Uveitic Ocular Hypertension and Glaucoma

Ocular hypertension (OHT) and glaucoma are common and often serious complications of uveitis.^1–9 Cross-sectional clinic-based studies have suggested a prevalence of OHT among uveitis referral patients of 20% or more, with many of these patients advancing to glaucomatous optic neuropathy.³ The Systemic Immunosuppression Therapy for Eye Diseases (SITE) Research Group has collected comprehensive, long-term data on over 8,500 patients with noninfectious ocular inflammatory disease followed at multiple academic referral centers in the United States.¹⁰ Several years ago the SITE Research Group reported their experience with 1593 eyes of 916 children less than 18 years of age who had elevated who had elevated intraocular pressure (IOP) in the setting of noninfectious uveitis.¹¹ At presentation, the prevalence of an IOP ≥ 21mmHg was 15.8%, whereas an IOP ≥ 30 mmHg was 2.9%. Factors associated with initially elevated IOP included age of 6 to 12 years, duration of uveitis > 6 months, contralateral IOP elevation, vision worse than 20/40, topical corticosteroid use - which had a dose-dependent effect, and prior cataract surgery or pars plana vitrectomy. The estimated two-year incidences of IOP ≥ 21mmHg, ≥ 30 mmHg, or an increase in IOP ≥ 10 mmHg were 33.4%, 14.8%, and 24.4%, respectively. Factors statistically associated with a subsequent IOP elevation included contralateral IOP elevation, pars plana vitrectomy, and corticosteroid use. More recently, the SITE Research Group reported their experience with OHT in 11,452 eyes of 7062 adults ≥ 18 year of age with noninfectious uveitis¹² and found the annual incidence rates for IOP ≥ 21 mmHg and ≥ 30 mmHg to be 14.4% and 5.1%, respectively. A Kaplan-Meier analysis performed on the adult cohort estimated that by year 10 of disease the proportion of eyes with IOP ≥ 21 mmHg and ≥ 30 mm Hg would exceed 50% and one-third, respectively. Risk factors associated with the subsequent development of OHT included contralateral IOP elevation, use of corticosteroids, and severe disease as indicated by poor presenting vision, the presence of anterior chamber synechiae, or the need for surgery. Dick et al. recently analyzed US insurance claims data to identify a 15.4% prevalence of glaucoma in patients with incident non-infectious intermediate, posterior or panuveitis (NIIPPU), verses 6.0% in matched controls (adjusted hazard ratio of 2.7, 95% Confidence Interval [CI] 2.13 - 3.36; p < 0.001). Kaplan-Meier analysis revealed an increase in the rate of glaucoma by approximately 10% by year one and 20% by year five in those with persistent NIIPPU.¹³

Ocular hypertension in eyes with uveitis can be caused by one or more of four contributing mechanisms.⁷ These include, first, inflammatory ocular hypertension syndrome (IOHS), which is characterized by a sudden elevation of IOP in the setting of acute or recurrent inflammation, but in the absence of angle closure. While the pathogenesis of IOHS is unknown and the condition is relatively uncommon, most cases are infectious, and so recognizing this characteristic clinical presentation is important for prompt diagnosis. Common causes of IOHS including herpes virus infection, toxoplasmosis, sarcoidosis, and syphilis. Second, acute uveitic angle closure, which can result either from extensive posterior synechiae formation leading to pupillary seclusion and iris bombé - common with fibrin-rich forms of uveitis such as HLA-B27 or sarcoid-associated anterior uveitis, or from uveal effusion producing detachment and forward rotation of the ciliary body and iris root - observed in eyes with Vogt-Koyanagi-Harada disease (VKH) or sympathetic ophthalmia, as just two examples. Third, corticosteroid-induced ocular hypertension, which is common and typically occurs following weeks to months of treatment with these agents. And fourth, mixed-mechanism ocular hypertension, which occurs when chronic damage to the trabecular meshwork and Schlemm’s canal leads to reduced outflow facility – typically over months to years. Optimal treatment, which can be complex and often includes both medical and surgical approaches, should be directed at the underlying cause(s) of OHT. Five original articles^14-18 in this issue of Ocular Immunology & Inflammation (OII) present important findings relevant to the clinical presentation, diagnosis, and management of uveitic OHT/glaucoma.

