43

Glaucoma Due to Intraocular Inflammation

Zvia Burgansky-Eliash, MD; Guy A. Weiss, MD; and R. Rand Allingham, MD

Ocular inflammation may result in elevated intraocular pressure (IOP) and glaucoma. The inflammatory process can be an isolated idiopathic finding or a manifestation of systemic inflammation or infection. Therefore, diagnosing glaucoma secondary to inflammatory disease deserves careful evaluation and investigation. Furthermore, treatment of uveitic glaucoma is frequently challenging to the ophthalmologist despite the numerous available therapies.

GENERAL CONSIDERATIONS

A diagnosis of glaucoma subsequent to intraocular inflammation is self-evident in cases in which glaucoma develops in conjunction with diagnosed uveitis. However, in many instances, clinical symptoms may be mild; the aqueous humor may be deceptively clear with only trace flare and a rare circulating white cell. Occasionally, the signs and symptoms of glaucoma develop rapidly over a period of a few days, and the first evidence of inflammation may appear only after several days. Indications of an inflammatory process, such as accumulation of inflammatory cells on the trabecular meshwork (TM), posterior synechiae, or inflammatory foci in the fundus, may be present. Clues that might prompt one to consider intraocular inflammation as a possible etiology are unilateral open-angle glaucoma and open-angle glaucoma of rapid onset. These features are atypical for primary open-angle glaucoma (POAG). Common causes of uniocular glaucoma, such as exfoliation, trauma, and pigmentary dispersion syndrome, can be eliminated after careful examination. Exclusion of these differential diagnoses should suggest inflammatory glaucoma as a possibility. It is important to make the correct diagnosis promptly because, in many respects, the management of glaucoma due to intraocular inflammation is different from that of other types of glaucoma.

Mechanism of Glaucoma

In association with various types of uveitis, the IOP may be normal, below, or well above normal. Inflammation tends to increase aqueous outflow resistance while reducing aqueous humor inflow. Because these forces act in opposite directions, IOP varies considerably; the IOP is low in most acute forms of uveitis while a tendency for elevated IOP is more common in the chronic forms of uveitis. Acute uveitis that tends to present with acute IOP elevation includes herpetic anterior uveitis¹ and Posner-Schlossman syndrome (PSS)² as well as less common entities, such as sarcoid uveitis, toxoplasmic retinochoroiditis, listeria endophthalmitis, cytomegalovirus (CMV) infection, and syphilis.³

In active inflammatory processes, if the character or intensity of the inflammation changes, IOP can change dramatically. If the formation of aqueous humor returns to a normal rate, then while the resistance to outflow remains high, the IOP will rise. The reverse is also true; if an eye has elevated IOP because of high resistance to aqueous outflow, change in intraocular inflammation may reduce aqueous formation and decrease IOP. Therefore, a careful monitoring of IOP in patients with uveitis is crucial.

Ocular inflammation is associated with production of prostaglandins, which affects the eye in various mechanisms.⁴ These effects may be mediated through alteration of aqueous humor production, uveoscleral outflow, or aqueous outflow resistance via the TM.

Figure 43-1. (A) Iris bombé and angle-closure glaucoma caused by posterior synechiae from chronic uveitis. (B) Ultrasound biomicroscopic image of a patient with iris bombé and secondary angle closure. (Reprinted with permission from Joel S. Schuman, MD, FACS.)

Aqueous Production

The decrease in IOP associated with intraocular inflammation can be completely reversible. The IOP may return promptly to normal level after the inflammation has subsided in some cases or very slowly in others. In some cases, a permanent decrease in aqueous formation appears to be induced by structural damage to the ciliary processes mediated by chronic intraocular inflammation. When this occurs, the ciliary processes, if visible, may appear atrophic. Occasionally, a distinct cyclitic membrane may be seen overlying the ciliary processes.

Outflow Resistance

Intraocular inflammation can affect aqueous outflow resistance through various mechanisms.

In most cases, the angle appears normal and the cause of elevated outflow resistance cannot be detected by gonioscopy. The TM may be obstructed by inflammatory cells or debris.5 Experimentally, serum proteins have been shown to increase aqueous outflow resistance.⁶ Swelling of phagocytic cells lining the lamellae within the TM or adjacent to Schlemm’s canal may also contribute to elevated IOP.⁷

In certain types of uveitis, focal accumulations of inflammatory cells resembling keratic precipitates (KPs) may be visible on the inner surface of the TM by gonioscopy. These trabecular precipitates can completely resolve as inflammation subsides, leaving few, if any, persistent changes in the angle.

Frequently, inflammatory changes in the TM are not reversible. The most conspicuous form of irreversible obstruction to aqueous outflow is caused by peripheral anterior synechiae (PAS), which form when the iris adheres to the TM. PAS are produced as a result of organization of inflammatory exudates in the angle or from secondary pupillary block. Permanent obstruction can also be caused by endothelial or fibrovascular membranes that may line the inner surface of the TM. Other alterations of the TM that may affect the permeability of the angle structures may only produce a dirty appearance of the TM gonioscopically. Occasionally, the TM does not have this appearance, but is blank, white, and lacking its normal, finely granular surface texture.

Pupillary block due to inflammatory membrane at the pupillary margin readily seals the iris to the lens, which causes considerable elevation of IOP. The iris is bowed forward in a characteristic fashion, iris bombé (Figure 43-1), by elevated posterior chamber pressure, which closes the angle. Laser iridectomy should be performed to relieve the angle closure. If extensive synechial closure of the angle is found after iris bombé is relieved by iridectomy, a filtering operation may be necessary. If synechiae are of recent onset and inflammation is well controlled, iridoplasty or synechiolysis can, on occasion, restore aqueous outflow.

In some cases, ocular inflammation might induce uveal effusion or massive serous retinal detachment that can cause acute closure of the anterior chamber angle by uveal effusion with forward rotation of the ciliary body.

In acute inflammation, the blood vessels of the anterior segment may be conspicuously dilated, but no demonstration has shown that this in itself has an influence on the facility of aqueous outflow. Occasionally, dilated iris vessels can be confused with those seen in neovascular glaucoma. However, blood vessels found in association with inflammation have a normal radial pattern and do not bridge the scleral spur or arborize over the TM as do those seen in neovascularization of the anterior segment (see Chapter 32). Neovascular glaucoma might complicate ocular inflammation as well, especially when severe ischemia of the posterior segment exists.

Corticosteroid treatment, commonly used to control inflammation, may adversely increase IOP (see Chapter 45). When evaluating the effect of steroids on IOP in patients with uveitis, possible separate actions on aqueous humor secretion and outflow must be considered. Steroids may suppress inflammation in the ciliary body so that aqueous humor formation returns to a more normal rate. If outflow facility is impaired by inflammation, the improvement in aqueous humor formation may produce an increase in IOP that is not secondary to steroid-induced outflow obstruction. If there is actual inflammation in the TM, steroids may, in fact, improve outflow facility, but the resulting IOP represents the balance between aqueous humor inflow and outflow effects. Steroid-induced IOP elevations typically occur after 7 to 10 days but may occur much sooner. Where this is a concern, topical steroid treatment should be tapered, or less potent steroid formulations can be substituted (eg, fluorometholone 0.12%). If possible, taper steroid therapy gradually to avoid rebound inflammation that may occur after rapid discontinuation.

Terminology

Ocular inflammation can affect any ocular tissue—the most common site is the uvea, causing uveitis. Uveitis was classified by the International Uveitis Study Group8 according to location, clinical course, and laterality. The anatomical categories include the following 4 groups:

1. Anterior uveitis where inflammation involves the iris (formally known as iritis) and ciliary body (formally known as iridocyclitis)
   
2. Intermediate uveitis where inflammation is centered primarily in the vitreous, pars plana, or anterior retina
   
3. Posterior uveitis affecting the choroid (choroiditis) or extending to the retina (chorioretinitis)
   
4. Panuveitis when 2 or more segments of the uvea are involved⁸

The clinical course is classified as acute, recurrent, or chronic if inflammation persists for more than 2 to 3 months. The chronic type is more prone to complications, including glaucoma.

