Pediatric Uveitic Glaucoma
Pediatric uveitis is a relatively rare condition with the majority of cases being idiopathic. The most common identifiable cause of pediatric uveitis is juvenile idiopathic arthritis (JIA); 14-47% of all pediatric uveitis cases are due to JIA. Population-based studies in North America and Europe estimate the prevalence of pediatric uveitis to be approximately 30 cases per 100,000 population.
Studies have reported that between 5-42% of those pediatric uveitis patients will develop glaucoma or ocular hypertension. 5.3-19% of all pediatric glaucoma cases are caused by uveitis.
Pediatric uveitic glaucoma progresses similarly to the adult course of the disease. Chronic inflammation drives pathological changes to the iridocorneal angle, elevating intraocular pressure (IOP) which if left untreated leads to glaucomatous optic neuropathy. The resulting glaucoma can be of the open-angle or closed-angle variety. In open-angle uveitic glaucoma, the cellular inflammatory materials, proteins, or chemical mediators within the eye plug the trabecular meshwork with subsequent aqueous outflow obstruction. Other mechanisms include trabeculitis, altered vascular permeability, or steroid-induced ocular hypertension/glaucoma. Chronic inflammation of the trabecular meshwork leads to permanent scarring. Angle-closure glaucoma results from peripheral anterior synechiae (PAS), posterior synechiae, or fibrinous membrane formation with pupillary block.
Steroid-induced IOP elevation has been reported in one-fifth of children treated with different forms of corticosteroids. Steroid-induced ocular hypertension in children tends to be more aggressive with earlier and more rapid glaucomatous progression if left untreated.
Increased duration and severity of the intraocular inflammation have been associated with more severe presentations of glaucoma. Less commonly, intermediate, and posterior uveitis may lead to glaucoma but infrequently compared to anterior uveitis. Glaucomatous changes to the optic nerve can occur rapidly but often present ten or more years after the initial onset of uveitis.
Treating the systemic inflammatory condition and controlling the uveitis are central to preventing subsequent glaucoma and ocular hypertension. Effectively managing ocular inflammation early in the course of disease reduces the risk of secondary glaucoma. Co-management with rheumatology will often be necessary given pediatric uveitic glaucoma’s strong correlation with systemic inflammatory conditions.
In addition to controlling inflammation, lowering IOP is the gold standard for minimizing the progression of glaucoma. Data on target IOP in the pediatric patient is scarce, with most information coming from primary congenital glaucoma (PCG) treatment. Children undergoing IOP lowering surgery for PCG achieved stability of their neuropathy between 6-15 mmHg. Glaucomatous changes to the optic nerve or visual field in older children can be used as evidence to modify the target IOP.
In the setting of uveitis and steroid use it is difficult to determine whether the rise in IOP is a result of inflammation or steroid-induced ocular hypertension. In the presence of active inflammation the rise in IOP is usually secondary to uveitis. Steroid frequency should be increased to control inflammation and subsequently the IOP will lower. However, in absence of inflammation, ocular hypertension is most likely due to steroid response and lowering the dose or cessation of steroids may be needed.
Medical therapy consists of topical eye drops in combination or monotherapy. It is essential to consider that systemic drug absorption is greater in children than in adults. Increased drug plasma levels put them at an increased risk for adverse effects. Punctal occlusion and gel formulations are recommended to minimize risk. Studies analyzing success rates of topical medications alone in pediatric uveitic glaucoma showed success in only 17% and 26% of patients.
Timolol is considered a first-line monotherapy that is generally well tolerated. Timolol gel-forming solution’s once-a-day timing promotes good compliance. Systemic side effects include hypotension, bradycardia, and bronchospasms and are therefore contraindicated in children with arrhythmias, asthma, or apnea. Betaxolol is a selective β-2 antagonist that reduces the risk of side effects. β -blockers’ mechanism of action is decreased production of aqueous humor from the ciliary body.
