and Ronnie George2
Department of Uvea and Medical Retina, Sankara Nethralaya, No 18, College Road, Nungambakkam, Chennai, Tamil Nadu, India
Senior Consultant, Smt Jadhavbai Nathmal Singhvee, Department of Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, No 18, College Road, Nungambakkam, Chennai, Tamil Nadu, India
The sight-threatening complications of uveitis include damage to the retina and glaucoma. Elevated intraocular pressure (IOP) is an important secondary complication that may result from ocular inflammatory sequelae or as a side effect of corticosteroids used to treat the inflammation .
Secondary glaucoma is more common in Fuchs’ heterochromic uveitis, Posner-Schlossman syndrome, uveitis associated with herpes infection, and juvenile idiopathic arthritis (JIA) [2, 3]. Approximately 20 % of patients with uveitis develop glaucoma without age, race, or sex predilection . In JIA, the frequency is as high as 46 % [2, 3].
The incidence of glaucoma is more common in chronic than in acute uveitis [5, 6]. Additionally, the development of secondary glaucoma is more frequent in uveitic eyes of corticosteroid nonresponders than in responders .
In the initial episodes of intraocular inflammation, the IOP is often reduced as a result of aqueous humor hyposecretion secondary to ciliary body inflammation coupled with increased uveoscleral outflow. Over time, multiple mechanisms can conspire to increase the resistance to aqueous outflow during episodes of uveitis. The ensuing imbalance between aqueous production and resistance to aqueous outflow from inflammation may lead to a subsequent rise in IOP.
Secondary Open-Angle Glaucoma
Increased outflow resistance occurs as a result of mechanical obstruction of the trabecular meshwork, which may be blocked by inflammatory cells or precipitates, proteins, debris, or fibrin liberated from a disrupted blood-aqueous barrier.
Swelling or dysfunction of the trabecular lamellae or endothelium may result in increased resistance to aqueous outflow .
Increased levels of protein in the aqueous due to increased permeability of the blood-aqueous barrier may lead to IOP elevation.
Cytokine and prostaglandin-mediated inflammation in uveitic eyes are known to cause elevated IOP.
Scarring and obliteration of trabecular meshwork beams or Schlemm’s canal or overgrowth of a fibrovascular membrane in the angle, as seen in chronic uveitis, can result in the obstruction of aqueous outflow.
Corticosteroids have been reported to cause biochemical and morphological changes in the trabecular meshwork, increasing the resistance to outflow.
Secondary Angle-Closure Glaucoma
With pupillary block: occurs when anterior chamber inflammation results in 360° posterior synechiae, blocking the flow of aqueous from the posterior chamber into the anterior chamber, resulting in iris bombé. Typical broad-based peripheral anterior synechiae can also result in total closure of the angle.
Without pupillary block: develops when inflammation and edema cause the ciliary body to rotate forward, closing the angle .
Combined Mechanism Glaucoma
Uveitic Conditions Associated with Glaucoma
Many different types of uveitis have been associated with glaucoma, but certain disorders may have a relatively higher risk.
Fuchs’ Heterochromic Iridocyclitis
It is a rare, idiopathic, chronic, low-grade iridocyclitis, without synechiae, with heterochromia, and with low-grade anterior chamber reaction with diffuse, small, stellate keratic precipitates, posterior subcapsular cataract, and secondary open-angle glaucoma. Glaucoma is believed to be the major long-term threat to vision, generally persisting after uveitis has subsided. Treatment of the inflammation with corticosteroids may further increase the IOP. Medications, particularly aqueous suppressants, may be effective in controlling glaucoma initially, although the glaucoma is resistant to medical therapy and may require surgery when chronic [9, 10].
It is also known as glaucomatocyclitic crisis and presents typically with unilateral recurrent episodes of mild cyclitis and heterochromia. Though inflammatory signs may be minimal, rise of IOP may be in the range of 40–70 mmHg during an acute attack. There may be a relationship between this syndrome and the development of primary open-angle glaucoma . Vascular incompetence due to segmental iris ischemia is associated with the release of prostaglandins, inflammation, and a subsequent rise in IOP. Although the pathogenesis of Posner-Schlossman syndrome remains unknown, possible associations include an immunogenetic factor involving HLA-Bw54 , viral infections (herpes simplex and cytomegalovirus) , gastrointestinal disease, and various allergic conditions . The prognosis for control of IOP in patients with glaucomatocyclitic crisis is good . Currently, the favored initial treatment is a topical nonsteroidal anti-inflammatory drug (NSAID) to control inflammation . Topical steroids, oral NSAIDs, or carbonic anhydrase inhibitors may also be used.
Juvenile Idiopathic Arthritis
The prevalence of glaucoma in JIA-associated uveitis has been reported in the range of 14–27 % . Patients with persistent low-grade inflammation are at greatest risk for developing glaucoma and an aggressive approach to treatment may reduce the risk of blindness. In JIA, glaucoma commonly occurs with open angles but may be of pupillary block, secondary angle-closure type, as a result of formation of posterior synechiae.
