Inflammation of the ciliary body usually results in decreased aqueous production. Decreased aqueous secretion in eyes with normal outflow facility results in the decreased intraocular pressure or hypotony that is frequently encountered in eyes with acute uveitis. If, however, there is concomitant or greater impairment of the aqueous outflow in eyes with decreased aqueous production as may happen due to decreased aqueous perfusion of the trabecular meshwork, the intraocular pressure may be normal or possibly increased.⁸ There is a disagreement as to whether aqueous hypersecretion can result from the breakdown of the blood-aqueous barrier in uveitic eyes. If this was possible, increased aqueous production could contribute to the development of high intraocular pressure in uveitic eyes. Relative to ciliary body function, the most likely explanation for the elevated intraocular pressure in eyes with intraocular inflammation, however, is that the aqueous production remains normal while the aqueous outflow is reduced.

Alteration in the aqueous humor content was one of the first hypotheses offered to explain the onset of elevated intraocular pressure associated with uveitis. The influx of proteins into the eye resulting from the breakdown of the blood-aqueous barrier is the earliest change in uveitic eyes that can affect the balance of aqueous flow and increase the intraocular pressure.⁹ In normal eyes, the protein content of the
aqueous humor is approximately 100 times less than that in normal serum.¹⁰ However, when the blood-aqueous barrier is disrupted, the aqueous protein concentration can resemble that of undiluted serum. An increased aqueous protein concentration can impair aqueous outflow by decreasing the flow rate of aqueous into the anterior chamber angle, mechanically obstructing the trabecular meshwork, and causing dysfunction of the endothelial cells lining the trabecular meshwork beams. In addition, the proteins promote the development of posterior or peripheral anterior synechiae. If the integrity of the blood-aqueous barrier is restored, the effect of the aqueous protein concentration on the aqueous outflow and intraocular ocular pressure can be reversed. However, if the permeability of the blood-aqueous barrier is permanently damaged, leakage of serum proteins into the anterior chamber may persist even after the intraocular inflammation has resolved.

An influx of inflammatory cells that secrete inflammatory mediators such as prostaglandins and cytokines occurs shortly after the protein influx in eyes with uveitis. Inflammatory cells in the anterior segment are believed to have a more direct effect on the intraocular pressure than aqueous proteins. Inflammatory cells can increase the intraocular pressure by infiltrating the trabecular meshwork and Schlemm canal, creating a mechanical obstruction to aqueous outflow. The risk for increased intraocular pressure is higher in granulomatous uveitis because of the greater infiltration of macrophages and lymphocytes compared with nongranulomatous uveitis entities in which the cellular infiltrate may contain higher proportions of polymorphonuclear cells.⁵ Chronic, severe, or recurrent episodes of uveitis can cause permanent damage to the trabecular meshwork from injury to the trabecular endothelial cells, scarring in the trabecular meshwork and Schlemm canal, or from the formation of a hyaline membrane overlying the trabeculum.⁶ Inflammatory cells and cellular debris in the anterior chamber angle can also contribute to the formation of peripheral anterior and posterior synechiae.

Prostaglandins are known to produce many of the signs of ocular inflammation, including vasodilatation, miosis, and increased vascular permeability, and have complex interactions on the intraocular pressure.¹¹,¹² Whether or not prostaglandins are directly responsible for increased intraocular pressure in uveitic eyes is unclear. Through their action on the blood-aqueous barrier, they may indirectly contribute to increased intraocular pressure by enhancing the influx of aqueous protein, cytokines, and inflammatory cells. Alternatively, they can also decrease the intraocular pressure by the enhancement of uveoscleral outflow.

Trabeculitis is diagnosed when the intraocular inflammatory response is localized to the trabecular meshwork. Clinically, trabeculitis is characterized by the presence of inflammatory precipitates on the trabecular meshwork in the absence of other signs of active intraocular inflammation such as keratic precipitates, aqueous cells, or flare. The aqueous outflow in trabeculitis is decreased by mechanical obstruction of the trabecular meshwork resulting from the accumulation of inflammatory cells, swelling of the trabecular beams, and decreased phagocytosis of the trabecular endothelial cells. Because aqueous production in the ciliary body function is usually unaffected, the intraocular pressure in eyes with trabeculitis can be significantly elevated from the reduced aqueous outflow.⁶

Corticosteroids are considered first-line drug therapy for patients with uveitis. Whether given topically, systemically, or by periocular or
sub-Tenon injection, corticosteroids are known to accelerate the formation of cataracts and cause increased intraocular pressure via increased outflow resistance.¹³ This may happen in three ways: by inducing physical and mechanical changes in trabecular meshwork microstructure, by increasing the deposition of substances in the trabecular meshwork, and by decreasing the breakdown of substances in the trabecular meshwork.¹³ Inhibition of prostaglandin synthesis is another mechanism by which corticosteroids may impair outflow facility.

