutyric acid (GABA)(b)-receptor,7 α1-glycine receptor (GlyR),8 metabotropic glutamate receptor 5 (mGluR5),9 leucine-rich, glioma-inactivated 1 (LGI1),10,11 contactin-associated protein-like 2 (CASPR2),11,12 dopamine receptor 2 (D2-receptor)13 and dipeptidyl-peptidase-like protein-6 (DPPX, a regulatory subunit of the KV4.2 potassium channel).14 The main clinical features, diagnostic clues and treatment of these disorders are the subjects of this review.

Epidemiology
With an annual incidence of 2–3/100,000 in northern Europe,15 encephalitis of any aetiology is half as common as newly diagnosed multiple sclerosis(4–8/100,000/year).16 While 40 % of cases are infectious and 40 % are due to unknown causes, at least 20 % are immune mediated, with the largest groups being anti-NMDA-receptor encephalitis (4 %) and VGKC-complex antibody positive encephalitis (3 %).15 One per cent of all young patients admitted to a large German neurointensive care unit17 were retrospectively identified as NMDA-receptor antibody positive. Less is known about the incidence of the other neuronal surface antibody-associated syndromes. However, GABA(b)-receptor antibodies are responsible for the majority of paraneoplastic limbic encephalitides in patients with SCLC who were previously considered seronegative.18

Immune Mechanisms
Antibody-associated encephalitides can be subdivided into those in which the antibodies are directed against neuronal surface or intracellular antigens. The latter group of antibodies define diseases that are usually of paraneoplastic origin and have a poor prognosis despite oncological and immunosuppressive therapy. These disorders are often described as encephalitis with onconeural (intracellular) antibodies or ‘classical paraneoplastic neurological syndromes’.19 The corresponding antibodies (Hu, Yo, Ri, CV2/CRMP5, Ma2, Amphiphysin, Tr) occur in association with cytotoxic T-cell mediated mechanisms which appear to be the main pathogenic effectors.20,21

In contrast, the neuronal surface antibodies so far studied exert a direct effect on their target antigens. In anti-NMDA-receptor and AMPA-receptor encephalitis, the antibodies result in a specific decrease of the corresponding synaptic receptors. The best studied disorder is anti-NMDA-receptor encephalitis, in which the antibodies produce a titre-dependent decrease of receptors by a mechanism of capping, cross-linking and internalisation of the receptors. These effects are reversible upon removing the antibodies from cultures of neurons. Continuous infusion of antibodies to animals results in similar effects.22–24 Patients’ autopsy data shows a decrease of NMDA-receptors and supports the concept that cytotoxic T-cell and complement-mediated mechanisms are not hallmarks of this entity.21,22,25 The pathogenic mechanisms in other neuronal surface antibody mediated syndromes are less clear, some data indicates a role of complement in VGKC-complex antibody-mediated encephalitis.21

To exert their direct pathogenic effect, the antibodies have to reach the target antigens in the central nervous system (CNS). In nti-NMDA-receptor encephalitis there is evidence of local production of antibodies in brain and meninges, supported by the demonstration of intrathecally produced antibodies and the presence of infiltrating B-cells and plasma cells in autopsy studies.5,26 A similar high intrathecal synthesis of antibodies appears to occur in anti-AMPA- and GABA(b)-receptor encephalitis, but the relative contribution of intrathecal versus systemic production is less clear for the other disorders.

All these syndromes occur with and without the presence of systemic tumours, whose frequencies and types vary according to the encephalitis subtype (see Table 1). As occurs with classical paraneoplastic syndromes, the associated tumour usually expresses the neuronal antigen. For example, in patients with anti-NMDA-receptor encephalitis the underlying ovarian teratoma contains nervous tissue that expresses he NMDA-receptor.7,18,25,28 The ectopic expression of this receptor in the tumour appears to contribute in breaking immune tolerance. Possible host factors and the mechanisms involved in homing and enhancing the immune response in the CNS are topics of investigation.

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Keywords: Encephalitis, limbic encephalitis, stiff-person-syndrome, basal ganglia encephalitis, anti-NMda-receptor encephalitis, synaptic autoimmunity, neuronal surface antigen antibody, GaBa(b) receptor antibody, aMPa receptor antibody, glycine receptor antibody, dopamine d2 receptor encephalitis, VGKc complex antibody, SREaT, hashimoto encephalopathy