Diagnosis and Treatment of Comorbid Uveitis and Glaucoma

Diagnosis and Treatment of Comorbid Uveitis and Glaucoma


Uveitis and glaucoma are 2 disease entities that are uniquely entwined. Several different uveitic mechanisms can cause glaucoma, some disease states manifest with both inflammation and glaucoma, and the mainstay of treatment for uveitis, corticosteroids, is an important cause of glaucoma. There are several different mechanisms by which ocular inflammation can lead to an alteration of aqueous humor flow dynamics, thereby resulting in increased intraocular pressure (IOP) and glaucoma, or hypotony.


In general, inflammation tends to cause, at least initially, a decrease in aqueous formation. This is typically offset by an increase in resistance at both the uveoscleral and trabecular meshwork (TM) outflow pathways. Therefore, the IOP can be increased, decreased, or normal. Moreover, the level of IOP can change throughout the course of the inflammatory process as the relative contributions of decreased inflow and increased outflow resistance change. These changes are mediated largely by various prostaglandins, cytokines, chemokines, and other diffusible substances. These substances create an inflammatory milieu that causes alterations in cellular structure and/or function, which can be reversible or permanent. In general, the more severe and protracted the course of inflammation, the more likely these changes are to be permanent.1

Changes at the level of the ciliary processes, including atrophy or occasionally an overlying fibrovascular membrane, are responsible for decreased inflow. Multiple mechanisms exist for the changes in outflow. These include TM blockage by inflammatory cells, debris, and serum proteins. Focal accumulations of inflammatory cells, analogous to keratic precipitates (KP), can also form along the trabecular lamellae — the clinical entity trabeculitis. Phagocytic cells lining the TM lamellae swell (due to increased phagocytic activity), contributing to increased resistance. Peripheral anterior synechiae (PAS) are another important cause of decreased outflow. PAS form when there is contact between the peripheral iris and the TM. This can occur when inflammatory exudates at the angle organize, creating permanent adhesions.

Robert J. Noecker, MD, MBA, is vice chairman and director of the glaucoma service at the University of Pittsburgh Medical Center (UMPC) Eye Center, where he is also an associate professor. Michael Herceg, MD, is a glaucoma fellow at the UPMC Eye Center. Dr. Noecker has been a speaker for Allergan, Alcon, Lumenis, and Endo-optics; is a grant or support recipient from Allergan, Carl Zeiss Meditec, and Lumenis; and is a consultant with Allergan. Dr. Herceg has no financial interests in any products mentioned in this article.

Alternatively, another mechanism of PAS formation is direct apposition via increased relative pupillary block (often from posterior synechiae between the posterior iris and the lens epithelium), which causes the peripheral iris to bow forward and contact the TM. Additionally, fibrovascular membranes can arise from endothelial-lined inner trabecular beams obliterating outflow channels. Thus, based on the primary mechanism of the alteration of the aqueous humor flow dynamics, glaucoma secondary to ocular inflammation can be classified as acute or chronic and secondary open or closed angle.

In general, conditions such as acute anterior uveitis present initially with low to normal IOP, as there is a relative reduction in aqueous secretion without significant outflow obstruction. Even as the inflammation persists and more outflow obstruction occurs, the IOP may remain normal because of this decreased aqueous production. With resolution of the inflammation, and normalization of aqueous production, the IOP may become severely elevated if the outflow obstruction persists. In addition, medical treatment, in the form of corticosteroids, is often responsible for the decreased inflammatory response, and one must consider the contribution of steroid response to this subsequent IOP elevation. This poses a significant (and frustrating) therapeutic dilemma of determining how and when to titrate corticosteroid dose, and one must be judicious with the use of this class of medications.


A thorough description of all of the known hypersensitivity, infectious, and neoplastic causes of ocular inflammation is beyond the scope of this article. It may be useful to discuss a few salient features of some of the more common and distinctive causes. Herpes simplex virus (HSV) keratouveitis is associated with secondary glaucoma in nearly 30% of patients — usually when the corneal stroma is involved. The IOP elevation is typically secondary to trabeculitis or inflammatory debris clogging the TM. Similarly, approximately one-third of cases of Herpes zoster ophthalmicus (HZO) are associated with a secondary open-angle glaucoma. Although posterior synechiae can form with both HSV and HZO, PAS are uncommon. A common associated feature, that may help diagnostically is virus-induced arteritis, causing ischemic necrosis of the iris stroma. This causes a patchy gray atrophic appearance on the iris with transillumination defects. Treatment in these cases includes antivirals, in addition to aqueous suppressants and anti-inflammatory agents. If medical treatment fails, filtering surgery or tube shunt placement may be successful.

