Febrile Infection-Related Epilepsy Syndrome without Detectable Autoantibodies and Response to Immunotherapy: A Case Series and Discussion of Epileptogenesis in FIRES

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.

Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

“…Electrophoresis of CSF proteins yielded no significant findings in the vast majority of patients, and no evidence of CSF oligoclonal bands has been observed in FIRES [138,155]. Furthermore, studies of autoantibodies against neuronal epitopes, such as glutamate receptors of type NMDA and type AMPA, GABA B -receptors, voltage-gated potassium channelassociated proteins (VGKC), LGI1 and contactin-associated protein like 2, and glutamic acid decarboxylase (GAD), associated with well-known immune-mediated neurological disorders and epilepsy, were also evaluated in patients with FIRES, yielding negative results [155].…”

“…Furthermore, studies of autoantibodies against neuronal epitopes, such as glutamate receptors of type NMDA and type AMPA, GABA B -receptors, voltage-gated potassium channelassociated proteins (VGKC), LGI1 and contactin-associated protein like 2, and glutamic acid decarboxylase (GAD), associated with well-known immune-mediated neurological disorders and epilepsy, were also evaluated in patients with FIRES, yielding negative results [155]. Only a few patients in a large retrospective study disclosed positive anti-(VGKC) and anti-(GAD) and anti-GluR3 antibodies [141].…”

Cognitive Outcomes in Febrile Infection-Related Epilepsy Syndrome Treated With the Ketogenic Diet

“…1 The underlying pathophysiology may be immune-mediated, but adjunctive therapies to anticonvulsant medications, including immunotherapy with intravenous immunoglobulin, steroids, and plasmapheresis, have been used with limited success. 5,6 One group suggested the ketogenic diet (KD) may be effective in the acute SE phase of FIRES, based on experience with 9 patients, but cognitive outcomes were not described. 7 The KD is a high-fat, adequate-protein, lowcarbohydrate diet that can reduce seizure burden via incompletely understood mechanisms.…”

The specific features and pattern of febrile infection-related epilepsy syndrome (FIRES) in children

“…Этот синдром встречается крайне редко (1 случай на 1 млн детского населения) [1]. Он характеризуется возникновени-ем эпилептических приступов у ранее здоровых детей во время или спустя несколько дней после неспецифичного, предположительно инфекционного, заболевания с фебри-литетом в дебюте.…”

“…Первоначально синдром носил названия: «острый энцефалит с устойчивыми повто-ряющимися парциальными приступами» (AERRPS -Acute Еncephalitis with Refractory Repetitive Partial Seizures) [2], «эпилептический статус с упорной лихорадкой ввиду пред-полагаемого энцефалита» [3], «идиопатическая злокачест-венная эпилептическая энцефалопатия» [4], «первичный рефрактерный эпилептический статус» (NORSE -NewOnset Refractory Status Epilepticus) [5], «разрушительная эпилептическая энцефалопатия у детей школьного возрас-та» (DESC -Devastating Epileptic encephalopathy in Schoolaged Children) [6,7] и, наконец, «синдром эпилепcии, инду-цированный фебрильной инфекцией» (FIRES) [1,8].…”