In 1813, Joseph Beer first reported the association of uveitis and glaucoma, describing it as arthritic iritis followed by glaucoma and blindness. In 1891, Priesley Smith proposed the first modern classification of uveitic glaucoma. Later, specific types of uveitic glaucoma were described by Fuchs in 1906 (Fuchs heterochromic uveitis) and Posner and Schlossman in 1948 (glaucomatocyclitic crisis).
The mechanisms by which uveitis leads to elevated intraocular pressure (IOP) are numerous and poorly understood. In general, iridocyclitis affects both aqueous production and resistance to aqueous outflow, with the subsequent change in IOP representing a balance between these two factors. Inflammation of the ciliary body usually leads to reduced aqueous production, and combined with increased uveoscleral outflow often seen in inflammatory states, hypotony often is a consequence.
Prostaglandins, which have been demonstrated to be present in the aqueous of eyes with uveitis, are known to cause elevated IOP without a reduction in outflow facility. Mechanisms of increased resistance to aqueous outflow with both acute and subacute forms of uveitis usually are of the open-angle type and include obstruction of the trabecular meshwork by inflammatory cells or fibrin, swelling or dysfunction of the trabecular lamellae or endothelium, and inflammatory precipitates on the meshwork. Uveitis also may be associated with secondary angle-closure glaucoma.
Alteration of the protein content of the aqueous humor may be a cause of elevated IOP in uveitis. Increased levels of protein in the aqueous are a result of increased permeability of the blood-aqueous barrier, which leads to an aqueous that more closely resembles undiluted serum. This elevated protein content may, in fact, lead to aqueous hypersecretion and IOP elevation.
The treatment of the uveitis can lead to elevated IOP. Although corticosteroids have proven to be effective in relieving inflammation, prolonged administration can result in elevated IOP. Corticosteroids increase IOP by decreasing aqueous outflow. Several theories have been proposed to explain this phenomenon, including accumulation of glycosaminoglycans in the trabecular meshwork, inhibition of phagocytosis by trabecular endothelial cells, and inhibition of synthesis of certain prostaglandins.
United States
The prevalence of uveitis has been estimated at approximately 115 people per 100,000 in the United States. Approximately 20% of uveitis patients develop glaucoma.
International
The prevalence of uveitis has been estimated at 38-730 people per 100,000 worldwide. Approximately 20% of uveitis patients develop glaucoma.
Acute iridocyclitis usually produces symptoms; however, subacute iridocyclitis produces few or no symptoms but can have serious consequences because its complications may go undetected until advanced damage has occurred. If the inflammation is not controlled promptly, posterior synechiae and peripheral anterior synechiae (PAS) can form, leading to progressive angle closure and irreversible optic nerve damage.
No known racial predilection exists.
No known sexual predilection exists.
No known age predilection exists.
Few published reports are available that address the results of surgery in patients with uveitic glaucoma.
Hoskins et al achieved successful lowering of IOP in 6 of 9 eyes undergoing trabeculectomy for uveitic glaucoma.[12]
Hill et al showed a success rate of 81% at 12 months. The success rate of trabeculectomy with antimetabolite supplementation has been reported to be higher (71-100%).[13]
Wright et al reported that 3 of 24 patients undergoing trabeculectomy with mitomycin-C required subsequent drainage implants and that 7 of 24 patients lost 2 or more lines of Snellen acuity.[14]
Hill et al reported a success rate of 79% of eyes undergoing Molteno tube implantation.[15]
Ceballos et al reported a success rate of 91.7% in eyes undergoing Baerveldt drainage device placement for uveitic glaucoma.[16]
Ozdal et al showed a 2-year success rate of 60% in eyes undergoing Ahmed drainage device placement for uveitic glaucoma.[17]
Rachmiel et al reported similar 30-month results between eyes that underwent Ahmed glaucoma valve implantation with uveitic glaucoma compared to open-angle glaucoma eyes.[18]
For patient education resources, see the Glaucoma Center and Eye and Vision Center, as well as Glaucoma Overview, Anatomy of the Eye, Glaucoma FAQs, Understanding Glaucoma Medications, and Iritis.
Symptoms with acute iridocyclitis may include blurred vision, ocular pain, brow ache, and other ocular disturbances.
It often is difficult to know if the blurred vision is due to glaucoma, uveitis, or complications associated with the uveitis.
Pain is a frequent finding in acute iridocyclitis but often is not seen with subacute or chronic iridocyclitis. Some patients with markedly elevated IOP often have severe eye pain associated with corneal edema.
Ocular pain associated with elevated IOP often is referred to the brow on the affected side.
