Corticosteroids can increase intraocular pressure regardless of potency, dose, or route of administration. This drug-induced intraocular pressure elevation and the resulting visual impairment are called steroid-induced glaucoma. It is classified as secondary (acquired) open-angle glaucoma1)2)7).
Steroid-induced glaucoma can occur not only with eye drops, ointments, subconjunctival injections, sub-Tenon injections, and intravitreal injections, but also with any route of administration, including nasal sprays, inhalants, topical skin preparations, oral medications, and intravenous injections2)6)7). Patients themselves are often unaware of steroid use, so careful history taking is necessary to avoid missing this information.
The risk of intraocular pressure elevation depends on the chemical structure (potency) of the steroid, daily dose, frequency of administration, duration of treatment, and route of administration 2)6). The stronger the anti-inflammatory effect, the greater the intraocular pressure-elevating effect, in the order: dexamethasone ≥ betamethasone > fluorometholone. Intraocular pressure elevation usually occurs 2 to 6 weeks after starting steroids, but can occur at any time depending on the administration conditions 2)7).
There is significant individual variation in intraocular pressure response to steroids, and patients who show an increase in intraocular pressure are called steroid responders. In classic studies by Armaly and Becker in the general population, after 4 to 6 weeks of 0.1% dexamethasone eye drops, approximately 5% showed a high intraocular pressure elevation of 15 mmHg or more from baseline, about 30% were moderate responders with an elevation of 6 to 15 mmHg, and about 65% were non-responders with an elevation of 5 mmHg or less 11)12). On the other hand, in patients with primary open-angle glaucoma (POAG) or those with first-degree relatives with POAG, the proportion of high responders has been reported to reach 92% 4)7).
Responder tendency is particularly pronounced in children and young adults 2)9). In pediatric cases, even short-term, low-dose steroid eye drops can cause a steep rise in intraocular pressure, requiring careful monitoring. It is also known that responsiveness increases in the elderly, and in both age groups, it is necessary to establish a system for intraocular pressure measurement before starting steroids.
Steroids are used as eye drops in many ophthalmic conditions (allergic conjunctivitis, vernal keratoconjunctivitis, anterior uveitis, scleritis, after corneal transplantation, after intraocular surgery, corneal epitheliopathy associated with dry eye, etc.). They are also administered as intravitreal injections or posterior sub-Tenon injections for uveitis, macular edema, age-related macular degeneration (resistant to anti-VEGF therapy), diabetic macular edema, and retinal vein occlusion. Therefore, the opportunity for developing steroid-induced glaucoma is not rare 6)9).
QWhat is a steroid responder?
A
Patients whose intraocular pressure (IOP) rises in response to corticosteroid administration are called steroid responders. In the classic classification, based on the IOP elevation after 4–6 weeks of 0.1% dexamethasone eye drops, they are divided into high responders (IOP rise ≥15 mmHg, about 5% of the general population), moderate responders (6–15 mmHg, about 30%), and non-responders (≤5 mmHg, about 65%) 11)12). The proportion of high responders is significantly higher among patients with primary open-angle glaucoma and their first-degree relatives 4). Children are particularly sensitive to steroids, and even short-term use can cause severe IOP elevation. Steroid responsiveness is thought to involve genetic predisposition, and pharmacogenomic studies on GPR158 and HCG22 are ongoing 10).
The clinical course is similar to that of primary open-angle glaucoma. In the early stages, subjective symptoms such as eye pain, redness, and decreased visual acuity are often absent, and many patients first notice visual impairment or visual field narrowing only after visual field defects have progressed 1)2). In cases with a rapid increase in intraocular pressure, eye pain, headache, blurred vision, and colored halos around lights may occur.
Elevated intraocular pressure is the main finding. The angle is open, and characteristic features include the absence of angle abnormalities such as peripheral anterior synechiae (PAS), angle pigmentation, or neovascularization1)2). When elevated intraocular pressure persists for a long time, it can lead to enlargement of the optic disc cupping, retinal nerve fiber layer defects, and corresponding visual field defects (glaucomatous optic neuropathy) such as Bjerrum scotoma, nasal step, and arcuate scotoma.
