Neuropsychiatric Symptoms of Epilepsy

15 Stress and Epilepsy
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when it is excessive or prolonged the cost of reinstating homeostasis becomes too
high leading to “allosteric load” [ 39 ]. This inappropriate stress response produces a
vulnerable phenotype and leaves genetically predisposed individuals and increased
risk of chronic disease affecting the cardiovascular system, the immune system, and
the brain [ 32 ]. This general model also appears broadly true for stress and seizures,
though as we shall go on to outline in animal models the effect of acute stress on
seizures depends on type of stressors and circuits involved.
Acute Stress and Seizures
Even in one brain region, in a single model, the consequences of an acute stress
reaction can vary. For example acute stress, via CRH and ACTH initially has a
largely pro-convulsant effect on CA1/CA3 excitation in the hippocampus. However,
enhanced calcium influx several hours later protects against further excessive activity
but is associated with a higher risk of neuronal injury if activation does occur. In
contrast, increased corticosteroid levels in the dentate gyrus have less effect on
activity, or calcium influx, but can enhance inhibition via effects on GABA receptors
and be mostly anticonvulsant at least in the short term [ 40 ]. This complexity,
together huge variation in the species, seizure triggers, stressors, and outcome studied
in the basic science literature probably accounts for similarly varied results and
conclusions, as reviewed by [ 41 ]. As they detail, the largest group of experiments is
in rodent models exposed to swim stress creating both physical and psychological
stress. If the seizures were induced by a GABA-A antagonist (e.g., picrotoxin, bicuculline,
pentylenetetrazol) acute stress was anticonvulsive, but exacerbated electroconvulsive
shock seizures, and had no effect on different various other models (e.g.,
kainite, strychnine, glycine, and acetylcholine antagonist or 4-aminopyridineinduced
seizures). The anticonvulsant effects are most likely mediated via neuroactive
steroids acting at GABA-A receptors increasing inhibition and decreasing
seizure activity [ 42 , 43 ]. Supporting this, changes in GABA-A subunit expression
have been demonstrated following acute stress [ 44 ]. Thus overall in terms of acute
stress, such studies demonstrate a range of putative pro- and anticonvulsant mechanisms,
but are of little use beyond that in terms of understanding the interaction
between stress and seizures in man. As Sawyer and Escayg [ 41 ] point out however,
the increasing availability of genetically modified mice carrying human epilepsy
mutations, or mutations in stress pathway genes provide an opportunity to examine
this relationship in a more direct manner in the future.
Chronic Stress and Seizures
The results of animal models of chronic stress consistently demonstrate that chronic
stress increases seizures [ 40 ]. Studies in different rodent models consistently show
that increasing corticosterone (equivalent to cortisol in man) by exogenous