Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome

Pediatric Epilepsy Unit, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Epilepsia (Impact Factor: 4.57). 08/2011; 52(11):1956-65. DOI: 10.1111/j.1528-1167.2011.03250.x
Source: PubMed


To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection-related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology.
We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers.
The 77 enrolled patients presented with prolonged refractory status epilepticus. A preceding febrile infection had been reported in 96% of them. Treatment modalities included antiepileptic drugs (a median of six), intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients), burst-suppression coma (BSC, 46 patients), and other less conventional agents. There was no evidence of efficacy for those treatment modalities except for IVIG (two patients), a ketogenic diet (one patient), and a prolonged cycle of barbiturate anesthesia coma (one patient). Nine patients (11.7%) died during the acute phase of FIRES. Only 12 of the 68 surviving patients (18%) retained normal cognitive level, but most of them had learning disabilities. Sixty-three patients (93%) had refractory epilepsy at follow-up. Cognitive levels at follow-up were significantly associated with duration of BSC (p = 0.005) and younger age at FIRES onset (p = 0.02).
The outcome of FIRES is poor. No therapeutic agent was efficacious in shortening the acute phase, with the possible exception of a ketogenic diet. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.

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Available from: Nicola Specchio
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    • "Epileptic syndromes following a febrile illness have been described in the paediatric literature under various nomenclatures including idiopathic catastrophic epileptic encephalopathy [15], severe refractory status epilepticus owing to presumed encephalitis [16], devastating epilepsy in school-age children [17], and acute encephalitis with refractory repetitive partial seizures (AERRPS) [18]. This clinical entity has been most recently termed febrile illness-related epilepsy syndrome or fever-induced refractory epileptic encephalopathy in school-aged children (FIRES) [19] [20] [21] [22] [23]. There are also descriptions of acute onset epilepsy syndromes in the adult population. "
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    ABSTRACT: We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of "autoimmune adult onset focal epilepsy and encephalitis" is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-d-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome.
    Full-text · Article · Dec 2013 · Journal of Clinical Neuroscience
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    • "A variety of terms have been used in the literature to refer to this syndrome, including ‘de novo cryptogenic refractory multifocal febrile status epilepticus’ [2], ‘idiopathic catastrophic epileptic encephalopathy’ [3], ‘status epileptics owing to presumed encephalitis’ [4], ‘devastating epilepsy in school-age children’ (DESC) [5], acute nonherpetic encephalitis with refractory repetitive partial seizures’ [6], ‘acute encephalitis with refractory repetitive partial seizures’ (AERRPS) [7], and ‘febrile infection-related epilepsy syndrome’ (FIRES) [8, 9]. "
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    ABSTRACT: New-onset refractory status epilepticus (NORSE) is a recently defined clinical entity that describes patients who present with status epilepticus of unclear etiology that is highly refractory to therapy. Magnetic resonance imaging (MRI) of NORSE usually discloses no specific abnormalities except for an occasional mild T2/FLAIR hyperintense signal of the mesial temporal lobe. Here, we report a peculiar case of NORSE in which brain MRI showed massive alteration of both temporal lobes, with features strongly supporting the diagnosis of herpes virus encephalitis, but lacking any laboratory evidence of viral infection in the blood and cerebrospinal fluid. It showed also striking signal alterations in the thalamus, which got worse in the course of the disease. This report emphasizes the possibility that seizure activity alone plays a critical role in both determining the disease and whether it will be self-sustaining.
    Full-text · Article · Sep 2013 · Case Reports in Neurology
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    • "Early MR brain scans may show bulging of the mesial temporal structures on coronal slices in the first weeks of the disease , with increased T 2 -weighted signal. The status epilepticus usually persists despite many antiepileptic drug (AED) trials (Mikaeloff et al., 2006; Kramer et al., 2011). A ketogenic diet helped almost half of the patients in our series (Nabbout et al., 2010). "
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    ABSTRACT: The role of immunity and inflammation in epilepsy have long been suggested by the anticonvulsant activity of steroids in some infancy and childhood epilepsies. The role of fever and infection in exacerbating seizures due to possible proinflammatory molecules, the increased frequency of seizures in systemic autoimmune diseases like systemic lupus erythematous, and, recently, the detection of autoantibodies in some unexplained epilepsies reinforced the causal place of immunity and inflammation in epilepsies with unknown etiology. In this article, we summarize epilepsies where clinical and biologic data strongly support the pathogenic role of autoantibodies (e.g., limbic encephalitides, N-methyl-d-aspartate [NMDA] encephalitis) and epilepsies where immune-mediated inflammation occurs, but the full pathogenic cascade is either not clear (e.g., Rasmussen's encephalitis) or only strongly hypothesized (idiopathic hemiconvulsion-hemiplegia syndrome [IHHS] and fever-induced refractory epilepsy in school-aged children [FIRES]). We emphasize the electroclinical features that would help to diagnose these conditions, allowing early immunomodulating therapy. Finally, we raise some questions that remain unclear regarding diagnosis, mechanisms, and future therapies.
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