Sarcoidosis can affect various ocular tissues in as many as 20% to 70% of cases, including iridocyclitis, of which ~10% develop glaucoma. Patients can develop inflammatory precipitates similar to KP on the TM. In addition, they can develop iris nodules and have a strong tendency towards the formation of large PAS — especially at the site of these KP and areas of iris elevated by nodules. As the inflammation becomes chronic, progressively more of the angle is compromised, secondary angle closure occurs, and increased IOP ensues.

Pars planitis is associated with glaucoma in up to 10% of cases, usually with open angle (although occasional PAS are commonly observed). Similarly, anterior scleritis can be associated with glaucoma in approximately 11% of cases, once again secondary to TM damage and/or PAS formation. Less commonly, posterior scleritis, with associated ciliochoroidal effusion/detachment, may cause secondary-angle closure. Treatment in the latter case is accomplished with aqueous suppressants, corticosteroids, and cycloplegics. Surgical drainage of suprachoroidal fluid may be required in refractory cases. AIDS has also been associated with angle closure secondary to choroidal effusion, which is typically bilateral.

Both the congenital and acquired forms of syphilis are associated with glaucoma. Congenital syphilis is associated with interstitial keratitis in about 15% of cases, with ghost vessels, PAS, and irregular pigmentation in the open portions of the angle. Subsequently patients can develop either open- or closed-angle glaucoma, each approximately equal in relative frequency. Early on, the latter form may be treatable with laser iridectomy (if the angle closure is still predominantly appositional). In the "open" angle type, angle appears "dirty" and postinflammatory. It is suspected that prior inflammation has damaged the TM and reduced the outflow facility, eventually causing a progressive increase in IOP over time.

Vogt-Koyanagi-Harada (VKH) syndrome is associated with glaucoma in 38% of eyes. Nearly 60% of these are associated with open angles and 40% closed. Closed-angle glaucoma is commonly secondary to forward displacement of the lens-iris diaphragm (associated with exudative retinal detachment), which can occur acutely and/or cause PAS (acute or chronic secondary angle-closure glaucoma). Sympathetic ophthalmia has similar pathology to VKH syndrome and follows a similar clinical course with regards to glaucoma.

One last specific clinical entity associated with ocular inflammation and glaucoma is Schwartz syndrome. Classically a small, often unnoticed, peripheral retinal tear with limited retinal detachment presents with severe anterior chamber reaction and glaucoma. As such, it can easily be mistaken for chronic iritis with glaucoma. The etiology is thought to be secondary to the release of photoreceptor outer segments into the aqueous humor, causing inflammation and obstructing the drainage angle. This condition commonly responds promptly to repair of the retinal detachment.


There are a few different types of idiopathic primary ocular inflammatory disorders associated with glaucoma. Glaucomatocyclitic crisis, or Posner-Schlossman syndrome, is characterized by discrete, unilateral, episodic, acute elevations in IOP, classically in patients 20 to 50 years old. Often the elevation in IOP can be quite impressive, with levels of 40 to 70 mm Hg commonly reported. Patients usually present with pain and blurred vision or halos. The disorder is primarily a trabeculitis, with the angle characteristically open and appearing normal or occasionally with a few discrete inflammatory precipitates.

The acute episode typically lasts 1 to 3 weeks and responds to treatment with aqueous suppressants (topical beta blockers, alpha-1 agonists, and carbonic anhydrase inhibitors), as well as topical corticosteroids to decrease the inflammation and therefore increase outflow. Typically corticosteroids can be tapered off once the episode has been controlled, although some patients do require a low maintenance dose to control the inflammation (and IOP). The role of cycloplegics-mydriatics is unclear but may help somewhat with patient comfort. Episodes can occur at regular intervals of a few months to years, and the disease eventually seems to burn itself out over time (episodes are rare after age 60). In between episodes, IOP tends to normalize — although there are reports of progressive glaucomatous optic neuropathy, and continued supervision is recommended.

