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Comment & Response
March 16, 2020

Limited Clinical Application and Concerns of Bias in Long-term Risk of Epilepsy, Psychiatric Disorders, and Mortality Following Febrile Seizures

Author Affiliations
  • 1Department of Pediatrics and Adolescent Medicine, Randers Regional Hospital, Randers, Denmark
  • 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  • 3Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
JAMA Pediatr. Published online March 16, 2020. doi:10.1001/jamapediatrics.2020.0190

To the Editor In the 2019 December issue of JAMA Pediatrics, Dreier et al1 reported on the long-term risk of epilepsy, psychiatric disorders, and mortality following febrile seizures. This large register-based study reports a 22.7% cumulative risk of recurrent febrile seizures after the first seizure and an increased risk of epilepsy and psychiatric disorders, increasing with additional hospital admissions of febrile seizures. These results require a comment.

In the Danish registries, all types of febrile seizures are registered with the same diagnostic code. However, in the clinical setting, a simple and a complex febrile seizure can easily be distinguished and the 2 types carry different risks of long-term outcomes.2,3 Consequently, the reported register-based risks cannot be applied to a clinical situation of neither simple nor complex febrile seizures.

Moreover, it is essential to the definition of a febrile seizure that the seizures are not associated with a preexisting abnormality of the brain.4 The authors appropriately exclude some preexisting conditions such as cerebral palsy. However, children with metabolic disorders, developmental disorders, and congenital malformations/syndromes, all associated with brain abnormalities, were not excluded.

Another potential source of bias relates to the failure to register all cases of febrile seizures. According to a validation study5 of the used register, 28.5% are not recorded or admitted. If admitted, the Danish national standard is to educate the parents on the management of recurrences at home. In our clinical, pediatric experience, admissions with recurrent febrile seizures mainly represent febrile status epilepticus and/or underlying complicating condition (eg, developmental or epileptic syndromes such as Dravet syndrome).

Moreover, the authors considered any psychiatric disorder within F00-F99 (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) as an outcome. This definition includes intellectual disability (F70-F79) and Rett Syndrome (F84.2), likely to represent preexisting abnormalities of the brain.

In summary, the lack of a distinction between complex and simple seizures makes the application of the results limited in a clinical setting. Moreover, we find the study by Dreier et al1 is likely to be subject to bias. The authors describe the reported risks associated with recurrent febrile seizures as conservative. We believe the risks have been overestimated owing to underlying neurologic conditions, complex febrile seizures, and the fact that recurring, simple, febrile seizures are managed outside the hospital setting.

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Article Information

Corresponding Author: Jakob Bie Granild-Jensen, MD, Child and Youth, Randers Regional Hospital, Oestervangsvej 54, Randers NE 8930, Denmark (jakgra@rm.dk).

Published Online: March 16, 2020. doi:10.1001/jamapediatrics.2020.0190

Dreier  JW, Li  J, Sun  Y, Christensen  J.  Evaluation of long-term risk of epilepsy, psychiatric disorders, and mortality among children with recurrent febrile seizures: a national cohort study in Denmark.  JAMA Pediatr. 2019;173(12):1164-1170. doi:10.1001/jamapediatrics.2019.3343PubMedGoogle ScholarCrossref
Sapir  D, Leitner  Y, Harel  S, Kramer  U.  Unprovoked seizures after complex febrile convulsions.  Brain Dev. 2000;22(8):484-486. doi:10.1016/S0387-7604(00)00187-XPubMedGoogle ScholarCrossref
Knudsen  FU.  Febrile seizures: treatment and prognosis.  Epilepsia. 2000;41(1):2-9. doi:10.1111/j.1528-1157.2000.tb01497.xPubMedGoogle ScholarCrossref
Capovilla  G, Mastrangelo  M, Romeo  A, Vigevano  F.  Recommendations for the management of “febrile seizures”: Ad hoc Task Force of LICE Guidelines Commission.  Epilepsia. 2009;50(suppl 1):2-6. doi:10.1111/j.1528-1167.2008.01963.xPubMedGoogle ScholarCrossref
Vestergaard  M, Obel  C, Henriksen  TB,  et al.  The Danish National Hospital Register is a valuable study base for epidemiologic research in febrile seizures.  J Clin Epidemiol. 2006;59(1):61-66. doi:10.1016/j.jclinepi.2005.05.008PubMedGoogle ScholarCrossref