Immune Mechanisms in Epileptogenesis: Update on Diagnosis and Treatment of Autoimmune Epilepsy Syndromes

Abstract

Seizures and epilepsy can result from various aetiologies, yet the underlying cause of several epileptic syndromes remains unclear. In that regard, autoimmune-mediated pathophysiological mechanisms have been gaining attention in the past years and were included as one of the six aetiologies of seizures in the most recent classification of the International League Against Epilepsy. The increasing number of anti-neuronal antibodies identified in patients with encephalitic disorders has contributed to the establishment of an immune-mediated pathophysiology in many cases of unclear aetiology of epileptic syndromes. Yet only a small number of patients with autoimmune encephalitis develop epilepsy in the proper sense where the brain transforms into a state where it will acquire the enduring propensity to produce seizures if it is not hindered by interventions. Hence, the term autoimmune epilepsy is often wrongfully used in the context of autoimmune encephalitis since most of the seizures are acute encephalitis-associated and will abate as soon as the encephalitis is in remission. Given the overlapping clinical presentation of immune-mediated seizures originating from different aetiologies, a clear distinction among the aetiological entities is crucial when it comes to discussing pathophysiological mechanisms, therapeutic options, and long-term prognosis of patients. Moreover, a rapid and accurate identification of patients with immune-mediated epilepsy syndromes is required to ensure an early targeted treatment and, thereby, improve clinical outcome. In this article, we review our current understanding of pathogenesis and critically discuss current and potential novel treatment options for seizures and epilepsy syndromes of underlying or suspected immune-mediated origin. We further outline the challenges in proper terminology.

Fig. 1

Overview of different aetiologies and overlapping pathophysiological mechanisms of autoimmune encephalitis (AIE), acute symptomatic seizures secondary to autoimmune encephalitis (ASSAE), autoimmune-associated epilepsy (AAE) and epilepsy leading to seizures. Aetiologies of immune-mediated seizures can be grouped into two main categories, (1) paraneoplastic (e.g., in teratoma or small cell lung cancer), and (2) non-paraneoplastic encompassing (a) infectious (e.g. in herpes simplex 1 encephalitis or varicella zoster virus encephalitis), (b) systemic/CNS autoimmune disorders (e.g., in multiple sclerosis or systemic lupus erythematosus), and (c) genetic predisposition (e.g., HLA-associated anti-LGI1 encephalitis). All of the aetiologies can lead to common pathophysiological mechanisms, such as the production of pathogenic autoantibodies, inflammation and subsequent structural damage, which then manifest in seizures in the context of AIE, ASSAE, AE and epilepsy. Figure was created using Biorender.

Fig. 2

Overview of pathophysiological mechanisms in autoimmune encephalitis (AIE) and related therapeutic targets on the horizon. Antigens are released following either peripheral cell destruction by triggers such as apoptosis by pathogens (mostly viral), by tumours, systemic autoimmune disease or genetic predisposition (1) or direct neuronal destruction by pathogen invasion through impaired blood brain barrier (BBB) into the cerebrospinal fluid (CSF) (6). Antigen presenting cells (APCs) recognise the antigens (2), prime T cells to secrete B cell-activating cytokines (3). In turn, B cells differentiate from CD19⁺/CD20⁺ B cells into CD138⁺ plasma cells (4), which produce and secrete autoantibodies (5). Both antibody- and T cell-mediated processes lead to neuronal dysfunction and degeneration (7). Novel therapeutics agents (pink boxes) on the horizon targeting the above described patho-mechanistic processes, including B cell-depleting agents [anti-CD19 (inebilizumab), anti-CD20 (rituximab, ocrelizumab, ofatumumab), anti-CD38 depleting therapy (daratumumab)], agents targeting pathogenic antibodies/plasma cells and downstream mechanisms [anti-FcRn antibody resulting in IgG degradation (rozanolixizumab, efgartigimod-α), anti-C5 complement antibody (eculizumab), proteasome inhibitor (bortezomib)], agents that are targeting or modifying cytokines [anti-IL-6R antibody (tocilizumab, satralizumab), anti-IL-1R antibody (anakinra), anti-IL-1ßR antibody (canakinumab), low-dose IL-2 therapy and Janus kinase inhibitor (tofacitinib)] and others [CD80/CD86 ligand blocker (abatacept), anti-TNF-α receptor antibody (e.g., adalimumab)]. Figure was created using Biorender.