Steroid induced glaucoma

Steroid-induced glaucoma affects the trabecular meshwork of the eye, caused by the effects of corticosteroids any of several steroid hormones secreted by the cortex of the adrenal glands, or any synthetic forms with similar properties. With this form of glaucoma, raised intraocular pressure is due to the reduced outflow facility of the pigmented trabecular meshwork and is usually seen within two to four weeks after starting topical steroids (medication applied to the surface of the body).


Introduction
Increased intraocular pressure and glaucoma following corticosteroid therapy are well known issues for the ophthalmologist for more than 50 years. Corticosteroids use has gained popularity in ophthalmology as anti-inflammatory and anti-allergic agents but can have important consequences and should be used only with judicious monitoring. The therapeutic use of corticosteroids can lead to the development of ocular hypertension and iatrogenic open-angle glaucoma in susceptible individuals. It can occur in any age group, either gender and from steroid therapy for any ocular or systemic disease and by any route of administration: topical, systemic or inhaled.

Epidemiology
About one in every three people is considered a potential "steroid responder", but only a small percentage will have a clinically significant elevation in intraocular pressure. 5-6% of the normal population develops a marked increase in intraocular pressure of more than 31 mmHg after 4-6 weeks of topical corticosteroids therapy. 33% are moderate responders (elevation of 6-15 mmHg) and the remaining are considered non responreds (less than 6mmHg of elevation in intraocular pressure). Although approximately 30%-40% of the normal population are "steroid responders" (i.e., develop reversible steroid-induced ocular hypertension), most of primary open angle glaucoma patients or with a family history are steroid responders. Normal individuals who are steroid responders are at higher risk for subsequently developing primary open angle glaucoma. In one study, high corticosteroid responders (intraocular pressure greater than 31 mm Hg during dexamethasone administration qid for 6 weeks), 13.0% developed glaucomatous visual field loss during the follow-up period of 5 years. In steroid induced glaucoma patients, glaucoma is triggered by steroid treatment, and intraocular pressure will not decrease after cessation of steroid application. Thus, steroid induced glaucoma patients necessitate anti-glaucoma medications to control intraocular pressure. Steroid responsiveness appears to be heritable, however low concordance of pressure response in monozygotic twins to topical testing may indicate a limited role for a genetic basis. In addition highly myopic patients and diabetic patients have a higher rate of elevated intraocular pressure response to topical steroids. Age is also an important factor. In pediatric patients taking oral prednisone for inflammatory bowel disease 32% were steroid responders. When children younger than 10 years of age where treated with topical instillation of dexamethasone, marked elevation in 560 intraocular pressure was noted. A dose-dependent hypertensive pressure response occurs more frequently, more severely and more rapidly in children than in adults.

