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.

Acetazolamide as an effective treatment for pilomotor seizures in autoimmune encephalitis

“…In addition to anti-LGI1 encephalitis, pilomotor seizures have been reported in association with anti-GAD65, anti-NMDAR, anti-Hu, and anti-Ma2 autoimmune and paraneoplastic encephalitides. 1,13 The cellular mechanisms of epileptogenesis in these different immune-mediated encephalitides vary substantially, 14 and it is unlikely that the marked effectiveness of acetazolamide observed in the patients in this series would be expected in patients with pilomotor seizures resulting from other, cellularly unrelated etiologies. Another consideration is whether the functional neuroanatomy of pilomotor seizures, presumed to involve the hypothalamus and central autonomic network, 10,15 might be relevant to pH hypersensitivity and acetazolamide responsiveness.…”

“…The LGI1 protein is expressed next to the VGKC Kv1.1, connecting ADAM23 to ADAM22, which are its presynaptic and postsynaptic receptors, respectively. 14 Antibodies against LGI1 have been shown to contribute to temporal lobe epileptogenicity by reducing Kv1 currents and increasing cellular excitability in dentate gyrus granule cells, CA1 and CA3 neurons. 16,17 Although the interaction between acetazolamide and LGI1-related pathology is unclear, it is noteworthy that other channelopathies affecting Kv1.1 have been reported to be acetazolamide responsive, including episodic ataxia type 1.…”

“…Most probably there is an unknown interaction between acetazolamide and the underlying pathogenesis of temporal lobe seizures in anti‐LGI1 AE. The LGI1 protein is expressed next to the VGKC Kv1.1, connecting ADAM23 to ADAM22, which are its presynaptic and postsynaptic receptors, respectively 14 . Antibodies against LGI1 have been shown to contribute to temporal lobe epileptogenicity by reducing Kv1 currents and increasing cellular excitability in dentate gyrus granule cells, CA1 and CA3 neurons 16,17 .…”

Perampanel for Treatment of People with a Range of Epilepsy Aetiologies in Clinical Practice: Evidence from the PERMIT Extension Study

“…Both innate and adaptive immunity may be involved in epilepsy [ 53 , 54 ] and a wide range of immune-mediated epilepsies have been identified, although the proportion of individuals with immune-mediated epilepsy is low overall (4‒8%) [ 55 – 57 ]. ASMs are often unsuccessful in controlling seizures in immune-mediated epilepsy [ 58 , 59 ], and PER may therefore be at least as effective as other ASMs in this setting. Treatment should target the underlying cause of immune system dysregulation and early diagnosis of the cause of immune-mediated seizures is required in order to ensure that appropriate treatment is initiated as soon as possible; for example, it is important to identify acute symptomatic seizures secondary to autoimmune encephalitis, since this has well-defined diagnostic criteria and requires early treatment with immunotherapy, including first-line treatment with high-dose intravenous corticosteroids, with or without intravenous immunoglobulins or plasma exchange [ 59 ].…”

Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies

“… 12 , 13 As a result, there would be less GABA available in the synaptic cleft and more presynaptic glutamate. 14 …”