In this chapter, we will discuss different disease entities as well as idiopathic forms of uveitis. Unfortunately, many cases remain undiagnosed despite extensive diagnostic evaluation.

Treatment

Medical Control of Inflammation

The treatment of ocular inflammation depends on the specific disease causing it. Most inflammatory processes are treated with topical, periocular, or systemic corticosteroids. Other therapeutic measures are topical or systemic nonsteroidal anti-inflammatory drugs (NSAIDs), cycloplegic agents to prevent synechiae formation, systemic immunosuppressive therapy, and biological agents.

Immunosuppressive Therapy

Corticosteroids have a wide range of adverse effects associated with their long-term use, such as hypertension, osteoporosis, hyperglycemia, and growth retardation in children; therefore, the use of corticosteroid-sparing agents is considered. These agents are also used when severe inflammation is threatening vision or in cases in which an associated systemic disorder exists.^9,10 Corticosteroid-sparing agents include antimetabolites (mycophenolate mofetil, methotrexate [MTX], and azathioprine), T cell calcineurin inhibitors (cyclosporine and tacrolimus), and alkylating agents (cyclophosphamide and chlorambucil).

Immunosuppressive agents have been proven effective in several uveitic conditions.^11,12 Nevertheless, the use of these therapeutic agents requires careful clinical and laboratory monitoring due to potential side effects. The antimetabolite medications were proven efficient in controlling a variety of uveitic conditions.^13–15 The T cell calcineurin inhibitors have also been used successfully in uveitis.^16,17 The alkylating agents are the least commonly used immunomodulatory agents for uveitis due to their serious side effects. Alkylating agents are reserved for cases with severe, bilateral refractory uveitis with a potential for visual recovery.^18,19

Biologic Agents

Biologic agents are a group of medications that target cytokines and other soluble inflammatory mediators. Three groups of biologic medications have been used for ophthalmic indications:

1. Tumor necrosis factor (TNF)-α antagonists (infliximab, adalimumab, and etanercept)
   
2. Interleukin (IL)-2 receptor antagonist (daclizumab)
   
3. IL-1 receptor antagonist (anakinra)

Infliximab was reported effective in the treatment of refractory uveitis like sarcoidosis, Behçet’s disease (BD), pars planitis, Crohn’s disease, juvenile idiopathic arthritis (JIA), and human leukocyte antigen (HLA)-B27–associated acute anterior uveitis (AAU).²⁰ It was used successfully alone as well as in combination with immunosuppressive therapy. Nevertheless, serious effects were reported with this treatment, including development of antinuclear antibodies, congestive heart failure, pulmonary emboli, vitreous hemorrhage, reactivation of latent tuberculosis (TB), unmasking of demyelinating disease, and possible development of lymphoma. Therefore, the exact application of this treatment for ocular diseases requires further investigation.²⁰ Adalimumab showed good response in 81% to 88% of pediatric uveitis patients.^21,22 Good efficacy was also reported in a small series of patients with BD.^23,24 Reported side effects are mainly at the site of injection, herpes simplex virus (HSV), keratitis, and elevation of liver enzymes. Etanercept is probably the least effective TNF-α antagonist in the treatment of uveitis.²⁵ Daclizumab has shown efficacy in the treatment of several uveitic disorders such as sarcoidosis, Vogt-Koyanagi-Harada (VKH) syndrome, idiopathic intermediate uveitis, anterior uveitis, idiopathic panuveitis, and multifocal choroiditis.²⁶ No serious side effects were reported with this treatment.²⁷ Anakinra has only limited but encouraging experience in treating ocular diseases.²⁸

Medical Control of Glaucoma

If IOP elevation secondary to uveitis requires treatment, aqueous suppressants, including topical beta-blockers, α2-adrenergic agonists, and systemic or topical carbonic anhydrase inhibitors (CAIs), are often effective.29,30 Frequent monitoring of IOP is needed in these patients because the lowering effect of most ocular hypotensive agents is highly variable in uveitis. The responses range from no response at all to profound reductions of IOP (70% to 80%) on relatively small amounts of ocular hypotensive medication, especially topical CAIs.³¹

Prostaglandin analogs are used with caution in cases of uveitic glaucoma. Although prostaglandins are mediators of inflammatory process in the eye, the antiglaucoma prostaglandin analogs have a very low dose and altered compounds and do not show breakdown of the blood-aqueous barrier in healthy individuals.³² However, there are rare reports of anterior uveitis associated with latanoprost therapy in patients with no history of uveitis³³ or in patients with prior inflammation or surgery.³⁴ Moreover, these agents are prone to induce cystoid macular edema in uveitis patients^35–38 and reactivation of herpetic keratouveitis^39,40; therefore, caution should be used in these cases.

Miotic treatment is generally contraindicated in the presence of anterior uveitis. Miotics can cause pain, intensify anterior segment inflammation, and increase formation of posterior synechiae, which can produce complete pupillary block.

If the optic nerve head is entirely normal, as is usual in AAU, treatment of moderate elevation of IOP may not be indicated. In these cases, once inflammation is controlled, the IOP will probably return to safe levels long before optic nerve damage occurs. Typically, a normal optic nerve can tolerate an IOP in the mid-30s for many weeks without damage. Only if there are frequent recurrences, or if inflammation becomes chronic, significant optic nerve damage is likely. In eyes with corneal endothelial disease, a moderate elevation of IOP may cause corneal edema, which calls for more vigorous efforts to lower the IOP.

Surgical Management of Glaucoma

Medical treatment may not adequately control glaucoma in cases associated with ocular inflammation. Surgical treatment must be directed at the mechanism responsible for outflow obstruction.

Laser Therapy

In cases in which pupillary block exists (eg, iris bombé), an iridectomy is indicated. Laser iridectomy is possible in these cases. In the presence of active inflammation, a tendency for small iridectomy to close exists. Additional sessions may be needed, or in some cases, a surgical iridectomy may be required.

Argon laser trabeculoplasty is not only ineffective in cases in which glaucoma is secondary to an inflammatory process but it may produce acute flare-up of uveitis and significant increase in IOP; therefore, it is not recommended for patients with uveitis-related glaucoma.⁴¹

Transscleral diode laser cyclophotocoagulation can be used in cases in which advanced optic nerve damage exists and visual potential is limited (see Chapter 57).⁴² Cycloablative procedures often increase intraocular inflammation or cause unpredictable severe hypotony with visual loss and phthisis due to further damage of an already sick ciliary body. In a report on 16 patients, the success rate was 75%, but 19% of eyes developed hypotony that was higher than in any diagnostic category other than uveitis.⁴³ Contradicting results were recently reported⁴⁴ in 18 uveitic glaucoma eyes with a 1-year success rate of 72%, but no case of phthisis, hypotony, or marked activation of the underlying inflammatory process. In this study, however, the repeated treatment rate was higher than in others (63.6%).⁴⁴

Incisional Surgery

Filtering surgery is prone to failure in patients who have uveitis (see Chapter 60). It is crucial to minimize ocular inflammation preoperatively by topical or systemic steroids before the operation. Unfortunately, glaucoma is, at times, an immediate threat to vision, and it is not possible to completely control inflammation prior to surgery.

In general, the use of adjuvant antimetabolites, such as 5-fluorouracil (5-FU) and mitomycin C (MMC), is important and improves surgical results.³¹ A qualified success rate (IOP of 21 mm Hg or higher with or without topical medications) of 78% at 1 year and 62% at 2 years was reported in 44 eyes with MMC (primarily) or 5-FU trabeculectomy.⁴⁵ Interestingly, the use of the less potent 5-FU in 50 eyes resulted in a similar, if not better, effect with a qualified success rate of 82% at 1 and 2 years after surgery and 67% at 5 years.⁴⁶ This rate of success is influenced largely by risk factors for surgical failure, such as prior incisional surgery, Black patients, idiopathic uveitis, and the degree of inflammation control before surgery. Therefore, in a cohort with minimal risk factors and long preoperative control of inflammation, even trabeculectomy without antimetabolites resulted in a comparatively good qualified success rate—78% in 5 years.⁴⁷ Cataract formation after filtration and antimetabolites was noted in more than half of the phakic patients. After cataract surgery, 25% required repeat glaucoma surgery due to failure of the filtering bleb and loss of IOP control.⁴⁵

Small pilot reports on the use of nonpenetrating deep sclerectomy demonstrate 1-year qualified success of 90%⁴⁸ to 100%⁴⁹ with a low rate of surgical complications.