The terms steroid-induced ocular hypertension and steroid responder are used to refer to patients who develop elevated intraocular pressures related to corticosteroid therapy. After 4 to 6 weeks of topical steroid treatment, 35% of the population will have an increase in intraocular pressure of at least 5 mm Hg, and 5% will have greater than a 16 mm Hg rise.¹⁴ The risk of a steroid response is related to the duration and the dose of corticosteroid therapy. Patients with glaucoma, glaucoma suspects, first-degree relatives of people with glaucoma, the elderly, patients with connective tissue disease, type 1 diabetics, high myopes, and children younger than 10 years are at greatest risk for a steroid response.⁶,¹³ Although steroid-induced ocular hypertension may occur at any time after the induction of corticosteroid therapy, it is most frequently detected within 2 to 8 weeks of the treatment being started. Compared with the other routes of administration, local steroids are most frequently associated with a steroid response. Periocular and intravitreal steroid injections can cause an acute pressure rise in susceptible patients that may be difficult to control. In most cases, the intraocular pressure returns to normal after discontinuation of the corticosteroid; however, in some cases, particularly following a steroid depot injection, the intraocular pressure can remain elevated for 18 months or longer. In these cases, surgical removal of the depot steroid or filtration surgery may be required if the intraocular pressure cannot be controlled medically (Fig. 14-1). For this reason, depot steroids should be avoided when possible in known steroid responders. A more recent steroid-delivery method for the treatment of posterior uveitis, the fluocinolone acetonide implant (Retisert), is associated with a 71% risk of an increase in intraocular pressure over 3 years; a combined surgery implanting the steroid device and a glaucoma drainage device may be beneficial in select patients.¹⁵,¹⁶

When a patient with uveitis who is being treated with corticosteroids develops an increased intraocular pressure, it is often difficult to know if the pressure rise is a result of the restored aqueous secretion, the impaired aqueous outflow caused by the intraocular inflammation, a steroid response, or a combination of all three. Although a fall in the intraocular pressure as the steroid is tapered may be evidence of steroid-induced ocular hypertension, the decline in pressure could also be secondary to improved outflow through the trabecular meshwork or a recurrence of inflammation with aqueous hyposecretion. If a steroid response that cannot be easily controlled medically is suspected in a patient who maintains active intraocular inflammation requiring systemic corticosteroids, this may be an indication for the initiation of a steroid-sparing agent. If steroid-induced ocular hypertension is suspected in a patient with controlled or quiescent uveitis, a reduction in the concentration, dose, or frequency of the corticosteroid used should be attempted.

Peripheral anterior synechiae are adhesions between the iris and the trabecular meshwork or cornea that can completely block or impair access of the aqueous to the trabecular meshwork. Best detected by gonioscopy, peripheral anterior synechiae are a common complication of anterior uveitis and occur more commonly in granulomatous than nongranulomatous causes of uveitis. Peripheral anterior synechiae result from the organization of inflammatory material that pulls the iris surface into the angle. They develop more frequently in eyes with preexisting narrow angles or those narrowed by iris bombé. The iris attachments are usually broad, covering large segments of the angle, but can also be patchy or peaked, affecting only small portions of the trabecular meshwork or cornea (Fig. 14-2). In cases of peripheral anterior synechiae related to uveitis, even though large portions of the angle may remain open, the patient may still have increased intraocular pressure because the remaining angle is functionally compromised because of prior inflammatory damage that may not be detectable by gonioscopy.⁵

In cases of recurrent or chronic uveitis, continued peripheral anterior synechiae formation can result in complete angle closure. Neovascularization of the iris and the angle should be sought in all cases of uveitis presenting with angle closure or extensive peripheral anterior synechiae. Contraction of the fibrovascular tissue in the angle or anterior iris surface may rapidly induce a complete and severe angle closure. Neovascular glaucoma secondary to uveitis is typically resistant to medical and surgical therapy and has a poor prognosis (Fig. 14-3).

Inflammatory cells, protein, and fibrin in the aqueous humor can stimulate posterior synechiae formation. Posterior synechiae are adhesions between the posterior iris surface and the anterior lens capsule, the vitreous face in aphakic patients, or the intraocular lens in pseudophakic individuals. The likelihood of developing posterior synechiae is related to the type, duration, and severity of the uveitis. The greater the extent of the posterior synechiae, the less the pupil is able to dilate and the greater the risk for further synechiae formation in subsequent uveitic recurrences.