Pathophysiology
There have been reports suggesting that endogenous cortisol may play a role in the pathogenesis of primary open angle glaucoma. Excess endogenous production of glucocorticosteroids (Cushing's syndrome) can also cause increase in intraocular pressure. Glucocorticosteroids alter several trabecular meshwork cellular functions including inhibition of cellular proliferation, migration, phagocytosis, and increased cell and nucleus size. Glucocorticosteroids also increase extracellular matrix synthesis and decrease its turnover. Many mechanisms have been proposed to explain the elevated intraocular pressure in response to glucocorticosteroids. One hypothesis is that glucocorticosteroids protect the lysosomal membrane and thus inhibit release of hydrolases responsible of depolimerization of glycosaminoglycans. Accumulated glycosaminoglycans in the ground substance of the outflow pathways retain water and narrow the trabecular spaces, causing increase in outflow resistance. In steroid-induced glaucoma there is also an increase in fine fibrillar material in the subendothelial region of Schlemm's cannal. These fibrils are deposited underneath the inner wall endothelium. The main finding in steroid-induced glaucoma is an accumulation of basement membrane-like material staining for type IV collagen. These accumulations are found throughout all layers of the trabecular meshwork. There are multiple isoforms of the glucocorticoid receptor (GR) a ligand-dependent transcriptional factor that activates or represses gene transcription. GRα is the ligand binding form of the receptor that is responsible for the physiologic and pharmacological effects of glucocorticosteroids. Most of the physiological and pharmacological effects of glucocorticosteroids are directly mediated by GRα. GRα resides predominantly in the cytoplasm in the absence of ligand as a multiprotein heterocomplex that contains Hsp 90, Hsp 70 and other proteins. Steroid binding to GRα causes a conformation change and activation of the receptor. Activated GRα can alter gene expression via GRE-dependent (classical) and GRE-independent (nonclassical) mechanisms. In the GRE-dependent pathway activated GRα translocates to the nucleus along microtubules. GRα bind to specific palindromic DNA sequence (GRE) as a homodimer on the promoter region of target genes to induce transcription. In addition, GRα functions as a negative regulator of transcription in a specific subset of genes that contains a negative GRE. The GRE-independent pathway is an additional way to inhibit gene expression. GRα physically interacts with other transcription factors to prevent them from binding to their response elements of genes that encode for proinflammatory cytokines. The anti-inflammatory and immune suppression are mediated via this GRE-independent pathway. GRβ is an alternatively spliced form of the receptor, that resides in the nucleus, which lacks the conventional ligand binding domain, does not bind glucocorticosteroids, and acts as a dominant negative regulator of glucocorticosteroids activity. Increased expression of GRβ appears to be responsible for unresponsiveness to anti-inflammatory therapy for asthma, inflammatory bowel disease rheumatoid arthritis and ulcerative colitis. Recent work has shown that glaucomatous trabecular meshwork cells have lower levels of GRβ compared with normal trabecular meshwork cells, and this appears to be responsible for increased glucocorticosteroids sensitivity in the glaucomatous trabecular meshwork cells. In primary open angle glaucoma an abnormal accumulation of dihydrocortisol may potentiate exogenous glucocorticosteroids activity and increased intraocular pressure. Changes in protein synthesis have also been implicated in steroid induced glaucoma. MYOC gene, located on chromosome 1, encodes a secretory glycoprotein of 504 amino acids named Myocilin, and is the first gene to be linked to juvenile open-angle glaucoma and some forms of adult-onset primary open-angle glaucoma. The gene was identified as an up regulated molecule in cultured trabecular meshwork cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (TIGR). Interestingly, the profile of MYOC up regulation by dexamethasone is in a dose-and timedependent manner very similar to the course of development of steroid induced glaucoma. This led many investigators to believe that an increased MYOC level is a cause of glaucoma. However, a putative association between MYOC induction and primary open angle glaucoma has not been firmly established. Glucocorticosteroids inhibit prostaglandin synthesis by trabecular cells. Prostaglandins E 2 and F 2a normal function is to lower the intraocular pressure by increasing the outflow facility. Endothelial cells of the trabecular meshwork can act as phagocytes of debris. Glucocorticosteroids can suppress phagocytic activity causing accumulation of debris in the trabecular meshwork and decrease in outflow facility. In a study on rabbit eyes, after topical treatment with dexamethasone, Transmission electron microscopy showed increased abnormality of nucleus of the trabecular meshwork cells, microfilament and microtubules among interstitial cells also increased, cytoplasmic vacuolation, rough endoplasmic reticulum expansion, as well as an increase in intercellular amorphous material. The mechanism of elevated intraocular pressure is thought to be increased aqueous outflow resistance owing to an accumulation of extracellular matrix material in the trabecular meshwork (fig 1). Effects of Glucocorticosteroids are mediated by the Glucocorticosteroids receptor, which is a ligand-dependent transcription factor altering the expression of trabecular meshwork genes. Glucocorticosteroids increase the expression of extracellular matrix (collagen, fibronectin, laminin), proteinase inhibitor genes (Serpina3) and decreased expression of proteinase genes (MMP1, TPA). Altered expression of cytoskeletal genes (ACTA2, FLNB, and NEBL) may be associated with Glucocorticosteroids mediated reorganization of trabecular meshwork cell microfibrils and microtubules. Glucocorticosteroids reorganizes the actin cytoskeleton to form cross-linked actin networks (CLANs) in cultured trabecular meshwork cells, and is reversible after Glucocorticosteroids withdrawel. In addition Glucocorticosteroids alters microtubules to form microtubule tangles.

