Abstract
Epilepsy is one of the most common chronic diseases in childhood, characterized by the enduring predisposition to generate epileptic seizures. Children with epilepsy and their parents often report seizures precipitated by stress. In order to increase our understanding of the pathophysiological mechanisms underlying the effects of stress on seizures in
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childhood epilepsy, we performed a variety of studies, which are described in this thesis.
In part I we evaluate the extent of stress sensitivity of seizures in childhood epilepsy and its associations with patient and disease characteristics. We show that stress sensitivity of seizures is reported in half of children with epilepsy and pertains to seizures precipitated by acute stress and an increase in seizure frequency during periods of stress. Stress sensitivity of seizures is more common in children who report a larger number of experienced negative life-events, suggesting a mediating role of stress hormone regulation. The association between acute stress-precipitated seizures and lowered thresholds for sensory stimulation suggests that sensory overload also contributes to stress sensitivity of seizures. Additional support for the association between stress and seizures is found using a ‘big data’ approach, where a country specific increase in epilepsy search behavior on the Internet (an indirect estimate of seizure incidence) is observed during a national festivity for children.
Part II focuses on the hormonal base of stress sensitivity of seizures. By exposing children with epilepsy and healthy controls to a standardized acute psychosocial stressor, we demonstrate an altered biological stress response in children with stress-sensitive seizures, with a decreased cortisol response to stress compared with children without stress-sensitive seizures and controls. In a systematic review of literature, we show similarities between seizure occurrence and the circadian rhythm of cortisol, with a sharp rise in the early morning and a state of quiescence at night. By simultaneous electroencephalographic and cortisol monitoring in adult patients with focal epilepsy, a positive association is revealed between cortisol levels and interictal epileptiform EEG activity, especially in patients with self-reported stress sensitivity of seizures. These results confirm the hypothesized relation between stress hormone levels and seizure-susceptibility.
In part III the effects of stress and stress hormones on epileptogenesis are evaluated in a mice model of experimental febrile seizures. Two weeks after induction of epileptogenesis, little morphological alterations are observed in animals not repetitively exposed to stress or stress hormones. However, after corticosteroid or mild stress exposure, epileptogenesis is associated with a lower number of immature cells, increased cell proliferation, and increased dendritic length and spine density in the dentate gyrus, while functional glutamatergic transmission is not affected. The increase in morphological changes during epileptogenesis after corticosterone and mild stress exposure supports the hypothesis that early-life stress stimulates epileptogenesis.
In conclusion, we investigated the effects of stress on epilepsy with a variety of approaches. We show that the effect of stress on seizures relates to early-life stress exposure, sensory modulation and hormonal regulation, and that stress and stress hormones aggravate epileptogenesis. These studies provide a first step towards elucidating the mechanisms underlying the relation between stress and epilepsy.
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