What Causes Steroid-Induced Glaucoma?

Question submitted by Srinivas Iyengar, MD, second-year resident, Department of Ophthalmology, University of Kansas Medical Center, Kansas City.

One third of the population may experience an increase in IOP in response to the local or systemic use of corticosteroids, but the response varies among individuals.¹ Becker and Mills reported that patients diagnosed with glaucoma or classified as glaucoma suspects experienced increases in IOP in response to chronic exposure to topical corticosteroids.² Specifically, the IOP rose from a mean of 16.9 to 32.1 mm Hg in patients diagnosed with glaucoma, from a mean of 17.1 to 28.3 mm Hg in glaucoma suspects, and from a mean of 13.6 to only 18.2 mm Hg in control subjects without glaucoma. The increase in IOP noted with steroid therapy appears to be dose and time dependent.

Most patients with elevated IOP in steroid-response glaucoma experience a return to pretreatment IOP levels within 10 days to 3 weeks after the discontinuation of steroid therapy.³ Elevated IOP has been linked to various routes (oral, topical, inhaled, and intravitreal) of steroid delivery.^4-9 The recent increase in the use of intravitreal steroid injections for posterior segment conditions has led to a greater incidence of ocular hypertension due to the higher level of localized exposure to steroids.^10,11 These cases are difficult to manage, because the surgeon cannot remove the offending agent without performing a vitrectomy. Fortunately, most of the IOP spikes can be controlled with topical medical therapy alone. Additionally, different steroid preparations are associated with varying degrees of IOP elevation (Table 1).¹²

Although the incidence and natural history of steroid-induced glaucoma are well known, the cause of this phenomenon is not well understood. Various theories exist as to the mechanism of the disease's development at the cellular level.

THEORETICAL CAUSES OF STEROID-INDUCED GLAUCOMA
Extracellular Matrix
Steroids appear to decrease the outflow of aqueous humor by inhibiting the degradation of extracellular matrix material within the trabecular meshwork. A buildup of glycosaminoglycans has been identified in the trabecular meshwork of steroid-responder patients.¹³ The subsequent accumulation of material in the outflow channels eventually produces an increase in IOP.¹⁴ Dexamethasone is known to inhibit the phagocytic abilities of trabecular meshwork cells so that debris accumulates within the drainage channels.^15,16 Although nonspecific, the finding of accumulated material in the trabecular meshwork has been reproducible and appears to support the theory of an atypically regulated extracellular matrix as a cause of rises in IOP.¹⁵

Morphologic changes such as the cross-linking of actin fibers between trabecular meshwork cells have also been reported.¹⁷

Myocilin
The myocilin gene product, known as myocilin or trabecular meshwork-inducible glucocorticoid response (TIGR) protein, is distributed intracellularly as well as in the extracellular matrix of the normal and glaucomatous trabecular meshwork and other ocular tissues.¹⁸ An estimated 3% to 5% of cases of primary open-angle glaucoma have myocilin gene mutations with most of them evident in the olfactomedin domain of exon 3.^19-21 Mutations of this gene appear to produce a dysfunctional secretion of the translated protein in trabecular meshwork cells, leading to decreased aqueous outflow.^22-25 Rozsa and colleagues noted a greater than 100-fold increase in myocilin gene expression along with other changes in gene expression after exposure to dexamethasone.²⁶ They believed that changes in gene expression led to actin and actin-associated proteins' developing cross-links that lead to an alteration of outflow facility.

Kirstein and colleagues found that glucocorticoids did not increase the expression of the gene but rather reduced the in vitro activity of myocilin's promoter.²⁷ These results implied that glucocorticoids may affect myocilin gene expression indirectly or through remotely located receptors not included in this in vitro model. Fingert and colleagues investigated 184 steroid responders and control patients for mutations in the myocilin gene and found no association between variations in myocilin and the steroid response (P>.05).²⁸ More studies are needed to explain the variations in the myocilin gene and whether glucocorticoids contribute to steroid-induced ocular hypertension.

