Elsevier

Physiology & Behavior

Volume 166, 1 November 2016, Pages 22-31
Physiology & Behavior

Review
Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy

https://doi.org/10.1016/j.physbeh.2016.05.015Get rights and content

Highlights

  • Stress is a commonly reported seizure-trigger

  • Stress-related psychopathologies are highly comorbid with TLE

  • The HPA axis is hyperactive in TLE

  • The structural integrity of limbic stress-regulatory regions is compromised in TLE

  • HPA axis dysfunction may result from aberrant connectivity of limbic structures

Abstract

Epilepsy is a common neurological disease, affecting 2.4 million people in the US. Among the many different forms of the disease, temporal lobe epilepsy (TLE) is one of the most frequent in adults. Recent studies indicate the presence of a hyperactive hypothalamopituitary- adrenocortical (HPA) axis and elevated levels of glucocorticoids in TLE patients. Moreover, in these patients, stress is a commonly reported trigger of seizures, and stress-related psychopathologies, including depression and anxiety, are highly prevalent. Elevated glucocorticoids have been implicated in the development of stress-related psychopathologies. Similarly, excess glucocorticoids have been found to increase neuronal excitability, epileptiform activity and seizure susceptibility. Thus, patients with TLE may generate abnormal stress responses that both facilitate ictal discharges and increase vulnerability for the development of comorbid psychopathologies. Here, we will examine the evidence that the HPA axis is disrupted in TLE, consider potential mechanisms by which this might occur, and discuss the implications of HPA dysfunction for seizuretriggering and psychiatric comorbidities.

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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