Sharon et al¹⁴ reviewed 53 eyes of 34 patients seen between 2003 and 2015 at two tertiary referral centers in Petach Tikva and Tel Aviv, Israel. Patients with less than 6 months of clinical follow up were excluded. Ocular hypertension was defined as an intraocular pressure (IOP) > 21mmHg. A diagnosis of glaucoma required objective evidence of glaucomatous optic neuropathy, which could include optic disc changes, glaucomatous visual field defects, or both. Fourteen of the subjects (41.2%) were children, defined as ≤ 16 years of age, and 19 (55.9%) had bilateral disease. The majority of affected eyes had isolated anterior uveitis (44; 83.0%), open as opposed to closed angle glaucoma (79.2%), and a history of corticosteroid-induced OHT (62.3%). While over two-thirds of eyes with isolated anterior uveitis (30 of 44; 68.2%) had no identifiable cause for their uveitis, commonly identified causes included JIA-associated uveitis (10 of 44; 22.7%); Fuchs Heterochromic Iridocyclitis - also known as Fuchs Uveitis Syndrome (FUS; 5 of 44; 11.4%); and herpetic uveitis (5 of 44; 11.4%). Two patients (5.9%) had VKH. Mean follow-up was seven years (range: 19 months – 19 years) and the mean time from onset of uveitis to the diagnosis of uveitic glaucoma was 4.5 ± 4.9 years. A high proportion of affected eyes were exposed at some point to topical (73.6%), periocular (34.0%), and/or systemic (30.2%) corticosteroids. An equally high proportion of eyes required long-term therapy to control IOP, including a systemic carbonic anhydrase inhibitor (43.4%), three or more IOP lowering drops (34.0%), and/or trabeculectomy surgery (32.1%). While more than half of all eyes developed visual filed defects during the course of the study, including approximately 15% with loss of fixation, the authors noted that visual field defects tended to remain stable over the course of the study once developed. The authors found that synechiae formation and longer duration of immunomodulatory therapy, both indicators of chronicity and severity, were independently associated with an increased need for IOP-lowering medications.

Veerappan et al¹⁵ retrospectively reviewed the prevalence of both OHT/glaucoma in 23 patients with VKH seen at two tertiary referral centers in North Carolina, USA, between 1996 and 2015. While the inflammation was bilateral in all patients, one eye was enucleated following the onset of disease and so was not included in the analysis. Twenty-eight of the remaining 45 eyes (62.2%) developed OHT/glaucoma, which was bilateral in 13 of 15 affected subjects (86.7%). Of these 28 affected eyes, 14 (50.0%) had developed posterior synechiae – including 10 with iris bombe configuration, and 10 (35.7%) were found to have peripheral anterior synechiae (PAS) formation. Ocular hypertension/glaucoma developing in the acute stage of VKH in seven (25.0%), and in the chronic stage in 21 (75%). Corticosteroids were determined to have contributed to the development of OHT/glaucoma in 16 of 22 eyes (72.7%) for which data were available, including five eyes that received a fluocinolone acetonide implant and in which the mean time to the development of OHT/glaucoma was 28 months. The authors found higher rates of both posterior synechiae and PAS in eyes with OHT/glaucoma. Treatments used to control IOP included topical medications (20 of 28; 71.4%), Ahmed valve placement (15 of 28; 53.6%), laser peripheral iridotomy (8 of 28; 28.6%), and surgical peripheral iridectomy (2 of 28; 7.1%). The authors concluded that OHT/glaucoma is common in patients with VKH disease, occurring in nearly two-thirds of affected eyes, and that synechiae formation, both posterior and peripheral anterior, are important risk factors associated with the development of both elevated IOP and glaucomatous optic neuropathy.