Topical route
Topical route includes ocular drops and ointments. Of various routes of administration, topical therapy most commonly induces elevated intraocular pressure and correlates with the duration and frequency of administration. Dexamethasone and prednisolone increase intraocular pressure more frequently than loteprendol (Lotemax), fluorometholone (FML), rimexolone (Vexol) or hydrocortisone. Fluorometholone (FML) in particular is less likely to increase intraocular pressure but is also a less potent steroid (table 1). Rimexolone has a low intraocular pressure elevating potential comparable to that of fluorometholone in adults. The chemical structure is responsible to the lower propensity to increase intraocular pressure of some steroids. Loteprendol is a site-active steroid that contains an ester rather than a ketone group at the C-20 position, rendering de-esterification to an inactive metabolite. It is highly lipid-soluble, with enhanced penetration into cells. Loteprendol appears to have an improved safety profile compared with ketone corticosteroids. Fluorometholone is deoxygenized at the C-21 position. Rimexolone lacks a hydroxyl substituent at the C-21 position. It has lower aqueous solubility and increased lipophilicity. It appears that the potency of topical steroids is directly correlated with the propensity to elevate intraocular pressure. Intraocular pressure elevation almost never occurs in less than 5 days and rarely in less than 2 weeks of steroid treatment. However, late rise in ocular pressure is not uncommon, even if intraocular pressure has been within normal limits during a treatment course of 6 weeks.

Intraocular route
Before the advent of anti VEGF, intravitreal steroid injections have been used largely in the treatment of exudative age related macular degeneration, chronic cystoid macular edema, proliferative diabetic vitreoretinopathy, retinal vascular occlusion and chronic uveitis. Rise in intraocular pressure is dependent on dose, presence of aphakia or pseudophkaia and a history of vitrectomy, facilitating penetration of the drug into the anterior segment. Intraocular pressure may rise in 30-50 % of patients as soon as 1-4 weeks after intravitreal injection of triamcinolone acetonide (Kenalog) and often returns to baseline several months after injection. It is advisable to perform a trial of topical prednisolone acetate before intravitreal triamcinolone acetonide injection is performed. Fluocinolone acetonide intravitreal implants are an effective therapy for non-infectious posterior uveitis. However, patients receiving this treatment are at high risk for development of vision-threatening increased intraocular pressure. Therefore, patients treated with these implants should have frequent intraocular pressure monitoring. Intractable glaucoma may necessitate removal of the depot by pars plana vitrectomy to lower intraoculare pressure. In the SCORE study grid photocoagulation and repeated injections of triamcinolone acetonide 1 or 4 mg seemed to be equally effective in producing improvements in best corrected visual acuity in patients with macular edema due to branch retinal vein occlusion. 41% of patients treated with triamcinolone acetonide 4 mg initiated www.intechopen.com Steroid Induced Glaucoma 563 intraocular pressure lowering medications during the 12 months study. In patient with central retinal vein occlusion 35% of the patients receiving 4 mg triamcinolone acetonide initiated glaucoma medications. Ozurdex is a slow release intravitreal implant of dexamethasone currently under clinical trials for the treatment of macular edema in retinal vein occlusion disease. It appears that the dexamethasone implant is well tolerated, producing transient, moderate and readily managed increase in intraocular pressure in less than 16% of eyes.

Periocular route
Subconjunctival, sub-Tenon and retrobulbar injections of triamcinolone acetonide may cause dangerous and prolonged elevation of intraocular pressure because of their long duration of action. Surgical excision of sub-Tenon triamcinolone acetonide deposit should be considered if the primary treatment for steroid-induced glaucoma is refractory to medical treatment. The application of topical corticosteroids to the eyelids and periorbital region, in the treatment of atopic dermatitis, even over long periods of time, was not related to the development of glaucoma or cataracts.

Systemic route
Systemic administration includes ingestion, inhalation and nasal spray. It is less likely to cause intraocular elevation. However, intraocular pressure may rise weeks to years after treatment. When administrated concurrently with topical steroids it may have an additive effect and higher intraocular pressure than a single route. Intranasal corticosteroids have become a gold standard in therapy for allergic rhinoconjunctivitis and recent evidence indicates that may be effective at alleviating ocular symptoms as well. Intranasal corticosteroids are absorbed systemically in small measurable amounts. Some studies suggest a relationship between intranasal steroids and increased intraocular pressure. Aerosolized drugs delivered with a facemask may inadvertently deposit in the eyes, raising concerns about ocular side effects. Inhaled corticosteroids have been associated with an increased risk of skin thinning, bruising, cataracts and possibly glaucoma in adults. The risks increase with advanced age, higher doses, and longer duration of use. In children, the risks of cataracts and glaucoma were negligible with inhaled corticosteroids, whether a mouthpiece or a mask interface was used. It is not known whether exposed children will have increased risks from inhaled corticosteroids later in life. Therefore, it is wise to avoid face and eye deposition when possible, to use the minimally effective dose and a regular follow up of intraocular pressure.