Endothelin
Endothelin-1 (ET-1) is a peptide produced in various tissues, including endothelial and vascular smooth-muscle cells, the nonpigmented ciliary epithelium, neurons, and astrocytes in the central nervous system. ET-1 acts as a modulator of vascular tone, cell proliferation, and hormone production with well-described effects on the ciliary body and trabecular meshwork.²⁹ The exposure of the trabecular meshwork and ciliary body to ET-1 leads to the contraction of tissue as well as the release of nitric oxide with variable effects on IOP. Concentrations of plasma and aqueous humor endothelin are increased in patients with glaucoma.^30-32 Zhang and colleagues found that ET-1 immunoreactivity rose after 24 hours of treatment with dexamethasone. The increase in ET-1 and corresponding unbalanced regulation of ET receptors A and B could lead to dysregulation in the endothelin effect on both the inflow of aqueous and the outflow facility, thus leading to elevated IOP.³³

A follow-up study by Zhang and colleagues investigated the downstream interaction of ET-1 with dexamethasone in human trabecular meshwork cells. They theorized that it might lead to an altered outflow resistance and eventual rise in IOP.³⁴ The researchers postulated that the increase in ET-1 expression from human nonpigmented ciliary epithelium cells coupled with decreased ET-B receptor expression could lead to increased contraction of the trabecular meshwork with accompanying declines in aqueous humor outflow. This idea may, in part, explain the increase in IOP witnessed with glucocorticoid therapy.

HOW TO DEAL WITH LIKELY STEROID RESPONDERS
The first problem in dealing with steroid responders is identifying them. Clinicians must remain vigilant after initiating steroid treatment due to the variable time of onset and severity in IOP responses between patients. IOP spikes may occur hours to weeks after the initiation of steroid therapy.^35-37 The initial step is to rule out other causes for elevated IOP. Because ocular inflammation is often present, it can be difficult to separate out trabeculitis as a cause. If inflammation is suspected to be the cause of the IOP spike and the pressure is not too high (eg, not greater than 30 mm Hg with a healthy optic nerve), intensifying the steroid therapy for a brief period of time may resolve the problem. If this approach does not work, one should try changing to a less potent steroid (eg, fluorometholone 0.1%) or a nonsteroidal anti-inflammatory drug.

When the elevated IOP is more obviously due to steroid therapy, as occurs shortly after an intravitreal injection of triamcinolone for retinal pathology unrelated to glaucoma, the ophthalmologist should make an effort to remove the offending agent. It may take days to weeks for a patient's IOP to return to baseline, and some individuals may require chronic medical or surgical therapy to control their IOP. Up to 3% of steroid responders may have irreversible elevations of IOP.5 If the steroids cannot be discontinued due to the presence of other ocular diseases such as uveitic processes, therapy can involve a switch to a less potent steroid preparation such as fluorometholone 0.1% or rimexolone 1%, which appear to have less effect on IOP.¹²

Once the offending agent is discontinued, the clinician should institute medical glaucoma therapy, including beta-blockers, alpha agonists, and carbonic anhydrase inhibitors (both topical and systemic). Although prostaglandin analogs may not be the physician's first choice, they can be helpful in some situations in which further IOP lowering is required. Laser trabeculoplasty should be considered as a temporizing measure.

If the patient's IOP is very high or remains elevated for a significant period of time, the ophthalmologist must consider surgical intervention. Also, if he anticipates the patient's repeated exposure to steroids, surgery may be in his best interest so that steroids can be used more freely in his therapy. Typically, the surgeon would attempt a trabeculectomy or implantation of a glaucoma drainage device, depending on the prior surgeries that the eye has undergone and the presence of ongoing inflammation.

New therapies are being considered for steroid-induced glaucoma, including the use of a mifepristone (RU 486-6) that is a peripheral progesterone antagonist and has been shown to reduce steroid-induced elevations in IOP in rabbits.³⁸ Topical diclofenac sodium containing a proprietary polymeric drug delivery system (ISV-205) has also been studied for the prevention of IOP spikes in patients taking 1% prednisolone acetate.³⁹ Newer surgical therapies such as canaloplasty and shunts in the suprachoroidal space may find a place in the treatment of this condition as well. o

Section editors Malik Y. Kahook, MD, and Robert J. Noecker, MD, MBA, are in academic glaucoma practice. Dr. Kahook is Assistant Professor of Ophthalmology and Director of Clinical Research in the Department of Ophthalmology at the University of Colorado at Denver & Health Sciences Center. Dr. Noecker is Director of the Glaucoma Service and Associate Professor/Vice Chair at the Department of Ophthalmology at the University of Pittsburgh. They acknowledged no financial interest in the products or companies mentioned herein.

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Fellows and residents are encouraged to submit their questions for consideration. Interested parties should send a question, their name, and their academic affiliation to Dr. Kahook at malik.kahook@uchsc.edu.