Carbonic anhydrase inhibitors (CAI)
(Dorzolamide, Brinzolamide, Acetazolamide)
Topical CAIs Dorzolamide and Brinzolamide are most often used as an adjunct therapy in combination with a β-blocker when monotherapy does not reach the target IOP. They are prescribed twice daily (BID) in combination or three times daily (TID) as monotherapy. Oral acetazolamide has also been shown to effectively lower IOP but is associated with more side effects. Contraindications include hypokalemia, hyponatremia, and sulfonamide hypersensitivity. The mechanism of action of CAIs is decreased production of aqueous humor from the ciliary body.
Prostaglandin analogs (PGA)
PGAs are prescribed as once-daily topical monotherapy with a mechanism of action of increasing uveoscleral outflow. Recent data showed that patients already affected by uveitis and glaucoma are not at an increased risk for uveitis and CME while using PGAs.
A retrospective review by Bello et al. examined the use of PGAs in children with glaucoma to determine their likelihood of causing uveitis. Included in the study were 147 eyes (103 patients) with glaucoma. Of the 20 eyes (15 patients) with a history of chronic uveitis, five eyes (five patients) experienced recurrences that were explained by an improper tapering of their topical steroid or methotrexate.
Brimonidine is not preferred in pediatric patients due to its ability to cross the blood brain barrier and commonly causes sleepiness and lethargy. It is absolutely contraindicated in children under two years old and in children with cardiovascular disorders due to potentially life-threatening complications. Children older than six years old and weighing more than 20kg have less risk of side effects. Their mechanism of action is decreased production of aqueous humor from the ciliary body and increased uveoscleral outflow. They are prescribed BID. Apraclonidine is used three times daily short-term to control IOP before and after glaucoma surgeries. In contrast to Brimonidine, several studies have demonstrated the safety of Apraclonidine use in both infants and children.
These are primarily used before and after surgery or in patients with aphakia. They are contraindicated in active uveitis.
Goniotomy utilizes an internal approach to open the trabecular meshwork with a sharp instrument or laser to improve outflow. Both goniotomy and trabeculotomy procedures have exhibited similar success rates in pediatric glaucoma dating back to 1984.
A study conducted by Ho and colleagues evaluated the efficacy of goniotomy in 31 pediatric uveitic glaucoma patients (40 eyes). Surgical success was achieved in 72% of eyes at final follow up (98.9 months). The mean IOP in the surgical success group decreased from 35.8±5.9 mmHg to 14.7±2.9 mmHg at the final follow-up (P<.001). 22 eyes (55%) maintained an IOP of <21 without glaucoma medications at final follow-up. Predictors of success were phakic lens status (P=.004) and age <10 years old (P=.03). The main complication was intraoperative hyphema (80%) that resolved within one week.
Freedman et al. evaluated 16 eyes of 12 pediatric uveitic glaucoma patients who have undergone goniotomy. The mean pre-operative IOP was 31.5±4.3 mmHg and decreased to 12±12.5 mmHg at final follow-up (mean 32.4 months) (P<.0001). Post-operative transient hyphema occurred in 9 eyes (56%).
Wang et al. demonstrated a statistically significant decrease in IOP from 31.4±7.6 mmHg to 15.0±3.6 mmHg post-operatively (P<.001) at final follow-up (mean 31 months). There was a considerable decrease in post-operative glaucoma medication requirements from 4.2±1 to 0.4±1 at final follow-up (P<.001).
Wiese et al. studied 21 eyes (17 children) with uveitic glaucoma who underwent mitomycin-C augmented (MMC) trabeculectomy. They reported that 70% of children had an IOP <15 mmHg after 1 year post-operatively. Heinz et al. presented 16 eyes (16 patients) who underwent trabeculectomy and reported a reduction in the mean IOP from 28.3±5.7 mmHg pre-operatively to 11.6±4.7 mmHg at one year post-operatively.