Medical management includes topical steroids, cycloplegics, regional steroid injections, and brief systemic steroid therapy. An oral NSAID may be used if inflammation recurs with steroid withdrawal. Immunomodulatory therapy with methotrexate has a high efficacy and low toxicity. Biologic response modifiers may also be tried in treatment failures. The management of glaucoma may be medical or surgical. Medical treatment is with topical beta blocker and sympathomimetics. Carbonic anhydrase inhibitors and prostaglandin analogues may be added if required . However, the use of PG analogues can often result in an inflammatory response and they should be withheld as a last resort.
Glaucoma surgery secondary to uveitis presents challenges as the postoperative inflammatory response is often magnified and complicates both control of the uveitis and IOP. Although goniotomy surgery is successful in many cases of childhood uveitic glaucoma, it was found to be less successful in eyes that were aphakic or eyes that had peripheral anterior synechiae . In eyes with significant peripheral anterior synechiae and a predominantly closed angle, a glaucoma drainage device as initial surgery may be considered. Thus, in determining appropriate surgical management of uveitic glaucoma, it is important to take into consideration whether the angle is open or not and the extent of synechia formation.
Compared with other surgical options, goniotomy offers higher rates of success, with fewer risks of complications such as infection, exacerbation of uveitis, or hypotony. It requires less operating time and preserves conjunctiva for future interventions. Goniosurgery is considered an effective, low-risk surgical intervention in the face of failure with maximal medical therapy. However, it requires expertise, a predominantly open angle, and a gonioscopic view, which may be difficult in cases of elevated IOP or severe band keratopathy. The placement of a glaucoma drainage device, particularly a valved implant, offers immediate IOP reduction and can be considered in eyes with significant synechia formation or those that immediately failed goniotomy. Glaucoma drainage devices are standard treatment for adult uveitic glaucoma [17–19]; however, studies on their use in children are limited by small patient numbers and relatively short follow-up [20, 21]. Problems with drainage devices include strabismus, corneal decompensation, increased inflammation, cataract, and pupil peaking [22, 23]. It has been found that in eyes with adequate IOP and uveitis control after goniotomy or glaucoma drainage device placement, cataract removal did not exacerbate the glaucoma . However, any surgical intervention for a child with glaucoma must consider a strategy that minimizes ocular damage while maximizing chances for vision preservation and IOP control over decades.
Secondary glaucoma is the most common complication in patients with herpetic uveitis . An estimated 28–45 % of patients with herpes simplex virus (HSV) keratouveitis develop transient elevated IOP , and 10–54 % may present with secondary glaucoma .
An acute rise in IOP in the presence of active iridocyclitis is the hallmark of a herpetic etiology . These hypertensive episodes are attributed to inflammation of the trabecular meshwork (TM) . This is supported by normalization of IOP in response to topical corticosteroids. The increase of IOP can also be secondary to swelling and obstruction of the TM by inflammatory cells and debris. Synechia formation may be seen typically during an episode of severe herpetic iridocyclitis [29, 30].
Inflammation of cells in the TM (trabeculitis) due to HSV-1 infection during corneal endotheliitis and uveitis is a major risk factor for glaucoma. Immunoreactivity for HSV-1 in the trabeculum has been demonstrated to induce inflammation of human TM cells, which impedes aqueous outflow and increases IOP. Cultured human TM cells are susceptible to HSV-1 entry and replication. HSV entry into cells is a complex process that is initiated by specific interactions of viral envelope glycoproteins and host cell surface receptors. Three classes of HSV entry receptors have been identified. They include herpes virus entry mediator (HVEM), nectin 1 and 2, and isoforms of 3-O-sulfotransferases. The relative abundance of the receptors varies with cell type, and this variation might influence the course of HSV-1-related trabeculitis .
Corticosteroids and Intraocular Pressure
Topical or systemic administration of steroids for the treatment of uveitis can lead to the development of ocular hypertension and vision loss, which is clinically similar to primary open-angle glaucoma. The risk of steroid-induced ocular hypertension varies by route of administration, duration of treatment, type of steroid, and preexisting history of glaucoma, among other factors. The elevated IOP associated with steroid treatment may be caused by increased aqueous humor outflow resistance and is associated with morphological changes in the TM. Human TM cells contain glucocorticoid receptors and are therefore targets for glucocorticoid action .
The possible mechanisms of steroid-induced TM dysfunction include:
Increased extracellular matrix deposition in the meshwork
The treatment of human TM cells with glucocorticoids has been shown to increase the expression of the extracellular matrix (ECM) collagen, glycosaminoglycans, elastin, and fibronectin. The expression of several extracellular proteinases including fibrolytic enzymes and stromolysin is decreased [34, 35].
Inhibition of TM cell functions
Dexamethasone inhibits phagocytic activity of cultured TM cells, resulting in accumulation of debris and pigment and reduction of outflow facility [34, 36]. Steroids stabilize lysosomes, resulting in accumulation of mucopolysaccharides, which in turn cause narrowing of the trabecular spaces and increased outflow resistance, consequently increasing IOP . In addition, steroid treatment causes a marked enlargement of TM cell nuclei and their DNA content .
