Claudia A. Arrigg
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Key Features: Corticosteroid-Induced Glaucoma |
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New advances in corticosteroid use have furthered the effective treatment of both ocular and systemic disorders. However, despite their popularity as antiinflammatory, antiallergic, and antiangiogenic agents,[1-4] corticosteroids can have tragic consequences and should be used only with judicious monitoring. Clinical and experimental investigations over the past several decades have documented the effects of corticosteroids on the eye. Clinical findings typically resemble primary open-angle glaucoma (POAG). It has been well established that topical, systemic, periocular, and intravitreal steroid administration can cause an increase in intraocular pressure (IOP) and a decrease in the facility of aqueous outflow.[5-9]
In 1954, François published the first report of an IOP rise after long-term therapy with topical cortisone. He also noted optic nerve cupping and atrophy and visual-field loss, which suggested a picture similar to open-angle glaucoma.[10]
Other reports followed shortly thereafter. Armaly found that the topical application of dexamethasone in normal eyes resulted in increased IOP and a reduction in outflow facility and rate of aqueous formation.[5] The magnitude of the effect was greatest among older people and those with glaucomatous eyes.[5,6] Becker and Mills also noted that chronically administered topical steroids not only produced a glaucoma-like state in otherwise healthy eyes but also exacerbated preexisting glaucoma.[7] However, unlike POAG, this condition was usually reversible with cessation of the drug.
A number of specific agents have been implicated in corticosteroid-induced glaucoma, including dexamethasone,[1,2,5,6,10-16] betamethasone,[7,8,17-20] prednisolone,[7,9,21] medrysone,[2,12] fluorometholone,[22,23] triamcinolone acetonide[3,4] hydrocortisone,[7,9,12,24] cortisone,[10,25] prednisone,[9,25] and flurandrenolide.[26]
EPIDEMIOLOGY
Corticosteroid-induced glaucoma can occur in any age group, in either sex, and from steroid therapy for any ocular or systemic disease. Approximately one-third of the normal population experiences a moderate increase in IOP after topical corticosteroid use.[7,8,27] Furthermore, 5-6% of the normal population develops a marked increase in IOP of more than 31 mmHg after 4-6 weeks of topical corticosteroid therapy.[17,28-30] In contrast, almost all patients with POAG or low-tension glaucoma experience some elevation of the IOP after topical steroid therapy.[6-8,17,30]
A genetic basis for this finding was proposed in landmark papers in the 1960s by Armaly[28-30] and Becker and Hahn.[8,17] Using different classification criteria, these authors independently postulated a relationship between the inheritance of the IOP response to topical corticosteroids and the inheritance of POAG. Becker and Hahn also proposed that the pressure response to topical steroid testing was genetically determined by a simple monogenic autosomal mechanism. The recessive homozygote state was hypothesized to be present in patients with POAG.[8] Schwartz and associates found a low concordance of pressure response in monozygotic twins to topical testing, which was thought to indicate either a limited role for the genetic basis of the monogenic inheritance of the corticosteroid response or poor reproducibility to topical steroid testing.[14,15] In addition, dexamethasone provocative testing was found to have limited reproducibility[31] and prognostic ability for both the development of glaucoma in steroid responders[11,32] and visual-field loss in glaucoma suspects.[33]
Although all patients receiving steroids have the potential for the development of corticosteroid-induced glaucoma, some persons are at a higher risk. Individuals particularly susceptible are those with POAG or a family history of glaucoma (Table 210.1).[1,6-8,17,18,34] In addition, highly myopic patients (>5 D) with no evidence or family history of glaucoma have a high rate (88%) of elevated IOP rise in response to topical steroid testing.[35,36] Persons with diabetes mellitus have a greater prevalence of POAG and an elevated IOP response to topical corticosteroids.[37] In addition, eyes with traumatic angle recession and their fellow eyes have shown significant IOP rise to topical dexamethasone testing.[38]
TABLE 210.1 -- Risk Factors for Corticosteroid-Induced Glaucoma
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Primary Open - Angle Glaucoma - Family History of Glaucoma |
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High myopia |
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Diabetes mellitus |
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Connective tissue disease |
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Age |
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Traumatic angle-recession glaucoma |
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Adrenal hyperplasia or neoplasia (Cushing's syndrome) |