Other ocular disturbances (eg, photophobia, colored halos) may be associated with acute iridocyclitis and corneal edema, respectively.
The cornea may reveal band keratopathy, epithelial dendrites, or stromal scarring from herpetic infections. Corneal epithelial edema associated with acutely elevated IOP may give rise to a steamy appearance. Keratic precipitates may be present on the endothelium and have different characteristics that signify various diagnoses.
The hallmark of anterior uveitis is the presence of cells and flare in the anterior chamber. Cellular infiltration is due to release of chemotactic factors into the anterior chamber, and flare results from leakage of protein into the anterior chamber.
The iris should be examined for evidence of stromal atrophy, nodules, and posterior synechiae and PAS. Inflammation can result in engorgement of the blood vessels in both the iris stroma and the angle, which can be confused with rubeosis iridis.
The lens may have pigment on the anterior capsule, and posterior subcapsular opacification may be due to uveitis or to chronic corticosteroid therapy.
The vitreous cavity may show the presence of cells or snowball opacities.
The IOP may be low, normal, or high due to variations in aqueous secretion, amount of outflow obstruction, and dose of corticosteroids being used.
Gonioscopy should be performed to detect the presence of PAS and to assess the degree of angle closure.
The posterior segment should be examined, paying particular attention to the optic nerve to document morphologic changes consistent with glaucoma. Other possible posterior segment findings include cystoid macular edema, retinitis, perivascular sheathing, choroidal infiltrates, or retinal detachment.
Many specific uveitic entities may lead to the development of glaucoma. Some of the more common syndromes are listed below.
Juvenile rheumatoid arthritis
Juvenile rheumatoid arthritis (JRA) is defined as an arthritis, with a duration of at least 3 months, that begins prior to age 16 years and is diagnosed after exclusion of other causes of arthritis.
Glaucoma is a common complication of chronic uveitis in patients with JRA and most frequently is caused by progressive closure of the angle by PAS.
Since the uveitis frequently is treated with prolonged topical corticosteroids, steroid-induced glaucoma may occur. The reported incidence of glaucoma varies from 14-22%.
Fuchs heterochromic iridocyclitis
Fuchs heterochromic iridocyclitis (FHI) usually is unilateral and appears between the third and fourth decades with the insidious onset of mild, chronic anterior uveitis that usually is asymptomatic.
The glaucoma associated with FHI resembles primary open-angle glaucoma.
Gonioscopic evaluation may reveal multiple fine blood vessels, arranged either radially or concentrically in the trabecular meshwork.
Cataract is a constant feature of FHI, whereas glaucoma has been reported to occur in 6-47% of cases.
Low-grade inflammation does not need treatment with anti-inflammatory or immunosuppressive agents.
Posner-Schlossman syndrome
Posner-Schlossman syndrome is characterized by a number of unusual features, including unilateral involvement, recurrent attacks of often very mild cyclitis, marked elevation of IOP, open angle, and occasional heterochromia. The condition typically affects individuals aged 20-50 years and resolves spontaneously regardless of treatment.
Herpetic uveitis
Herpes simplex
Ocular manifestations of herpes simplex virus have been classified in accordance with the site of the corneal involvement and the presence or absence of associated uveitis, including herpetic superficial keratitis, disciform keratitis, disciform keratouveitis, and necrotic stromal keratitis. Disciform keratouveitis and necrotic stromal keratitis are associated more commonly with elevated IOP than epithelial keratitis.
The elevated IOP may be caused by trabeculitis, inflammatory obstruction of the trabecular meshwork, and angle closure in severe keratouveitis. The management of elevated IOP initially is directed toward controlling the viral replication and inflammation.
Varicella zoster
Ocular involvement of cutaneous varicella zoster occurs in two thirds of patients when the ophthalmic division of the trigeminal nerve is involved. Dendritic keratitis, stromal keratitis, and exposure keratitis are common.
IOP elevation and glaucoma are believed to be caused by decreased outflow facility due to trabecular obstruction from inflammatory debris, trabeculitis, and damage to the trabecular meshwork by recurrent inflammation. Treatment with systemic acyclovir when the cutaneous lesions are still active appears to reduce the risk of elevated IOP.[1]
Complications of uveitis include the following:
Laboratory investigation should be tailored to appropriate studies based on both the history and the physical findings and may include serology and/or skin tests.
See the list below:
Ocular imaging studies, including anterior-segment optical coherence tomography (OCT) and ultrasound biomicroscopy, are used to identify possible causes of inflammation and to understand the extent of structural changes caused by inflammation. Optic nerve imaging studies and visual field tests are useful to evaluate the stage of glaucoma and to plan appropriate treatment.