The term pupillary block is used to denote impaired aqueous flow between the posterior and anterior chamber through the pupillary aperture as a result of posterior synechiae. Seclusio pupillae, posterior synechiae that extend for 360 degrees around the pupil, and pupillary membranes can cause complete pupillary block. In this condition, there is no flow of aqueous from the posterior to the anterior chamber. The buildup of aqueous in the posterior chamber may produce a severe elevation of the intraocular pressure that causes forward bowing of the iris into the anterior chamber, or iris bombé (Fig. 14-4). Iris bombé in an eye with ongoing inflammation may result in the rapid development of angle closure caused by the formation of peripheral anterior synechiae owing to appositional iridocorneal contact, even in an eye that may have previously had an open angle.¹⁷ In some cases of uveitis with pupillary block, if the iridolenticular adhesions are sufficiently
broad, only the peripheral iris may bulge forward, and the iris bombé may be difficult to diagnose without the use of gonioscopy.

Acute intraocular inflammation can cause ciliary body swelling and supraciliary or suprachoroidal effusions that may result in the forward rotation of the ciliary body, causing angle closure not associated with pupillary block. Elevated intraocular pressure because of this type of angle closure occurs most often in patients with iridocyclitis, annular choroidal detachments, and posterior scleritis and can be seen in the acute stage of Vogt-Koyanagi-Harada syndrome.⁵

Once the intraocular inflammation has been adequately addressed, specific therapy should also be administered to control the intraocular pressure. In general, the medical therapy for uveitis-induced ocular hypertension and uveitic glaucoma relies primarily on aqueous suppressants for pressure control. Antiglaucoma medications used in the treatment of uveitic glaucoma include beta-blockers, carbonic anhydrase inhibitors, adrenergic agents, and hyperosmotic agents for emergent control of acute pressure elevations. As a group, miotic agents and prostaglandin-like agents are generally avoided in patients with uveitis because they may exacerbate the intraocular inflammation. Topical adrenergic antagonists are the drugs of choice for the treatment of increased intraocular pressure in patients with uveitic glaucoma because they decrease aqueous humor production without affecting the pupil size. Beta-blockers commonly used in patients with uveitis include timolol, betaxolol, carteolol, and levobunolol. Betaxolol, which has fewer pulmonary side effects, may be safer to use in patients with sarcoid uveitis and known pulmonary disease. Metipranolol has been reported to cause a granulomatous iridocyclitis in some patients and should probably be avoided in patients with uveitis.²³

Carbonic anhydrase inhibitors that reduce intraocular pressure by inhibiting aqueous humor production can be given topically, orally, or intravenously. The oral carbonic anhydrase inhibitor acetazolamide (Diamox) has been reported to reduce cystoid macular edema, which is a common cause of visual loss in patients with uveitis.²⁴ Topical carbonic anhydrase inhibitors are unlikely to have a similar effect on macular edema because sufficient concentrations probably do not reach the retina.

Adrenergic agents used in the treatment of uveitic glaucoma include apraclonidine, particularly to control acute intraocular pressure elevations that can occur after a neodymium (Nd):YAG capsulotomy and brimonidine; both are alpha-2 agonists that lower intraocular pressure by decreasing aqueous humor production and increasing uveoscleral outflow. Granulomatous anterior uveitis has also been reported as a late adverse effect of treatment with brimonidine (11 to 15 months after starting treatment).¹⁷ Although they are now used infrequently, epinephrine and dipivefrin, which both lower intraocular pressure primarily by increasing aqueous outflow, also cause mydriasis, which could be helpful in the prevention of synechiae in uveitic eyes.

Prostaglandin analogs are thought to reduce intraocular pressure by increasing uveoscleral outflow.⁵ Although effective at lowering intraocular pressure, the benefit of this class of agents in the treatment of uveitis is questioned because latanoprost (Xalatan) has been reported to induce intraocular inflammation and cystoid macular edema.²⁵,²⁶ However, randomized controlled trials have not established a causal relationship.¹⁷ More recently, there have been comparison studies in patients with uveitic glaucoma treated with latanoprost versus combination dorzolamide/timolol and there was no statistical difference between the two groups in regard to relapse of inflammatory disease.²⁷

Hyperosmotic agents rapidly lower intraocular pressure, primarily by a reduction in the vitreous volume, and are helpful in the management
of uveitic patients with acute angle closure. Glycerin and isosorbide can be administered orally, whereas mannitol is given intravenously.

Cholinergic agents such as pilocarpine, echothiophate iodide, eserine, and carbachol are generally avoided in patients with uveitis. This is because the induced miosis caused by these agents may potentiate formation of posterior synechiae, aggravate ciliary body muscle spasm, and contribute to a prolongation of the ocular inflammatory response by enhancing the breakdown of the blood-aqueous barrier.