The iris is the anterior extension of the ciliary body dividing the aqueous compartments into anterior and posterior chambers. The anterior surface of the iris consists of loosely structured stromal tissue of mesodermal origin lined posteriorly by a pigmented layer that extends from the pupillary margin of the iris back to the ciliary body. The pupil is the central iris aperture that changes in size to control the amount of light entering the eye. The pupillary sphincter muscle is supplied by the parasympathetic fibers of cranial nerve III, and the dilator pupillary muscle is supplied by the sympathetic nervous system (see Chapter 13).

The ciliary body is the posterior extension of the iris and contains the ciliary muscle, which functions in accommodation. The epithelium extending posteriorly from the iris becomes two distinct layers. The outer pigmented epithelial layer is continuous posteriorly with the retinal pigment epithelium (RPE). The inner nonpigmented epithelial layer of the ciliary body produces aqueous humor and extends posteriorly to become the sensory retina.

The choroid makes up the major portion of the uveal tract. It runs between retina and sclera from the ora serrata to the optic nerve. This vascular layer supplies nutrition to the external half of the retina and is composed primarily of an inner layer of capillaries known as choriocapillaris and externally by succeeding larger collecting veins (medium vessels—Sattler layer; outer large vessels—Haller layer). The choroid is thickest posteriorly (0.25 mm) and thin near the ora serrata (0.1 mm). The anterior uveal tract is fed primarily by long posterior ciliary arteries;
the posterior uveal tract is fed primarily by short ciliary arteries, although there is free anastomosis between vessels. Bruch membrane is part of the choroid and lies between the choriocapillaris and the retinal rods and cones. Uveal melanocytes are scattered throughout the choroid, and their numbers account for variation in degree of choroidal pigmentation. The nerve supply to the choroid is from both short posterior and long anterior ciliary nerves.

Definition. Uveitis is a general term referring to inflammation of the uveal tract. It may be divided into iritis, cyclitis (ciliary body inflammation), iridocyclitis, and choroiditis, according to specific areas of the uveal tract involved. Although the term uveitis refers primarily to inflammation of this vascular structure, adjacent structures such as retina, vitreous, sclera, and cornea are also frequently involved secondarily in the inflammatory process.

Incidence. In a population of 100,000 people, over a period of 1 year, 15 individuals will develop uveitis. Uveitis afflicts 2.3 million people in the United States, with 45,000 cases reported each year. Uveitis is responsible for 10% of all blindness. Among patients with ocular inflammation, about 75% will have anterior uveitis (iritis, iridocyclitis), 8% intermediate uveitis (pars-planitis), and 17% posterior or panuveitis.

Granulomatous versus nongranulomatous uveitis. Although morphologic description is still of some value, the rigid division of uveitis into these two categories has become largely anachronistic. By the original definition, nongranulomatous uveitis was typically acute or chronic, located in the iris and ciliary body, and characterized by a cellular infiltrate of lymphocytes and plasma cells that tended to form hypopyon and fine precipitates on the corneal endothelium, known as keratic precipitates (KPs). The etiology was thought to be noninfectious, such as in Fuchs heterochromic uveitis. Granulomatous uveitis was thought to be chronic and to involve any portion of the uveal tract, but with a predilection for the posterior area. It was typically characterized by nodular collections of epithelioid cells and giant cells surrounded by lymphocytes. The KPs were larger than those seen in nongranulomatous disease, greasy in appearance (mutton fat), and composed primarily of epithelioid cells and pigment. The etiology was thought to be infectious and due to such organisms as tuberculosis (TBC), toxoplasmosis, and spirochetes; however, granulomatous uveitis was also seen in noninfectious disease, such as sarcoidosis and sympathetic ophthalmia. It is now known that transitional forms of uveitis are not uncommon and that the basic pathology lies somewhere between the rigidly defined granulomatous and nongranulomatous uveitides. Nonetheless, the classification is often useful in orienting the physician toward workup and therapy.