See the list below:
Treatment of glaucoma in uveitis depends on the underlying disease and on the individual patient. The treatment rationale consists of (1) treating any underlying systemic disease, (2) treating the ocular inflammation, and (3) treating the glaucoma. The ocular inflammation and glaucoma usually can be controlled with eye drops. Often, treatment of the inflammation will control the IOP.
It is a general rule that surgery should be avoided, when possible, in the inflamed eye. However, if surgery is required, the eye should receive maximal preoperative anti-inflammatory therapy to decrease the inflammation as much as possible.
In eyes with active uveitis, preparation for intraocular surgery should include perioperative topical and, occasionally, systemic corticosteroid therapy to avoid exacerbation of uveitis and failure of filtering surgery. If an elective surgical case is to be performed, the uveitis should be as quiet as possible for 3 months prior to surgery. One week prior to surgery, topical prednisolone 1% solution should be given hourly, and oral prednisone 40 mg daily should be considered.
At the conclusion of surgery, a depot of corticosteroid should be injected subconjunctivally. Postoperatively, topical and oral corticosteroids may be tapered according to control of the inflammation. In emergency cases, severe postoperative exacerbation of existing inflammation should be anticipated; therefore, aggressive perioperative topical and systemic corticosteroid therapy is warranted.
More recently, the injection of intraocular corticosteroids such as triamcinolone has been found to be effective in reducing macular edema and improving vision in uveitic eyes that have proved refractory to systemic or periocular corticosteroids. The effect is usually transient but can be repeated, although the adverse effects of cataract and raised intraocular pressure (IOP) are increased in frequency with intraocular versus periocular corticosteroid injections. This has led to the development of new intraocular corticosteroid devices designed to deliver sustained-release drugs and obviate the need for systemic immunosuppressive treatment.
The first such implant was Retisert, which is surgically implanted and is designed to release fluocinolone over a period of about 30 months. Callanan et al reported a reduced recurrence rate of uveitis from 62% to 20% during the 3-year postimplantation period after Retisert implantation.[1] Despite successful control of the uveitis, IOP elevation was common, and 40% of implanted eyes required glaucoma surgery. The most common adverse events associated with a sustained delivery fluocinolone acetonide device include eye pain, procedural complications, cataract progression (managed by standard cataract surgery), and elevated IOP (managed with the use of IOP-lowering eye drops or surgery. In one retrospective study, almost 50% of eyes followed over the course of the 8-year study period required glaucoma surgical intervention following Retisert implantation.[2]
More recently, Ozurdex, a bioerodible dexamethasone implant that can be inserted in an office setting, has gained approval for the treatment of macular edema and noninfectious posterior uveitis. This implant lasts approximately 6 months and has been found to be effective with a much better adverse effect profile than Retisert or intravitreal triamcinolone injection, at least for one injection.[3]
The Multicenter Uveitis Steroid Treatment Trial (MUST) was a randomized comparison of systemic anti-inflammatory therapy (systemic corticosteroid and/or corticosteroid-sparing immunomodulatory therapy) with the fluocinolone acetonide 0.59-mg implant in 279 patients with noninfectious intermediate, posterior, and panuveitis.[4]
At 24 months after randomization of patients to implant or systemic therapy, both groups had substantial improvement in visual acuity to a degree that was not significantly different (other than a small visual acuity improvement advantage in the implant group at 6 mo). In addition, most eyes with active uveitis at baseline were controlled within 9 months in both groups; however, control of uveitis was more frequent (88% vs 71% at 24 mo, P = .001) in the implant group. MUST also showed that relative to the systemic group, the implant group had a more than 4-fold higher rate of IOP elevation of 10 mm Hg or more, an absolute IOP of 30 mm Hg or more, and of needing medical and surgical treatments for elevated IOP.
Extensive posterior synechiae formation can lead to pupillary block glaucoma, so it is important to reestablish communication between the posterior and anterior chambers before a full-blown attack of pupillary block occurs. Performing laser iridotomy prophylactically is preferable to performing this procedure during an attack of acute angle-closure glaucoma because visualization of the iris may be difficult due to corneal edema caused by high IOP.
An argon laser or an Nd:YAG laser may be used to perform the iridotomy. In patients with uveitis, the Nd:YAG laser may have the advantage of inducing less postoperative inflammation and requiring less energy compared with the argon laser. Combined Nd:YAG laser and argon laser is preferable in eyes with thick brown irides. Also, combined laser may allow for a larger iridotomy, which may be less prone to close.