For chronic childhood uveitis, goniotomy was suggested as a good first-line surgical option with a qualified success rate of 75% after 1 year and minimal complications.⁵⁰

Glaucoma drainage devices (GDDs) are preferred in many high-risk cases for trabeculectomy failure, especially when significant postoperative inflammation is likely.⁵¹ The long-term qualified success rate of Molteno implants (Nova Eye Medical) in 40 eyes with uveitic glaucoma was 87% at 5 years and 93% at 10 years.52 The reported 2-year success rate with a Baerveldt GDD (Johnson & Johnson Vision) was 91.7% in 24 uveitic eyes.⁵³ Two studies^54,55 with the Ahmed GDD (New World Medical) report a 1-year success rate of 94%, although this rate drops to 60% at 2 years.⁵⁵ The most common complication was valve occlusion, which is probably related to the inflammatory process.

ANTERIOR UVEITIS

Most inflammatory-associated IOP elevations and glaucoma are caused by anterior uveitis.

Acute Anterior Uveitis

AAU is typically associated with anterior segment hyperemia, cells and flare in the anterior chamber, and KPs (Figure 43-2). Usually, IOP remains normal or low despite common increases in outflow resistance because the rate of aqueous humor formation is typically lowered to a degree that is compensatory or even disproportionately greater.

In AAU, the angle is typically open gonioscopically. The treatment of the inflammation is the same whether glaucoma is present or not, relying principally upon topical administration of cycloplegic agents and corticosteroids (except in herpetic epithelial keratopathy). If inflammation has caused an increase in outflow resistance, topical steroids may improve aqueous outflow over the short term. In cases where a cause for the uveitis is discovered, a specific treatment is required.

Recurrent and Chronic Anterior Uveitis

The majority of cases of recurrent or chronic anterior uveitis are idiopathic. The uveitic glaucoma subtypes related to specific disease entities represent a small proportion of all cases of recurrent anterior uveitis and will be discussed individually later in this chapter. In idiopathic chronic anterior uveitis, the signs of inflammation, particularly cells, flare, and KPs, come and go, or persist over a long period, responding incompletely to treatment. Glaucoma becomes a serious problem in some of these cases because of significantly elevated IOP and a chronic course.

In cases in which anterior segment inflammation has been prolonged, IOP may remain normal for a long time because of a low rate of aqueous production, but when the inflammation subsides, the rate of aqueous formation may return to normal. The IOP may then rise considerably if outflow facility remains reduced secondary to changes in the TM. In some instances, control of inflammation may result in an IOP that is uncontrollable by any medical means. Under these circumstances, one may be forced to choose between reducing anti-inflammatory treatment and permitting mild inflammation, or proceeding with invasive high-risk glaucoma surgery.

IDIOPATHIC INFLAMMATORY CONDITIONS

Posner-Schlossman Syndrome

PSS, also termed glaucomatocyclitic crisis, was first described by Posner and Schlossman² in 1948 as a rare self-limiting unilateral condition characterized by recurring acute attacks of mild anterior uveitis with an IOP elevation. In between attacks, the IOP is normal with open angles. Although originally considered a benign syndrome, it was shown that there is an association between PSS and concomitant POAG.⁵⁶ Moreover, one-quarter of PSS patients’ eyes might develop glaucoma due to repeated attacks. Patients with disease duration of a decade or more have a 2.8 times higher risk of developing glaucomatous optic nerve and visual field damage in comparison to patients with shorter disease duration.⁵⁷

The syndrome appears between the third and sixth decades of life, with a mean age at onset of 35 years.⁵⁷ Diagnosing PSS can be challenging at presentation of the first attack, with only mild inflammation that may go undetected, or the elevated IOP might be confused with acute angle-closure glaucoma. There are no specific diagnostic laboratory tests, and the diagnosis is based on clinical findings.

Onset of symptoms is usually acute. Patients present with slight ocular discomfort, blurred vision, or appearance of colored haloes around lights secondary to corneal edema. Examination reveals a highly elevated IOP, usually between 40 and 70 mm Hg. The eye is generally quiet with little or no hyperemia. The cornea may have mild to moderate epithelial edema with a few fine KPs. KPs may not be noted for 2 or 3 days after the onset of symptoms and tend to vary in number and position from day to day. In some cases, there is focal segmental ischemia of the iris during the attack.⁵⁶ Gonioscopy reveals a normal-appearing angle, open throughout, with no abnormal pigmentation. Occasionally, one may find a few tiny inflammatory precipitates on the TM. Characteristically, no posterior or anterior synechiae are formed. If tonography is performed, it demonstrates a highly elevated resistance to aqueous outflow in the affected eye but a normal value in the unaffected eye.

Figure 43-3. Patient with Fuchs’ heterochromic iridocyclitis. Iris stromal atrophy of the left eye is responsible for the heterochromia. (Reprinted with permission from Glenn J. Jaffe, MD.)

The etiology of this PSS is unknown. HSV may play a role in this syndrome, as viral DNA was found in aqueous humor samples of PSS patients during acute attacks.58 CMV was demonstrated in half of the patients in aqueous analysis.⁵⁹ Immunogenetic factors might also play a role in PSS. An association with the major HLA-Bw54 was found in 41% of Japanese patients.⁶⁰

During the acute attack, the optic nerve head undergoes morphologic as well as hemodynamic changes. These changes are usually transient and mostly do not cause permanent damage.⁶¹

A selective reduction in the S-cone component of an electroretinogram b-wave was demonstrated during acute PSS attacks. This finding may reflect the relative susceptibility to damage of the S-cone pathway, in comparison to the L- and M-cone systems, as a result of elevated IOP.⁶²

The IOP elevation might be due to trabeculitis, with histological evidence of mononuclear cells in the meshwork, blocking the aqueous outflow.⁶³ In addition to a decrease in the outflow facility, increased levels of aqueous prostaglandin, mainly prostaglandin E, might also explain the elevated IOP, through excessive aqueous production.⁶⁴ The correlation of PSS to chronic open-angle glaucoma may have a role in the elevated IOP mechanism.⁵⁶

An attack of glaucomatocyclitic crisis generally subsides within 1 to 3 weeks, with or without treatment. Medical treatment is indicated to prevent pressure-related optic nerve damage and to reduce inflammation. The condition usually responds to topical corticosteroids and aqueous-suppressant ocular hypotensive drugs: beta-blockers, α2-adrenergic agonists, and CAIs. The use of 1% apraclonidine lowered IOP during attacks by half, regardless of the initial level of IOP, and had a more significant hypotensive effect in PSS in comparison to POAG.⁶⁵ It is unclear whether cycloplegics are beneficial.

Surgery should be restricted to cases with severe and disabling symptoms or progressive glaucomatotic optic neuropathy with visual field loss.⁶¹ Filtering surgery with antimetabolites might be used to control elevated IOP, although reports concerning efficacy are controversial.⁵⁷

The risk of developing chronic glaucoma in some cases dictates funduscopic follow-up and visual field monitoring in all individuals. Glaucomatocyclitic crises are prone to recur at intervals of a few months to 1 or 2 years over 15 to 25 years. Eventually, episodes appear to stop; this condition is almost never seen after age 60. Repeated episodes usually occur in the same eye but rarely occur in one eye and then the other.