Age is also an important factor. In young patients taking oral prednisone for inflammatory bowel disease, one study found that 22% of children experienced a rise in IOP and 32% were characterized as steroid responders.[39] However, in 1993, a long-term study of 23 children with kidney disease found no evidence of elevated IOP in patients receiving less than 0.3 mg kg?1 day?1 of oral prednisone for up to 5 years.[40] Of note, 30% of these patients acquired posterior subcapsular cataracts.[40] With topical instillation, several studies have found a marked elevation in IOP when children younger than 10 years of age were given 0.1% dexamethasone.[41] A dose-dependent ocular hypertensive pressure response occurs more frequently, more severely, and more rapidly in children than in adults.[42-44] This pressure rise has also been shown with topical 0.1% dexamethasone in children being treated for vernal conjunctivitis.[45,46]
In adult patients with ocular complications of renal and connective tissue disease (e.g., rheumatoid or psoriatic arthritis, systemic lupus erythematosus), treatment is often with topical and systemic steroids.[25,47] Adult renal transplantation patients receiving oral prednisone were found to have a 10% elevation in IOP.[48] Unlike the 5-6% of normal eyes found by Becker and Armaly to have a marked pressure rise, Gaston and associates found that 15% of patients with connective tissue disease had a dramatic IOP response to topical steroid testing and concluded that damage to the trabecular meshwork from their disease may be the cause of their glaucoma.[49]
Patients undergoing surgery are at risk if steroids are used either preoperatively or postoperatively. Corticosteroid-induced glaucoma has developed in patients using topical corticosteroids after cataract surgery,[50] strabismus surgery,[42,51] as well as filtration surgery, despite the presence of a functioning filtering bleb.[23,52,53] Topical steroids are often used with photorefractive keratectomy (PRK)[54] and laser in situ keratomileusis (LASIK).[55] However, an elevated IOP may be difficult to monitor accurately as corneal edema or thinning or fluid beneath the flap may give a falsely low IOP reading.[55]
ROUTES OF ADMINISTRATION
Experts, such as Shields, Kass and others, categorize corticosteroid-induced glaucoma as caused by 1) exogenous steroids, which may be given topically, periocularly, intravitreal, or systemically or 2) endogenous steroids.[56,57]
TOPICAL ROUTE
Of the various routes of steroid administration, topical therapy most commonly causes elevated IOP by having a greater effect on aqueous outflow facility than does systemic therapy.[58] When administered to normal eyes, topical steroids can cause an IOP rise that correlates with the duration and frequency of drug administration.[5,8,28] Nevertheless, the topical application of corticosteroids is still considered safer than the systemic route because of the multiple potentially devastating side effects of systemic steroid administration. The topical route includes ocular drops and ointment, as well as steroid lotions, creams, and ointment applied to the face or eyelids.[19,26,59-63]
The dramatic increase in the use of inhaled and nasal steroids in the management of asthma, rhinitis, sinusitis, and chronic obstructive pulmonary disease serves as yet another important topical route of steroids.[64-66] Garbe et al, in a case-control study, found the prolonged continuous duration and the high-dose administration of inhaled glucocorticoids increased the risk of ocular hypertension or open-angle glaucoma[64] This effect was particularly noted in patients with a glaucoma family history.[67] There was no association between the use of inhaled steroids and glaucoma or elevated IOP in those persons without a family history of glaucoma.[67] The discontinuation of nasal steroids in patients with glaucoma resulted in a significant IOP reduction.[68]
PERIOCULAR ROUTE
Subconjunctival,[69-71] sub-Tenon's,[72-78] and retrobulbar injections[56,57] may cause dangerous and prolonged elevations of IOP because of their long duration of action.[56,57] The increased pressure from these repository steroids can be sustained for 1 year or more after the injection.[70,72] A patient's IOP response to topical steroids does not predict the response to periocular steroids.[56,57,73] The advantages of periocular steroids are (1) a high local concentration; (2) a long duration of action, determined by the solubility of the steroid and the location of the injection; and (3) their effectiveness against inflammatory disorders of the posterior segment.[69-72] The duration and severity of IOP rise is inversely related to the solubility of the injected steroid.[73] Triamcinolone acetonide (Kenalog) is a very high-risk agent as it is the least soluble and a long acting repository steroid.[79] Repeated periocular injections may increase the risk of developing glaucoma.[3] The inferior quadrant is the preferred injection site in order to save the superior conjunctiva for possible future filtration surgery.
