Neuropsychiatric Symptoms of Epilepsy

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C.M. Galtrey and H.R. Cock
Stress Increases the Excitability of Brain Activity
As discussed previously, stress may act as an insult of itself, and lower the seizure
threshold and promote hyperexcitability via a range of mechanisms, rendering the
brain more susceptible to unprovoked seizures, or at risk of more severe or frequent
seizures (and their consequences) in the event of an additional insult (see Fig.
15.3a,b ). There is evidence of HPA axis dysfunction with epilepsy in rodent models
with acutely provoked (kindled) seizures [ 61 , 68 – 71 ] as well as in clinical studies of
status epilepticus [ 72 – 74 ], although antiepileptic drug treatment is a potential confounder
in all the clinical studies. What is less clear, there is something inherently
different about the HPA axis regulation in people who go on to develop epilepsy, or
if having seizures and epilepsy is stressful leading to secondary HPA axis dysfunction,
or both. It is possible the hippocampus normally acts to shut off the HPA axis
but excessive exposure to glucocorticoids can cause the hippocampus to shrink,
disinhibiting the HPA axis and resulting in a vicious cycle of unopposed allostatic
load. Functional imaging studies in humans are starting to try unlock the link and
causality between the cortical and physiologic responses to acute stress and the
relationship between seizure control in epilepsy and both the HPA axis and fMRI
signal reactivity [ 75 ], though, have a long way to go. Stress has been postulated to
be of particular importance in patients with temporal lobe epilepsy, in which context
Fig. 15.3 Putative mechanisms underlying relationship between stress and epilepsy. Dashed black
line seizure threshold in “normal” brain, Solid black line seizure threshold in brain with epilepsy,
gray line brain activity fluctuations, arrows seizures occur. ( a ) Normal brain and stable epilepsy:
It is possible to trigger seizures in a “normal” brain only with extreme physiological challenge
(e.g., hypoxia, hypoglycemia, mechanical insults; acute symptomatic seizures, not shown). In a
person with epilepsy, seizures occur at a lower threshold and are by definition unprovoked, though
may be triggered at this lower threshold by lesser events, which may include stress. ( b )
Epileptogenesis: After brain insult (e.g., neurodevelopmental, genetic, traumatic, stroke, infectious,
or prolonged seizures) a process of epileptogenesis begins by which the previously normal
brain is functionally altered and biased towards the generation of the abnormal electrical activity.
This can take a variable period of time from days to years. At some point an individual’s seizure
threshold reaches the level at which unprovoked (± triggers) spontaneous recurrent seizures occur,
i.e., the threshold defining epilepsy. The individual seizure threshold may continue to decrease
after the onset of epilepsy, as shown, or may stabilize, which may vary between individuals. ( c ) (i)
Early life stress lowers the starting threshold: Early life stress may create a vulnerable phenotype,
meaning they start with a lower than normal seizure threshold, such that on a subsequent epileptogenic
insult it will reach the epileptic threshold, with unprovoked seizures sooner. (ii) Early life
stress disregulates stress response: Early life stress has minimal effect on the background threshold,
but alters the HPA axis so that background and/or stress responses, and their effects on brain
activity are exaggerated resulting in seizures. ( d ) (i) Chronic stress accelerates epileptogenesis:
Chronic stress accelerates the process of epileptogenesis so that following an epileptogenic insult
the epilepsy threshold is reached sooner in the time course and earlier seizures occur. (ii) Chronic
stress increases brain activity: Increases in background brain activity during periods of chronic
stress result in seizures being triggered more readily, including by fluctuations that would not
previously have been ictogenic