Fuchs’ Heterochromic Iridocyclitis

Fuchs’ heterochromic iridocyclitis (FHI) is a chronic low-grade anterior uveitis, associated with iris stromal atrophy, cataract formation, and glaucoma. It accounts for 2% to 3% of all cases of uveitis⁶⁶ and continues to be underdiagnosed (Figure 43-3). Because of the diverse number of abnormalities that may be present, this may be one of the more difficult uveitides to diagnose. FHI occurs mainly in the third and fourth decades of life and affects men and women equally.⁶⁶ FHI typically affects only one eye; however, in up to 15.6% of cases, it affects both eyes.⁶⁷

Patients are usually asymptomatic. When symptomatic, the most common presenting symptoms are floaters⁶⁸ and visual deterioration.^67,69 The eye is typically white and quiet. The prominent signs reported are typical KP in all cases, cataract in nearly 80% of cases, and heterochromia in 70% to 80% of patients.^67–69 Characteristically, the KPs are fine and colorless; some are round, but the most typical are filamentary or star shaped, scattered over the posterior surface of the cornea (Figure 43-4). The KPs are best seen by retroillumination. There may be trace flare in the aqueous humor with an occasional white cell. A cataract in the affected eye is the rule, initially presenting as a posterior subcapsular cataract.

The iris is infiltrated with plasma cells with accompanying degeneration and atrophy.⁷⁰ Clinically, atrophy of the iris affects the pupil collarette (transforming it to a hyaline border) and produces hypochromia of the iris stroma with abnormal transillumination of the posterior pigment layer.⁷¹ Fluorescein may leak from vessels at the pupil, but these are not new vessels. In 50% of patients, there is only discrete iris heterochromia,⁶⁸ which may delay diagnosis. The iris heterochromia depends on the level of stromal atrophy, iris color, and pigment amount in the iris pigmented epithelium; it may not be recognized in darkly pigmented irides.⁶⁶ Some patients develop iris nodules mainly on the pupillary margin and less frequently on the iris stroma.⁷² In some cases, congenital Horner’s syndrome has been reported.⁷³ Vitreous opacities are frequent.⁷⁴ Chorioretinal scars similar to those seen in toxoplasmosis have been described in FHI, but the association of these 2 diseases is unclear.⁷⁵

Gonioscopy characteristically reveals a few fine new blood vessels on the surface of the ciliary band, scleral spur, and on the corneoscleral meshwork. These blood vessels appear to be different from those associated with neovascular glaucoma because they do not proliferate or produce synechial closure of the angle. Abnormal vessels in the angle may also be seen in cases of heterochromia without glaucoma.76 These abnormal blood vessels may lead to hyphema. Most affected eyes do not develop synechiae.⁶⁶ The angle typically remains open, and the TM may be covered by an inflammatory membrane that is demonstrable only histologically.⁷⁷ In some cases, Schlemm’s canal appears to be collapsed.⁷⁸

One of the most serious complications is glaucoma.⁶⁸ Fourteen percent to 27% of patients develop glaucoma and nearly 10% of FHI patients require filtration surgery.^67,69,79,80 After diagnosis, there is a 0.5% risk per year to develop glaucoma, decreasing substantially after 15 years of follow-up.⁸⁰ Typically, glaucoma is of the open-angle variety, but a number of mechanisms have been observed, including secondary synechial angle closure, neovascular glaucoma, lens-induced, and glaucoma secondary to recurrent hyphemas.⁸⁰ Cataract surgery might also precipitate glaucoma.⁸⁰

The pathogenesis of FHI is unknown; however, many reports suggest an infectious origin. Intraocular antibody production against rubella virus was demonstrated, with evidence of the rubella genome in the aqueous humor of FHI patients.⁸¹ Another potential causative agent is herpes simplex.⁸² Its DNA was found in the aqueous humor of FHI patients.⁸² In another report, the serology of toxoplasma was found positive in one-third of patients.⁶⁸ An infectious origin of the disease might explain the low efficacy of corticosteroid therapy in treating this disease.⁸³ Another theory suggests there is an immunological impairment in FHI. Various reports discovered depressed suppressor-T-cell activity,⁸⁴ cellular immunity to corneal antigens (demonstrated in most patients),⁸⁵ autoantibodies against corneal epithelium present in nearly 90% of cases,⁸⁶ and nonspecific immune complexes found in the iris vessel walls.⁸⁷

Active treatment is not required in 75% of patients,⁶⁹ though all should be screened routinely for glaucoma.⁶⁷ Symptomatic exacerbations are treated with a short course of corticosteroids.⁶⁶ More than 40% of patients required cataract surgery.^67,69

In most cases of heterochromic iridocyclitis, once glaucoma develops, it appears to be permanent. Unfortunately, control of the associated inflammation has little influence on the IOP, and it is questionable whether it is even worthwhile, especially because there is little tendency to form synechiae. The inflammation usually continues for many years, but even if the inflammation eventually clears, the glaucoma invariably remains. Medical antiglaucoma treatment may be effective initially. As time passes, the glaucoma responds poorly to medical treatment. In one series, 73% of glaucoma patients did not respond successfully to maximal medical treatment.⁷⁹ Glaucoma filtration surgery is generally well tolerated and causes little or no increase in the inflammation. Trabeculectomy had a 72% rate of successful IOP control for more than 2 years of follow-up.⁷⁹ Adjunctive antimetabolites appear to improve the glaucoma surgical success rate.^79,80,88

In general, the visual prognosis of FHI is good,⁶⁶ with glaucoma, posterior capsule opacification, and vitreous opacity causing most of the visual impairment following cataract surgery.⁶⁹

Keratic Precipitates on the Trabecular Meshwork (Grant’s Syndrome)

Chandler and Grant were the first to describe a relatively rare cause of idiopathic secondary glaucoma consisting of inflammatory precipitates on the TM,⁸⁹ subsequently given the eponym Grant’s syndrome. Although it is uncommon, it is important to diagnose this disorder correctly because treatment with topical steroids in most cases is effective.⁹⁰

Typically, onset of the syndrome is acute,⁹⁰ the IOP is elevated in both eyes, and the eyes are white and quiet, with few (if any) inflammatory precipitates on the cornea endothelium. There may be a few cells in the aqueous, but in most cases, no cells are seen.

Gonioscopy is crucial to differentiate this condition from POAG. Gonioscopy reveals inflammatory precipitates projecting from the surface of the corneoscleral meshwork. These are generally colorless or tapioca-colored and tend to be broader and flatter than KPs seen on the cornea endothelium and may be confluent. In rare instances, the KPs in the angle are large and striking in appearance. In all other cases, the KPs have been small and inconspicuous and therefore easily overlooked. It is not unusual that after careful examination of the entire angle, only a few KPs may be identified; however, with repeated examinations, more KPs may be observed. Irregularity in the level of the attachment of the iris root might also be noted. KPs in the angle tend to organize and thus cause irregularities in the width of the angle. In POAG, although the angle may be narrower above or below, there are never any abrupt changes in the width of the angle. Such abrupt changes are almost certainly the result of organization of KPs in the angle or trauma. The only other conditions in which such abrupt changes in the width of the angle are seen include old interstitial keratitis, multiple cysts of the iris and ciliary body, essential atrophy of the iris, and Chandler’s syndrome.

Ultrasound biomicroscopy may demonstrate the pathology and supplement gonioscopy. Sonographic findings may include inflammatory precipitates overlying the TM and PAS, without abnormalities of the TM or ciliary body.90

The level of IOP elevation may not be proportional to the number of inflammatory precipitates observed in the angle. In some cases, many KPs are visible in the angle, but the IOP is normal or only slightly elevated and vice versa. High IOP despite few KPs suggests that inflammatory debris must be present within the TM, which is blocking the outflow pathways but cannot be seen gonioscopically.

In early cases of glaucoma associated with inflammatory precipitates on the TM, the disc is normal and the field is full, but in long-standing cases, cupping of the disc with field loss is found. If the true condition is not recognized and the patient is treated mistakenly as POAG, there is usually a poor response. Moreover, the exudates in the angle may gradually organize to bring about synechial closure of the angle and permanent glaucoma.

The cause of this disorder is unknown. Some patients who initially present with this disorder will develop other inflammatory conditions, such as sarcoidosis, ankylosing spondylitis (AS), rheumatoid arthritis, or chronic uveitis.⁵

Medical treatment consists of topical corticosteroids and aqueous-suppressant ocular hypotensive drugs, as required. Topical corticosteroids are given at first every hour during the day, and then are gradually tapered. Trabecular precipitates typically clear over a 1- to 2-week period, and in the absence of advanced peripheral synechial closure, the IOP returns to normal levels.