Another idiopathic primary inflammatory disorder associated with glaucoma is Fuchs heterochromic iridocyclitis (HIC). Patients typically present in their 20 or 30s, either asymptomatically with different colored irides or monocular painless decreased vision (owing to cataract formation — most typically posterior subcapsular). Most commonly the condition is unilateral (hence the heterochromia), although up to 13% have been reported as bilateral. The iris stroma becomes infiltrated with plasma cells, which leads to cellular destruction, atrophy, and eventually hypochromia. The cornea is involved with characteristic colorless, diffuse, fine, stellate-shaped KPs. Another characteristic feature is the presence of fine, fragile blood vessels on the ciliary body band, the scleral spur, and the corneoscleral meshwork.

Glaucoma is associated with approximately 25% (13% to 59%) of cases of Fuchs HIC — usually later on in the course of the disease. Medications, particularly aqueous suppressants, may be effective in controlling glaucoma initially, but characteristically the glaucoma associated with this disease is relatively resistant to medical therapy, and surgical filtering procedures are often necessary. As with other uveitic glaucomas, laser trabeculoplasty is ineffective and not recommended. An additional important point here is that controlling inflammation has little or no effect on IOP, and many practitioners do not routinely treat the associated inflammation. It may be argued that treatment of the inflammation with corticosteroids does little more than accelerate cataract formation and increase IOP further via steroid-response mechanisms.


As previously mentioned, the mainstay of treatment for ocular inflammation and associated glaucoma continues to be corticosteroids. The effect of steroids on the IOP can also be variable and depends once again on the primary location and effect of the inflammation. Steroids can decrease inflammation in the TM, thereby increasing outflow. They can also decrease inflammation in the ciliary processes, thereby increasing aqueous production. Therefore, the resulting IOP will depend more on the balance between inflow and outflow effects.

Additionally, there is the clinical entity whereby steroids actually increase the outflow resistance, causing so-called steroid response glaucoma. It is important to note, that in the situation of ocular inflammation where the IOP increases with corticosteroid treatment, this is more commonly due to increased inflow (improved aqueous production) rather than true steroid response. Multiple different mechanisms have been suggested as the cause of steroid response.2 Steroids decrease the phagocytic activity of TM cells, thereby decreasing degradation of extracellular matrix material there, and subsequently increasing outflow resistance.3,4 Another finding with corticosteroids is that they stabilize lysosomal hyaluronidase, which in turn alters metabolism of mucopolysaccharides (MPS) in the angle. These MPS then accumulate in the angle and cause water retention leading to biologic edema in the TM.5,6

These responses to corticosteroids are not universal, but rather some individuals seem to be predisposed. Risk factors that have been identified include presence of primary open angle glaucoma (POAG), POAG suspect status, family history of glaucoma, younger age (<10 years), presence of connective tissue disease, type 1 diabetes mellitus, and high myopia.7 Recently, genetics studies have shown certain genes to be upregulated in dexamethasone-treated TM cells. The most extensively studied of these is the GCL1A gene on chromosome 1q, which was initially referred to as the TM-inducible glucocorticoid response (TIGR) gene.8 This gene encodes a 55 kDa protein, myocilin, which has also been linked to autosomal-dominant juvenile-onset POAG and some forms of adult POAG. The exact role that this gene plays is still largely unclear. However, it is known that different mutations within myocilin lead to widely variable glaucoma phenotypes.

In general, increased steroid potency and ocular hypertensive effect are directly proportional — with dexamethasone being most potent. The timing of IOP increase has also been directly linked to relative potency, with the more potent steroids causing IOP elevation earlier. Typically the IOP response is delayed on the order of weeks to months (for topical use), although this point is highly variable, with cases of acute rises within hours being reported.

