PART ONE | CHAPTER 2
life stress on epilepsy and epileptogenesis could thus well be mediated by epigenetic mechanisms.
Variation between studies Although the results of the various studies appear to be highly consistent, variations might be caused by differences in the definition of stress, the stress model used (mediators involved, frequency of stress exposure), the applied epilepsy model or subtype, the stage of brain maturation, brain region, sex, species, control condition and/or outcome parameter. Human studies Almost all human studies looking into stress and epileptic seizures found positive correlations between the two. However, we should keep in mind that most human studies were performed retrospectively and depended on subjective interpretation of the definition of stress, as well as cooperation of, and recall by, caregivers and patients. This is reflected in the large range of reported stress sensitivity of seizures in the different questionnaire studies (8-83%). Human research is further complicated by the fact that patients, often non-intentionally, try to find cause-consequence relationships to get grip on their otherwise unpredictable disease, which may lead to overestimation of the reported stress sensitivity of seizures, limiting the reliability of the results. Also, a variety of other factors might contribute to or mediate the effects of stress on epilepsy, such as lack of sleep, medication non-compliance, hyperventilation and consumption of alcohol and drugs (Mattson et al., 1970; Mattson, 1991). It is important to take these factors into account when investigating stress sensitivity of epilepsy. Although patients with infantile spasms have been investigated separately, most human studies included a wide variety of epilepsy patients. As epilepsy is a very heterogeneous disease, the relation between stress and epilepsy might differ for different epilepsy subtypes, for example related to epilepsy syndrome, etiology or age. Moreover, specific characteristics of the stressor, the cumulative stress exposure earlier in life and the genetic vulnerability of the individual could account for the variability. Studies in a controlled environment are difficult to perform in humans, for obvious ethical reasons. Another confounder (in human as well as in animal studies) is the stress inherent to epilepsy itself. This includes chronic stress caused by living with the diagnosis of epilepsy and the risk of often unpredictable seizures, as well as repetitive acute stress caused by experiencing the seizures themselves. Especially in childhood epilepsy, the early life stress caused by seizures and seizure-risk could have severe effects on the developing brain. Distinguishing between this epilepsy-related stress and other epilepsy related variables such as disease duration and seizure frequency seems often impossible, and is usually not taken into account. Animal studies In animal studies, most genetic as well as environmental variation can be controlled for. Using a combination of injections with specific stress hormones or exposure to standardized
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