Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1ß) are recommended.

De las convulsiones febriles a las epilepsias relacionadas / From febrile seizures to related epilepsies

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The role of neutrophil-lymphocyte ratio and red blood cell distribution width in the classification of febrile seizures.

OBJECTIVE: Most febrile seizures occur outside of hospitals, and in most cases, information about the characteristics of the seizures is obtained from the parents. This makes it difficult to differentiate between simple and complex seizures. The aim of this study is to evaluate the significance of the Neutrophil-Lymphocyte Ratio (NLR) and the red blood cell (erythrocyte) distribution width (RDW) in distinguishing between simple and complex febrile seizures. PATIENTS AND METHODS: The files of 142 patients between the ages of 6 months and 5 years who were admitted to the Emergency Department with the diagnosis of first febrile seizure were reviewed retrospectively. Complete blood count and C-reactive protein (CRP) parameters obtained from the venous blood samples collected from the patients at admission were evaluated. RESULTS: The average values of NLR for simple and complex seizure groups were 2.38 ± 1.60 and 3.42 ± 1.77 respectively, and the difference was statistically significant (p < 0.001). The average values of RDW for simple and complex seizure groups were 16.15 ± 1.37 and 16.27 ± 1.53, respectively; the difference was not significant (p = 0.631). We used receiver operating characteristic (ROC) analysis and chose a cutoff value of 2.315 for the NLR, and we found that the sensitivity and specificity were 62.7% and 53.8%, respectively (area under the curve [AUC]: 0.665, p = 0.001, confidence interval [CI] 0.573-0.756). CONCLUSIONS: We suggest that NLR may provide clinicians with an insight into differentiating between simple and complex febrile seizures; however, it does not produce a clear-cut distinction. We found that the RDW ratio is not useful in this differentiation.

Etiología y factores asociados a las crisis convulsivas febriles en Ecuador / Etiology and factors associated with febrile seizures in Ecuador

Introducción: Las convulsiones febriles son sucesos comunes en la infancia y de carácter benigno, que se producen en niños de 6 meses a 6 años de edad, afectando del 2 al 5% de la población infantil. Se ha implicado la interleukina 1β en la génesis de las convulsiones en un terreno fértil genéticamente determinado y mapeado en los cromosomas 8 y 19p en las áreas FEB1 y FEB2; sin embargo, han sido implicados factores de riesgo como prematuridad, anemia, polimorfismos genéticos, antecedente familiar de epilepsia e historia de inmunizaciones. Objetivos. Identificar las principales causas de convulsiones febriles en la edad pediátrica en el Hospital General Ambato, la caracterización de las mismas y su asociación con la edad, género e historia familiar. Metodología. Se realizó un estudio descriptivo transversal epidemiológico de cohorte, en 115 pacientes hospitalizados con el diagnóstico de convulsión febril, de junio 2012 a agosto 2016. Resultados. Los hallazgos evidenciaron que el género masculino fue el más afectado, con el 51,3%, y la enfermedad diarreica aguda y la gingivoestomatitis herpética fueron las responsables de la fiebre en el 31,3% y 15,6%, respectivamente. La expresión semiológica de la crisis en la mayoría de los casos fue tónico-clónica generalizada. Del total de casos, el 84,3% no presentaron antecedentes familiares, pero los que presentaron tienen mayor riesgo de recurrencia. El 93% de los pacientes tuvieron una edad gestacional a término. Conclusión: Las enfermedades infecciosas son las principales causas de estos eventos convulsivos en esta serie de casos; es prioritario identificar factores de riesgo asociados para decidir una conducta oportuna y el seguimiento de acuerdo al caso

Introduction: Febrile seizures are common events in childhood and benign in nature. Typically affecting 2-5% of the children population between the ages of 6 months and 6 years of age. Interleukin 1β has been implicated in the genesis of seizures in genetically determined fertile ground and mapped on chromosomes 8 and 19p in areas FEB1 and FEB2, although risk factors such as premature birth, anemia, genetic polymorphisms, known family history of epilepsy and immunization have been associated. Objective. This study sought to identify the main causes of febrile seizures in children at the General Hospital Ambato, as well as characterizing them and their association to age, gender and family history. Patients and Method. A descriptive transversal epidemiological cohort study was carried, including 115 patients with febrile seizure diagnosis, from june 2012 to august 2016. Results. Findings showed that males presented more seizure events at 51.3%. Acute diarrheal disease and her petic gingivostomatitis were responsible for fevers in 31.3% and 15.6% respectively. The semiological expression in most cases were generalized tonic-clonic type. Of the total cases of seizures, 84.3% did not express family history, but the ones who did presented with a higher risk of reccurance. 93% of patients were full-term infants. Conclusions: Infectious diseases were the primary cause of seizure events in this cases series. It is of high priority to identify risk factors associated to determine an appropriate approach and follow-up according to the case

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence.