INTRAOCULAR ROUTE
Recently, intravitreal steroids have been used in patients with chronic cystoid macular edema, exudative age-related macular degeneration, proliferative diabetic vitreoretinopathy, retinal vascular occlusion, neovascular disease, and chronic uveitis.[3,4,80,81] The rise in IOP after an intravitreal injection is dependent on drug dose[82] and volume, rate of clearance, presence of aphakia or pseudophakia and, possibly, a previously vitrectomized eye.[79,83] IOP can become elevated as early as 1-4 weeks after intravitreal injection and often returns to pre-injection baseline ~8-9 months after injection.[4,84] Results of recent studies have shown elevated pressures in 30-50% of patients[4,80,82,84,85] after receiving intravitreal triamcinolone acetonide. Also, a younger age was associated with elevated IOP.[4,85,86] Preexisting glaucoma or diabetes mellitus are not a contraindication to intravitreal steroids but close observation both within the first few weeks to several months is merited.[3,4] It is thought that elevated IOP may be due to deposition of extracellular material, such as myocillin and collagen.[87] Particulate matter from the injected steroids obstructing the trabecular meshwork has been noted by gonioscopy[81] Triamcinolone acetonide crystals have been found to be ophthalmoscopically visible in the vitreous during trabeculectomy.[4] Yet even after a fluocinolone implant which does not involve the release of particles, the drug can cause an elevated IOP indicating perhaps a pharmacological rather than a mechanical obstructive effect.[3] Intractable glaucoma has been reported necessitating the removal of the depot corticosteroid by pars plana vitrectomy with resultant IOP lowering.[88-90]
SYSTEMIC ROUTE
Although systemic administration of corticosteroids is the route least likely to cause IOP elevation, the pressure rise may occur as long as weeks to years after treatment.[21,25,56-58,91,92] Weijtens et al showed that an oral dose of dexamethasone resulted in an intravitreal dexamethasone concentration with far more antiinflammatory potency than physiological intravitreal cortisol levels.[93] When systemic steroids are administered concurrently with topical corticosteroids (e.g., in patients with uveitis with underlying collagen vascular disease or patients with asthma),[58,91] the combined treatment may have an additive effect, resulting in a higher IOP than if a single route were used. Even steroids applied to the skin at remote sites can be systemically absorbed, raising the IOP in susceptible individuals.[52,92] Children are more prone to complications from the cutaneous route due to their higher ratio of total body surface area to body weight.[94]
ENDOGENOUS ROUTE
The excess endogenous production of glucocorticoids, e.g., in adrenal hyperplasia or neoplasia (Cushing's syndrome), can also cause an increase in the IOP. In one report, the increased IOP and decreased outflow facility returned to normal after adrenalectomy.[56,95]
CLINICAL COURSE
An increase in IOP may occur as soon as a few hours[16] or as long as months to years after the administration of steroids.[7,27,92] The height and duration of the pressure rise depend on factors such as drug potency, penetration, frequency, length, and route of administration, as well as on individual susceptibility, age, and underlying ocular or systemic disease.[5,6,26,39-41,45,48,56]
Both chronic and acute forms of corticosteroid glaucoma respond to cessation of the corticosteroid therapy and to treatment with antiglaucoma medication, if needed. Even in patients with visual-field loss and optic cupping and atrophy, the outflow facility and IOP generally return to baseline values in days to weeks after discontinuation of the medication.[7,27] Rarely, the IOP remains persistently elevated for months or years after the steroids have been discontinued, perhaps as a result of damage to the outflow channels.[92] In one report, despite cessation of therapy, increased IOP reversed in one eye but remained elevated in the other eye, which had received greater and more prolonged flurandrenolide therapy.[26]
CLINICAL FINDINGS
The clinical findings in corticosteroid-induced glaucoma typically resemble those of POAG in teenagers and adults: (1) open and normal-appearing angle by gonioscopy, (2) white and painless eye, (3) optic disk cupping, (4) visual-field defects, (5) elevated IOP, and (6) decreased outflow facility.[7-9,27] Patients are usually asymptomatic. However, an acute presentation can occur if the IOP is elevated enough, such as after intensive systemic steroid therapy (rarely after topical treatment).[56,57] In this situation, patients may experience corneal edema, blurred vision, ciliary hyperemia, and pain, although the anterior chamber depth and angle remain normal.[27]
The age of the patient may determine the clinical form of corticosteroid-induced glaucoma. Infants may have a picture similar to that in congenital glaucoma. Signs include tearing, photophobia, blepharospasm, cloudy corneas with an enlarged corneal diameter, Descemet's membrane breaks, elevated IOP, and optic disk cupping.[56] Unlike congenital glaucoma, however, the anterior chamber angle is normal.[96]
Additional ocular findings from topical steroid use include mydriasis,[97,98] increased corneal thickness,[99] corneal ulcers,[59,100,101] posterior subcapsular cataracts,[40,43,59,100,101] delayed wound healing, ptosis,[97,98] and skin atrophy of eyelids.[59] Importantly, systemic steroids are known to cause Cushingoid facies, truncal obesity, hirsutism, buffalo hump, cutaneous striae, easy bruisability, delayed wound healing, osteoporosis, fluid retention, peptic ulcers, diabetes, hypertension, and psychiatric disorders.[56]
PATHOGENESIS