The essential nature of tumor necrosis factor (TNF) inhibition in the trabeculectomy procedure for JIA-related uveitic glaucoma was suggested in 2015 by Leinonen et al. 29 eyes (29 patients) were included in the study. Compared to trabeculectomy with MMC alone, trabeculectomy with MMC and TNF inhibitors was associated with more successful outcomes (P=.003). Success was defined as IOP ≤21mmHg without glaucoma medications and without the need for further IOP lower surgeries. By Kaplan-Meier analysis, 5-year success rates for trabeculectomy with MMC alone was only 16%, while 5-year success for trabeculectomy with MMC and TNF inhibitors was 73%.
A retrospective review of 8 eyes (8 patients) conducted by Heinz et al. reported a mean reduction of IOP from 30.3±6.3 mmHg to 18.5±11.4 mmHg at one-year post-operatively. They compared the MMC-augmented trabeculectomy group (16 eyes) to those who underwent deep sclerectomy. The deep sclerectomy group was associated with a statistically significant higher rate of failure when compared to trabeculectomy (P=.041). Deep sclerectomy failed to achieve IOP ≤21 mmHg without medications in 50% of eyes at final follow up (mean 29.4 months) while trabeculectomy failed to achieve IOP ≤21 mmHg without medications in only 6% of eyes at final follow up (mean 21.5 months).
Glaucoma drainage devices (GDD)
The first study of GDD in JIA-associated glaucoma was conducted by Välimäki et al. including 27 eyes (19 patients) who underwent Molteno GDD. The mean IOP was decreased from 38.3±5.6 mmHg pre-operatively to 14.4±4.3 mmHg (P<.001) at the final follow-up (mean 40 months). Glaucoma medications were reduced from 2.7±0.9 pre-operatively to 1.0±1.1 post-operatively (P<.001). 90% of patients achieved success which was defined as IOP ≤22 mmHg and ≥6 mmHg without loss of light perception and equal or fewer glaucoma medications at 52 months post-operatively.
Kafkala et al. evaluated the efficacy of Ahmed glaucoma valve in 7 pediatric uveitic glaucoma eyes (6 patients). At the final follow-up (mean 36.8 months), all 7 eyes had an IOP between 7 and 18 mmHg. Glaucoma medications were decreased from 3±0.82 to 0.71±0.75 at final follow-up (P=.001).
A case series conducted Bohnsack et al. reported a success rate of 80% at final follow-up (mean 102 months) after GDD implantation in 5 eyes with pediatric uveitic glaucoma. Success was defined as a final IOP <21 mmHg without inflammation, serious complications or need for further IOP lowering surgery. The mean IOP was decreased from 27.2±7.6 mmHg pre-operatively to 13.6±3.2 mmHg at the final follow-up (mean 57.6 months). Glaucoma medications decreased from 3.0 ±1.2 pre-operatively to 0.6 ±0.9 at final follow up. The data included both Ahmed and Baerveldt devices and reported no intraoperative complications.
In patients with co-existing corneal pathologies, combined pars-plana vitrectomy and sulcus placement of the GDD may be needed.
A retrospective review conducted by Heinz et al. included 19 pediatric uveitic open-angle glaucoma eyes who were treated with trans-scleral cyclophotocoagulation as a primary procedure. IOP was decreased by 8.8 mmHg after three sessions of treatments (P=.018), but only 6 eyes (32%) achieved IOP ≤21 with glaucoma medication at the final follow-up (mean 10.1 months). None of the patients developed hypotony or serious adverse events.
Minimally invasive glaucoma surgery (MIGS)
Sachdev et al. published a case series in 2020 showing promising results from gonioscopy-assisted transluminal trabeculotomy (GATT) in JIA-associated glaucoma. Sachdev et al. presented three eyes from three patients with a 40% to 66% reduction in mean IOP following GATT. The procedure resulted in one patient requiring fewer glaucoma medications post-operatively, and two patients were able to discontinue their glaucoma medications altogether.