BACKGROUND: A history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy. METHODS: Information on the history of seizures was obtained by a questionnaire from twin pairs in the Mid-Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes. RESULTS: Histories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group. CONCLUSION: A twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities.

Neutrophil-to-lymphocyte ratio and red blood cell distribution width is a practical predictor for differentiation of febrile seizure types.

OBJECTIVE: Febrile seizures (FS) are the most common neurological emergency in childhood. They are divided into two groups accordingly clinical features, simple febrile seizure and complex febrile seizure. Until now laboratory tests have not been used as a parameter of classification of them. The objective of this study is to estimate the usefulness of the hematogical parameters especially neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in the differentiation of febrile seizure types. PATIENTS AND METHODS: A retrospective review was conducted on patients from 6 months to 6 years old presenting with first febrile seizure admitted to a tertiary care hospital. Epidemiological and laboratory variables of the patients were collected. RESULTS: The mean NLR in the simple FS and complex FS groups was 2.18±1.9 and 3.8±4.2 respectively, and the difference was significant (p=0.024). The mean serum red blood cell distribution width in the simple FS and complex FS groups was 16.1±1.1 and 16.6±0.8 respectively, and the difference was significant (p=0.019). NLR and RDW values in complex FS patients were statistically higher than simple febrile patients. ROC analysis showed that if the chosen cut-off point for NLR is 1.98 the sensitivity and specificity are 66.7% and 60.3% respectively. These were statistically significant (p=0.040 AUC 0.623, CI 0.503-0.743). If the chosen cut-off point for RDW is 16.350, the sensitivity and specificity are 59.0% and 58.6%, respectively. These were statistically significant (p=0.037 AUC 0.626, CI 0.515-0.736) too. CONCLUSIONS: NLR and RDW were simple, effective and practical predictors for differentiation of FS types. They will have potential values in public health practice for management of FS patients.

Recent advances in febrile seizures.

Febrile seizures are the most common seizures of childhood. A family history of febrile seizures is common, and the disorder is genetically heterogenous. While guidelines are available for management of simple febrile seizures, the management of complex febrile seizures is individualised. After a febrile seizure, it is important to rule out CNS infection and the decision to perform a lumbar puncture should be based on the clinical condition of the child. Neuroimaging and EEG are not required immediately in workup for simple or complex febrile seizures. Recurrence of febrile seizures may be managed at home by the parents with benzodiazepines. If the recurrences are multiple or prolonged and parents are unable to give home treatment, intermittent benzodiazepine prophylaxis may be given. Continuous antiepileptic prophylaxis may be given only to the children where intermittent prophylaxis has failed. Febrile seizures are also associated with increased risk of epilepsy, but this cannot be prevented by any form of treatment. There is also an increased risk of mesial temporal sclerosis, but whether this is an effect or cause of febrile seizures is as yet unclear. There is no increase in neurological handicaps or mortality following febrile seizures.

Convulsión febril / Febrile seizure

Febrile seizures are the most common seizure disorder in the pediatric population and represent a frequent cause of consultation in emergency departments, confirming its importance. We present an updated and practical review regarding this pathology, along with an operative definition that supports the application of a flowchart that integrates concepts and procedures that can be easily applied at any location nationwide. This review is designed to provide an analytic framework regarding pediatric febrile seizures, as well as present a guideline based on our experience in the emergency department by summarizing the main benzodiazepines in actual use that have been proved to be both safe and effective in treating this disorder, such as lorazepam and midazolam...

"Simple febrile seizures plus (SFS+)": more than one febrile seizure within 24 hours is usually okay.

This study aimed to investigate whether children with recurrent febrile seizures within a 24-hour period need to be worked up differently from children with simple febrile seizures. Inclusion criteria included the following: (i) children with first seizure cluster between 4 months and 3 years of age, (ii) children who had more than one febrile seizure within 24 hours, and (iii) children who returned to baseline between and after each event. Thirty-two patients met the inclusion criteria over a 3-year period. All patients underwent brain CT and/or MRI and EEG. All head CTs were normal. Two children had abnormal MRI findings - both benign: one is thought to represent postictal changes, and the other one is an incidental arachnoid cyst. Of the 4 abnormal EEGs, one showed epileptiform discharges, while the others showed generalized ictal or postictal features. We propose the term "simple febrile seizures plus (SFS+)" to describe children who have more than one seizure within 24 hours but who are otherwise not different in presentation from children with SFS.

Complex febrile seizures: a practical guide to evaluation and treatment.

Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children. A complex febrile seizure is one with focal onset, one that occurs more than once during a febrile illness, or one that lasts more than 10 to 15 minutes. Confusion still exists on the proper evaluation of a child presenting with a complex febrile seizure. There are ongoing research attempts to determine the link between complex febrile seizures and epilepsy. Further clarification and understanding of this disorder would be of great benefit to primary care providers and child neurologists.

Epileptic encephalopathies (including severe epilepsy syndromes).

Epileptic encephalopathies represent a group of devastating epileptic disorders that appear early in life and are characterized by pharmacoresistant generalized or focal seizures, persistent severe electroencephalography (EEG) abnormalities, and cognitive dysfunction or decline. The ictal and interictal epileptic discharges are age-specific and are the main etiologic factors causing cognitive deterioration. This is most obvious in the idiopathic group. In the symptomatic group, the most common causes are structural, congenital, or acquired and rarely some metabolic disorders. In certain cases, clinical and EEG abnormalities persist and may evolve from one type to another as the child grows older. Various factors trigger and sustain the underlying pathophysiologic process and the ongoing epileptic and epileptiform activity during the most critical periods of brain maturation, perpetuating their deleterious effect on the brain. Immune-mediated mechanisms may have a role, suggested by certain encephalopathies responding to immune-modulating treatments and by the finding of various autoimmune antibodies. The chance of a better cognitive outcome improves with early diagnosis and treatment that is appropriate and effective. Current antiepileptic drugs are, in general, not effective: we urgently need new trials in this very special epileptic category. This article briefly reviews the most common epileptic encephalopathies and analyzes the most important clinical issues.

Genetic epilepsy with febrile seizures plus: definite and borderline phenotypes.

Generalised epilepsy with febrile seizures plus (GEFS+) is the most studied familial epilepsy syndrome. However, characteristics of UK families have not previously been reported. Among the first 80 families recruited to our families study, four broad subphenotypes were identified: families with classical GEFS+; families with borderline GEFS+; families with unclassified epilepsy; and families with an alternative syndromal diagnosis. Borderline GEFS+ families shared many characteristics of classical GEFS+ families-such as prominent febrile seizures plus and early onset febrile seizures-but included more adults with focal epilepsies (rather than the idiopathic generalised epilepsies predominating in GEFS+) and double the prevalence of migraine. Thus the authors believe that a novel and robust familial epilepsy phenotype has been identified. Subcategorising families with epilepsy is helpful in targeting both clinical and research resources. Most families with GEFS+ have no identified causal mutation, and so predicting genetic homogeneity by identifying endophenotypes becomes more important.

AERRPS, DESC, NORSE, FIRES: multi-labeling or distinct epileptic entities?

In this review, we report a case of an adolescent girl presenting with epileptic encephalopathy preceded by febrile illness, demarcate the clinical phenotypic homogeneity among previously reported cases, and hypothesize on potential mechanisms based on current experimental evidence. Our literature review revealed >249 cases that share several main features: febrile illness with no preceding condition, negative laboratory studies including cerebrospinal fluid (CSF) analysis, status epilepticus refractory to conventional pharmacotherapy, and long-term developmental delays. This condition appears to have many names, the most recent of which is "FIRES" (fever-induced refractory epileptic encephalopathy). It seems likely that the described cases are representing the same entity. The possibility of a genetic or acquired channelopathy can be raised in light of negative infectious, autoimmune, microscopic, and gross pathology findings.

Evaluation and management of pediatric febrile seizures in the emergency department.

Febrile seizures are common in children, who are often brought to the nearest emergency department (ED). Patients who meet the case definition of simple febrile seizure are not at higher risk for serious bacterial illness than clinically similar febrile children who have not experienced a convulsion. Children who have had complex febrile seizures must be evaluated on a case-by-case basis, and treated with diagnostic and therapeutic measures based on the differential diagnosis. Round-the-clock prophylactic administration of antipyretics has not been demonstrated to affect recurrence of simple febrile seizure. Parents should be informed that recurrence is common, and that these convulsions are benign with an excellent prognosis. Care-givers should be informed that the risk of developing epilepsy after a simple febrile seizure is low, but that complex febrile seizures carry a significantly higher risk.

Febrile seizures.

Febrile seizures are the most common form of childhood seizures occurring in 2 to 5% of children in the United States. Most febrile seizures are considered simple, although those with focal onset, prolonged duration or that occur more than once within the same febrile illness are considered complex. Risk factors for a first febrile seizure, recurrence of febrile seizures and development of future epilepsy are identifiable and varied. Children with febrile seizures encounter little risk of mortality and morbidity and have no association with any detectable brain damage. Recurrence is possible, but only a small minority will go on to develop epilepsy. Although anti-epileptic drugs can prevent recurrent febrile seizures, they do not alter the risk of subsequent epilepsy. This has led to a changing view of how we approach the treatment of these common and largely benign seizures.