A history of steroid administration and the absence of other conditions that cause elevated intraocular pressure (such as uveitis, exfoliation syndrome, pigment dispersion syndrome, or neovascular glaucoma) strongly suggest this condition. If intraocular pressure normalizes after discontinuation of steroids, the diagnosis is confirmed 1)2).
Triamcinolone approximately 50%, persists for 9 to 12 months13)
Systemic administration (oral, intravenous)
3–6 weeks
Dose-dependent
Onset with long-term administration
Intranasal, inhalation, topical
Several months or later
Rare
Difficult to recognize
For eye drops, higher-potency steroids carry a greater risk of elevated intraocular pressure. The intraocular pressure-elevating effect of the drug is proportional to its anti-inflammatory effect and is dose-dependent6)7). They are generally classified as high-potency (dexamethasone 0.1%, betamethasone 0.1%, difluprednate 0.05%), medium-potency (prednisolone 1%), and low-potency (fluorometholone 0.1%, loteprednol etabonate 0.5%).
Intravitreal injection of triamcinolone acetonide 4 mg causes elevated intraocular pressure in more than 50% of cases, but surgical intervention is required in only 1–2%13). Intraocular pressure elevation due to triamcinolone may persist for 9 to 12 months, requiring long-term management6).
With intravitreal steroid sustained-release implants, intraocular pressure must be monitored for several weeks to months after administration. The risk varies depending on the type of drug, number of injections, and presence of pre-existing glaucoma.
In recent years, cases involving intravitreal injection or posterior sub-Tenon injection of triamcinolone have increased. With posterior sub-Tenon injection, the drug remains in the sub-Tenon space for three months; if elevated intraocular pressure occurs, physically removing the visible triamcinolone from the conjunctival side may sometimes achieve intraocular pressure control. Elevated intraocular pressure due to systemic absorption from inhalants, nasal sprays, or topical skin preparations has also been reported, albeit rarely, and follow-up is necessary regardless of the route of administration2)7).
Additionally, in patients who have long-term use of nasal steroids for allergic conjunctivitis or hay fever, inhaled steroids for bronchial asthma, or continuous use of steroid ointments on the face for atopic dermatitis, this condition should be suspected based on medication history during ophthalmologic visits 7)9). Particularly in children, increased intraocular pressure has been reported with long-term use of inhaled steroids, and regular ophthalmic screening is recommended 9).
Primary Open-Angle Glaucoma (POAG): Patients with existing POAG have significantly high steroid responsiveness, with the proportion of high responders reaching 92% 4)7)
First-degree relatives of POAG patients: Having a family history increases the responder rate 4)
Pharmacogenomics: Associations between genetic loci such as GPR158 and HCG22 and steroid responsiveness are being studied 10)
High myopia: High sensitivity to intraocular pressure elevation and a high frequency of glaucoma complications 4)
Type 1 diabetes: An association with steroid responsiveness has been reported 7)8)
Other Risk Factors
Children and the elderly: In children especially, steroid responsiveness is pronounced, and even short-term administration can cause severe intraocular pressure elevation9)
Connective tissue diseases: Risk associated with long-term systemic steroid use
After full-thickness corneal transplantation: High risk in eyes with corneal endothelial degeneration or keratoconus
History of steroid-induced ocular hypertension: Previous response is an indicator of future risk
During uveitis treatment: Difficult to differentiate from inflammatory glaucoma1)
QWhich route of steroid administration carries the highest risk?
A
Intravitreal administration carries the highest risk of intraocular pressure elevation. With intravitreal triamcinolone injection, intraocular pressure elevation occurs in over 50% of cases, and approximately 1–2% require surgical intervention 13). Next highest risk is periocular administration such as sub-Tenon injection and retrobulbar injection, followed by eye drops. Even with eye drops, long-term use of high-potency steroids (dexamethasone 0.1%, difluprednate 0.05%) carries a high risk of intraocular pressure elevation. Systemic administration (oral, intravenous) and non-ocular topical administration (nasal spray, inhalation, skin application) can also cause intraocular pressure elevation, so monitoring is important regardless of the route, especially 2–6 weeks after initiation 2)7)8).
