Efficacy of different treatment modalities for acute and chronic phases of the febrile infection-related epilepsy syndrome: A systematic review.

BACKGROUND: Febrile infection-related epilepsy syndrome is associated with high mortality and morbidity rates. No systematic review of demographics, aetiologies, good treatment options, and causes of deaths has been performed. Thus, we aimed to focus on these factors to provide a structure for patient management and research. METHODS: A deep literature search was performed in PubMed and Embase of all years until May 2019. RESULTS: We retrieved 45 aSrticles: 3 multicentre cohort studies, 13 single-centre cohorts, 1 case series, and 28 case reports. We identified 229 cases: most were from Asia; 53% were males; 11.4% had several types of antibodies, and the most common was anti-glutamate receptor epsilon 2; 30% (69 cases) had good treatment outcomes; 12.2% died; and 56% remained with drug-resistant epilepsies. Univariate analysis revealed a statistically significant association between positive outcomes in Japan and China, the use of the ketogenic diet either acutely or chronically, and the use of steroids acutely or chronically. Taiwan showed a statistically significant association with negative outcomes. Multivariate logistic regression revealed the utilisation of the ketogenic diet in the acute phases (P = 0.008, OR = 3.613) and being in Japan (P = 0.003, OR = 3.146) as independent determinants of positive outcomes. Most of the deaths occurred because of the progress of the disease rather than complications of the drugs. CONCLUSIONS: Asians are more affected and several cases have antibodies. Positive outcomes are associated with being in Japan and the utilisation of the ketogenic diet in the acute phase.

Extinguishing Febrile Infection-Related Epilepsy Syndrome: Pipe Dream or Reality?

Febrile infection-related epilepsy syndrome (FIRES) is a rare and devastating epileptic encephalopathy with historically abysmal neurocognitive outcomes, including a high incidence of mortality. It tends to affect children and young adults and is characterized by superrefractory status epilepticus following a recent febrile illness. Growing evidence suggests a heterogeneous etiology resulting in fulminant nonantibody-mediated neuroinflammation. For some children with FIRES, this aberrant neuroinflammation appears secondary to a functional deficiency in the endogenous interleukin-1 receptor antagonist. A precise etiology has not been identified in all FIRES patients, and current treatments are not always successful. Limited treatment evidence exists to guide choice, dosing, and duration of therapies. However, the ketogenic diet and certain targeted immunomodulatory treatments, including anakinra, appear safe and have been associated with relatively excellent clinical outcomes in some FIRES patients. Future prospective multicenter collaborative studies are needed to further delineate the FIRES heterogeneous disease pathophysiology and to determine the safety and efficacy of treatment strategies through a robust measurement of neurocognitive outcomes.

Febrile Infection-Related Epilepsy Syndrome (FIRES): An Overview of Treatment and Recent Patents.

BACKGROUND: New-Onset Refractory Status Epilepticus (NORSE) refers to a clinical presentation in a patient without active epilepsy or other existing relevant neurological disorder, with new onset of refractory status epilepticus in the absence of a clear acute or active structural, metabolic, or toxic cause. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE that requires a febrile infection between 24 hours and 2 weeks prior to the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus, and with no restriction to the age of the patient. The literature on FIRES is scarce. OBJECTIVE: This article reviews the pathophysiology, clinical features, and various treatment modalities in the treatment of FIRES. METHODS: A Medline/Pubmed search was conducted using Clinical Queries with the key terms "Febrile Infection-Related Epilepsy Syndrome", "FIRES", "New-Onset Refractory Status Epilepticus" and "NORSE". The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term "FIRES", "NORSE" and "Febrile Epilepsy Syndrome" from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. RESULTS: FIRES almost invariably begins with a mild nonspecific febrile illness in an otherwise healthy individual. Twenty-four hours to two weeks later, seizures begin and quickly become very frequent and worsen, becoming status epilepticus. Seizures can be simple motor, complex partial or secondary generalized. The exact etiology is not known. It is possible that the syndrome is caused by an inflammatory or autoimmune mechanism. Seizures in FIRES are notoriously very difficult to treat. Treatment modalities include, among others, various antiepileptic drugs, ketogenic diet, intravenous corticosteroids, intravenous immunoglobulin, and burst-suppression coma. The outcome is poor; most children are left with significant cognitive disability and refractory epilepsy. Recent patents for the management of FIRES are discussed. CONCLUSION: FIRES is a rare epilepsy syndrome of unclear etiology in which children, usually of school age, suddenly develop very frequent seizures after a mild febrile illness. Seizures in FIRES are typically difficult to treat. The prognosis is poor.

Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.

BACKGROUND: Febrile infection-related epilepsy syndrome (FIRES) has been described as an epileptic encephalopathy of unknown etiology affecting previously healthy children following febrile illness. Despite large investigations on autoimmune pathogenesis no membrane antibodies has been associated since now. CASE STUDY: We report a 13 years-old girl with negative history for neurological or autoimmune disease that developed at the sixth day of high fever a super-refractory status epilepticus. All investigations, including the most common antibodies related to immune-mediated encephalitis were negative. Seizures continued despite several therapeutic trials with anesthetics (midazolam, propofol) and antiepileptic agents as well as i.v. immunoglobulins but responded, at day 10 from the onset, to ketamine and high dose i.v. steroids. Due the high suspicion of autoimmune encephalitis we tested patient's CSF and plasma on mouse brain with positive response. We subsequently detected a high titre of GABAAR antibodies. After the resolution of the status epilepticus the patient achieved complete recovery of neurological functions. CONCLUSION: this is the first reported case of a FIRES-like condition due to autoimmune encephalitis mediated by GABAAR antibodies. Our case suggests that GABAAR antibodies should be investigated FIRES.