Interleukin-6 Blockade With Tocilizumab in Anakinra-Refractory Febrile Infection-Related Epilepsy Syndrome (FIRES)

Stredny, Coral M.; Case, Siobhan; Sansevere, Arnold J.; Son, Mary Beth F.; Henderson, Lauren A.; Gorman, Mark

doi:10.1177/2329048x20979253

Cited by 45 publications

(53 citation statements)

References 8 publications

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“…In the remaining five cases, anti-IL-1 treatment was administrated after more than 4 months. Except for five cases in which there weren't improvements (three of them died after drug discontinuation) ( 105 , 110 , 114 ), the use of anti-IL-1 was effective in reducing the seizure burden. Indeed, its use significantly reduced seizures (>50%) in 11/15 of the patients described in the cohort by Lai et al with available clinical data ( 110 ), and in 9/12 of the patients described in case reports ( Table 2 ).…”

Section: Resultsmentioning

confidence: 94%

“…Concerning safety, although tocilizumab has been well-tolerated by the majority of the patients, our analysis evidenced three cases of infection (one pneumonia and two cases of sepsis), and two patients developed leukopenia ( 123 , 124 ). The motor, behavioral, and cognitive outcome has been reported mostly with qualitative assessment, showing a reported improvement in seven out of the nine single case reports, with the persistence of behavioral dysregulation ( 114 ), mild cognitive impairment, and mild ataxia ( 118 ) in two patients. In the study by Jun et al and the case presented by Benucci et al the modified Rankin scale (mRS) was used, demonstrating an improvement at follow-up in 4/7 survived patients ( 122 , 124 ).…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…All of these patients were adult, however Cantarín-Extremera et al reported two paediatric cases of refractory status epilepticus treated successfully with tocilizumab [39]. Stredny et al, reported a case of successful tocilizumab treatment in a patient with FIRES refractory to anakinra [40].…”

Section: Treatment Of Firesmentioning

confidence: 99%

Dramatic Course of Paediatric Cryptogenic Febrile Infection-Related Epilepsy Syndrome with Unusual Chronic Phase Presentation—A Case Report with Literature Study

2021

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Febrile Infection-Related Epilepsy Syndrome (FIRES) is a catastrophic, extremely rare epileptic encephalopathy. It strikes previously healthy school-aged children and is usually cryptogenic. Its dramatic onset with refractory status epilepticus is always preceded by a nonspecific febrile illness. The seizure activity in FIRES may last for several weeks with little to no response to antiepileptic treatment, usually resulting in the usage of anaesthetics. This acute phase is followed by a chronic, refractory epilepsy and cognitive deficit, that persist for the rest of the patient’s life. Still to this day no definite cause has been described. In this study we review the current finding in FIRES and describe a case of a 4-year-old patient with a dramatic course of the acute phase in FIRES and unusual presentation of the chronic phase, which is dominated by extrapyramidal symptoms such as dystonia. This case highlights that the clinical presentation of FIRES may differ from those frequently described in literature.

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“…Hence, the potential of immunomodulatory therapies is increasingly considered, and certain strategies to modulate the immune system have been applied with anakinra or tocilizumab [ 125 , 126 , 127 ].…”

Section: From Monogenic To Multifactorial: Il-1β-related Brain Disordersmentioning

confidence: 99%

Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain

Tesser

Mencaroni

et al. 2021

IJERPH

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More and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified “models” to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders.

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Interleukin-6 Blockade With Tocilizumab in Anakinra-Refractory Febrile Infection-Related Epilepsy Syndrome (FIRES)

Cited by 45 publications

References 8 publications

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

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

Dramatic Course of Paediatric Cryptogenic Febrile Infection-Related Epilepsy Syndrome with Unusual Chronic Phase Presentation—A Case Report with Literature Study

Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain

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