For the diagnosis of steroid-induced glaucoma, a detailed history is most important. A thorough history including systemic diseases should be taken to comprehensively check for steroid use. Items to confirm include ophthalmic eye drops, eye ointments, subconjunctival injections, sub-Tenon injections, intravitreal injections, as well as systemic steroid use such as oral, intravenous, inhalation, nasal spray, skin application, and intra-articular injections 1)2)9).
Diagnostic criteria: This condition is diagnosed when all of the following are met 1)2)7).
History of steroid use
Open angle with no angle abnormalities (peripheral anterior synechiae, neovascularization, pigment deposition, exfoliation material, etc.) on gonioscopy
Other conditions causing intraocular pressure elevation have been excluded
Intraocular pressure normalizes after discontinuation or reduction of steroids
The time to normalization of intraocular pressure is usually proportional to the duration of steroid administration. In cases of intravitreal triamcinolone injection, elevated intraocular pressure may persist for approximately 9 to 12 months6)13). With long-term use, trabecular meshwork tissue changes may become irreversible, and intraocular pressure may not normalize even after steroid discontinuation.
Steroid challenge test: As a method to assess intraocular pressure responsiveness in advance, 0.1% dexamethasone eye drops can be administered 3 to 4 times daily for 4 weeks to observe intraocular pressure changes. However, even if negative, intraocular pressure elevation may occur depending on administration conditions, and it can essentially happen in anyone11)12).
Gonioscopy: Confirmation of open angle and no angle abnormalities
Visual field testing: Detection of glaucomatous visual field changes using Humphrey static automated perimetry
Optical coherence tomography (OCT): Evaluation of retinal nerve fiber layer thickness (RNFL), peripapillary and macular ganglion cell complex (GCC)
Fundus examination: Observation of optic disc cupping enlargement and nerve fiber layer defects
Differential diagnosis: When steroids are used for uveitis treatment, differentiation from uveitic glaucoma is the most important issue 1). Since uveitis itself can cause intraocular pressure elevation due to trabecular meshwork obstruction by inflammatory products, formation of peripheral anterior synechiae, and scarring from chronic inflammation, cases where both conditions coexist are not uncommon 1). If inflammation recurs and intraocular pressure rises when steroids are reduced, uveitic glaucoma is more likely; if intraocular pressure decreases with steroid reduction, it suggests steroid-induced glaucoma.
Other conditions requiring differentiation include exfoliation glaucoma (exfoliative material deposition on the pupillary margin and lens surface), pigmentary glaucoma (pigment dispersion from the posterior iris surface and Krukenberg spindle), neovascular glaucoma (angle neovascularization and peripheral anterior synechiae), and primary open-angle glaucoma (no history of steroid use). In pediatric cases, differentiation from primary congenital glaucoma and juvenile open-angle glaucoma is necessary, and corneal diameter, axial length, corneal edema, and the presence of Haab striae should be assessed.
The first choice of treatment is reduction or discontinuation of steroids 1)2)6). If complete discontinuation is difficult due to the underlying disease, the following stepwise approach should be taken.
Switch to a low-potency steroid: Consider switching to 0.1% fluorometholone ophthalmic solution (Flumetholon®, Fluorometholone®) four times daily 2)7). Fluorometholone has moderate anti-inflammatory effects and weak intraocular pressure-elevating effects, making it useful for controlling mild to moderate anterior segment inflammation.
Steroid-sparing therapy: If systemic steroids are being administered, consider reducing steroids by using immunosuppressants or biologics in collaboration with the department treating the underlying disease14).
Intraocular pressure-lowering medications are used according to the same principles as for primary open-angle glaucoma1)4). The following are combined as appropriate.
