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

Abstract

IntroductionRecent 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.MethodsA 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.ResultsOur 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.ConclusionThe 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.

The value of immunotherapy in children with initial short-term frequent seizures

“…The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant and refractory epileptic status has shown good therapeutic results. Current experience with TNF inhibitors is limited to Rasmussen encephalitis ( 30 ). Moreover, our study had some limitations, 1 of which is that the number of cases in this study was small.…”

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

“…A case report on a patient with generalised epilepsy and poor response to multiple ASMs-reported clinical response after therapeutic IL-1 blockade, first by treatment with anakinra followed by canakinumab with near resolution of seizures [ 199 ]. Additionally, a recent systematic review by Costagliola et al showed that the use of anakinra/canakinumab reduced or arrested seizure frequency in over 50% of all patients [ 200 ].…”

“…Conversely, some patients developed AIE after the initiation of infliximab treatment [ 203 ]. A recent systematic review by Costagliola et al, highlighted a study by Lagarde et al on the use of adalimumab in RE where a decrease in seizure frequency/seizure remission in more than 50% of patients was observed [ 145 , 200 ].…”

Systemic inflammation as a biomarker of seizure propensity and a target for treatment to reduce seizure propensity

“…A plethora of recent reviews has linked inflammation and epilepsy. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 31 , 32 Although elevated body temperature is probably the best‐known indicator of inflammation that provides predictive information about increased risk of a seizure, we do not know of any study that has assessed how well serum/plasma levels of inflammation‐related proteins convey information about impending seizures.…”