In the majority of cases, when the topical corticosteroids are reduced below a certain level or are discontinued, the precipitates in the angle tend to recur and IOP again becomes elevated. In such cases, the maintenance dose of topical steroids in preventing recurrence is determined by trial and error. Once the KPs have cleared after treatment, the IOP returns to normal, but if there are many recurrences, eventually, the patient may have a permanent open-angle glaucoma. Individuals with this condition should be monitored indefinitely because of a significant risk of recurrence, which is usually asymptomatic.

If there is extensive synechial closure of the angle when the diagnosis is first established, eliminating the precipitates in the open portions of the angle may improve the condition, but there may be severe residual glaucoma because of the secondary angle closure. In such cases, a glaucoma filtering operation may be necessary.

Sarcoidosis

Sarcoidosis is a multisystem disorder of unknown etiology, characterized by the formation of noncaseating granulomas and a remissions and exacerbations pattern. Sarcoidosis usually presents with bilateral hilar adenopathy, pulmonary infiltrates, and cutaneous and ocular involvement. Incidence of sarcoidosis varies between different geographical areas and ethnic groups. It is more prevalent in Black patients compared to White patients. Sarcoidosis affects mainly young adults between 20 and 40 years of age.⁹¹

Ocular involvement exists in up to 80% of patients with sarcoidosis.⁹¹ Sarcoid uveitis can affect individuals at any age; the mean age is around 40 years.⁹² It has a higher prevalence in postmenopausal women.⁹³ Ocular disease may present with acute or chronic granulomatous or nongranulomatous eye disease. A report of 60 patients described 81% of cases as granulomatous, while only 15% had nongranulomatous uveitis. In that cohort, the majority of patients (91%) suffered from a chronic disease, 7% had recurrent flares, and only one patient had a monophasic acute uveitis.⁹² Young patients commonly suffer from an acute disease, whereas in older patients, the chronic disease is more common.⁹³

There is a wide spectrum of ocular inflammation in sarcoidosis; the most common manifestation is sole anterior or intermediate uveitis.⁹² Ninety percent of sarcoid uveitis cases are bilateral.⁹³ Sarcoid uveitis may clinically include some distinctive features. KPs may appear in a form of mutton-fat KPs or small granulomatous KPs. Sarcoid nodules may appear on the iris (Koeppe or Busacca nodules), the TM, or ciliary body and create tent-shaped PAS or posterior synechiae (Figure 43-5). In the vitreous, opacities with snowballs or strings of pearls appear. Posterior manifestations include multiple chorioretinal peripheral lesions, segmental periphlebitis, candle-wax–like drippings, retinal macroaneurysm, optic disc nodules or granulomas, and solitary choroidal nodule. Other ocular manifestations include Sicca syndrome and orbital and lacrimal gland involvement. Causes of vision loss include cataract, glaucoma, macular edema, vitreous hemorrhage, and retinal detachment.⁹⁴

Glaucoma was found in approximately 10% of patients with sarcoid uveitis.⁹⁵ The most prominent glaucoma mechanism is aqueous outflow obstruction due to granulomatous infiltration of the angle.⁹⁶ Sarcoidosis inflammatory precipitates in the angle are sometimes the only sign of inflammation in a subacute uveitis and may result in IOP elevation.5 Histologically, there are inflammatory mononuclear cell infiltrates around the inner and outer walls of Schlemm’s canal and granulomatous and fibrotic tissue obstructing its lumen.⁹⁷ A chronic course of the uveitis may induce the development of secondary angle-closure glaucoma due to PAS formation.⁹³ Neovascularization of the iris and angle causing neovascular glaucoma may also develop in these patients.⁹⁸

The etiology of sarcoidosis is unclear and multifactorial. The immunological response might be triggered by an environmental antigen exposure in genetically predisposed individuals. Several different microorganisms, including mycobacteria, human herpes virus type 8,⁹⁹ Propionibacterium acnes, and Propionibacterium granulosum,¹⁰⁰ were isolated from sarcoid tissues, suggesting an infectious origin.¹⁰¹ First- and second-degree relatives of sarcoidosis patients have an increased risk of developing sarcoidosis supporting a genetic theory.¹⁰² A linkage was found to chromosomes 5 and 6 in sarcoidosis patients¹⁰³ as well as association to HLA-DRB1.¹⁰⁴

The diagnosis of ocular sarcoidosis is made according to clinical ocular signs and ancillary investigations. In 2006, the International Workshop on Ocular Sarcoidosis⁹¹ published a combined criteria based on a combination of clinical, laboratory, and histologic findings. Laboratory studies include serum angiotensin-converting enzyme, lysozyme, serum and urinary calcium, chest radiography, computed tomography scan, bronchoscopy with bronchoalveolar lavage, and gallium scan.⁹¹ Measuring the levels of angiotensin-converting enzyme and performing whole-body gallium scan are good in diagnosing patients with clinically suspicious ocular sarcoidosis with normal chest radiographs.¹⁰⁵ Gallium uptake in the eye was found in one-fifth of the cases, while uptake in the lacrimal glands was found in two-thirds of cases.¹⁰⁵ The definitive test is biopsy, showing typical noncaseating granulomas.⁹¹

Effective treatment consists primarily of long-term use of corticosteroids.⁹³ Half of the patients with uveitis require treatment with oral corticosteroids, and another 11% require additional immunosuppressive therapy.¹⁰⁶ Severe systemic disease, refractory cases, or sight-threatening conditions require immunosuppressive (mainly MTX) or biological treatments.^91,101 TNF has been found to be a contributing factor in the formation of sarcoid granulomas. Infliximab, a TNF-α antagonist, has been used for refractory sarcoidosis and produced successful results, while etanercept, another TNF-α antagonist, failed to show improvement and may even precipitate the disease.¹⁰⁷

Glaucoma associated with uveitis resolved with treatment of uveitis in nearly 90% of cases.¹⁰⁵ Glaucoma may respond well to topical corticosteroids early in the disease course, but later it may become increasingly difficult to control, especially when PAS are extensive. There is evidence showing controlled ocular inflammation following a surgical excision of iris nodules in patients with refractory granulomatous uveitis.¹⁰⁸ In some cases, despite extensive PAS, IOP may remain well controlled. In this situation, topical corticosteroid treatment may cause an IOP elevation by increasing aqueous humor formation or in conjunction with a true steroid response.

Anterior uveitis is related to a better visual outcome, in comparison to multifocal choroiditis or panuveitis.⁹⁴ After 6 months, half of patients had improvement in visual acuity,⁹² and after a decade, more than half of patients retained normal visual acuity.¹⁰⁶ Nevertheless, despite the mild nature of the uveitis, 15% of patients suffer from poor visual outcome.⁹³ Glaucoma is one of the risk factors for unfavorable visual prognosis.⁹²

AUTOIMMUNE DISORDERS

Juvenile Idiopathic Arthritis

Also known as juvenile rheumatic arthritis, JIA is the most common disorder associated with uveitis in children and usually presents as anterior uveitis. This disorder accounts for approximately 70% of all cases of juvenile arthritis.^109,110 The following are the 3 major forms:

1. Systemic-onset JIA is associated with fever, generalized lymphadenopathy, hepatosplenomegaly, pericarditis, or rash and accounts for 20% of cases
   
2. Polyarticular-onset JIA affects 5 or more joints within the first 3 months
   
3. Pauciarticular-onset JIA affects 4 or fewer joints within the first 3 months

Uveitis occurs rarely in systemic-onset JIA, in about 10% to 15% of those children with polyarticular-onset JIA, but in more than 75% of those with pauciarticular-onset JIA.^109,110 Overall, 8% to 20% of JIA pediatric patients suffer from uveitis.^111–113 This incidence also varies geographically, being highest in Scandinavia, followed by the United States, then Asia, and lowest in India.¹¹³ In more than 60% of cases, arthritis precedes uveitis, while in about 25% they appear simultaneously, and in up to 13%, uveitis precedes arthritis.^112,114 Children who developed uveitis prior to or along with arthritis suffered from a more chronic ocular disease and high rate of complications.112 Patients with JIA who develop uveitis are significantly younger at presentation than those without uveitis.¹¹¹ The average age of uveitis diagnosis is 4.5 years.¹¹⁴ Female gender was not found as a risk factor for the development of uveitis among patients with JIA.^111,113 Uveitis is more frequent in antinuclear antibody–positive patients.¹¹³

Uveitis is bilateral in more than two-thirds of the cases.^109,110 Patients with uveitis are usually asymptomatic even when inflammation is marked; this might delay diagnosis and increases the rate of complications.¹¹⁴ The uveitis is typically nongranulomatous in nature. KPs are small and frequently confined to the inferior cornea. When inflammation is marked, there may be cells in the anterior vitreous. Nearly 70% have chronic anterior uveitis, 16% acute anterior, 12% recurrent anterior, and only 3.5% panuveitis.¹¹⁵ JIA is associated with a high rate of complications in adulthood like cataract, glaucoma, posterior synechiae, band keratopathy, papilledema, macular edema, and hypotonia^111–114 (Figure 43-6).