Prostaglandin analogs (latanoprost 0.005%, travoprost 0.004%, tafluprost 0.0015% once daily): Increase uveoscleral outflow, expected to lower intraocular pressure by 25–33%4)
Alpha-2 agonists (0.1% brimonidine 2–3 times daily)
ROCK (Rho kinase) inhibitors (0.4% ripasudil twice daily): Directly act on the cytoskeleton of trabecular meshwork cells, expected to improve function of the trabecular outflow pathway. High affinity with the disease mechanism
Oral: Acetazolamide 250 mg 2–4 times daily (short-term use; electrolyte and renal function monitoring required)
Hyperosmotic agent infusion: Emergency treatment for acute intraocular pressure elevation
In cases where intraocular pressure elevation due to triamcinolone injection is confirmed with residual triamcinolone mass in the vitreous cavity or under the Tenon capsule, physical removal of the mass may be effective 6). Residual drug in the vitreous cavity is removed by anterior vitrectomy, and drug under the Tenon capsule is removed by mass excision through conjunctival incision. It has been reported that even removing only the triamcinolone visible from the conjunctival side can lower intraocular pressure.
If intraocular pressure is poorly controlled with medication and visual function is progressively deteriorating, and a decrease in intraocular pressure cannot be awaited through steroid reduction or discontinuation, surgical treatment should be considered 1)6). For steroid-induced glaucoma, since the trabecular meshwork is the main cause of aqueous outflow resistance, outflow reconstruction surgery is particularly effective.
Outflow Reconstruction Surgery (First Choice)
Trabeculotomy: Particularly effective for steroid-induced glaucoma 1). The Japan Glaucoma Society Guidelines for Glaucoma, 5th edition, states with evidence level 1B that “a greater intraocular pressure-lowering effect is obtained than for primary open-angle glaucoma” 1).
Surgical options: In addition to the external approach, microhook trabeculotomy, internal approach (Kahook Dual Blade, Trabectome, iStent), etc., are widely performed.
Rationale for first choice: Many patients are young, complications are few, safety is high, postoperative management is easy, and options for future additional surgeries are preserved.
Trabeculectomy: Selected for advanced cases requiring lower postoperative intraocular pressure1). Antimetabolites (mitomycin C 0.02–0.04%) are used concomitantly to increase success rate
Tube shunt surgery: Ahmed valve or Baerveldt implant is indicated for refractory cases and reoperations2)3)
Argon laser synechialysis: Reported as a minimally invasive alternative for internal ostium occlusion (peripheral anterior synechiae formation) after trabeculectomy5)
A case has been reported of a 15-year-old boy with steroid-induced ocular hypertension associated with vernal keratoconjunctivitis, in whom argon laser synechialysis successfully treated bleb dysfunction due to peripheral anterior synechiae after trabeculectomy5). Argon laser treatment can be performed on an outpatient basis under local anesthesia and carries lower risks of bleeding, infection, and surrounding tissue damage compared to reoperation5).
QWill intraocular pressure definitely decrease if steroids are discontinued?
A
Usually, intraocular pressure gradually normalizes after discontinuation of steroids 2)7). The recovery period is generally proportional to the duration of steroid administration, with improvement occurring within days to weeks in many cases. For triamcinolone acetonide intravitreal injections, intraocular pressure elevation may persist for approximately 9 to 12 months 6)13). However, if long-term use has caused irreversible tissue changes in the trabecular meshwork, intraocular pressure may not normalize even after steroid discontinuation. In such cases, outflow reconstruction surgery or filtering surgery is required 1). It is important to check intraocular pressure within two weeks after starting steroids to assess responsiveness early.
The main pathology of steroid-induced glaucoma is increased resistance to aqueous humor outflow in the trabecular meshwork2)6)10). Corticosteroids enhance the production of extracellular matrix (ECM) components by trabecular meshwork cells, reducing the permeability of the aqueous outflow pathway. The increase in ECM components includes fibronectin, type IV collagen, laminin, and myocilin, which deposit in the intercellular spaces of the trabecular meshwork, leading to increased outflow resistance2)10).
Glucocorticoids have significant effects on the cytoskeleton of trabecular meshwork cells. Representative changes are shown in the table below2)6)10).