Many mechanisms have been proposed to explain the elevated IOP and decreased outflow facility seen in corticosteroid-induced glaucoma. The most commonly held hypothesis is that glycosaminoglycans accumulate in the outflow pathways, causing an increase in outflow resistance.[5,6,92,102,103] Glycosaminoglycans, normally present in the aqueous outflow channels, are depolymerized by hyaluronidase that is contained in lysosomes. François showed that corticosteroids protect the lysosomal membrane and thus inhibit the release of hydrolases from the lysosomes.[104] In turn, glycosaminoglycans cannot depolymerize and accumulate in the ground substance, retain water, and narrow the trabeculae. It is only when glycosaminoglycans become depolymerized from the liberation of the catabolic enzymes from lysosomes that they no longer retain water, the trabeculae widen, and aqueous outflow is facilitated.[27,92,104,105]
Changes in protein synthesis have also been implicated in steroid-induced glaucoma. MYOC/TGIR (a trabecular meshwork-induced glucocorticoid response protein) has been found to be upregulated in trabecular meshwork endothelial cells with steroids and altered in some forms of juvenile open-angle glaucoma and POAG.[106,107] In a recent study by Lo et al, MYOC/TGIR was significantly inducted by dexamethasone only in human trabecular meshwork. They found multiple genes may be involved in protective and damaging mechanisms for the regulation of IOP upregulated with dexamethasone.[108]
Other investigators have postulated that in POAG, an abnormal accumulation of dihydrocortisols in cultured trabecular cells may potentiate exogenous glucocorticoid activity. In particular, 5?-dihydrocortisol can potentiate the increased IOP caused by exogenous glucocorticoids in POAG. This theory may explain why patients with POAG. have an increased susceptibility to pressure elevation from corticosteroids.[109-115]
An alternative explanation is that corticosteroids inhibit prostaglandin synthesis by human trabecular cells. Dexamethasone can inhibit synthesis of both prostaglandins E2 and F2? whose normal function is to lower the IOP by increasing the outflow facility.[116,117]
Another theory involves phagocytosis. Endothelial cells lining the trabecular meshwork can act as phagocytes of debris in aqueous humor. Corticosteroids suppress phagocytic activity, causing accumulation of aqueous debris in the trabecular meshwork and, therefore, decreased outflow.[57,118] Ultrasound studies show granular and fibrous material in eyes with corticosteroid-induced glaucoma[119] A study of the morphologic changes in dexamethasone-treated isolated perfusion-cultured human eyes found not only a significant rise in IOP in ~30% of these eyes but also that changes in the trabecular meshwork were similar to findings in corticosteroid glaucoma and open-angle glaucoma, such as thickened trabecular beams, decreased intertrabecular spaces, and thickened juxtacanalicular tissue.[119-122]
DIFFERENTIAL DIAGNOSIS
To diagnose corticosteroid-induced glaucoma, the most important consideration is a careful history of any type of past or present use of steroids. For example, when previously stable open-angle glaucoma becomes difficult to control, the physician must consider whether topical or systemic steroids, being taken to treat some other disease, such as skin disease, asthma, or a connective tissue disease disorder, could be contributing to this change or whether the underlying glaucoma is progressing. The history and examination of the patient should also include observation for symptoms and signs of endogenous corticosteroid production.
A history of steroid use may also be important in evaluating a patient with a shallow anterior chamber. In the presence of corticosteroid-induced glaucoma, a shallow anterior chamber can be mistaken for chronic angle-closure glaucoma. In presumed low-tension glaucoma, the IOP and outflow facility may be of normal range, but advanced cupping and visual-field loss may be present. Since the latter findings may be sequelae of corticosteroid-induced glaucoma, a comprehensive history is crucial.[56] In patients with uveitis, it is often difficult to determine whether elevated IOP is due to preexisting glaucoma, an inflammatory condition, or the steroids used to treat the disease.[73,123,124] In unilateral cases, provocative testing with a topical steroid and examination of the pressure of the uninvolved eye may be helpful in determining steroid responsiveness.[125] Clinical findings can be helpful, i.e., a patient with new onset of uveitis may initially have a normal IOP. However, if the IOP becomes elevated after a few days of starting steroids, then it is probably due to the uveitis. Elevated IOP from topical steroids usually takes weeks to months and usually returns to normal after discontinuation of the drug.[125]
MANAGEMENT
The most effective management of corticosteroid-induced glaucoma is discontinuation of the drug.[27] The IOP generally returns to normal within a few days to several weeks,[7] although it may take months or years.[92] Once the corticosteroid is discontinued, the time required to regain normal IOP does not correlate with either the height of IOP rise or the extent of decreased aqueous outflow facility.[57]
Whenever steroids must be used for a particular disease, it is important to choose the safest drug with the fewest side effects, lowest concentration, shortest action, lowest dosage frequency, and most effective route of administration.[12,126] Because corticosteroid-induced glaucoma can develop at any point during therapy, the baseline IOP should be established before treatment is initiated and followed closely every 2-3 weeks and then every few months for the duration of treatment. Corticosteroid-responsive individuals should be followed carefully for the development of glaucoma-like visual-field defects and disk changes.[20,32,33] Medical management with antiglaucoma therapy may be necessary. If there are no contraindications, topical beta-blockers should be tried. Prostaglandin and miotic agents should be used with caution.
