Chronic Stress as a Causal Contributor to Epilepsy: How Years of Hypothalamic–Pituitary–Adrenal Acti

Abstract
Stress is the most frequently reported seizure precipitant among people living with epilepsy, but the more consequential question is whether stress sustained over years participates in the development of epilepsy itself. This paper argues that chronic stress lasting five or more years is a causal contributor to epileptogenesis rather than an incidental correlate. Evidence from cellular neuroscience, animal models, and population studies converges on a coherent causal pathway: prolonged hypothalamic–pituitary–adrenal axis activation delivers sustained corticosteroid and corticotropin-releasing hormone signalling to the hippocampus and amygdala, which remodels dendritic architecture, suppresses dentate gyrus neurogenesis, depletes the neurosteroids that positively modulate GABA-A receptors, and primes a microglial inflammatory response that increases blood–brain barrier permeability. Each change shifts the excitation–inhibition balance toward hyperexcitability, and together they resemble the circuit reorganization that defines epileptogenesis. The paper further argues that chronic stress is a uniquely problematic risk factor: unlike a head injury or a stroke, it is cumulative rather than discrete, it is reinforced by epilepsy itself, and it remains largely unaddressed in routine epilepsy care despite being modifiable. Limitations of the causal claim: reverse causation, the confound of functional seizures, reliance on self-report, and the modest effect sizes observed in human cohorts are examined directly.

Keywords: chronic stress, epileptogenesis, hypothalamic–pituitary–adrenal axis, hippocampus, neuroinflammation, seizure threshold