The preparation type and mode of delivery of the corticosteroids is also intricately related to the effect on IOP. For topical medications, in addition to the variable potency of the specific glucocorticoids, the chemical structure is also important. Acetates are more lipophilic and thus penetrate through the cornea better, achieve higher intraocular levels, and subsequently have more effect on both inflammation and IOP. Conversely, phosphates are relatively hydrophilic and thus have less ocular penetration. In general, after topical steroid use for 4 to 6 weeks, 30% of the population experiences a rise of IOP between 5 to 16 mm Hg, while 5% increase greater than 16 mm Hg.9 Compared to topical administration, systemic corticosteroids tend to have less ocular penetration, and hence less (and more delayed) effect on both inflammation and IOP. Comparatively, intravitreal administration is associated with more dramatic and faster IOP increase, with 41% of patients given 20 mg of intravitreal triamcinolone (Kenalog, Bristol-Myers Squibb; IVTA) experiencing IOP elevation greater than 21 mm Hg.10 Whereas topical or systemic corticosteroids can be stopped if significant IOP elevations occur, another important consideration with IVTA is that it may last up to 9 months or longer once instilled into the vitreous, necessitating topical medications, filtration surgery, or vitrectomy to remove the depot of steroid. Similarly, vitreous corticosteroid inserts such as fluocinolone acetonide (Retisert, Bausch & Lomb, Rochester, NY) have been associated with significant IOP effects. Thirty-four week safety and efficacy trials of the implant have shown an IOP increase of greater than 10 mm Hg in 59% of patients, with 49% requiring topical antihypertensive treatment and 6.5% requiring surgical intervention (filtering surgery vs explantation).11

Although steroid agents (by either topical, periocular, intravitreal, or vitreous implant insertion) remain the standard treatments for controlling intraocular inflammation, because of the multitude of side effects, including increased IOP, there is a trend toward the use of nonsteroid agents to control inflammation. For systemic diseases, although there is not always a direct relationship between systemic and ocular inflammation, there is at least some trend toward correlation between systemic and ocular disease activity. The presence of newer-generation antimetabolites, alkylating agents, and other immune-cell modulators, with more tolerable side-effect profiles, has helped to limit somewhat the need for steroid agents. Similarly, the trend (and success) within the field of ophthalmology with the use of intravitreal bevacizumab (Avastin, Genentech) for an increasing number of predominantly inflammatory disorders (instead of IVTA), has helped to limit somewhat the glaucoma-related adverse effects.


Intraocular pressure, glaucoma and ocular inflammation are uniquely intertwined disease entities. Depending on the relative effect of inflammation on aqueous production vs outflow resistance, the IOP may increase, decrease, or remain the same. In addition, as the relative contribution to each can change depending on the stage or chronicity of the disease, the IOP effect can change. Furthermore, the mainstay of treatment for ocular inflammatory disorders continues to be corticosteroid use, which can increase the IOP. The increased use of intravitreal injections and slow-release steroid implant devices is increasing the prevalence of steroid induced glaucoma. Therefore all ophthalmologists need to be well schooled in the mechanisms of this disease, as well as treatment options for both inflammation and IOP. RP

  1. Allingham RR. Glaucoma due to intraocular inflammation. In: Epstein DL, Allingham RR, Schuman JS, eds. Chandler and Grant's Glaucoma. Baltimore, MD: Williams & Wilkins, 1997; 375-394.
  2. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of the literature. Eye. 2006;20:407-416.
  3. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin. 1992;10:505-510.
  4. Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retina Eye Res. 1999;18:629-667.
  5. Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics: I. The effect of dexamethasone in the normal eye. Arch Ophthalmol. 1963;70:482-491.
  6. Francois J. Corticosteroid glaucoma. Ann Ophthalmol. 1977;9:1075-1080.
  7. Jones R, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol. 2006;17:163-167.
  8. Polansky JR, Fauss DJ, Chen P, Chen H, Liltjen-Drecoll E, Johnson D et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica. 1997;21:126-139.
  9. Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal eye. Invest Ophthalmol Vis Sci. 1965;4:198-205.
  10. Jonas JB, Degenrigh RF, Kreissig I, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology. 2005;112:593-598.
  11. Jaffe GJ, Martin D, Callanan D, Pearson A, Levy B, Comstock T. Fluocinolone acetonide implant (retisert) for noninfectious posterior uveitis. Ophthalmology. 2006;113:1020-1027.