Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications

Abstract

Introduction: Recent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field.

Methods: A systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms "status epilepticus," "epilepsy," and "seizure." The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis.

Results: Our search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants.

Conclusion: The experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.

Keywords: adalimumab; anakinra; canakinumab; cytokines; epilepsy; neuroinflammation; rituximab; tocilizumab.

Figure 1

Framework for epilepsy classification designed to allow diagnosis at multiple levels depending on the informationand resources available. At all levels of diagnosis, we should consider more broadly the etiology of the patient's epilepsy. A range of six etiological groups has been recognized: genetic, structural, metabolic, immune, infectious, and unknown.

Figure 2

Overview of inflammatory pathways involved in epilepsy and main therapeutic targets.

Figure 3

Anti-IL-1 agents and epilepsy, literature review.

Figure 4

Anti-IL-6 agents and epilepsy, literature review.

Figure 5

Anti-TNF agents and epilepsy, literature review.

Figure 6

Anti-CD20 agents and epilepsy, literature review.

Figure 7

Anti-α4-integrin agents and epilepsy, literature review.

Figure 8

Use of anakinra and tocilizumab in epilepsy, data from the literature.