Second‐line immunotherapy in new onset refractory status epilepticus

Abstract

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection‐related epilepsy syndrome (FIRES). Consensus‐driven recommendations have been established to guide the initiation of first‐ and second‐line immunotherapies in these patients. Here, we review the literature to date on second‐line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long‐term disability and drug‐resistant post‐NORSE epilepsy. Initiation of second‐line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post‐NORSE epilepsy or long‐term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes.

The Purinergic P2X7 Receptor as a Target for Adjunctive Treatment for Drug-Refractory Epilepsy

“…Most notably, P2X7R activation promotes the formation of the NLRP3 inflammasome, leading in turn to the activation of caspase-1 and the subsequent release of the cytokine interleukin-1β (IL-1β) [72]. IL-1β is a wellestablished proinflammatory and proconvulsive cytokine, and drugs interfering with IL-1β signalling (e.g., anakinra) have shown promising anti-seizure effects [73][74][75]. The P2X7R has also been shown to contribute to the activation and proliferation of microglia [76,77], and reactive microglia, in turn, are recognised to contribute to seizures and epilepsy [78,79].…”

“…Moreover, IL-1β receptor blockers such as anakinra protected the brain from SE-induced brain damage and ameliorated SE-induced epileptogenesis in mice [133][134][135]. Anakinra has also shown seizure-suppressive potential in patients with drug-refractory SE and epilepsy [75,135]. More direct evidence suggesting that P2X7R-induced inflammation contributes to its proconvulsant function stems from studies showing the absence of the antiepileptic effects of P2X7R antagonists in the presence of the anti-inflammatory drug minocycline.…”