Anterior uveitis clinical findings vary between the acute and chronic form. In acute nongranulomatous uveitis, there is an acute onset of ocular pain (a few days) with hyperemia, photophobia, and blurred vision, lasting 2 to 6 weeks. There is perilimbal flush caused by dilation of the radial vessels and frequently fine white KPs on the posterior corneal, inferiorly in a vertical or base-down pyramidal distribution. KPs can also be found in the trabecular meshwork. The pupil is miotic, and cells and flare are found in the anterior chamber with or without fibrin exudation. Posterior synechia formation between iris and lens may be present, but iris nodules (pupillary Koeppe and anterior iris Busacca) and vitreous haze are typically absent. However, in severe iritis, spillover cells may be present in the anterior vitreous. The disease course is acute and the prognosis is relatively good, although recurrences are common. More than 50% of cases are associated with HLA-B27. Chronic anterior uveitis is often insidious in onset and lasts longer than 3 months. Chronic iridocyclitis may be either nongranulomatous or granulomatous in character and usually is not associated with much hyperemia. In fact, in several forms the eyes may be white (JIA and Fuchs’ heterochromic iridocyclitis). Old KPs, iris stromal atrophy, posterior synechiae, and cataract formation are common findings. Diagnoses associated with chronic iridocyclitis are sarcoidosis and Fuchs heterochromic iridocyclitis.

Intermediate uveitis (pars-planitis) is usually bilateral, with patients presenting with signs and symptoms of blurred vision (macular edema), floaters, and little or no pain, photophobia, or anterior segment inflammation. Active inflammatory cells in the vitreous are white, round, and with equal distribution in the formed and liquid vitreous. Old vitreous cells are small, irregular, pigmented, and confined to the formed vitreous. The ora serrata is the site of vitritis and exudates that may progress to “snowbank” appearance, especially inferiorly. Progression of vitreous gel damage can result in membrane formation, with retinal traction and detachment. Multiple sclerosis and sarcoid are often associated. Twenty percent of children with uveitis have pars-planitis.

Posterior uveitis. In disease limited entirely to the posterior segment of the eye, the onset may be acute, but is often more insidious with little or no pain, minimum photophobia and blurring of vision (unless the macular area is involved), and no perilimbal flush. Inflammation of the posterior segment can affect the sensory retina, retinal vasculature, the retinal pigmented epithelium, the choroid, and optic nerve. Retinitis is associated with yellowish-white thickening, with secondary hemorrhages and focal ischemia. Inflammation of the retinal vessels usually is segmental, seen as a perivascular whitish cuff or sheathing. Choroidal lesions may be diffuse, but tend to be focal patchy yellow-white areas of infiltrate with overlying vitritis. Because of the anatomic relationship between choroid and retina, a retinitis is also usually present, and resolution of the process results in a chorioretinal scar with a corresponding visual field scotoma. If the macula is not involved, central visual acuity may return to normal. Examples of diseases predominantly involving the choroid are sympathetic ophthalmia and Vogt-Koyanagi-Harada (VKH), often with exudative retinal detachment. Optic nerve pathology in uveitis can be due to direct inflammation, ischemia secondary to vasculitis, glaucoma, or papilledema caused by involvement of the central nervous system (CNS).

Toxoplasmosis is a necrotizing retinitis with secondary inflammation in the choroid, as are the viral infections CMV, herpes simplex, herpes zoster, rubella, and rubeola. Behçet disease, however, is a retinitis with retinal vasculitis and only rarely has choroidal involvement. It is not, then, truly a uveitis, although it is almost always included in this ocular disease category.

Panuveitis may involve the entire uveal tract in any inflammatory type. Onset may be acute or insidious and the course variable, depending on etiology. The KPs, if present, tend to be large and greasy (mutton fat), and the pupils small and occasionally scarred down to the lens by posterior synechiae. In the anterior chamber, cells and flare are sometimes present, but not to the extent commonly seen with acute anterior uveitis. Iris nodules and vitreous haze are occasionally present. The course tends to be chronic, with a variable prognosis.