Alterations in TM cytoskeleton
There are three major classes of cytoskeletal elements in the TM – microfilaments, microtubules, and intermediate filaments. The cytoskeleton is essential for controlling cell shape, adherence to ECM, motility, and phagocytic activity . Steroids alter trabecular cytoskeletons, causing a progressive reorganization of microfilament into polygonal lattice-like cross-linked actin networks that are reversible on withdrawal of steroids .
Increase in cell adhesion molecules
Steroid treatment causes realignment of gap junctions in TM cells, altering trabecular tissue permeability and reducing hydraulic transendothelial conductivity, which results in increased aqueous outflow resistance .
In addition to the abovementioned possible mechanisms for a rise in IOP due to TM dysfunction, intravitreal (IVT) steroids may also cause secondary ocular hypertension by:
Direct volume effect
An acute increase in vitreous volume immediately following IVT injection can induce a short-term increase of IOP .
Particulate matter obstructing the trabecular meshwork
The use of IVT steroids in noninfectious posterior uveitis has increased significantly in recent times because of their beneficial effects on macular edema secondary to uveitis. The two main methods of IVT steroid delivery are injection and implantation of sustained-release devices. IVT steroids are eliminated from the vitreous by two main mechanisms: the anterior pathway via aqueous humor that flows through the anterior chamber angle and the posterior pathway via permeation through the retina across the blood-retinal barrier into retinal and choroidal microvasculature . The longer the half-life of the steroid injected, the greater is the duration of effect.
Time Course of Ocular Hypertension (OHT) Following IVT Steroid
Triamcinolone Acetonide IVT Injection
Fluocinolone Acetonide IVT Implant
Dexamethasone IVT Injection and Implant
Following the injection, IOP rises as early as the first day and returns to baseline after approximately 1 month. The time to peak IOP is 60 days following implantation, returning to baseline within 6 months .
Risk Factors for Steroid-Induced OHT
Patient-Related Risk Factors
Higher baseline IOP and history of glaucoma:
Patients with baseline IOP ≥ 15 mmHg and preexisting glaucoma have an increased risk of OHT following IVT steroids .
Medication-Related Risk Factor
Type of steroid:
The prevalence of OHT post IVT steroid was highest in fluocinolone acetonide implants, followed by IVT TA injection and IVT dexamethasone implants .
Dosage of steroid:
A trend has been established between increased dose of steroid and increased risk of OHT .
Multicenter Uveitis Steroid Treatment (MUST) Trial
It was a randomized, partially masked trial conducted across 23 centers in the United States, the United Kingdom, and Australia over 2 years, to compare the benefits and risks of fluocinolone acetonide (FA) intravitreous implant (0.59 mg; Bausch & Lomb, Rochester, NY) with systemic steroid therapy in the treatment of noninfectious intermediate, posterior, and panuveitis .
Two-hundred and fifty five patients were randomized to one of the two groups by center and site of inflammation (intermediate versus posterior or panuveitis). Patients with bilateral uveitis received implants in each eye for which it was indicated. Systemic therapy typically started with high-dose prednisolone (up to 60 mg/day) and was then tapered to low doses (≤7.5 mg/day); immunosuppressive drugs were used when indicated .
The primary outcome of the study was the change in visual acuity from baseline to 2 years. Other important outcomes were elevation of IOP, incidence of glaucoma, visual field sensitivity, and quality-of-life measures . Patients assigned to receive FA implant had a 4- to 5-fold greater risk of developing IOP elevations compared with those who received systemic therapy, and about 1 in 6 uveitic eyes in the implant group developed glaucomatous optic neuropathy. Those who were already on IOP-lowering medication were at greater risk of developing glaucoma, as were those with active uveitis, presumably due to less outflow facility and initially impaired aqueous secretion, respectively .
In patients with substantial IOP elevation after implantation, filtering surgery was considered. Frequent follow-up, at least once in every 2 months, was recommended to monitor IOP elevation in patients receiving implant therapy .
Treatment of glaucoma in uveitis depends on the underlying disease. It is important therefore to treat the underlying systemic disease, the ocular inflammation, and the glaucoma.
Medical management consists of four main classes of agents. They include beta-adrenergic antagonists, carbonic anhydrase inhibitors, alpha-adrenergic agonists, and prostaglandin analogues [1, 57, 58]. Although prostaglandin analogues have been reported to exacerbate inflammation, they are safe and effective in lowering IOP in patients where the uveitis is controlled on immunomodulatory therapy . When indicated, careful monitoring for inflammatory signs is recommended .
If medical management fails to lower the IOP, surgical options including laser therapy, trabeculectomy, glaucoma drainage devices, and cycloablation may be tried.
Pupillary-block glaucoma may be treated with an argon or Nd:YAG laser iridotomy. If the iridotomy seals secondary to intense inflammation, a surgical iridectomy may be required .
Argon laser trabeculoplasty (ALT) usually fails to control the IOP in uveitic glaucoma because of angle alterations. Selective laser trabeculoplasty (SLT) however spares the adjacent cells from collateral thermal damage and preserves structural integrity and can be used when medical therapy fails .