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Corticosteroid Glaucoma

Mina Pantcheva, MD

Corticosteroid-induced elevation of intraocular pressure (IOP) may accompany the use of topical, periocular, intravitreal, oral, intravenous, or inhaled corticosteroid therapy. The potential for steroids to increase IOP and cause subsequent glaucomatous optic neuropathy mandates a regular monitoring of IOP in patients on steroids.

Use of corticosteroids in ophthalmic conditions started within 2 years of the preparation and clinical use of cortisol by Hench and colleagues¹ at the Mayo Clinic in 1949.² In 1950, McLean³ reported elevated IOP associated with systemic administration of adrenocorticotropic hormone. A report by Francois⁴ on pressure elevation caused by topical steroids appeared in 1954. Landmark studies by Armaly^5–8 and Becker et al^9–11 in 1963 led to a profusion of studies on the effect of corticosteroids on IOP in the years to follow.

The clinical resemblance of corticosteroid-induced glaucoma to primary open-angle glaucoma (POAG) led to the initial hope that corticosteroids could be used to create a model of POAG, allowing insights into its development and possible genetic nature.^5–12 In addition, the finding of high-responder patients, with a marked elevation of IOP after steroid provocative tests, was hoped to identify patients at risk for the later development of POAG. The similarities between corticosteroid-induced glaucoma and POAG are indeed striking: asymptomatic, quiet eyes with open angles and no distinguishing or specific findings on clinical examination. Unfortunately, the relationship between the 2 conditions may not be as close as was originally thought as these initial hopes were not realized in later studies.^13–15

KEY CLINICAL POINTS

• How common is corticosteroid glaucoma? Although all patients may respond with some change in pressure after prolonged corticosteroid use, studies by Armaly^5–8 and Becker et al^9–11 indicate that 30% to 40% of the normal population may be intermediate responders, with a pressure increase of at least 6 mm Hg or attain pressure levels of 20 mm Hg or higher. A small group of high responders had elevations of 16+ mm Hg or achieved levels of 32+ mm Hg (Table 45-1).
  
• How soon after starting steroids can IOP increase? Although most prospective studies used topical corticosteroids for 3 to 6 weeks to assess pressure response, some elevation of pressure can be found in most patients as early as the first or second week.^5–9 Armaly noted a hypertensive effect at the end of the first week in normal patients, with a mean increase in pressure of 19%.⁵ High responders had more rapid and higher increases in pressure, with a few patients developing an increase of 60% at the end of the first week of therapy.^5,6 Patients with POAG, most of whom were considered high responders, also show a faster rate of pressure increase than normal patients. One study found more than 50% of patients with POAG developed elevations of pressure 15 mm Hg higher than baseline by the end of the second week. (In some cases, elevation in IOP from the use of frequent, potent topical steroid preparations, such as hourly prednisolone acetate 1%, may occur within 3 to 5 days. Additionally, patients on chronic lower dose steroids may not develop IOP elevation for months, which may make the diagnosis more problematic.)
  

  It is unknown whether patients with little elevation of pressure after a 6-week steroid provocative test would develop higher pressures with prolonged use.

• How long will the elevated pressure remain once corticosteroids are stopped? The IOP increase is usually short lived. Both Armaly and Becker reported pressures to return to baseline values in a matter of days to weeks after stopping steroids in the majority of participants; Armaly5 found this to occur by 2 weeks in all participants. The duration of corticosteroid use, or the height of the pressure, may not necessarily predict the time course for the decrease of pressure. Case reports include that of increased pressure discovered in a patient after 1 year of topical corticosteroid use in which the pressure returned to normal 19 days after discontinuing the medication, whereas a second patient with a pressure increase that occurred after 8 weeks of corticosteroid use required 5 weeks to decrease.¹⁶ Pressure elevation accompanying several years of steroid use may not decrease, however, once steroids are discontinued.¹⁷ In other situations, pressure may attain such a high level, or enough damage may have occurred, that laser trabeculoplasty or filtering surgery is required before the IOP would have a chance to diminish.
  
• Are certain patients more likely to develop the problem? Patients with POAG are particularly susceptible to the pressure-elevating effect of corticosteroids. Steroid provocative tests in this population indicate that 94% to 100% of these patients will develop IOP increases of at least 6 mm Hg or IOPs between 20 and 31 mm Hg.^6,7,9,11 At least half of these were actually considered high responders, with pressures elevating at least 16 mm Hg or to levels above 31 mm Hg. Studies¹⁸ in patients with secondary open-angle glaucoma generally do not find such high response rates.
  

