Nearly 30 to 40 percent of all normal adults, and almost all primary open-angle glaucoma patients are steroid responders,1 demonstrating clinically significant elevated intraocular pressures following corticosteroid use. It’s important to intervene early in the course of steroid-induced glaucoma to prevent irreversible optic neuropathy and vision loss. This condition can be tricky to treat in patients who require continued steroid therapy for underlying conditions. 

Though it’s considered a form of open-angle glaucoma, steroid-induced glaucoma has a different pathophysiology from primary open-angle glaucoma. 

Here, I’ll discuss why these two diseases may require different management approaches. 


Risk Factors for a Steroid Response

Key risk factors for a steroid response include high myopia, type 1 diabetes mellitus, connective tissue disorders (e.g., rheumatoid arthritis), pigment dispersion, traumatic angle recession,2 primary open-angle glaucoma, prior penetrating keratoplasty, the duration of steroid therapy and the steroid’s anti-inflammatory potency.

Age is also a risk factor. Children have a strong intraocular pressure response to topical steroids,3 and younger patients (under 10 years old) are at the greatest risk for steroid-induced glaucoma. This glaucoma subtype accounts for about a quarter of all acquired glaucoma in children.4

The risk for steroid-induced glaucoma is partially influenced by the site of administration. In general, the closer to the center of the eye, the greater the risk. The steroid’s anti-inflammatory potency and the duration of steroid therapy also play a role.


Route of Administration

As a general rule of thumb, the closer to the center of the eye the steroid is administered, the greater the risk. So, for example, steroid response risk is very low with intra-articular joint and intranasal administration and increases with inhaled, oral, intravenous, topical, periocular and intraocular administration.

  • A meta-analysis on intranasal corticosteroids (484 studies with 10 RCT) reported a relative risk of 2.24 (95% CI, 0.68 to 7.34 percent) compared with placebo.5 The absolute increase in incidence of elevated intraocular pressure was 0.8 percent (95% CI, 0 to 1.6 percent) compared with placebo in non-glaucomatous individuals—a risk of less than 1 percent. 
  • A single case report described elevated intraocular pressure with inhaled steroids in a young child.6 
  • The risk with systemic administration of steroids varies, but it’s been reported to be low, ranging from less than 1 percent to 10 percent.7
  • About 3 to 4 percent of patients treated with topical difluprednate experience a significant IOP increase >10 mmHg above baseline to 21 mmHg or more.8-9 Steroid-induced IOP responses after corneal transplantation are also well documented.10-11 Steroids are readily absorbed by the thin skin of the eyelids and around the eyes—anecdotally, many ophthalmologists have heard of a physician self-treating with a steroid face cream who comes in with pressures of 40 mmHg and massive vision loss. 
  • Periocular administration carries a significantly greater risk of steroid response compared with topical steroids.12 The sub-Tenon’s route has a significantly high risk, likely due to its proximity to the anterior chamber angle.13 A multicenter study of individuals treated with cortisone for uveitis demonstrated a 35-percent incidence of IOP elevation >24 mmHg.14
  • For intravitreal administration, there’s a reported 12- to 15-percent risk of a >10-mmHg IOP rise after Ozurdex (dexamethasone), and an up to 50-percent risk with intravitreal triamcinolone acetonide.15


Two Unique Pathophysiologies

Though they share a mechanism of increased aqueous outflow resistance, steroid-induced glaucoma and primary open-angle glaucoma aren’t the same disease. Unlike primary open-angle glaucoma, steroid-induced glaucoma typically resolves spontaneously once steroids are discontinued. Based on their respective pathophysiologies, different approaches to treatment may be warranted.

• Primary open-angle glaucoma. The mechanism of primary open-angle glaucoma involves an increase of transforming growth factor beta-2 (TGFB2), which causes dysregulation of the extracellular matrix within the juxtacanalicular trabecular meshwork.

Another probable mechanism of this glaucoma subtype may be decreased trabecular meshwork cellularity.16 However, this mechanism has been observed only in cadaver eyes that were medically treated and/or had previously undergone surgery, not in untreated trabecular meshwork tissue. So, it’s unclear whether decreased cellularity was the result of the disease itself or its treatment. Another challenge with this theory is that the rate of cellularity decline is the same for non-glaucomatous eyes. If decreased cellularity were disease pathophysiology, one would expect the rate of cell loss to be greater in glaucomatous eyes.

• Steroid-induced glaucoma. One way steroids increase resistance to outflow by inducing dysregulation of the actin cytoskeleton (cross-linked actin networks [CLANs]). CLANs cause endothelial cellular stiffness and subsequently trigger an IOP increase.17 This has been observed within trabecular meshwork cells in cell cultures, cadaveric organ perfusion and in live mice. Very limited evidence suggests CLAN formation may also play a role in primary open-angle glaucoma pathophysiology, but the mechanism hasn’t been observed in untreated trabecular meshwork tissue.

In addition to CLAN formation, steroid-induced glaucoma involves dysregulation of the extracellular matrix, but this dysregulation is markedly different from that of primary open-angle glaucoma when seen on electron microscopy. Steroid-induced glaucoma exhibits more extracellular matrix accumulation in the juxtacanalicular region, as well as increases in curly collagen 6 and inhibition of matrix metalloproteinase enzymes from increasing levels of TIMPs. Additionally, a buildup of fine fibrillar material resembling fingerprints occurs, along with collagen IV, heparin sulfate, fibronectin, and an increase in other matrix proteins such as decorin, myocilin, fibrillin and secreted frizzle-related protein. 


