Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome

Dilena, Robertino; Mauri, Eleonora; Aronica, Eleonora; Bernasconi, Pia; Bana, Cristina; Cappelletti, Cristina; Carrabba, Giorgio; Ferrero, Stefano; Giorda, Roberto; Guez, Sophie; Catenacci, Stefano Scalia; Triulzi, Fabio; Barbieri, S.; Calderini, Edoardo; Vezzani, Annamaria

doi:10.1002/epi4.12317

Cited by 88 publications

(102 citation statements)

References 16 publications

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“…Interference of the IL‐1β proinflammatory cascade has been shown to decrease seizure frequency, whereas amplification of this pathway has been reported to cause worsening of seizures and a worse outcome in animal models . Although there are early reports of effect of anakinra (IL‐1R antagonist) and tacrolimus (targeting T cells) in reducing the severity of FIRES in experimental models and case reports, more data are needed to determine whether this inflammatory process is modifiable …”

Section: Discussionmentioning

confidence: 99%

“…53 Although there are early reports of effect of anakinra (IL-1R antagonist) and tacrolimus (target ing T cells) in reducing the severity of FIRES in experimental models and case reports, more data are needed to determine whether this inflammatory process is modifiable. 10,27,54,55 A strength of our study is that we studied cytokines/ chemokines in acute CSF samples of FIRES/FRD and fe brile and afebrile status epilepticus groups, and compared these with chronic epilepsy subgroups with ongoing fre quent daily seizures. The fact that FSE and ASE had a similar duration and severity of seizures allowed us to compare the effects of "seizures themselves" on inflam mation.…”

Section: Discussionmentioning

confidence: 99%

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Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus

et al. 2019

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Objective To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. Methods We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection‐related epilepsy syndrome (FIRES)/FIRES‐related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. Results The median age of onset of seizures was 2.4 years (range = 0.08‐12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1‐2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1‐associated cytokines/chemokines (TNF‐α, CXCL9, CXCL10, CXCL11), IL‐6, CCL2, CCL19, and CXCL1 (P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases. Significance We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus

et al. 2019

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“…IL‐1β drives the pathologic role of brain inflammation in epilepsy . Studies on surgically resected epileptogenic foci from drug‐resistant forms of epilepsy with structural or infectious etiologies showed that the IL‐1α–IL‐1R1 axis is activated in neurons, glia, and endothelial cells of the BBB .…”

Section: Anakinramentioning

confidence: 99%

“…IL-1β drives the pathologic role of brain inflammation in epilepsy. [104][105][106][107][108][109][110][111][112] Studies on surgically resected epileptogenic foci from drug-resistant forms of epilepsy with structural or infectious etiologies showed that the IL-1α-IL-1R1 axis is activated in neurons, glia, and endothelial cells of the BBB. 104,107,[113][114][115] Similar findings were reported in animal models of acute symptomatic seizures, febrile and nonfebrile SE, and models of acquired epilepsies, 107,114 absence epilepsy, and progressive myoclonic epilepsy.…”

Section: Anakinramentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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“…In contrast, administration of the IL-1R antagonist is anticonvulsive (Heida and Pittman, 2005), while IL-1R-deficient mice are resistant to FS, independent of the genetic background strain (C57Bl or 129/Sv) (Dube et al, 2005). This mechanism holds strong promise for clinical translation, with two case reports demonstrating that treatment with the IL-1R antagonist reduced seizure burden and relapse in children with febrile infection-related epilepsy syndrome (Kenney-Jung et al, 2016;Dilena et al, 2019).…”

Section: Hyperthermia-induced Febrile Seizuresmentioning

confidence: 99%

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

2020

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The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic-ischemic injury, perinatal stroke), and insults sustained during early postnatal life-such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological antiepileptogenic therapeutic strategies.

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Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome

Cited by 88 publications

References 16 publications

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

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