  Although older patients are at an increased risk, the frequency of steroid responsiveness with age may occur in a bimodal distribution. A study by Lam and colleagues¹⁹ showed that 71.2% of children receiving topical dexamethasone 0.1% 4 times a day responded with an IOP rise greater than 21 mm Hg. Among children under 6 years of age, the peak IOP was greater, the net increase in IOP was greater, and the time required to obtain the peak IOP was less. Those older than 6 years (up to 10 years of age studied) had a similar net increase in IOP, but did not show a significant difference in peak IOP or the time required to reach a peak IOP. This potential should be kept in mind when prescribing steroids for uveitis, after strabismus surgery, or for other conditions in children, especially as lack of cooperation may make it difficult to measure the IOP in these patients. First-degree relatives of patients with POAG, patients with diabetes, high myopes, and patients with rheumatoid arthritis or other connective tissue diseases have also been reported to be likely steroid responders.^{8,10,13,20–22}

  
  
• Can systemic or other forms of corticosteroids elevate IOP? All methods of corticosteroid use have the potential to elevate IOP. Systemic steroid use is less likely to cause elevations of IOP than topical application; a study²³ found a 10% incidence of ocular hypertension in renal transplant patients receiving systemic steroids after transplant, although pretreatment pressures were not obtained.
  

  Endogenous corticosteroids may cause elevation of IOP in patients with Cushing’s syndrome and other forms of hypersecretion.

  
  

  Periocular injections of corticosteroids may elevate IOP. Long-acting preparations, such as triamcinolone acetonide, may be especially likely to cause increases, as reports indicate active steroid may be released for months.²⁴ Some patients may require the surgical removal of a repository steroid injection for IOP control. In consideration of this, such injections should be given in an easily retrievable spot, such as the inferior fornix.

  
  

  Recently, the use of intravitreal corticosteroid injections or implants for macular edema, adjunctive therapy in the treatment of choroidal neovascularization, and noninfectious posterior segment uveitis has led to increased incidence of steroid-induced ocular hypertension.25–29

  
  

  Dermal applications of corticosteroids have caused elevation of IOP, whether administered to the periocular region or at distant sites.³⁰ Inhaled corticosteroids may also cause an increase in pressure.³¹

  
  
• Steps in the management of corticosteroid-induced glaucoma. Recognition of the condition is the most important step in its management. Measurement of IOP on a regular basis in any patient placed on long-term topical corticosteroids is essential. Prevention is also key: use of nonsteroidal anti-inflammatory agents rather than steroids, use of steroid preparations less likely to elevate IOP when possible^32–34 (rimexolone [Vexol], fluorometholone [FML], medrysone [HMS]), and avoidance of using extremely long-acting steroid preparations for subconjunctival injections. Prevention of the unmonitored use of steroids by patients should be considered by writing nonrefillable prescriptions for only small quantities of corticosteroids, when possible.

Once the possibility of steroid glaucoma is seriously considered, stopping steroid treatment and observation of the eye for several weeks will usually result in spontaneous lowering of the IOP. If the IOP has reached a dangerous or worrisome level, the use of IOP-lowering agents or surgery may be required.³⁵ No specific treatment, such as an antisteroid eye drop, is available.

More perplexing is the situation of elevation of IOP in an eye that has been on steroid therapy for chronic iritis or uveitis (see Chapter 43). It is difficult to know if the inflammatory condition has worsened and caused elevation of the pressure or whether the patient has now become a steroid responder. It is usually advisable to increase the steroid therapy for several days to attempt to suppress any increase in inflammation. If the IOP decreases with the increased steroid, inflammation, not a steroid response, was the explanation for the increased IOP. If, however, the IOP remains unchanged or elevates, then a steroid response in IOP, whether due to obstruction of aqueous outflow or increased aqueous inflow, is likely and the amount of steroid use must be decreased. This may entail using the drops less often, decreasing the strength of the drops, or switching to a preparation less likely to affect IOP. Addition of an IOP-lowering agent may also be considered if steroid use cannot be decreased.

Corticosteroids are a family of compounds related in structure to the cholesterol molecule from which they are derived. They share structural similarities with the 2 other major classes of steroids: mineralocorticoids and sex steroids (Figure 45-1). Addition of an extra double bond in the ring structures or small modifications of side groups of the steroid base molecule may cause significant changes in both effect and potency; prednisolone, which has a second double bond in the A ring, has significantly greater anti-inflammatory activity and less fluid-retaining effects than cortisol (Table 45-2).^36,37 The creation of derivative compounds (ie, the addition of an acetate group) can also change the clinical effect of the base molecule by affecting its penetration into the eye, release characteristics, and degradation rate. Although these factors determine bioavailability, other factors, such as affinity of binding to the steroid receptor, are also involved in determining anti-inflammatory activity.³⁶ In topical therapy, experimental studies of inflammatory keratitis indicate that the acetate derivative (more lipophilic) is the most effective, followed by the alcohol, and, finally, the steroid-phosphate compounds (relatively hydrophilic).³⁸

Attempts to separate the IOP-elevating effect from the anti-inflammatory effect have been met with mixed results. While studies indicate that rimexolone (Vexol), fluorometholone (FML), and medrysone (HMS) are less likely to cause elevation of IOP,^32–34 they also appear less efficacious for intraocular inflammation than prednisolone or dexamethasone (Table 45-3).^36,38 The decreased tendency of fluorometholone to elevate IOP may be due to an increased degradation rate in the ocular tissues, resulting in a shorter duration of action or a smaller amount reaching the target tissue.36

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