Medical Management

Discontinue steroids first, if possible. If the patient has been on steroid therapy for more than 18 months, IOP elevation may last for several weeks.18 Topical steroids can be switched to a lower potency. Then, start a prostaglandin analog—either topical or sustained release bimatoprost.

I recommend trying a rho kinase inhibitor sooner, rather than following the usual stepping pattern after a prostaglandin analog to the medications that decrease aqueous, because the rho kinase inhibitor mechanism of action potentially targets the pathophysiology of steroid-induced glaucoma. 

Rho kinase inhibitors affect the actin cytoskeleton by disrupting the actin stress fibers and focal adhesions in trabecular meshwork cells.19-20 In a steroid-induced OHT mouse model study published earlier this year (n=56), morphological changes (extracellular matrix accumulation) and reduced trabecular meshwork effective filtration area induced by dexamethasone were partially reversed after one week of treatment with a rho kinase inhibitor (p<0.05) or five-week discontinuation of dexamethasone (p<0.01).21 This correlated with reduced IOP. IOP reductions were greater in rho kinase inhibitor-treated eyes than eyes that discontinued dexamethasone treatment.

Prostaglandin analogs should remain the first-line treatment, however, because they impact MMPs and TIMPs, targeting another part of steroid-induced glaucoma’s pathophysiology. These drugs shift the MMP/TIMP balance in the ciliary body and the trabecular meshwork toward greater turnover of extracellular matrix.22-29


Selective Laser Trabeculoplasty

It’s unclear whether there are any meaningful differences between primary open-angle glaucoma and steroid-induced glaucoma with regard to SLT success. A retrospective study reported a 72-percent SLT success rate (≥20 percent reduction from baseline IOP) in 25 eyes with steroid-induced glaucoma.30 

Another retrospective study (n=608 eyes) reported that steroid-induced glaucoma patients did better with SLT than primary open-angle (p=0.005) or pseudoexfoliation (p=0.01) glaucoma patients, but a significantly higher baseline IOP for steroid-induced glaucoma eyes may have been a confounder.31 

In the same study, the two-year failure rate for steroid-induced glaucoma patients was 54-percent failure, compared with 84 percent (p=0.01) for pseudoexfoliation glaucoma and 84 percent for primary open-angle glaucoma (p=0.005). 


Surgical Management

There’s a paucity of literature specifically comparing the efficacy of our incisional surgical procedures in POAG versus steroid-induced glaucoma. 

• Goniotomy. A retrospective study of steroid-induced glaucoma versus primary open-angle glaucoma using Trabectome found no difference in the survival curve.32 A greater IOP response was seen in the steroid-induced eyes, but they also had a much higher baseline IOP—a problem with retrospective cohort comparisons.

The incidence of steroid response after either Trabectome or iStent goniotomy is about 12 percent.33 Greater axial length, low-tension glaucoma and traumatic glaucoma were risk factors for steroid response after goniotomy. In eyes with axial length >25 mm, the incidence was 40 percent.

• GATT. A retrospective chart review of 13 patients demonstrated that GATT was effective for steroid-induced glaucoma,34 which isn’t surprising. GATT resulted in a significant IOP reduction at all postop visits, with all patients experiencing IOP reduction >20 percent at two years. The number of glaucoma medications also decreased significantly from an average of 3.1 medications preoperatively to 0.8 medications at the last follow-up. 

Another retrospective chart review of 46 eyes reported that GATT was effective for short-duration steroid-induced glaucoma.35 IOP decreased from mean 30.8 ±8.3 mmHg at baseline to 11.2 ±2.6 mmHg after one to two years (n=28). At the final follow-up, 45 eyes had IOP <21 mmHg and 39 eyes had IOP <18 mmHg with or without medication. Steroid response wasn’t seen in any eyes after surgery. A few other case reports have reported GATT efficacy.36-37

In conclusion, SLT and incisional procedures have comparable efficacies in steroid-induced glaucoma and primary open-angle glaucoma. Anecdotally, I’ve observed that trabeculectomies do better if the depot steroid remains in the eye. For medical management, I recommend using a prostaglandin analog as a first-line agent because these drugs alter the MMP/TIMP balance and can reduce the buildup of extracellular matrix. Consider using a rho kinase inhibitor as a second-line agent after the prostaglandin analog because this drug class directly affects CLANs.

Dr. Rhee is a professor and chair of the Department of Ophthalmology and Visual Sciences at Case Western Reserve University School of Medicine. He is also the director of the Eye Institute, University Hospitals of Cleveland. He receives researching funding from Allergan/Abbvie, Glaukos, Ivantis/Alcon, Cleveland Eye Bank Foundation and Ocular Therapeutix. He is also an ad hoc consultant for Alcon, Allergan, Avellino and Iantrek.

Dr. Singh is a professor of ophthalmology and chief of the Glaucoma Division at Stanford University School of Medicine. He is a consultant to Alcon, Allergan, Santen, Sight Sciences, Glaukos and Ivantis. Dr. Netland is Vernah Scott Moyston Professor and Chair at the University of Virginia in Charlottesville.

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21. Ruiyi R, Humphrey AA, Kopczynski C, Gong H. Rho kinase inhibitor AR-12286 reverses steroid-induced changes in intraocular pressure, effective filtration areas and morphology in mouse eyes. Invest Ophthalmol Vis Sci 2023;64:7.

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37. Hopen ML, Gallardo MJ, Grover DS. Gonioscopy-assisted transluminal trabeculotomy in a pediatric patient with steroid-induced glaucoma. J Glaucoma 2019;28:10:e156-e158.