Conjunctivitis is an inflammatory condition of the mucous membrane overlying the sclera. In conjunctivitis, vision is generally not blurred and pupillary responses are normal. Moderate irritation, itching, and a watery or purulent discharge may be present. There is no notable photophobia or deep pain. Hyperemia is usually diffuse or may be confined to just the lateral and medial angles but is not primarily confined to the perilimbal area as in iritis. Papillae or follicles are found on the the palpebral conjunctivae.

Anterior scleritis, while not a disease of the retinal vasculature, may have a sufficiently intense inflammatory reaction to induce an anterior or intermediate uveitis in about 40% of patients (see Chapter 5). Posterior scleritis is also not a uveitis but may cause ocular pain, boggy conjunctiva, vitritis, and chorioretinal edema. Ultrasound will reveal the posterior scleral inflammatory process, indicating the need for systemic steroid therapy.

In acute angle-closure glaucoma the vision is markedly reduced, and pain may be so severe that the patient presents with nausea and vomiting. Attention may be incorrectly misdirected to the gastrointestinal tract and the red eye ignored as the source of this disturbance. The pupil is fixed in middilation at about 4 mm to 5 mm and nonreactive. The cornea is diffusely hazy. Occasionally, it may be difficult to differentiate angle-closure glaucoma from glaucoma secondary to uveitis. Gonioscopy of an eye with angle closure will reveal obstruction of the trabecular meshwork by iris, whereas an eye with acute glaucoma secondary to uveitis will have a normal open angle unless there has been extensive peripheral anterior
synechia formation to the posterior cornea. In this latter case the scarring will be self-evident (see Chapter 10).

Retinoblastoma is seen in young children and characterized by pseudohypopyon with nodules in the iris as well as free-floating cells in the aqueous humor. The fundus should be carefully searched for retinal lesions. An x-ray of the globe revealing calcification scattered throughout the retinoblastic tumor is helpful in differentiating the disorder. Anterior chamber aspiration should be performed only if there is serious doubt concerning diagnosis (see Chapter 1 and Chapter 11).

Juvenile xanthogranuloma of the iris (nevoxanthoendothelioma) is characteristically associated with recurrent hyphema (blood in the anterior chamber), elevated IOP, and yellowish, poorly defined tumors. Therapy varies and includes local systemic corticosteroids, local irradiation, and excision. This disease is most commonly seen in the first year of life, but it may occur in adults. The physician should look for yellow tumors in the skin.

Malignant leukemias and lymphomas can masquerade as an anterior uveitis with iris involvement. Biopsy of involved iris tissue and anterior chamber aspiration aid in the diagnosis. Intraocular involvement of primary CNS lymphoma, which presents with a vitritis and occationally choroidal nodules, is another malignant masquerader. Occasionally, the diagnosis may be made by aqueous or vitreous tap, with the better yield being from vitrectomy. Malignancy should be suspected in individuals over 40 years of age, particularly those with neurologic manifestations.

Pigment “cells” in the anterior chamber may be confused with iritis. The anterior chamber should be graded for flare and cells before dilating drops, especially phenylephrine hydrochloride, are used, because the process of dilation may release cells into the aqueous that are actually benign pigment granules. This is most common in patients under the age of 40 years and in myopes. These cells are one-tenth the size of white cells and brownish in color. This benign pigment dust may also appear on the back of the cornea and is finer in appearance and more diffuse than that seen with leukocytic KPs. Other clinical signs of pigment dispersion include radial iris transillumination defects and a heavily pigmented trabecular meshwork.

Primary familial amyloidosis may present as globules that are slightly larger than inflammatory cells suspended in the anterior vitreous or as dense veillike opacities of wavy contour resembling glass wool. Protein electrophoresis and biopsy are indicated.

Reactive lymphoid hyperplasia frequently presents as an iridocyclitis. This condition may also simulate malignant melanoma. These pseudotumors respond to topical or systemic corticosteroid.

A chronic rhegmatogenous retinal detachment can present with a mild cellular reaction of the anterior chamber and vitreous. A thorough dilated fundoscopic examination clarifies the diagnosis.