Endogenous route
Elevated blood levels of corticosteroids of endogenous production, as seen in adrenal hyperplasia or neoplasia (Cushing syndrome) can also cause increase in the intraocular pressure. After adrenalectomy, increased intraocular pressure may retune to normal values

Clinical course
An increase in intraocular pressure may occur days to weeks and even months after the administration of steroids. The increase in intraocular pressure depends on potency, penetration, frequency and route of administration. Individual susceptibility, older age and ocular disease are also important factors. An acute presentation may occur after intense systemic steroid therapy. Patient may complain on pain, decreased vision and conjunctival hyperemia. In infants the clinical picture may resemble that of congenital glaucoma. Signs are tearing, Descement's membrane breaks, corneal edema, enlarged corneal diameter, elevated intraocular pressure and optic disc cupping. Unlike congenital glaucoma, the anterior chamber angle is normal.

Management
This secondary glaucoma clinically mimics many features of primary open angle glaucoma. Currently, the propensity to develop steroid-induced ocular hypertension must be determined empirically. Therefore, all patients on protracted steroid therapy should have their intraocular pressure monitored periodically. Steroid induced glaucoma usually responds to cessation of steroid therapy and to topical anti-glaucoma medication. In steroid responders the intraocular pressure generally returns to normal within few days to weeks after discontinuation of steroids. Rarely, intraocular pressure remains elevated despite steroid cessation and may result from damage to outflow channels. In these cases management is similar to that of open angle glaucoma patients. If anti-inflammatory therapy is needed in known steroid responders or glaucoma patients, treatment with FML 0.1% or medrisone (MHS) are possible options. Loteprendol (Lotemax) and Rimexolone (Velox) are potent anti-inflammatory corticosteroids with reduced propensity to raise intraocular pressure.
Alternative topical anti-inflammatory agents are the nonsteroidal anti-inflammatory agents (NSAIDs), such as diclofenac (Voltaren), ketorolac tromethamine (Acular LS) and bromfenac (Xibrom). NSAIDs do not induce increase in intraocular pressure but their antiinflammatory potential is lower than that of corticosteroids. When indicated, topical anti-glaucoma medications should be used. Prostaglandins should be used with caution as they may have pro-inflammatory effect. If intraocular pressure remains intractable despite maximal tolerated medical therapy, Argon laser trabeculoplasty and Nd:YAG laser selective trabeculoplasty (SLT) have variable success and patients required additional surgical procedures. Repeat SLT treatments may be necessary. SLT is a temporizing procedure to consider in patients with steroid-induced elevated IOP. A possible new treatment under investigation is anecortave acetate injection into the anterior sub-Tenon space in eye with uncontrolled steroid-related ocular hypertension following intravitreal or sub-Tenon injections of triamcinolone acetonide. Anecortave acetate is a synthetic molecule derived from cortisol. The resulting molecule is referred to as a cortisene. The modification renders the molecule free of all glucocorticoid and mineralocorticoid activity. Anecortave acetate possesses antiangiogenic activity via inhibition of the proteases necessary for vascular endothelial cell migration and has been evaluated as a potential therapy for neovascular age-related macular degeneration. In one preliminary, uncontrolled study a rapid and sustained reduction of intraocular pressure was noted as soon as 1 week after treatment. The mechanism by which anecortave acetate lowers intraocular pressure in eyes with steroid-related ocular hypertension is unknown. With glucocorticoid treatment, trabecular meshwork cells increases the expression of plasminogen activator inhibitor-1, a protein that inhibits activation of extracellular proteinases and leads to enhanced extracellular matrix deposition. Recent studies have shown that anecortave acetate blocks glucocorticoid induction of plasminogen activator inhibitor-1, which may be partially responsible for anecortave acetate's intraocular pressure lowering activity. Surgical treatments include filtration surgery, tube shunt, excision of the sub-Tenon steroid depot, explantation of steroid implant and pars plana vitrectomyfor the removal of the intravitreal depot.