Is There a Link Between Chronic Stress, Autonomic Dysregulation, and Glaucomatous Progression?

Glaucoma is an optic neuropathy characterized by progressive retinal ganglion cell death and is the leading cause of irreversible blindness worldwide.¹ Although the exact causes of the disease have yet to be elucidated, its pathophysiology is currently explained by (1) the mechanical theory and (2) the vascular theory. The mechanical theory contends that elevated IOP is a modifiable risk factor that leads to compression of the optic nerve fiber bundle, resulting in retinal ganglion cell degeneration.¹ The vascular theory holds that optic nerve damage results from ischemia to the optic nerve head (ONH).²

Attention has also been paid to the role of the autonomic nervous system (ANS), specifically dysregulation of the ANS, and its effect on ONH perfusion. This article considers the role of chronic stress in glaucomatous progression.

THE ANS AND THE EYE

The ANS is composed of the sympathetic nervous system (SNS), which stimulates the body’s fight-or-flight response, and the parasympathetic nervous system (PNS), which regulates the body’s rest-and-digest activity. In the eye, parasympathetic innervation increases choroidal blood flow and decreases aqueous humor production, whereas sympathetic innervation decreases choroidal blood flow and increases aqueous humor production.^2,3 When the ANS functions improperly, specifically via dysregulation with sympathetic predominance, the SNS may cause overconstriction of the blood vessels supplying the ONH; this compromises nutrition and perfusion, resulting in glaucomatous damage.² It has been shown that glaucomatous eyes exhibit blood flow abnormalities in the vessels of the ONH and choroid, evidence supporting the relationship between the vascular theory of glaucoma and autonomic dysregulation.²

Researchers have sought to link autonomic dysregulation and glaucoma by measuring markers of autonomic response, such as heart rate variability (HRV) and cold provocation test (CPT) outcomes.^2,4 HRV is an indicator of autonomic dysfunction with sympathetic predominance. Recent studies found that lower HRV in patients with primary open-angle glaucoma or normal-tension glaucoma was associated with faster rates of central visual field loss and retinal nerve fiber layer thinning.^2,4,5 In another study, patients with normal-tension glaucoma had a more pronounced ANS activation in response to the CPT than patients with high-tension glaucoma.²

MODIFIABLE RISK FACTORS OF AUTONOMIC DYSFUNCTION

Research detailing the association between autonomic dysfunction and glaucomatous progression raises the question of how patients develop autonomic dysfunction. Glaucoma, specifically primary open-angle glaucoma, has a range of risk factors encompassing nonmodifiable and modifiable risk factors. Nonmodifiable risk factors include older age, race, a family history of glaucoma, a large cup-to-disc ratio, thin central cornea thickness, chronic systemic hypertension, and chronic systemic hypotension.^6,7 For years, IOP was considered the only modifiable risk factor.^6,7 An emerging modifiable risk factor may be chronic stress, with stress defined as a state of thwarted homeostasis following exposure to extrinsic or intrinsic adverse forces.⁸

Two major pathways are activated when a person is stressed: the hypothalamic-pituitary-adrenal axis (resulting in increased serum cortisol levels) and the ANS.^6,7 In someone with chronic stress, the SNS continues to be activated without the opposition of the PNS, and an ANS imbalance develops.⁶ Both acute and chronic stress can cause IOP elevation, which is a risk factor for glaucomatous progression.^7,8 Cortisol increases IOP by altering the trabecular meshwork morphology and reducing aqueous humor outflow; this may be considered an endogenous steroid-response effect on the angle because an exogenous steroid response–mediated ocular hypertension from medication is well documented in the ophthalmic literature.^7,11-14 Chronic stress can also lead to arterial remodeling, endothelial dysfunction, an increased demand for tissue oxygenation, and vascular dysregulation of the microcirculation to the eye.^4,8

When evaluating a patient, glaucoma specialists typically consider a variety of clinical markers, including IOP, central corneal thickness, corneal hysteresis, pupillary block status, and systemic history such as uncontrolled chronic hypertension. Uncertainty, fear, stress, and anxiety can all activate the ANS and hypothalamic-pituitary-adrenal axis. Physicians as a whole have become more attuned to the notion that patients can experience long-term stress after exposure to difficult situations such as, but not limited to, grief after the loss of a loved one and a stressful work environment or home situation.

A small randomized controlled trial evaluated the effect of slow, deep breathing on patients with open-angle glaucoma (n = 80).⁷ Those in the intervention group used the 365 breathing technique, which involves three daily sessions of six breath cycles (5-second inhalation, 5-second exhalation) per minute for 5 minutes. Investigators measured the technique’s effect on IOP, autonomic functions, and stress biomarkers. At the 6-week follow-up visit, patients in the intervention group exhibited a significant decrease in serum cortisol and IOP and an increase in parasympathetic reactivity compared with the control group.⁷ In autonomic dysfunction, there is a blunting of the PNS; this study demonstrated that slow, deep breathing over an extended period could improve parasympathetic reactivity and thus ANS homeostasis to improve stress and IOP.⁷ It has been suggested that deep breathing lowers IOP by decreasing serum cortisol, which has been shown to reduce IOP, and increasing parasympathetic activity, leading to increased aqueous outflow and decreased IOP.⁷

CONCLUSION

Given the possibility of elevated IOP and compromised choroidal blood flow due to autonomic dysregulation or chronic stress, it may be worthwhile to ask patients regularly about chronic emotional stressors and discuss how stress can negatively influence glaucomatous vision loss. It is important to note that chronic stress may not be the reason a patient’s glaucoma is progressing; nonetheless, it is worth considering as a modifiable risk factor if the disease is still progressing despite stable IOP and secondary optic neuropathies have been ruled out. Moreover, amenable patients who have confirmed experiencing chronic stress may benefit from a suggestion that they meditate with deep breathing. This suggestion, however, should be given within the context of continued screenings, follow-up visits, imaging, perimetry, pharmacotherapy, and, if indicated, laser treatment or surgery.