ReviewHypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy
Introduction
Temporal lobe epilepsy (TLE) is the most prevalent form of epilepsy in adults, often with high rates of pharmacoresistance [1]. To date, there are no FDA-approved therapies or interventions to cure or prevent TLE. Epilepsy is a paroxysmal disorder, with the defining feature (seizures) occurring with little to no warning. Unpredictable seizures make many normal activities, like driving a car or holding down certain jobs, impossible [2]. Stress is repeatedly reported as one of the most common seizure triggers in patients with an epilepsy diagnosis, including TLE [3], [4], [5], [6], [7], [8], [9]. Understanding the molecular mechanisms underlying this association may allow clinicians to predict seizure episodes and/or mitigate their disruptive effect. A second unmet need for TLE patients is a better understanding of, and treatments for, the high incidence of comorbid stress-related psychopathologies, such as depression and anxiety [10], [11], [12], [13], [14].
Increased activity of the hypothalamo-pituitary-adrenocortical (HPA) axis is hypothesized to link core epilepsy symptoms and associated stress-related psychopathologies [15], [16], [17]. The relationship may be bidirectional [18], [19]. Therefore, HPA axis dysfunction in TLE may be a common etiological mechanism underlying stress-evoked seizures and stress-related psychopathologies. The purpose of this review is to 1) summarize the basic functions of the HPA axis, 2) discuss the current evidence that this system is disrupted in TLE, 3) consider potential mechanisms by which the HPA axis is damaged in rodent models of TLE and 4) discuss the implications of HPA axis dysfunction in humans for seizure triggering and psychiatric comorbidities.
Section snippets
The HPA axis stress response and the importance of temporal lobe structures in its regulation
The physiological response to stress is highly conserved throughout vertebrate phylogeny. The HPA axis stress response allows individuals to adapt and cope when faced with real or perceived threats of physical or emotional significance. Upon exposure to stress, neurons in the paraventricular nucleus of the hypothalamus release corticotrophin releasing hormone (CRH), which travels through the hypophyseal portal system to cause release of adrenocorticotrophic hormone (ACTH) from the anterior
HPA axis dysfunction in TLE
To date, studies examining the causal relationship between HPA axis dysfunction and epilepsy are limited. To continue exploring this relationship, it is important to consider four complexities that obscure the causal relationship between HPA axis function and epilepsy. Firstly, injuries that precipitate the development of epilepsy can also directly disrupt HPA axis function (3.1). Secondly, single seizures acutely alter HPA function (3.2). Thirdly, chronic recurrent seizures (epilepsy) may
Excess glucocorticoids may compromise the structural and functional integrity of limbic regions
Persistent exposure to excess levels of glucocorticoids can physically change the structure and function of neurons located in key stress-regulatory limbic regions, including the hippocampus and prefrontal cortex [113], [114], [115], [116]. These changes have been hypothesized to increase vulnerability to injury [117], which could be particularly relevant in the context of epilepsy.
The hippocampus contains a high density of glucocorticoid receptors (GR and MR) [118] and is thought to be
Implications of HPA axis dysfunction in TLE
The data discussed in this review suggest that HPA axis hyperactivity is present in TLE. Although more studies are needed to understand the mechanisms by which HPA axis dysfunction develops, we hypothesize that damage to temporal lobe structures, either as a result of an initial epileptogenic injury and/or as a consequence of recurrent ictal activity, may contribute to aberrant top-down regulation of HPA axis activity. Damage would ultimately result in the hypersecretion of stress hormones
Conclusion
The relationship between stress, seizures and comorbid psychopathology in epilepsy is highly complex. Here, we briefly discuss some evidence that suggests that HPA axis hyperactivity may act as a common physiological mechanism underlying both stress as a precipitant of seizures and the high incidence of comorbid psychiatric illness in TLE. In our proposed model (Fig. 2), the initial epileptogenic injury (i.e. the first seizure, brain trauma, hypoxia/ischemia) leads to neuronal damage
Conflict of interest
ACW is supported by NINDSF30-NS-095578 and T32-GM-063483. MBS has funding from K12-HD-051953. MDP receives research support from Eisai (HRA1970A) and UCB (NO1199). He has served on data safety monitoring boards for Upsher Smith and Astellas. SCD receives funding from NINDS grants NS-062806 and NS-065020. JPH is supported by MH-049698 and MH-101729. NIH and other funding agencies had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of
Contributions
ACW wrote the manuscript and created all tables and figures. All other authors participated in the editing process.
Acknowledgements
We would like to thank Katja Jylkka M.A. for helpful editing of the manuscript
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University of Cincinnati, Department of Psychiatry and Behavioral Neuroscience, 2170 E. Galbraith Rd. Bldg A. Room 145, Cincinnati OH 45237-0506.