Secondary glaucoma is a major cause of vision loss in JIA and carries a poor prognosis. The rate of secondary glaucoma ranges between 5% and 33%.¹¹³ Glaucoma is usually caused by pupillary block, although direct infiltration of outflow facility with inflammatory process was observed as well.¹¹⁶

Treatment mainly includes the use of topical cycloplegic agents and corticosteroids. Systemic corticosteroids, immunomodulating agents (like MTX and cyclosporine), and biological agents (like TNF-α antagonists) are needed in severe cases or to help reduce the use of topical corticosteroids.^111,114

Aqueous suppressants are useful in managing glaucoma. However, systemic CAIs (as well as MTX) should be used with caution in these patients because it might interact with the NSAIDs used to treat the arthritis. Unfortunately, 9% to 30% require surgical intervention for IOP control.^114,115 Goniotomy was proved an effective and safe first-line surgery, although most patients require anti-glaucoma therapy after the surgery.⁵⁰ Nonpenetrating deep sclerectomy with the placement of a collagen GDD was tried successfully in one report.¹¹⁷ Overall, JIA-associated glaucoma outcomes with trabeculectomy are disappointing, and primary drainage device implantation is preferred by many with good long-term IOP control, even better than in other types of refractory glaucoma.¹¹⁸ Transscleral diode cyclophotocoagulation was proved to be unsatisfactory as a primary surgical treatment.¹¹⁹

Patients with JIA need routine ophthalmic evaluation, even while their arthritis is inactive, because of the silent asymptomatic nature of the eye disease.^112,114 Parents should be educated to be aware of first signs and symptoms.¹¹² Secondary glaucoma is a diagnostic and therapeutic challenge, but if treated with an aggressive approach, early in the course of the disease, most patients will have a good visual prognosis. Good visual acuity was found in nearly 90% of cases, despite uveitic complications.^113,115

Human Leukocyte Antigen-B27–Associated Uveitis

Approximately 50% of patients with AAU have HLA-B27 haplotype,^120,121 either when uveitis is the only disorder or when it is a part of a systemic immunological disease. The incidence of AAU in patients with HLA-B27 is between 33% and 88% depending on the population studied.^122,123

Fifty percent to 77% of the patients with HLA-B27–associated AAU have a systemic inflammatory disorder (ie, seronegative spondyloarthropathies [SSA]).^123,124 SSA is a group of inflammatory conditions that involve the spine, sacroiliac, and shoulder joints. The disease entities are described separately in the following sections. This group has a strong genetic association to the HLA-B27 haplotype. Patients with SSA had an earlier onset of uveitis and more uveitis attacks compared to patients with AAU without associated systemic disease.¹²⁴ Thirty-three percent of SSA patients develop uveitis, most commonly unilateral AAU, which is typically self-limited. This prevalence is higher in HLA-B27–positive patients and varied according to the specific SSA type. At the onset of AAU, the prevalence of HLA-B27–associated systemic disease is higher in males, but after the onset of uveitis, the risk of developing a HLA-B27–associated systemic disease has no gender discrepancy.¹²⁵

HLA-B27–positive patients, either with or without systemic disease, have a more severe anterior chamber inflammation with hypopyon formation, higher frequency of uveitis attacks, and more complications than HLA-B27–negative patients.¹²⁶ Ocular complications include secondary glaucoma, cataract, pupillary synechiae, vitritis, cystoid macular edema, and optic disc edema.¹²⁶

During acute inflammation, pressure is usually lowered due to ciliary body underproduction of aqueous. However, secondary glaucoma may develop due to synechial angle and pupillary closure.120 Extensive persistent pupillary synechiae were found in one-fifth of HLA-B27–associated AAU.¹²⁶ In this study, secondary glaucoma developed in 2% of HLA-B27–associated AAU patients with no systemic disease and in 6% of patients with systemic disease. Another study¹²⁵ reported a higher rate of secondary glaucoma (11%) among 80 HLA-B27–positive uveitis patients.

The exact mechanism of HLA-B27–associated uveitis is not known. There is antigenic similarities between gram-negative bacteria, including Helicobacter pylori and HLA-B27.¹²³ HLA-B27–associated uveitis was associated with high levels of serum prolactin.¹²⁷

The treatment of HLA-B27–positive uveitis requires more aggressive treatment than in HLA-B27–negative patients.¹²⁶ The use of periocular and systemic corticosteroid therapy is often effective.¹²⁸ Immunomodulatory therapy, such as MTX, is effective in patients resistant to conventional steroid treatment^128,129; it may reduce recurrence of uveitic attacks when initiated within 3 years of the disease onset.¹²⁹ TNF-α antagonists, such as infliximab and etanercept, were found to be highly efficient in these cases.¹²⁸ Secondary pupillary block glaucoma is treated with peripheral iridectomy. Intracameral tissue plasminogen activator was reported to be successful in dissolving the fibrinous membranes and in breaking the synechiae in a patient with posterior synechiae.¹³⁰

Recurrence of severe AAU attacks occurs frequently among HLA-B27–positive patients, usually in the same eye.¹²² Despite that, visual prognosis is fairly good.¹²¹

Ankylosing Spondylitis

AS is the most frequent subtype of SSA. It mainly affects the spine and sacroiliac joints. The mean age at onset is 26 years. According to different reports, 14% to 33% of patients with AS develop uveitis.^131,132 AS uveitis is typically a unilateral AAU. Recurrences are common, often involving the contralateral eye. Presence of AAU in patients with AS is in correlation with higher disease activity and poor functional ability. Of patients with AS uveitis, HLA-B27 haplotype was detected in 36%.¹³³ On the other hand, among patients with HLA-B27–associated uveitis, AS was found in more than 40%, more in men than in women.^124,133

Reactive Arthritis

Reactive arthritis, formerly termed Reiter’s syndrome, is a multiorgan disease characterized by arthritis, conjunctivitis, and mucocutaneous lesions.¹³⁴ Reactive arthritis is precipitated by gram-negative intestinal or genitourinary tract flora bacteria.¹³⁵ Most patients can report on a history of infection, most frequently urethritis.¹³⁴ Patients are commonly young adult males; 85% are HLA-B27 positive.¹³⁴ The risk of reactive arthritis development in HLA-B27 carriers is more than 27 times higher than the mean incidence in the general population.¹³⁶ Most patients have a positive family history.¹³⁴

Ocular manifestations were reported in 58% of 113 reactive arthritis patients¹³⁷; the most common manifestation is conjunctivitis with papillary reaction and mucopurulent discharge. Anterior uveitis developed in 7.8% of 254 patients and can be recurrent and chronic. Other possible manifestations are pars planitis scleritis and episclertitis.^134,137 Secondary glaucoma occurs in up to 2% of reactive arthritis patients.^136,137

Systemic therapy with corticosteroids is typically required for intraocular inflammation control, with additional immunosuppressive therapy, mainly MTX.¹³⁴

Inflammatory Bowel Disease–Associated Arthritis

Inflammatory bowel diseases (IBDs) include Crohn’s disease and ulcerative colitis and may have extra-intestinal manifestations, mainly arthritis and ocular inflammation.