Future studies may show a novel therapy anecortave acetate (AA), a synthetic derivative of cortisol, to be an effective inhibitor of ocular blood vessel growth without evidence of glucocorticoid receptor-mediated bioactivity.[127] In a recent study by Robin et al, a single inferior anterior juxtascleral depot administration of AA was given to eyes with markedly elevated IOP from intravitreal triamcinolone acetonide.[128] The IOP was markedly decreased by 48% and sustained for 6 months. AA may have an important role in controlling IOP and avoiding surgery in patients with injected steroids.[128]
Possible treatment options for patients with glaucoma or for known steroid responders can be progesterone-like agents medrysone (HMS) or fluorometholone 0.1% (FML)[12,22,23,129,130] because these two less potent agents have a lesser effect on IOP. Fluorometholone is less likely to increase the IOP than is dexamethasone because of its chemical structure, specifically, deoxygenation at the C21 position.[22,23,129,130] Fluorometholone acetate 0.1% displays an antiinflammatory potency similar to prednisolone acetate 1.0% and greater than fluorometholone alcohol 0.1%, yet it has a slower rate of IOP rise when compared with dexamethasone and a similar rate of IOP rise when compared with fluorometholone alcohol 0.1%.[57,131-133]
Rimexolone 1.0% (Vexol) and loteprednol 0.5% (Lotemax) are potent antiinflammatory glucocorticoids with a reduced propensity to raise IOP. Rimexolone, like fluorometholone, lacks a hydroxyl substituent at the 21 position of its chemical structure.[134,135] It has lower aqueous solubility and increased lipophilicity compared with other ophthalmic corticosteroids.[134,135] Rimexolone 1.0% induces a rise in IOP similar to that seen with fluorometholone but less than that seen with 1.0% prednisolone acetate and 0.1% dexamethasone sodium phosphate.[126,134,135] Loteprednol is a site-active steroid that has an absent ketone group at the C-20 carbon position rendering a predictable hydrolysis to an inactive carboxylic acid metabolite.[136] It is highly lipid-soluble, enhancing penetration into cells. It has less of a tendency to cause clinically significant elevations in IOP than prednisolone actetate.[137] (Novack 1998).
Alternative agents are the topical nonsteroidal antiinflammatory agents (NSAIDs), such as diclofenac (Voltaren), ketorolac tromethamine, 0.4% (Acular LS), bromfenac (Xibrom), and the prodrug nepafenac (Nevanac) that act as cycloxygenase inhibitors and have been shown not to cause any pressure elevation.[57,129,138] They are being more widely used to treat inflammation.
In some patients, glaucoma may persist even after discontinuation of steroid therapy.[92,139] IOP may become intractable, despite maximal medical therapy. Argon laser trabeculoplasty has variable success in treating corticosteroid-induced glaucoma[140,141] However, with uncontrolled IOP, progressive optic nerve changes or visual-field loss, possible surgical treatment options include filtering surgery[142], tube shunt,[3] excision of the depot site of the injection,[70-73,77] explantation of the steroid implant,[3] or pars plana vitrectomy.[88-90,143]
In all cases, if additional systemic steroid therapy is used, it is important to watch for the development of a pressure rise in the contralateral eye.
CONCLUSION
The development of potent new steroids and drug delivery systems provides patients with more effective and beneficial means of treatment. However, corticosteroid therapy still remains a common and insidious cause of visual loss. All physicians should be aware of the potentially devastating and deleterious consequences of unrestricted or prolonged use of topical and systemic corticosteroids. A careful patient history is imperative. Caution should be taken in judiciously choosing the steroid with the appropriate degree of antiinflammatory efficacy and potency so as to decrease the risk of adverse side effects. The recognition and management of corticosteroid-induced glaucoma should be well understood by every physician.
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