Abstracts

The impact of febrile seizures on the developing brain is not well known. Observational studies indicate that febrile seizures are benign, but neuroimaging studies have demonstrated acute swelling and edema of the hippocampus after prolonged febrile seizures, and experiments on animals suggest that prolonged febrile seizures may cause long-lasting modifications of channels, synapses, and neuronal networks within the hippocampus leading to sustained dysfunction of these cells. The hippocampus may play an important role in the development of schizophrenia. Post mortem examinations and neuroimaging studies have shown that the volume of the hippocampus is reduced in people with schizophrenia. The reduced size of the hippocampus is present at the onset of the symptoms indicating that it is not caused by the disease or its treatment. Thus, febrile seizures may increase the susceptibility to schizophrenia.
We conducted a cohort study of all persons born in Denmark between January 1977 and December 1986, who were followed from their 15th birthday until onset of schizophrenia, death, emigration, or December 31, 2001, whichever came first. The cohort was established by means of data from the Danish Civil Registration System. We obtained information on febrile seizures, epilepsy, and schizophrenia by linking the cohort with the two national registries: the National Hospital Register and the Psychiatric Central Register.
We followed 558,958 persons for 2.8 million person-years and identified 952 persons who were diagnosed with schizophrenia. We found that febrile seizures were associated with a 44% increased risk of schizophrenia (adjusted relative risk, 1.44; 95 percent confidence interval, 1.07 to 1.95) after adjusting for various potential confounding factors such as age, sex, degree of urbanization at birth, and history of mental illness in a parent or sibling. The association between febrile seizures and schizophrenia was neither confounded nor modified by a history of epilepsy prior to the onset of schizophrenia. We found no increased risk of schizophrenia among siblings of children with febrile seizures (adjusted relative risk, 1.03; 95 percent confidence interval, 0.72 to 1.47) as compared with siblings of children without a history of febrile seizures.
To our knowledge, we are the first to show an association between febrile seizures and schizophrenia. Our cohort study was based on data from nationwide registries, which provided virtually complete follow-up. The association may be due to a damaging effect of prolonged febrile seizures on the developing brain or to confounding by unmeasured factors. The absolute risk of schizophrenia after febrile seizures was small.
[Supported by: The Stanley Medical research Institute and the Danish Research Agency (j.no: 22-02-0207). The Danish National Research Foundation funds the activities of the Danish Epidemiology Science Centre and the National Centre for Register-based Research.]