Transient anterior chamber inflammation occurs in all eyes after this procedure, so topical corticosteroids should be used as warranted postoperatively. When laser iridotomies are unsuccessful or when the use of a laser is not possible, a surgical iridectomy should be performed in cases of inflammatory angle-closure glaucoma. Since this procedure can lead to increased postoperative inflammation, topical and, sometimes, systemic corticosteroids are required in the perioperative period.
Trabeculectomy surgery is indicated for eyes with closed-angle, open-angle, or combined mechanism glaucoma when IOP is believed to be too high, despite maximum tolerated medical and laser therapy. Due to an accelerated wound healing response in uveitis, the results of trabeculectomy generally are poor, particularly in young patients.
Antimetabolite therapy in association with trabeculectomy has been shown to improve the success rate of trabeculectomy in patients with a high risk of failure. Intraoperative application of mitomycin-C is used widely to supplement standard trabeculectomy. The mitomycin can be applied to the eye for a variable duration prior to or after dissection of the scleral flap. Irrigation of the subconjunctival tissues should be carried out to prevent intraocular exposure.
A 2017 retrospective study evaluated intermediate and long-term outcomes of mitomycin C–enhanced trabeculectomy as a first glaucoma procedure in uveitic glaucoma.[5] Seventy eyes were studied for a mean follow-up period of 77 months, with the probability of success at only 35.7% at 60 months. Hypotony was a common complication, seen in 30% of eyes.
Dhanireddy et al studied the outcomes of the Ex-Press filtration device in patients with uveitic glaucoma. Surgical success was seen in 90.9% of the eyes in the simple glaucoma group, compared to 75% of eyes in the uveitic glaucoma group.[6]
Drainage implants are designed to route aqueous from the anterior chamber to a posterior reservoir. They are particularly useful in cases with significant conjunctival scarring due to previous surgery. Drainage valves, such as the Ahmed valve, may be safer than trabeculectomy, as less risk of hypotony exists, which can be seen in postoperative uveitic eyes due to decreased aqueous production.
In eyes with chronic uveitis, long-term corticosteroid therapy may induce glaucoma or glaucoma may occur secondary to the ocular inflammation. In these eyes, it would be beneficial to simultaneously control inflammation and IOP. To this end, a retrospective case series described 7 eyes of 5 patients in which a fluocinolone acetonide implantation was inserted and a glaucoma tube shunt was placed in a single surgical session.[7] This procedure was well tolerated and was associated with reduced inflammation, decreased concurrent systemic immunosuppressive therapy, and good IOP control.
Zivneyet al conducted a study to determine whether patients who underwent combined Ahmed tube shunt and Retisert implantation had superior outcomes than did patients with Ahmed implants only in the setting of uveitic glaucoma.[8] At 6 months, no significant differences in terms of mean IOP, mean number of IOP-lowering medications, visual acuity, surgical success, or adverse events were noted between Ahmed implantation alone or combined Ahmed and Retisert implantation in patients with uveitic glaucoma. However, Hennein et al found that patients who received Retisert implantation had lower IOP and used fewer glaucoma eye drops compared with control eyes at 1-year following Ahmed valve surgery.[9]
As a last resort, cycloablative techniques can be employed. Diode or Nd:YAG laser cyclophotocoagulation can be used to destroy the secretory ciliary epithelium, leading to decreased aqueous production. Unfortunately, cycloablative procedures often exacerbate the inflammation. These methods are reserved for eyes with poor visual potential due to the relatively high risk of further vision loss and phthisis bulbi.
Postoperative complications include the following:
Common anti-inflammatory treatment entails use of nonsteroidal anti-inflammatory drugs (eg, topical, systemic); corticosteroids (eg, topical, subconjunctival, systemic); and, rarely, immunosuppressive agents. Mydriatic-cycloplegic agents may be used to prevent or break posterior synechiae and to relieve pain and discomfort of ciliary muscle spasm. Available agents include atropine 1%, homatropine 1-5%, scopolamine, phenylephrine 2.5-10%, and tropicamide 0.5-1%.
Topical corticosteroids are effective in the control of anterior uveitis but vary in strength, ocular penetration, and adverse effect profile. Systemic corticosteroids are widely used for the management of posterior segment inflammation, which requires treatment, particularly when it is associated with systemic disease or when bilateral ocular disease is present. However, when ocular inflammation is unilateral, or is active in one eye only, local therapy has considerable advantages, and periocular injections of corticosteroid is a useful alternative to systemic medication and is very effective in controlling mild or moderate intraocular inflammation.