Anterior uveitis is the most common ocular manifestation in IBD. Bilateral relapsing uveitis has been reported to be synchronous with bowel relapse.¹³⁸ HLA-B27 is significantly more common in patients with IBD who develop uveitis than in those who do not.¹³⁹ Secondary glaucoma may develop as a result of posterior synechiae causing pupillary block, or neovascular glaucoma due to retinal vasculitis.¹³⁸

Treatment with topical corticosteroids, sometimes combined with systemic corticosteroids, controls the ocular inflammation.¹³⁸ Glaucoma is treated according to manifestation with peripheral iridectomy,¹³⁵ panretinal photocoagulation, or surgically.¹³⁸

Psoriatic Arthritis

Psoriatic arthritis is a chronic inflammatory arthropathy. The prevalence of uveitis in psoriatic arthritis patients ranges between 18% and 25%^132,140 and is associated with the rate of HLA-B27.¹⁴⁰ Predicting factors for development of uveitis in psoriatic arthritis patients include extensive axial involvement and the HLA-DR13 antigen.¹⁴⁰

The uveitis is solely anterior in almost 80% of patients, with indigos onset in two-thirds of the cases. Nearly 40% of uveitis cases are bilateral.¹⁴⁰ Psoriasis-associated uveitis presents at an older age and has a more prolonged course compared to idiopathic or HLA-B27–associated AAU.¹⁴¹

Oral corticosteroids are required in many cases. Many patients also require additional immunosuppressive therapy¹⁴⁰ and oral NSAIDs.¹⁴¹

Synovitis-Acne-Pustulosis-Hyperostosis-Ostitis Syndrome

Synovitis-acne-pustulosis-hyperostosis-ostitis (SAPHO) syndrome is considered another member of the SSA family. Clinical manifestations may include skeletal changes, mainly in the chest wall and skull, arthritis, and dermatologic involvement.¹⁴² Cases have frequent association with sacroiliitis.¹⁴³ SAPHO syndrome was also described in association with IBD and BD.143 Ocular complications of the syndrome include recurrent uveitis, which may induce severe secondary bilateral glaucoma.¹⁴³

Behçet’s Disease

BD, also named Adamantiades-Behçet disease, is a multiorgan immune-mediated vasculitis of unknown origin. The disorder is characterized by recurrent oral and/or urogenital ulcerations, skin lesions, intraocular involvement, central nervous system manifestations, arthritis, and gastrointestinal lesions.^144,145 It is rare in the United States, occurring more commonly in the Middle and Far East. At the onset of the symptoms, most patients are younger than 40 years old.¹⁴⁶

Sixty percent to 80% of BD patients develop an ocular disease.¹⁴⁵ Most patients experience recurrent bilateral anterior uveitis, frequently with hypopyon that resolves spontaneously with little or no evidence of inflammation between attacks.^144,147 The minority of patients suffer from chronic posterior uveitis with retinal vaso-occlusive disease causing visual loss¹⁴⁶ (Figure 43-7). Men tend to suffer from a more severe disease with worse visual prognosis and a higher incidence of panuveitis.¹⁴⁴ BD might be complicated with retinal and optic atrophy, vitreous hemorrhage, neovascular glaucoma, and retinal detachment.¹⁴⁷

Glaucoma was diagnosed in about 11% of eyes, either open-angle glaucoma secondary to inflammation or corticosteroid treatment (44%), angle-closure glaucoma with PAS and pupillary block (44%), or neovascular glaucoma (12%).¹⁴⁶

Although the pathogenesis of the disease was not fully discovered, genetic factors play an important role. The disease has been associated with HLA-B5 and HLA-B51 alleles in populations of various ethnicities.¹⁴⁸ The ocular inflammation is associated with both innate immune response (neutrophils, NK cells) and adaptive immune response (T cells).¹⁴⁵ Selenium-binding protein was found to be an autoantigen in BD-associated uveitis.¹⁴⁹

Treatment includes a high-dose intravenous corticosteroid, which is effective initially. Eventually, most patients require treatment with cytotoxic agents like cyclosporine, FK506, antimetabolites, or biologic drugs.¹⁴⁷ Biological drugs like infliximab, adalimumab, and interferon-alpha have been proven beneficial and safe in controlling BD-associated uveitis.¹⁴⁵

Antiglaucoma medication is effective in some cases; laser iridotomy is recommended for angle-closure and pupillary block. However, nearly one-third of the patients required trabeculectomy, GDD implantation, or diode-laser cyclodestruction.^146,150 A 1-year follow-up after primary trabeculectomy with MMC demonstrated a success rate of more than 80%.¹⁵¹ If ocular surgery is required, complete preoperative control of inflammation is essential.¹⁵² Using interferon-alpha, prior, during, and after vitrectomy and trabeculectomy was tried effectively.¹⁵³

Throughout the 1990s, following the use of immunosuppressive regimens, the clinical outcome of BD has improved significantly.¹⁵⁴ Nevertheless, an international case series of 1465 patients with ocular disease published¹⁴⁴ in 2007 found that, despite modern therapy, one-quarter of the patients were legally blind.

Vogt-Koyanagi-Harada Syndrome

VKH syndrome is a chronic systemic autoimmune disease characterized by alopecia, vitiligo, poliosis, dysacousia, and meningeal irritation. In a study of 101 patients, two-thirds of patients were female, and the mean age was 34 years, although it may present in a wide range of ages (8 to 75 years).¹⁵⁵ VKH syndrome is more prevalent in Asian, Middle Eastern, Indian American, and Hispanic populations.¹⁵⁶

Ocular involvement is characterized by granulomatous uveitis and exudative retinal detachment (Figure 43-8).¹⁵⁷ Half of the eyes develop at least one complication, such as cataract, glaucoma, choroidal neovascularization, and subretinal fibrosis.^155,156 Complicated cases are associated with longer disease duration and a higher number of intraocular inflammatory episodes.¹⁵⁵

Glaucoma is a common complication in VKH syndrome, occurring in 27% to 33% of patients. In a study of 16 patients with VKH glaucoma, 56% had open-angle and 44% closed-angle glaucoma.¹⁵⁸ Angle-closure glaucoma is often secondary to uveal effusion with forward displacement of the lens-iris diaphragm, which may be acute and cause extensive PAS formation.^159,160 Ultrasound biomicroscopy demonstrates swelling of the ciliary body and supraciliary space with anterior rotation of the ciliary body.¹⁶¹ Similar findings were described with anterior segment optical coherence tomography.¹⁶²

The autoimmune process responsible for the disease is directed against melanocytes-associated antigen.156 There is a genetic contribution as well; several HLA-DQB1 alleles were associated with VKH syndrome.¹⁶³ On histopathologic examination, there is a non-necrotizing diffuse granulomatous panuveitis and formation of Dalen-Fuchs’ nodules. Choriocapillaris are spared initially but are involved later.¹⁶⁴

VKH treatment includes initial high-dose intravenous corticosteroid therapy followed by prolonged oral corticosteroid treatment.¹⁶⁴ Other immunosuppressive therapy, such as cyclosporine or cytotoxic agents, may be required.^156,164 In a report on adjunctive oral MTX in refractory pediatric cases, MTX was shown to be safe and effective in controlling inflammation.

