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

Kothur, Kavitha; Bandodkar, Sushil; Wienholt, Louise; Chu, Stephanie; Pope, Alun; Gill, Deepak; Dale, Russell C.

doi:10.1111/epi.16275

Cited by 96 publications

(126 citation statements)

References 54 publications

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“…Subsequently, several reports of positive effects of anakinra have been published 62–64 . These findings can be considered as a support for the therapeutic efficacy of anakinra, considering the known association of FIRES with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity 38 …”

Section: Treatment Of Norse and Firesmentioning

confidence: 91%

New‐onset refractory status epilepticus and febrile infection‐related epilepsy syndrome

Specchio

Pietrafusa

2020

Develop Med Child Neuro

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New‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) are relatively rare clinical presentations. They are characterized by de novo onset of refractory status epilepticus (RSE) without clearly identifiable acute or active cause (structural, toxic, or metabolic). We reviewed the literature using PubMed reports published between 2003 and 2019 and summarized the clinical, neurophysiological, imaging, and treatment findings. Focal motor seizures, which tend to evolve into status epilepticus, characterize the typical presentation. Disease course is biphasic: acute phase followed by chronic phase with refractory epilepsy and neurological impairment. Aetiology is unknown, but immune‐inflammatory‐mediated epileptic encephalopathy is suspected. Electroencephalograms show variety in discharges (sporadic or periodic, focal, generalized, or more frequently bilateral), sometimes with a multifocal pattern. About 70% of adult NORSE have abnormal magnetic resonance imaging (MRI); in paediatric series of FIRES, 61.2% of patients have a normal brain MRI at the beginning and only 18.5% during the chronic phase. No specific therapy for FIRES and NORSE currently exists; high doses of barbiturates and ketogenic diet can be used with some effectiveness. Recently, anakinra and tocilizumab, targeting interleukin pathways, have emerged as potential specific therapies. Mortality rate is around 12% in children and even higher in adults (16–27%). What this paper adds Diagnosis for febrile infection‐related epilepsy syndrome (FIRES) requires prior febrile infection. FIRES is considered a subcategory of new‐onset refractory status epilepticus (NORSE). Clinical features, differential diagnosis, and pathophysiologic hypothesis are reviewed.

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Section: Treatment Of Norse and Firesmentioning

confidence: 91%

New‐onset refractory status epilepticus and febrile infection‐related epilepsy syndrome

Specchio

Pietrafusa

2020

Develop Med Child Neuro

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“…Of note, IL‐6 and IL‐8 elevation as well as elevation of neopterin, a nonspecific marker of immune activation, was also found in the CSF of febrile SE patients at significantly higher levels than in noninflammatory neurologic conditions or chronic epilepsy patients with daily seizures. This indicates that there is an inflammatory milieu in febrile SE 149 and that these markers are not specific to FIRES patients. On the other hand, there were differing cytokine profiles among FIRES and afebrile SE controls, suggesting that the alterations are not solely due to seizure activity 149 .…”

Section: Inflammatory Status Epilepticusmentioning

confidence: 95%

“…Of interest, a few studies, mainly in FIRES, demonstrate a pro‐inflammatory alteration in CSF cytokine profiles, although without comparator non‐inflammatory SE groups within these studies 143,148 . Whether this alteration is a cause or effect of SE is still unclear and the clinical utility of these cytokines to predict response to immunotherapy is unknown 128,143,148–152 …”

Section: Inflammatory Status Epilepticusmentioning

confidence: 99%

“…In FIRES, proinflammatory cytokines such as IL‐6 143,148,149,151,152 and cytokines involved in the innate immune response such as C‐X‐C motif chemokine ligand 8/interleukin‐8 (or CXCL8/IL‐8), 151,152 a neutrophil chemoattractant, and C‐C motif ligand 4 (CCL4) and C‐C motif ligand 3 (CCL3) 149 involved in macrophage recruitment, are elevated in CSF. Of interest, IL‐6 tended to be elevated in CSF more than plasma suggesting CNS‐specific inflammation 148,152 .…”

Section: Inflammatory Status Epilepticusmentioning

confidence: 99%

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Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease

et al. 2020

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Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.

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“…An inflammatory cause is supported by the frequent observation of transient increases in cerebrospinal fluid pleocytosis. Additionally, abnormally high levels of pro-inflammatory cytokines and chemokines are found in the cerebrospinal fluid in the early stage of onset, presumably due to strong activation of the immune system in the central nervous system [ 15 , 16 ]. Such marked pro-inflammatory cytokine changes may be seen in infectious encephalitis but not in many autoimmune neurological disorders.…”

Section: Clinical Features Of Firesmentioning

confidence: 99%

Neurocritical care and target immunotherapy for febrile infection-related epilepsy syndrome

2020

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Febrile infection-related epilepsy syndrome (FIRES) is an intractable neurological disease characterized by an unexplained refractory status epilepticus triggered by febrile infection. A Consensus definition of FIRES was proposed in 2018, and its clinical features and prognosis are gradually being clarified. However, the development of effective treatments has been hindered as the etiology of this rare disease is as yet unelucidated. The basic approach to the management of FIRES, like other forms of epilepsy, is based on the control of seizures, however seizures are extremely intractable and require intravenous administration of large doses of anticonvulsants, mainly barbiturates. This treatment strategy produces various complications including respiratory depression and drug hypersensitivity syndrome, which make it more difficult to control seizures. Consequently, it is crucial to predict these events and to formulate a planned treatment strategy. As well, it is important to grow out of conventional treatment strategies that rely on only anticonvulsants, and alternative therapies are gradually being developed. One such example is the adoption of a ketogenic diet which may lead to reduced convulsions as well as improve intellectual prognosis. Further, overproduction of inflammatory cytokines in the central nervous system has been shown to be strongly related to the pathology of FIRES which has led to attempts at immunomodulation therapy including anti-cytokine therapy.

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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

Cited by 96 publications

References 54 publications

New‐onset refractory status epilepticus and febrile infection‐related epilepsy syndrome

New‐onset refractory status epilepticus and febrile infection‐related epilepsy syndrome

Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease

Neurocritical care and target immunotherapy for febrile infection-related epilepsy syndrome

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