The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications

Orsini, Alessandro; Foiadelli, Thomas; Costagliola, Giorgio; Michev, Alexandre; Consolini, Rita; Vinci, Francesco; Peroni, Diego; Striano, Pasquale; Savasta, Salvatore

doi:10.1016/j.eplepsyres.2021.106588

Cited by 23 publications

(26 citation statements)

References 201 publications

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“…Moreover, the higher seizure burden in mice treated with anti-NMDAR antibodies was associated with higher expression levels of this chemokine. Other studies in patients with intractable temporal lobe epilepsy and rodents with induced seizures have demonstrated the upregulation of CCL2 in the hippocampus and other brain areas (Wu et al, 2008;Banks and Erickson, 2010;Varvel et al, 2016;Orsini et al, 2021). In pharmacoresistant epilepsy, CCR2 is highly expressed in neurons and monocytes suggesting that CCL2 and its receptor may play a role in epileptogenesis (Bozzi and Caleo, 2016;Varvel et al, 2016).…”

Section: Discussionmentioning

confidence: 96%

Monoclonal Antibodies From Anti-NMDA Receptor Encephalitis Patient as a Tool to Study Autoimmune Seizures

et al. 2021

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Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis manifests with precipitous cognitive decline, abnormal movements, and severe seizures that can be challenging to control with conventional anti-seizure medications. We previously demonstrated that intracerebroventricular (i.c.v.) administration of cerebrospinal fluid from affected patients, or purified NMDA receptor antibodies from encephalitis patients to mice precipitated seizures, thereby confirming that antibodies are directly pathogenic for seizures. Although different repertoires of anti-NMDA receptor antibodies could contribute to the distinct clinical manifestations in encephalitis patients, the role of specific antibodies in the expression of seizure, motor, and cognitive phenotypes remains unclear. Using three different patient-derived monoclonal antibodies with distinct epitopes within the N-terminal domain (NTD) of the NMDA receptor, we characterized the seizure burden, motor activity and anxiety-related behavior in mice. We found that continuous administration of 5F5, 2G6 or 3C11 antibodies for 2 weeks precipitated seizures, as measured with continuous EEG using cortical screw electrodes. The seizure burden was comparable in all three antibody-treated groups. The seizures were accompanied by increased hippocampal C-C chemokine ligand 2 (CCL2) mRNA expression 3 days after antibody infusion had stopped. Antibodies did not affect the motor performance or anxiety scores in mice. These findings suggest that neuronal antibodies targeting different epitopes within the NMDA receptor may result in a similar seizure phenotype.

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Section: Discussionmentioning

confidence: 96%

Monoclonal Antibodies From Anti-NMDA Receptor Encephalitis Patient as a Tool to Study Autoimmune Seizures

et al. 2021

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“…Although inflammatory mediators are central in maintaining brain homeostasis, being implicated in the initiation of tissue repair after CNS injury, the process of neurogenesis, neuronal plasticity, and in the behavioral responses related to stress, neuroinflammation can be responsible for neuronal damage, altered cellular function, and impaired secretion and response to neurotransmitters, thus participating to the process of epileptogenesis ( 14 ). The CNS inflammatory response depends on the activity of the resident innate immune cells (particularly, microglial cells and astrocytes) and the release of inflammatory mediators, including cytokines, chemokines, prostaglandin, nitric oxide (NO), and reactive oxygen species (ROS) ( 17 ). Among the cellular effectors of neuroinflammation, microglial cells play a central role.…”

Section: Seizures and Neuroinflammation—an Overviewmentioning

confidence: 99%

“…Indeed, seizures themselves can be responsible for neuronal and glial damage followed by an inflammatory response, while experimental studies investigating the effects of the administration of pro-inflammatory molecules in the central nervous system (CNS) evidenced that inflammation significantly reduces the seizure threshold ( 15 ). Although different authors have focused on the identification of the molecular mechanisms responsible for the inflammatory-dependent induction of seizures and the research for potential therapeutic agents targeting neuroinflammation for the treatment of epilepsy ( 16 , 17 ), there is no uniform agreement on their use, and data from large cohorts of patients and randomized studies are missing.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Autoimmune dysfunction has been proposed in the pathogenetic mechanism of many central nervous system (CNS) diseases. Immunologic factors are implicated in neurodevelopment, and their alteration could result in different disorders, such as tic disorders, developmental encephalopathies ( 9 , 10 ), epilepsy ( 11 ), neuropsychiatric disorders ( 12 ), neurodegenerative diseases ( 13 ), genetic white matter disorders and other related diseases. Recent studies found that the meningeal lymphatic system is directly connected to the brain and the lymphatic system ( 14 ), which strengthens the interconnection between the nervous system and the immune response.…”

Section: Introductionmentioning

confidence: 99%

“…Comparison of cytokines in three diagnostic category groups with or without medication.Minimal tics (YGTSS score, 1-9), Mild tics (YGTSS score,[10][11][12][13][14][15][16][17][18][19], and Moderate to severe tics (YGTSS score, >19). SD, standard deviation.…”

mentioning

confidence: 99%

Changes of Cytokines in Children With Tic Disorder

Tao

Zhu

et al. 2022

Front. Neurol.

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Tic disorder (TD) is a common childhood-onset disease associated with abnormal development of brain networks involved in the motor and sensory processing. The underlying pathophysiological mechanisms in TD are still unclear. An involvement of immune mechanisms in its pathophysiology has been proposed. This study investigates the association between the changes of cytokines and the etiology and development of TD. Different expressions of cytokines in a larger number of samples in our study may provide new insights to the field. The levels of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were evaluated in 1,724 patients who were clinically diagnosed with TD from 1 to 17.5 years old and 550 were from 6 months to 14.5 years old in the control group. We assessed the levels of cytokines according to the patient's medication status and the severity of the disease. Of the cytokines we investigated, the serum IL-6 concentration of children with TD was significantly higher than that of the control group, while the levels of other cytokines were lower in TD patients. In the patient group whose YTGSS score ranged from 1 to 9, the IL-4, IL-10, and IFN-γ levels increased in medication group compared to unmedication group. Our data suggested that the cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) may play an important role in the etiology and the severity in TD. Whether drug intervention in the early stage of tic disorder has a better effect on children needs further research.

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The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications

Cited by 23 publications

References 201 publications

Monoclonal Antibodies From Anti-NMDA Receptor Encephalitis Patient as a Tool to Study Autoimmune Seizures

Monoclonal Antibodies From Anti-NMDA Receptor Encephalitis Patient as a Tool to Study Autoimmune Seizures

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

Changes of Cytokines in Children With Tic Disorder

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