Toniolo et al¹⁶ studied the prevalence and predictors of OHT/glaucoma in a cohort of 88 patients with FUS seen at three referral centers in Melbourne, Australia, between 1992 and 2011. Median follow up was 2.7 years (range: single visit to 18.2 years). Of the six subjects (6.8%) with bilateral disease, only the first eye to develop FUS was included in the analyses. The cumulative incidence of both cataract and glaucoma was analyzed using a Kaplan-Meier method. Univariate analyses were used to explore prognostic factors possibly associated with the development of glaucoma, followed by a multivariate analysis of these factors to minimize the risk of confounding. The median patient age was 38 years (range: 13 to 73 years), and 60% were male. Most eyes (81.8%) had active anterior chamber inflammation, and a sizable majority (67.0%) had vitritis at first visit. Seventy-two of the 88 eye (81.8%) were seen more than once. That important caveat notwithstanding, cataract was present or developed in 62 analyzed eyes (70.4%), and Kaplan-Meier analysis estimated that 71% (95% CI 58–81%) would have developed cataract within four years and 76% (95% CI 63–86%) within eight years of referral. Just over half, or 55%, underwent cataract surgery. Ocular hypertension/glaucoma developed in 30 eyes (34.1%), and Kaplan-Meier analysis again estimated that 39% (95% CI 28–51%) would have developed OHT/glaucoma within four years and that this cumulative prevalence would have remained unchanged at eight years. Nine of the 30 affected eyes (30.0%) underwent trabeculectomy with mitomycin-C. Both univariate and multivariate analyses identified both age ≥ 50 years (HR 8.2; 95% CI 1.8 – 37.5; p = 0.0065) and the presence of cataract (HR 2.5; 95% CI 1.1–5.6; p = 0.032) at presentation as independent risk factor for the development of OHT/glaucoma. The authors hypothesized that cataract may be a surrogate for disease duration and severity in eyes with FUS.

Voykov et al¹⁷ retrospectively reviewed their experience with the use of Ahmed valve implantation in 17 eyes of 17 patients with FUS and OHT/glaucoma seen in a referral center in Tuebingen, Germany, between 2007 and 2014. The median baseline IOP was 30 mmHg (range: 22–44 mmHg). The median number of baseline IOP lowering medications was 4.5 (range: 3–5). All but two subjects had prior IOP lowering surgeries. Post-operative IOP stabilized to between 15–20 mmHg within 4 weeks of surgery, and stayed in that range for three years, at which point 23.0% had an IOP ≤ 21 mmHg. Common post-operative complications included bleb encapsulation (47.0%), device exposure (23.5%), tube obstruction (23.5%), hypotony (11.7%), and diplopia (6.0%). The authors hypothesized that the relatively high rate of bleb encapsulation in their patients may have been due to the presence of persistent anterior chamber inflammation typical of patients with FUS.

Dhanireddy et al¹⁸ described their experience with the Ex-PRESS glaucoma filtration device in 11 eyes of patients with uveitic glaucoma seen at a uveitis referral center in Boston, USA, between 2011 and 2013. Inflammation was controlled in all patients prior to surgery. Twelve simple glaucoma patients who underwent similar surgery were used as controls. Surgical success was definded as > 25% reduction in IOP without hypotony and/or a decrease in the numberof glaucoma medications at the 6 month follow-up. While the numbers were quite small, both cohorts showed similar IOP reduction and control at six months and beyond, with a mean IOP between 10 and 15 mmHg, with a need for mean of 1 to 1.5 glaucoma drops. While not statistically significant, the success rate in the non-uveitis patients with simple glaucoma tended to be higher at 90.9%, compare to 75.0% in patients with uveitic glaucoma. The rate of complications was similar in both groups, with bleb leaks occurring most commonly - in 36.4% of controls verses 25.0% of eyes with uveitic glaucoma. The authors concluded that the Ex-PRESS glaucoma device offers a well-tolerated and effective surgical alternative for the management of IOP in patients with uveitic glaucoma.

Together, these studies highlight the high prevalence and often serious nature of OHT/glaucoma in patients with uveitis, particularly those with chronic and severe inflammation requiring repeated and/or long-term use of corticosteroids. Management of OHT/glaucoma is often complicated, but is best directed at the underlying cause(s) of elevated IOP. Surgical control of IOP can be effective, although, when possible, should be reserved for eyes with inactive inflammation.