Repeated febrile convulsions linked to epilepsy and psychiatric disorders — large Danish study

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The risk of febrile convulsions increases with the child’s fever, and approximately 4% of Danish children suffer from febrile convulsions. A study from the Danish National Centre for Register-based Research and the department of clinical medicine at Aarhus University and Aarhus University Hospital now shows an association between repeated febrile convulsions and the risk of epilepsy and psychiatric disorders such as schizophrenia and depression.

The register-based study is based on 2m Danish children born between 1977 and 2011. The researchers have identified health data from approx. 17,000 children with more than a single febrile convulsion. This makes the register-based study the most comprehensive so far to study the long-term consequences of repeated febrile convulsions.

“Though previous research has documented an increased occurrence of epilepsy among children with febrile convulsions, this is still one of the first studies to demonstrate such a convincing correlation between febrile convulsions and psychiatric disorders. Not least due to the size of the study, the long period of time that the study covers and the valid Danish data,” says the study’s lead author, postdoc Julie Werenberg Dreyer from the National Centre for Register-based Research.

The researcher emphasises that although the study demonstrates a clear correlation, this is not the same as concluding that febrile convulsions in themselves cause epilepsy or psychiatric disorders.

“A statistical correlation does not necessarily mean that one thing causes the other and that it is the febrile convulsions themselves which have a damaging effect on the brain. But the study’s results are so significant that looking into this more closely is more than relevant when it comes to possibly being able to provide the best possible prevention and treatment,” says Dreier.

According to Dreier, a future study could look into the significance of genetics for the child’s risk of suffering febrile convulsions and subsequent epilepsy or psychiatric disorders.

“There are still many unknown factors that we don’t know enough about. As we learn more about the importance of genes for health and disease, it may be that it is here we will find an explanation for why some children suffer repeated febrile convulsions and then later in life also develop epilepsy and psychiatric disorders,” she says.

The study shows that among children who have three or more attacks of febrile convulsions, the risk of developing epilepsy within thirty years is approximately 15%. The risk of a psychiatric disorder that requires treatment is approximately 30%. In comparison, children without prior febrile convulsions have a risk of developing epilepsy of approximately 2% and children without prior febrile convulsions have a seventeen per cent risk of developing a psychiatric disorder.

The study points towards new correlations that can in the long-term improve the possibilities of prevention and treatment of patients with epilepsy and psychiatric disorders. This is according to another of the project contributors, Jakob Christensen. He is a clinical associate professor at Aarhus University and consultant at the department of neurology at Aarhus University Hospital. He has conducted intensive research into epilepsy over many years.

“Both epilepsy and psychiatric disorder can be extremely serious and associated with high morbidity and mortality — so in this way the diseases have major consequences for both the individual patient, their family and society,” says Christensen.

Both researchers hope that the study will help to provide impetus for an intensified effort to clarify the cause of the correlation between the febrile convulsions and the long-term consequences.

“Our results may be frightening reading for parents who have a child that suffers from repeated attacks of febrile convulsions. But these are families who are already deeply concerned about their children. The new knowledge can help them and healthcare professionals to be extra aware of these children’s health and development,” says Dreier.

Abstract
Importance: Febrile seizures occur in 2% to 5% of children between the ages of 3 months and 5 years. Many affected children experience recurrent febrile seizures. However, little is known about the association between recurrent febrile seizures and subsequent prognosis.
Objective: To estimate the risk of recurrent febrile seizures and whether there is an association over long-term follow-up between recurrent febrile seizures and epilepsy, psychiatric disorders, and death in a large, nationwide, population-based cohort in Denmark.
Design, Setting, and Participants: This population-based cohort study evaluated data from all singleton children born in Denmark between January 1, 1977, and December 31, 2011, who were identified through the Danish Civil Registration System. Children born in Denmark who were alive and residing in Denmark at age 3 months were included (N = 2 103 232). The study was conducted from September 1, 2017, to June 1, 2019.
Exposures: Hospital contacts with children who developed febrile seizures between age 3 months and 5 years.

Main Outcomes and Measures: Children diagnosed with epilepsy were identified in the Danish National Patient Register and children diagnosed with psychiatric disorders were identified in the Psychiatric Central Research Register. Competing risk regression and Cox proportional hazards regression were used to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, psychiatric disorders, and death.
Results: Of the 2 103 232 children (1 024 049 [48.7%] girls) in the study population, a total of 75 593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. Febrile seizures were more common in boys (3.9%; 95% CI, 3.9%-4.0%) than in girls (3.3%; 95% CI, 3.2%-3.3%), corresponding to a 21% relative risk difference (hazard ratio, 1.21; 95% CI, 1.19-1.22). However, the risks of recurrent febrile seizures, epilepsy, psychiatric disorders, and death were similar in boys and girls. The risk of (recurrent) febrile seizures increased with the number of febrile seizures: 3.6% at birth, 22.7% (95% CI, 22.4%-23.0%) after the first febrile seizure, 35.6% (95% CI, (34.9%-36.3%) after the second febrile seizure, and 43.5% (95% CI, (42.3%-44.7%) after the third febrile seizure. The risk of epilepsy increased progressively with the number of hospital admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% (95% CI, (2.1%-2.2%) at birth compared with 15.8% (95% CI, 14.6%-16.9%) after the third febrile seizure, while the corresponding estimates for risk of psychiatric disorders were 17.2% (95% CI, 17.2%-17.3%) at birth and 29.1% (95% CI, 27.2%-31.0%) after the third febrile seizure. Mortality was increased among children with recurrent febrile seizures (1.0%; 95% CI, 0.9%-1.0% at birth vs 1.9%; 95% CI, 1.4%-2.7% after the third febrile seizure), although this risk was associated primarily with children who later developed epilepsy.
Conclusions and Relevance: A history of recurrent febrile seizures appears to be associated with a risk of epilepsy and psychiatric disorders, but increased mortality was found only in individuals who later developed epilepsy.

Authors
Julie Werenberg Dreier, Yuelian Sun, Jakob Christensen

Aarhus University material JAMA Neurology abstract

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