Autoimmunity and inflammation in status epilepticus: from concepts to therapies

Abstract

The understanding of immunological mechanisms underlying some forms of epilepsy and encephalitis has rapidly increased for the last 10 years leading to the concept of status epilepticus of autoimmune origin. Actual treatment recommendations regarding autoimmune status epilepticus are based on retrospective case studies, pathophysiological considerations and experts' opinion. In addition, there are no clear indicators to predict outcome. In situations where autoimmune mechanisms are suspected in patients with status epilepticus, there is evidence that earlier treatment is related to better outcome. Increased awareness is mandatory to decrease the number of patients with major neurological problems or fatal outcome, which is overall about 50%. We here summarize findings of all pediatric and adult patients reported to date, and review the current state of knowledge in the field of immune therapeutic approaches of status epilepticus.

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

“…Conversely, autoimmune etiologies have received far less attention to date and globally seem rarer, accounting for only about 2–3% of all SE episodes [15]. Patients with autoimmune SE tend to be relatively young; most of the episodes are related to anti-NMDA-receptor antibodies, anti-glutamic acid decarboxylase antibodies or multiple sclerosis, while other antibodies, including those associated with paraneoplastic syndromes, as well as Rasmussen encephalitis seem rarer [15,17,18]. Outcome seems globally better for SE episodes triggered by antibodies with surface cellular targets (e.g., anti-NMDA-receptor, GABA B receptor, voltage-gated potassium channel complex including leucine-rich glioma-inactivated-1) than for those related to intracellular targets (e.g., paraneoplastic syndromes, anti-glutamic acid decarboxylase) [17].…”

“…In adults, such forms have been called ‘malignant’ [19] or ‘new-onset refractory SE’ [20], while in children the acronym ‘febrile infection-related epilepsy syndrome’ has been proposed [21,22]. The exact incidence of these entities is still unclear, as case series [17,23] lacks a denominator and often suffers from a publication bias; nevertheless, they may account for a significant proportion of super-refractory SE episodes.…”

“…As inflammatory causes may go unrecognized, as discussed below, it is also common practice to administer intravenous corticosteroids after formally ruling out an infection, while more specific immunosuppressive/anti-inflammatory treatments, such as plasma exchange, intravenous immunoglobulins, rituximab or cyclophosphamide, are generally reserved for patients in whom an autoimmune cause is suspected [17,47–49]. These immunological approaches, which may be considered as corroborating the third-line of treatment (at the bottom of Figure 1 ), are not evidence-based, but in current clinical practice rely on the assumption that inflammation is the direct cause of SE; their administration typically occurs after the start of the refractory SE episode.…”

Immunological GABAergic interactions and therapeutic applications in autoimmune diseases

“…It is increasingly recognized that autoantibodies against GAD and GABA receptors are a feature of some forms of autoimmune encephalitis and/or epilepsy [72,74,[86][87][88][89][90]. However, these patients often have autoantibodies to other neuronal target molecules, and the relative pathogenic role of each antibody is not always clear.…”

“…This disease is recalcitrant to anticonvulsant treatment. As in SPS, these conditions can be improved by therapy targeting the autoimmune manifestations [88][89][90]. As well, a search for a tumor (often malignant) is always indicated, due to the high risk of a paraneoplastic factor (as in SPS).…”