Monday, July 8, 2019

A history of recurrent febrile seizures was associated with a high risk of epilepsy and mental illness

Recurrent febrile seizures in children are associated with a higher risk of psychiatric disorders and epilepsy in later life, new research shows.

Danish investigators found the 30-year risk of epilepsy and psychiatric disorders in children who had three or more febrile seizures was 15% and 30%, respectively. In comparison, the risk of mental illness and epilepsy in unaffected individuals is 2% and 17%, respectively.

"These findings are very important since both epilepsy and psychiatric disorders may have a major impact on the quality of life in affected individuals and their families, and because these disorders are associated with great societal costs," study investigator Julie Werenberg Dreier, PhD, postdoc, National Center for Register-based Research, Aarhus Univerity, Denmark, told Medscape Medical News.

The study also showed that mortality is increased in patients with recurrent febrile seizures who go on to develop epilepsy. 

The findings were presented here at the Congress of the European Academy of Neurology (EAN) 2019.

Stepwise Increased Risk

Febrile seizures are relatively common in childhood, affecting an estimated 3% to 4% of children. In general, such seizures are considered benign. However, children who have one episode are likely to have recurrent seizures.

Previous studies have not been large enough to investigate the long-term consequences of recurrent febrile seizures, said Dreier. From the relevant Danish registries, she and her research team identified a cohort of 2.1 million singleton children born between 1977 and 2011. Of these, 75,593 (3.6%) were diagnosed with a febrile seizure for the first time. 

Using a graph to illustrate ages of first hospital admission for febrile seizures, Dreier demonstrated that the incidence rapidly increases starting at about 6 months of age, peaks at about age 16 months, then declines. At about age 3 years, "90% of all the children with febrile seizures will have presented," she said.

Investigators defined three subpopulations of children with febrile seizures and no previous diagnosis of epilepsy, cerebral palsy, intracranial tumors, severe head trauma or intracranial infections. These subpopulations included children who had experienced at least one febrile seizure; those who had experienced at least two; and those who experienced at least three.

The risk of recurrence before age 5 years in children who had one febrile seizure was 22.7%. This risk increased with each additional febrile seizure.

From other national registries, the investigators collected data on epilepsy and psychiatric disorders. They used competing risk regression to estimate cumulative incidences, and Cox regression to arrive at hazard ratios (HRs) for risk of onset of these disorders at various ages depending on the number of febrile seizures.

The cumulative incidence of epilepsy over a 30-year follow-up period started at 2% at birth. For every febrile seizure, there was a stepwise increase in the risk of epilepsy, so for children with three or more febrile seizures, the 30-year cumulative incidence was just over 15%.

The researchers found that children with one febrile seizure had a sevenfold increased risk of an epilepsy diagnosis before 5 years of age (HR, 7.11). However, if the child had three or more febrile seizures, the risk was elevated 42-fold (HR, 42.06).

Looking at admissions for psychiatric disorders, the researchers found that the 30-year risk at birth was about 17%. Here again, there was a stepwise increase with each additional febrile seizure. In the subgroup with three or more febrile seizures, the risk approached 30%. 

Dreier noted that when looking at the broad spectrum of psychiatric disorders associated with febrile seizures, the "most pronounced" were psychotic disorders including schizophrenia.

The researchers wanted to know if the association between febrile seizures and psychiatric disorders could be explained by comorbid epilepsy. After adjusting for epilepsy, "the association was somewhat attenuated but was still significant," said Dreier. "So epilepsy can't explain the entire pattern that we see."

Researchers also collected mortality data from the national death registry. They found increased mortality in children with recurrent febrile seizures, but after adjusting for epilepsy, "this association completely disappears," said Dreier. 

"This suggests that there's only an increased mortality in children with recurrent febrile seizures who later develop epilepsy," she said.

It is unclear whether the associations uncovered by the study were directly related to the seizures themselves or were as a result of some common underlying conditions, such as genetic susceptibility, said Dreier.

Interesting Research

Commenting on the study following the presentation, session co-chair Marte-Helene Bjørk, PhD, associate professor, University of Bergen, Norway, described the study as "very elegant and interesting." 

She speculated that the increased risk of psychiatric disorders may be an effect of febrile seizures on the temporal lobe.

"It could be a direct effect of the seizures, but it's also possible that it might be some genetic confounding that could increase the risk of febrile seizures as well as the risk of psychiatric disorders," said Dreier.

The second session co-chair, Hanna Cock, MD, professor of epilepsy and medical education, St. George's University Hospital, London, United Kingdom, said parental anxiety may also play a role in the association of febrile seizures with psychiatric disorders.

"There is so much evidence that the social background and parenting in those early months and years is a huge predictor of future psychiatric outcomes," said Cock.

She also wondered if these data may have implications for counseling of families regarding psychiatric risk associated with febrile seizures.  

Long-term consequences of recurrent febrile seizures. J. Dreier1, Y. Sun1, J. Christensen2
1Aarhus University, Aarhus, Denmark, 2Viby, Denmark

Background and aims: We studied the long-term effect of recurrent febrile seizures on the risk of subsequent epilepsy, mental illnesses, and death.

Methods: We carried out a register-based cohort study of all singleton children born in Denmark between 1977 and 2011 (N=2,103,232). Hospital contacts with febrile seizures between 3 months and 5 years of age of all cohort members were identified using the Danish National Patient Register. We used competing risks regression and Cox regression to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, mental illnesses, and death.

Results: A total of 75,593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. The risk of recurrent febrile seizures was 22.7% after the first febrile seizure, 35.6% after the second febrile seizure, and 43.5% after the third febrile seizure. The risk of epilepsy increased progressively with the number of admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% at birth compared with 15.8% after the third febrile seizure, while the corresponding estimates for risk of mental illnesses were 17.2% and 29.1%, respectively. Mortality was increased among children with recurrent febrile seizures, although this risk was driven by children who later developed epilepsy. 

Conclusion: A history of recurrent febrile seizures was associated with a high risk of epilepsy and mental illness, but increased mortality was found only in individuals who later developed epilepsy.

Disclosure: This study was supported by the Novo Nordisk Foundation (grant number: NNF16OC0019126), the Central Denmark Region, and the Danish Epilepsy Associationsk associated with febrile seizures.  

Congress of the European Academy of Neurology (EAN) 2019. Abstract #O3219. Presented July 1, 2019.

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