Stress and childhood epilepsy

Epilepsy is very common in childhood. Seven out of every 1000 children is
diagnosed with epilepsy. Stress is one of the most frequently self-reported
provocations of seizures in children with epilepsy. Animal studies showed that
in animals with epilepsy, stress hormones influence the susceptibility to
seizures. The underlying mechanism of stress-sensitivity of seizures in
childhood epilepsy is unknown.

We hypothesise that in children with stress-sensitive seizures, stress hormone
regulation is altered compared to children whose seizures are not sensitive to
stress and healthy controls; and that stress sensitivity of seizures is related
to hippocampal function as well as genetic background. More knowledge of the
relation between stress and childhood epilepsy will lead to better counselling
of children with epilepsy and their parents on how to deal with stressful
situations, and may provide directions for the development of new treatment
strategies.

The overall aim of this project is to elucidate the interaction between stress
and epileptic seizures in childhood epilepsy. The specific aim of this study is
to compare the possible differences in stress hormone regulation, hippocampal
function and genetic background between children with stress sensitive
seizures, children without stress sensitive seizures and healthy controls.

Prospective observational explorative study without invasive measurements

The burden for participating children consists of completing a six-week diary,
two questionnaires for children 11-17 years of age, one testing day and 4
saliva samples at home. For parents, the burden consists of helping the child
with the diary and saliva samples, accompanying the child at the testing day
(one parent), and four to six questionnaires for both parents.
The burden of keeping this diary is expected to be minor, as most parents of
children with epilepsy already keep a diary of seizures. The testing day will
take approximately 3 hours and 15 minutes, in which study participants undergo
the Trier Social Stress Test for Children (TSST-C). During this test, heart
rate and blood pressure will be monitored. This is non invasive, but blood
pressure measurement can cause an unpleasant tight feeling around the upper
arm. At nine time points, saliva samples will be obtained by chewing on a
cotton swab. This is non invasive, but the child may find the taste
objectionable. The code of conduct related to expressions of objection by
minors participating in medical research, as stated by the CCMO, will be
followed. Participants are asked to perform two tasks, comparable to a school
examination. The evoked moderate psychosocial stress response is of comparable
intensity to stressful situations experienced in daily life, with the advantage
that the stress response can be measured in a controlled setting (this test was
previously used in study 08/271, *Long-term effects of neonatal glucocorticoid
treatment on health in later life (follow-up study)*). For this reason, the
risk of provoking seizures, even in patients with stress sensitive seizures, is
not expected to be increased compared to the everyday situation. As two-thirds
of the study population consists of children with active epilepsy, it is
possible that the test will coincidence with a seizure. Although these seizures
could also happen while being at home, extra medical safety is expected because
the experiments take place in a study environment. For this reason, children of
whom parents report a prolonged or life threatening seizure in response to
acute stress are excluded. During the TSST-C a parent/caregiver of the child
will be waiting nearby, so that anti-epileptic medication can be administered
by the parent if necessary. Also, a general physician will be present during
the total duration of the TSST-C.
The four saliva samples at home will be taken by children themselves or with
assistance from their parents, with the same cotton swabs used during the
TSST-C. This will take 45 seconds at three mornings just after awakening and at
one evening. For this procedure, the same considerations apply as mentioned
above. The parental questionnaires take 10 minutes per parent to complete, the
questionnaire about life events also takes 10 minutes to complete.

We believe that using these precautionary measures, the risks of this study are
negligible. Because this study will include children below 12 year of age, the
risks will be upgraded to *minimally exceeding the negligible risk*.

The study population consists of children instead of adults because the
research main question about the difference in stress response between children
with and without stress sensitive seizures can not be answered studying an
adult population. Hormonal stress response is age dependent and characteristics
of paediatric epilepsy differ from epilepsy in adults. Overall, children with
epilepsy have a high seizure frequency compared to adults. Also, children are
more sensitive to seizure precipitating factors. We therefore expect results in
adults to differ from results in children.
By participating in this study, children and their parents will contribute to
improvement of the current knowledge of the pathogenesis of stress sensitive
seizures. We aim to improve counselling children with epilepsy as well as their
parents and school teachers on how to deal with stressful situations, and
desirably will also provide a foundation for the development of new treatment
strategies for children with stress sensitive seizures.