Table 1: Summary of the retrospective case reviews analyzing surgical therapy outcomes specific to pediatric uveitic glaucoma.
|Name of study, year published⬇||Procedure||# of eyes (# of patients)||Pre-operative IOP (Mean±SD)||Post-operative IOP (Mean±SD)||Pre-operative medications (Mean±SD)||Post-operative medications (Mean±SD)||Follow-up time, months
|Definition of success||Success Rate|
|Wang et al., 2016||Trabeculotomy||28(22)||31.4±7.6||15±3.6 at final follow-up||4.2±1.1||0.4±1.0||31±17.8||IOP <22 and ≥6 with or without medications||81.8% at final follow-up|
|Leinonen et al., 2015||Trabeculectomy with MMC||15(15)||96 (12-224.4)||IOP ≤21, without medications or futher surgery||57% at 1 year, 16% at 5 years, and 0% 10 years|
|Trabeculectomy with MMC and TNF inhibitors||14(14)||87.6 (12-152.4)||IOP ≤21, without medications or futher surgery||73% at 1 year, 5 years, and 10 years|
|Wiese et al., 2014||Trabeculectomy with MMC||21(17)||31.1±6.7||10.1±4.7 at 1 year||59.5 ± 23.3||1. IOP ≤15 without medication
2. IOP ≤15 with medication
|1. 55% at 1 year, 38% at 5 years.
2. 70% at 1 year, 62% at 5 years
|Bohnsack et al., 2012||GDD (Ahmed and Baerveldt)||5(5)||27.2±7.6||13.6±3.2 at final follow up||3.0±1.2||0.6±0.9||28.8±20.4||IOP <21 without inflammation, serious complications or need for further IOP lowering surgery||80% at final follow-up|
|Goniotomy||22(22)||34.0±7.8||13.5±4.5 at final follow up||3.3±1.1||1.5±1.4||57.6±52.8||IOP <21 without inflammation, serious complications or need for further IOP lowering surgery||76% at 1 year, 57% at 2 years, 48% at 10 years|
|Heinz et al., 2011||Trabeculectomy||16(16)||28.3±5.7||11.6±4.7 at 1 year||3.3||21.5||1. IOP ≤21 without glaucoma meds
2. IOP ≤15 without glaucoma meds
|1. 88% at last visit
2. 75% at last visit
|Modified deep sclerotomy||8(8)||30.3±6.3||18.5±11.4 at 1 year||3.4||29.4||1. IOP ≤21 without glaucoma meds
2. IOP ≤15 without glaucoma meds
|1. 50% at last visit
2. 38% at last visit
|Heinz et al., 2006||Transscleral diode laser cyclophotocoagulation||19(12)||30.2±5.5||28.7±6.4 before third treatment||3.3±0.7||2.7±1.6 after third treatment||10.1±9.3 (3–30)||IOP ≤21 with medications||32% at final follow-up|
|Kafkala et al., 2005||GDD (Ahmed)||7(6)||37 ± 8||12.1±3.4 at final follow-up||3||0.71||36.8 (6-60)||IOP <22 and >4 at final 2 follow-ups, with or without medications||100% at 3 months|
|Ho et al., 2004||Goniotomy||40(31)||35.8±5.9*||14.7±2.9 at final follow-up*||2.9±1.1||1.6±1.1||98.9±87.8 (2-324)||IOP ≤21 without medications||55% at final follow-up|
|Freedman et al., 2002||Goniotomy||16(12)||32.3±4.6||12±2.5 at final follow-up||2.5±1.1||1.4±1.1||32.4 (6-84)||IOP ≤21 after one or two goniotomies with or without medications||75% at final follow-up|
|Välimäki et al., 1997||GDD (Molteno)||27(19)||38.3 ± 5.6||14.4 ± 4.3 at final follow-up||2.7±0.9||1.0 ± 1.1||40 (6-116)||IOP ≤22 and ≥6 at the final 2 follow-ups, with equal or fewer medications||89% at final follow-up|
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