Molecular change
Action
Result
Increased myocilin (MYOC/TIGR) expression
Extracellular secretion and aggregation
Outflow pathway obstruction
Increased fibronectin
Enhanced ECM deposition
Increased outflow resistance
Cross-linked actin networks (CLANs) formation
Cross-linking of actin cytoskeleton
Trabecular meshwork stiffness
RhoA/ROCK pathway activation
Stress fiber formation
Cell contraction
Decreased MMP expression
Reduced ECM degradation
Accumulation of deposits
Myocilin (MYOC)/TIGR gene: Also called TIGR (trabecular meshwork inducible glucocorticoid response), it is a protein whose expression is induced by steroids2)10). MYOC mutations are known in some cases of primary open-angle glaucoma, but a direct causal relationship with steroid responsiveness has not been established. Recent pharmacogenomics studies suggest that GPR158 and HCG22 may be involved in steroid responder status10).
Cross-linked actin networks (CLANs): These are geodesic dome-like cross-linked structures of actin within trabecular meshwork cells that characteristically appear after steroid exposure. CLAN formation alters the contractility and mechanical properties of trabecular meshwork cells, impairing outflow pathway function10).
Glucocorticoids bind to the nuclear receptors GRα (glucocorticoid receptor α) and GRβ. GRβ acts as a dominant negative inhibitor of GRα and is involved in steroid resistance10). The overlap of ECM changes and cytoskeletal changes in the trabecular meshwork increases aqueous humor outflow resistance.
Recent models have shown changes in Schlemm’s canal endothelial cells via the ALK5 (TGF-β receptor)/VEGFC pathway, and further mechanisms of outflow resistance changes are being studied.
QHow do you differentiate between uveitic glaucoma and steroid-induced glaucoma?
A
A detailed history and careful follow-up are important for differentiation 1). In uveitic glaucoma, inflammatory cells and proteins accumulate in the trabecular meshwork, causing edema of the trabecular lamellae and peripheral anterior synechiae. In contrast, steroid-induced glaucoma is primarily attributed to extracellular matrix changes in the trabecular meshwork (increased myocilin expression, CLAN formation, fibronectin deposition) 10). A reduction in intraocular pressure after tapering or discontinuing steroids suggests steroid-induced glaucoma. Conversely, if inflammation recurs and intraocular pressure rises upon steroid reduction, uveitic glaucoma is more likely. Both conditions may coexist, requiring comprehensive assessment of anterior chamber cells, flare, gonioscopic findings, and fundus inflammatory signs. In cases of active inflammation where differentiation is difficult, outflow reconstruction surgery may be chosen over trabeculectomy1).
Research on steroid-induced glaucoma is advancing in the following areas.
Predictive markers for onset: Quantitative assessment of anterior segment OCT and trabecular meshwork morphology is being studied as a candidate for pre-risk evaluation.
Comparison of intravitreal steroid sustained-release formulations: Dexamethasone 0.7 mg implant and fluocinolone acetonide 0.59 mg implant have different intraocular pressure profiles, aiding risk stratification and treatment selection 13).
Pharmacogenomics: Identification of novel genetic loci such as GPR158 and HCG22 is progressing, and full elucidation of the genetic background of steroid responders is expected 10).
ROCK inhibitors: ROCK inhibitors (ripasudil), which act on the cytoskeleton of trabecular meshwork cells, have high affinity with the molecular pathology of steroid-induced glaucoma and are expanding in clinical application.
Minimally invasive glaucoma surgery (MIGS): Microhook trabeculotomy, Kahook Dual Blade, iStent, etc., are expanding as options for outflow reconstruction surgery, and are becoming positioned as first-line choices due to ease of postoperative management and low complication rates.
Minimally invasive management of postoperative complications: The efficacy of argon laser suture lysis for internal ostium obstruction after trabeculectomy has been reported5).
New low-potency steroids: Development of new steroids with suppressed intraocular pressure elevation (loteprednol etabonate sustained-release formulation, fluorometholone derivatives).
Future challenges include complete elucidation of the genetic background of steroid responders, standardization of optimal monitoring intervals by route of administration, development of new low-potency steroid formulations, and establishment of long-term intraocular pressure management protocols after intravitreal injection. In clinical practice, it is important to obtain sufficient informed consent before starting steroid use and to explain to patients the risk of intraocular pressure elevation and the need for regular examinations. It is also desirable to collaborate with other departments (rheumatology, dermatology, respiratory medicine, otorhinolaryngology) and to institutionalize regular ophthalmologic screening for patients receiving steroids.
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