Many agents are available for lowering of IOP, including topical beta-blockers, adrenergic agents, and topical and systemic carbonic anhydrase inhibitors.
Miotics are avoided in uveitic glaucoma because of the risk of formation of posterior synechiae or a pupillary membrane. They also may increase inflammation by enhancing breakdown of the blood-aqueous barrier.
The role of prostaglandin analogs (PGAs) in uveitic glaucoma is unknown; PGAs have been used to help lower IOP in these often difficult to manage eyes. However, controversy exists concerning their use in uveitic patients owing to the theoretically higher risk of anterior uveitis, development of cystoid macular edema, and reactivation of herpes simplex keratitis. Little evidence suggests that PGAs disrupt the blood-aqueous barrier and only anecdotal evidence suggests an increased risk of these rare findings. PGA may be used in uveitic glaucoma if other topical treatments have not lowered IOP to the patient's target range.[10]
Markomichelakis et al, reported that latanoprost was safe and equally effective compared with a fixed combination of dorzolamide and timolol in the treatment of uveitic glaucoma.[11]
Clinical Context: Blocks beta1- and beta2-receptors and has mild intrinsic sympathomimetic effects.
Clinical Context: Nonselective beta-adrenergic blocking agent that lowers IOP by reducing aqueous humor production.
Clinical Context: Inhibits enzyme carbonic anhydrase, reducing rate of aqueous humor formation, which, in turn, reduces IOP.
Clinical Context: Reduces aqueous humor formation by inhibiting enzyme carbonic anhydrase, which results in decreased IOP.
Clinical Context: Both act by inhibition of carbonic anhydrase in the ciliary processes that decreases aqueous humor formation.
Lower IOP by decreasing aqueous production. Oral and topical forms are available.
Clinical Context: Reduces IOP whether or not accompanied by glaucoma. Selective alpha-adrenergic agonist (alpha2) without significant local anesthetic activity. Has minimal cardiovascular effect.
Clinical Context: Selective alpha2-receptor that reduces aqueous humor formation and possibly increases uveoscleral outflow.
Lower IOP by a combination of decreasing production of aqueous and increasing aqueous outflow.
Clinical Context: Decreases IOP by increasing outflow of aqueous humor.
Clinical Context: A prostamide analogue with ocular hypotensive activity. Mimics the IOP-lowering activity of prostamides via the prostamide pathway. Used to reduce IOP in open-angle glaucoma or ocular hypertension.
Clinical Context: Prostaglandin F2-alpha analog. Selective FP prostanoid receptor agonist believed to reduce IOP by increasing uveoscleral outflow. Used to treat open-angle glaucoma or ocular hypertension. Now with BAK-free formulation called travoprost-Z.
Clinical Context: The mechanism of action is believed to be due, in part, to its ability to inhibit prostaglandin biosynthesis.
Clinical Context: Believed to inhibit cyclooxygenase, which is essential in the biosynthesis of prostaglandins.
Have analgesic and anti-inflammatory activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms also may exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.
Clinical Context: Inhibits the edema, fibrin deposition, capillary dilation, and phagocytic migration of the acute inflammatory response and capillary proliferation. Causes the induction of phospholipase A-2 inhibitory proteins.
Clinical Context: Believed to act by the induction of phospholipase A-2 inhibitory proteins. Shows a lower propensity to increase IOP than dexamethasone in clinical studies.
Clinical Context: Nonsteroidal anti-inflammatory prodrug for ophthalmic use. Following administration, converted by ocular tissue hydrolases to amfenac, an NSAID. Inhibits prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production. Indicated for treatment of pain and inflammation associated with cataract surgery.
Clinical Context: Nonsteroidal anti-inflammatory drug for ophthalmic use. Blocks prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2. Indicated to treat postoperative inflammation and reduce ocular pain after cataract extraction.
Clinical Context: Ophthalmic corticosteroid indicated for inflammation and pain associated with ocular surgery. Available as a 0.05% ophthalmic emulsion.
Clinical Context: Selective alpha-2 adrenergic receptor agonist with a nonselective beta-adrenergic receptor inhibitor. Each of them decreases elevated IOP, whether or not associated with glaucoma.
Clinical Context: Carbonic anhydrase inhibitor that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably slows bicarbonate ion formation with subsequent reduction in sodium and fluid transport.
Timolol is a nonselective beta-adrenergic receptor blocker that decreases IOP by decreasing aqueous humor secretion and may slightly increase outflow facility.
Both agents administered together bid may result in additional IOP reduction compared with either component administered alone, but reduction is not as much as when dorzolamide tid and timolol bid are administered concomitantly.