Review
Autoimmune encephalitis: Recent updates and emerging challenges

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Abstract

The knowledge of immune dysregulation and autoimmunity in neurological disorders has expanded considerably in recent times. Recognition of clinical syndromes, reliable methods of diagnosis, and early targeted immunotherapy can lead to a favourable outcome in acute and subacute neurological disorders that may be associated with significant morbidity and mortality if left untreated. This review focuses on the rapidly expanding field of autoimmune encephalitis. We describe the differences between limbic encephalitis associated with antibodies targeting intracellular antigens, and neuronal surface antibody syndromes (NSAS) where the antigens are primarily receptors or synaptic proteins located on the neuronal cell surface. We chronologically highlight important developments in NSAS by focusing on voltage gated potassium channel complex-associated antibody mediated encephalitis, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, and anti-dopamine 2 receptor antibody-associated basal ganglia encephalitis. Contentious issues such as the complexities of using serum antibodies as biomarkers, the initiation of central nervous system autoimmunity, and possible pathogenic mechanisms of these antibodies will be reviewed. The therapeutic challenges that clinicians face such as the timing of therapy and the role of second-line therapy will be discussed, with crucial concepts highlighted in the form of clinical vignettes. Future directions will involve the identification of novel antigens and methods to establish their pathogenicity, as well as evaluation of the most efficacious therapeutic strategies in patients with established NSAS.

Introduction

The role of immune dysregulation and autoimmunity in neurological disorders has been the subject of considerable research in recent times. This review focuses on the rapidly expanding field of autoimmune encephalitis.

Limbic encephalitis (LE) was first described in the 1960s and refers to the subacute onset of episodic memory loss, confusion, and agitation [1]. LE is frequently associated with hallucinations, seizures, sleep disturbance, and signal change in the medial temporal lobe and hippocampi on imaging. LE is classically described as being paraneoplastic [1]. Antibodies to onconeural intracellular antigens which are nuclear or cytoplasmic proteins such as Hu, Ma, and Ri are associated with certain malignancies such as lung cancer and testicular tumours [1], [2]. These antibodies are clearly demonstrated by standardised tests, associated with limited subtypes of malignancies, and have a variety of neurological manifestations [2]. The clinical course is usually monophasic and relentlessly progressive with a guarded prognosis, and treatment is directed to the underlying malignancy [3], [4]. The antibodies targeting onconeural antigens are believed to be biomarkers of associated tumours rather than being directly pathogenic, and their detection should prompt investigation for an associated underlying malignancy [2], [4], [5]. Previous studies including passive transfers or active vaccination with the antigen in animal models have failed to reproduce these clinical syndromes, and newly published results have shown that neuronal cell death was due to T-cell mediated cytotoxicity, lending further weight to the contention that this group of antibodies is not directly pathogenic [2], [4].

There is a second distinct group of patients with autoimmune encephalitis, where autoantibodies targeting neuronal cell surface antigenic epitopes that are extracellular rather than intracellular have been identified [2], [3], [6], [7]. This group of antibodies are collectively referred to as “neuronal surface antibodies” (NSAbs), and the neurological manifestations associated with them as “neuronal surface antibody syndromes” (NSAS) [5]. Lancaster et al. characterised NSAbs as demonstrating five features – the epitopes are extracellular, antibody binding is visible in cells transfected with the target antigen, the antibodies should alter the function or structure of the neural antigen, the downstream effects of the antibody are often reversible, and the clinical picture corresponds with genetic or pharmacologic models in which the antigen is disrupted [3]. The antigens are often receptors or synaptic protein complexes intimately involved with mechanisms of synaptic transmission and plasticity [8]. Identified targets include components of the voltage gated potassium channel complex (VGKC) such as leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2); the N-methyl-d-aspartate receptor (NMDAR), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the γ-aminobutyric acid receptor (GABABR), and the glycine receptor [3], [8], [9]. NSAS collectively appear to be far more prevalent than LE, are associated with onconeural antibodies, often have a relapsing course, have an overall better prognosis, and are less commonly paraneoplastic [3], [4]. The prevalence of an associated malignancy varies depending on the antibody in question, however, this is rarely more than 70% [2]. A more detailed description of the clinical and laboratory features of each of the syndromes associated with established and emerging NSAbs is outlined in Table 1, Table 2. As some NSAbs such as AMPAR, GABABR and those identified in Table 2 have been identified in relatively small numbers of patients, it is possible that with the increasing recognition of such syndromes and greater patient numbers the clinical phenotype associated with these NSAbs will evolve and expand.

Glutamic acid decarboxylase (GAD), another antigen of interest, is dissimilar to the intracellular onconeural antigens as anti-GAD antibody associated neurological syndromes are usually non-paraneoplastic and immune responsive. Anti-GAD antibody-associated syndromes do not fulfill the criteria for a NSAS as GAD is an intracellular antigen. Anti-GAD antibodies have been identified in some patients with LE (including those with other confirmed NSAbs such as AMPAR), as well as being associated with type 1 diabetes mellitus, stiff person syndrome, temporal lobe epilepsy, and cerebellar ataxia [2], [10], [11], [12]. Anti-GAD antibodies associated with neurological disorders are typically of much higher titre (>1000 international units/mL) compared with the titres found in patients with Type 1 diabetes.

Section snippets

VGKC complex-associated antibody mediated encephalitides

VGKC on cell surface membranes have been identified as being a key protein determining neuronal excitability [1]. Antibodies against this target were initially associated with disorders of the peripheral nervous system such as acquired neuromyotonia or Isaacs’ syndrome, and cramp-fasciculation syndrome [13]. Subsequently, involvement of the central nervous system (CNS) in patients with VGKC complex-associated antibodies was also described such as in Morvan’s syndrome where neuromyotonia is

Serum or CSF antibodies as biomarkers?

While obtaining serum to test for autoantibodies is extremely convenient and relatively non-invasive, the caveats of using serum antibodies as a diagnostic tool need to be considered. One should remain wary of the potential non-specificity of NSAbs. Anti-NMDAR antibodies have been described in patients with presentations consistent with multiple sclerosis, seronegative neuromyelitis optica, and even Creutzfeldt–Jakob disease [67], [68], [69]. Similarly, VGKC complex-associated antibodies have

Therapeutic challenges: Clinical vignettes

There remain many practical challenges in the field of therapeutics of NSAS. What defines failure of first-line treatment? At what stage is it reasonable to escalate therapy to second-line agents? Do patients who have a particularly significant clinical episode warrant second-line therapy despite improvement with first-line therapy? To what degree does second-line therapy reduce the relapse rate? What role does maintenance immunosuppression have? The following clinical vignettes further expand

Future directions

It is clear that they are many patients who have a clinical and laboratory phenotype suggestive of an autoimmune process who respond to immunomodulatory therapy, but are negative for the existing panel of NSAbs [77], [91]. Such patients provide a compelling argument to pursue the identification of novel antigens. We believe that in patients with a clinical history and investigation findings that support an autoimmune basis, the lack of detection of an established NSAb should not dissuade

Conflicts of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

The authors have funding from the National Health and Medical Research Council, Australia, the Star Scientific Foundation, the Petre Foundation, Tourette Syndrome Association (USA) and Multiple Sclerosis Research Australia.

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