Nearly one-third of glaucoma cases can be controlled medically with systemic corticosteroids,¹⁶⁵ cycloplegics, and aqueous suppressants. Two-thirds require surgical treatment by iridectomy, trabeculectomy, or GDD implantation.¹⁵⁸ In cases where there are multiple complications, such as severe cataracts and secondary glaucoma, a one-stage procedure including pars plana lensectomy-vitrectomy and peripheral anterior synechiolysis is optional. Following the procedure, IOP control was achieved with timolol only in all 6 operated eyes.¹⁶⁶

Pediatric cases present with an aggressive course,¹⁶⁶ although their visual prognosis is usually favorable.¹⁶⁷ Overall, nearly 60% of patients retained 20/30 vision or better.¹⁶⁴ Prognostic factors associated with a worse visual prognosis include multiple complications, older age at onset, worse acuity at presentation, delayed treatment, recurrence of inflammation, and use of intravenous corticosteroids.^155,167

Sympathetic Ophthalmia

Fortunately rare but potentially devastating, sympathetic ophthalmia (SO) occurs weeks to months after trauma or ocular surgery, mainly pars plana vitrectomy and cyclodestructive procedures,¹⁶⁸ and causes a bilateral non-necrotizing, granulomatous uveitis.¹⁶⁸ More than 70% of patients are men,^168,169 with an average patient age of 30 to 46 years in different reports.^168,169

Most patients present with reduced vision, redness, and photophobia.^168,170 More than one-quarter of SO patients have a visual acuity of 20/200 or worse at presentation, with further vision loss to 20/200 or worse at a rate of 10% per person-year.¹⁷¹ In more than half of patients, only fundus lesions are evident, mainly exudative retinal detachment, yellowish-white mid-peripheral lesions (Dalen-Fuchs’ nodules), papilledema, vasculitis, peripapillary choroidal neovascularization, and choroidal scarring.¹⁷² The pathology is similar to that seen in VKH syndrome, although chorioretinal scarring is less severe here. Recurrence, mainly in the anterior segment, occurs in 30% of eyes, even years after the resolution of the initial episode.^169,172

Secondary glaucoma developed in more than 40% of cases in one study.¹⁷³ The glaucoma mechanism is unclear, though plasma cell infiltration of the iris and ciliary body was found in many SO biopsy samples.¹⁷³

SO is caused by bilateral autoimmune hypersensitivity reaction against exposed ocular antigens, possibly found on choroidal melanocytes, in the injured eye.¹⁶⁸ Photoreceptor mitochondrial oxidative stress mediated by iNOS and TNF-α was found in SO, which might lead to photoreceptor apoptosis and subsequent decreased visual outcome.¹⁷⁴ HLA-DR15 has been associated with SO.¹⁷⁵

Treatment includes oral or high-dose intravenous corticosteroid, sub-Tenon dexamethasone, intravitreal corticosteroid treatments, or immunomodulator therapy.^168,170,171 Intravitreal fluocinolone slow-release device was found to be an effective and safe alternative to multiple intravitreal triamcinolone injections in chronic SO.¹⁷⁶ Although enucleation of the injured exciting eye before the disease develops in the contralateral sympathizing eye is the only known prevention of SO, this remains a controversial procedure and is not justified in most cases.^172,177 The glaucoma is difficult to treat, requiring frequent adjustments of corticosteroid therapy and possible glaucoma surgery.¹⁷²

Despite the high ocular complication rate in the sympathizing eye, 50% of patients regain a visual acuity better than 20/40 after a decade.^169,177 Prompt and aggressive therapy is key in obtaining a good visual prognosis. Poor visual prognosis is associated with complications such as glaucoma, chorioretinal macular scars, and exudative retinal detachment.^171,177

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving multiple organs. It is more prevalent in women. The prevalence of SLE in patients with uveitis varies in the literature from 0.1% to 4.8%.178–180

Ocular involvement in SLE patients is fairly common, consisting of mostly dry eye syndrome, and is found in 31% of patients. Steroid-related complications like bilateral subcapsular cataract and glaucoma are also prevalent, up to 21% and 2.9%, respectively.^181,182 Nearly all parts of the eye and visual pathways might be involved by inflammation or thrombus.¹⁸² Possible sight-threatening manifestations include uveitis, optic neuritis, ischemic optic neuropathy, scleritis, episcleritis, and retinopathy.¹⁸² Retinopathy can manifest as drusen, retinal pigment epithelium atrophy, vascular changes, macular chorioretinitis scar, or branch retinal vein occlusion.¹⁸¹

Several mechanisms were described as causing glaucoma: bilateral uveal effusions,¹⁸³ posterior scleritis causing angle-closure glaucoma,¹⁸⁴ as well as open-angle glaucoma.¹⁸⁵ In patients with antiphospholipid antibodies, retinal vascular occlusive disease may result in neovascular glaucoma.¹⁸²

Anterior uveitis, as well as episcleritis and dry eyes, are commonly treated topically, whereas scleritis and severe retinopathy require systemic therapy ranging from NSAIDs to corticosteroids and other immunosuppressive agents.¹⁸² Vaso-occlusive disease is treated with anticoagulation and laser photocoagulation.¹⁸²

Treatment of glaucoma requires antiglaucoma medications in addition to inflammation control. In refractory cases, sclerectomies and choroidal drainage were reported as effective.¹⁸³ Glaucoma secondary to scleritis was treated with corticosteroids and antiglaucoma therapy, with a good response.¹⁸⁴

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease with inflammatory demyelinization of the central nervous system.¹⁸⁶ Fifteen percent to 40% of patients with MS develop uveitis, although more than half of them are asymptomatic.¹⁸⁷ The uveitis preceded the onset of MS in 25% to 56% of cases.^188,189

The most common form of uveitis is pars planitis. The next most common form is granulomatous anterior uveitis, characterized by development of extensive posterior synechiae and large mutton-fat KPs.¹⁸⁷ The uveitis is bilateral in almost all cases.¹⁸⁸ Complications of uveitis include cataracts, symptomatic vitritis, occlusive peripheral retinal vasculitis with neovascularization, macular edema, and epiretinal macular membrane.¹⁸⁷ Glaucoma was found in 15% of patients with MS uveitis.¹⁸⁷

Uveitis treatment includes systemic corticosteroids and immunosuppressive treatment.^187,189 Glaucoma is treated with aqueous suppressants and trabeculectomy with anti-metabolites as needed. In a study¹⁸⁷ describing 5 operated eyes, 60% achieved normal IOP with surgery alone, whereas the rest needed additional antiglaucoma medication for IOP control.

Visual prognosis is fairly good in treated patients.¹⁸⁸ More than 80% of patients had the same or better visual acuity during follow-up.¹⁸⁹

INFECTIOUS DISEASES

Viral Infections

Herpes Virus Family

The herpes virus family includes 8 human herpes viruses—HSV-1, HSV-2, varicella zoster virus (VZV), CMV, Epstein-Barr virus (EBV), human herpes virus type 6 (HHV6), type 7 (HHV7), and type 8 (HHV8). Several of these DNA viruses may cause ocular manifestations, including keratitis, uveitis, and secondary glaucoma.¹⁹⁰

Herpes Simplex Virus

Ocular involvement in HSV infection may include conjunctivitis, keratitis, and uveitis. HSV keratouveitis is often accompanied by IOP elevation and secondary glaucoma.¹⁹¹ HSV uveitis might present without keratitis. In these cases, the uveitis is more severe than uveitis with previous corneal involvement and results in a worse glaucoma.¹⁹²

In different reports, 28% to 54% of patients with ocular HSV developed increased IOP, mostly with corneal disciform or stromal disease^193–195 (Figure 43-9). Increased IOP is usually related to obstruction of the TM by trabeculitis or inflammatory debris.¹⁹⁶ HSV-1 was found to have the ability to enter and produce infection of the TM, through a receptor named herpes virus entry mediator.¹⁹⁷ A rabbit model of herpetic uveitis showed biphasic elevation of IOP. The primary uveitis is caused by the active HSV infection of uveal tissue during the first few days, whereas the secondary uveitis derives from immunological mechanisms.¹⁹⁸ A devastating condition consisting of anterior segment ischemia secondary to chronic keratouveitis has been reported.¹⁹⁹ In these cases, severe secondary angle-closure glaucoma developed due to extensive corneoscleral and intraocular inflammation that was unresponsive to maximal medical therapy.

HSV type 1 is the dominant causative agent of herpetic uveitis, although there are reports of keratouveitis caused by HSV type 2.^200,201 Diagnosis of HSV keratouveitis can be confirmed by polymerase chain reaction (PCR) from the aqueous humor.¹⁹³

Treatment of herpetic uveitis is complex and involves close monitoring and balance between antiviral and anti-inflammatory therapy. Treatment includes inhibiting activation of the virus with antiviral therapy in conjunction with topical corticosteroids in tapered doses and aqueous suppressants.¹⁹¹ Long-term prophylaxis with oral antiviral medications is effective in preventing recurrences.193,202 Periocular and systemic corticosteroids are required more frequently in HSV patients in comparison to VZV patients.¹⁹⁴ Filtration surgery is rarely required.^191,193

Stay updated, free articles. Join our Telegram channel

Join