Blood tests used in the diagnosis of uveitis are numerous; the shotgun approach is rarely rewarding and very expensive. The tests should, therefore, be based on a high index of suspicion based on clinical findings and review of systems. All patients with uveitis should be evaluated with the Venereal Disease Research Laboratory (VDRL) and the Fluorescent Treponemal Antibody (FTA) tests to rule out syphilis.
Lyme antibody testing should be conducted in Lyme endemic areas. Others tests should be ordered as guided by the history; all are listed in Table 9.3. The laboratory workup can be divided into three broad categories: (i) hematology/chemistry, (ii) special chemistry, and (iii) immunological tests.

Radiographic and other imaging analyses. All patients with ocular inflammation need chest imaging, as saroidosis and TBC can have various ocular manifestations. Specific radiographic analyses include

Skin testing is less often used as a diagnostic tool in uveitis.

Fluorescein angiography may be of use in diagnosis and clinical follow-up of chorioretinitis secondary to toxoplasmosis, toxocariasis, and histoplasmosis, and as an invaluable aid in following the clinical course of the many changes seen in a variety of uveitis patients.

Echography (ultrasound) is extremely useful in evaluating anterior and posterior disease, particularly when the view is obscured. Methods include anterior immersion technique and ultrasound biomicroscopy, and posterior A- and B-scans (see Chapter 1). This test is helpful in the evaluation of

Other ophthalmic tests of use in uveitis are as follows:

Ocular tissue sampling can be extremely valuable in the diagnosis of a systemic disorder in patients with uveitis.

Corticosteroids are very effective, not too difficult to administer, and not too expensive, and therefore are the most common agents used. These drugs reduce inflammation by (a) reduction of leukocytic and plasma exudation, (b) maintenance of cellular membrane integrity with inhibition of tissue swelling, (c) inhibition of lysozyme release from granulocytes and inhibition of phagocytosis, (d) increased stabilization of intracellular lysosomal membranes, and (e) suppression of circulating lymphocytes. Corticosteroids should be used with caution in uveitis secondary to an infectious process, particularly that of HSV, bacterial etiology, TBC, and toxoplasmosis, and they should never be used with fungus. The relative drug potency, the aqueous penetration, and relative ocular anti-inflammatory effect are listed in Table 9.3. Corticosteroids can be administered locally or systemically.

Mydriatic–cycloplegics are used to give comfort by relieving iris sphincter and ciliary muscle spasm and to prevent scarring between the pupillary border and anterior lens capsule (posterior synechiae). Atropine, the strongest mydriatic–cycloplegic, is used in a strength of 1%. It should be reserved for moderately severe to severe anterior uveitis and should be used one to two times daily. As uveitis lessens, the atropine dosage may be reduced or the patient placed on homatropine 5%. For mild to moderate anterior uveitis, homatropine 5% qd to bid will suffice to move the pupil. Bedtime use is beneficial in milder cases, because the pupil is mobilized primarily during sleep and iatrogenic presbyopia is not present during the day. Eyes with pupils that fail to dilate on atropine should have the lids taped shut between applications to increase the effect of the atropine. Phenylephrine 2.5% (in the absence of significant cardiovascular disease) and cocaine 4% applied to the ocular surface with a sterile Weck-cell by the ophthalmologist are also useful in mobilizing the otherwise scarred-down pupil. Atropine may complicate or precipitate urinary retention in patients with prostatism. Scopolamine 0.25% has almost the same cycloplegic strength as atropine and may be substituted in patients with urinary retention problems. Scopolamine itself, however, in very frequent doses may also aggravate this condition. Cyclopentolate may aggravate iritis because of its neutrophilic chemotactic effect; however, this has not been proven true in clinical experience.

NSAIDs. Oral NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins, leukotrienes, and thromboxane from arachidonic acid. NSAIDs thereby block the formation of these local mediators of the inflammatory response. The prostaglandins are one of the many chemical mediators involved in the pathogenesis of uveitis; they are synthesized by the enzyme prostaglandin synthetase and found in all tissues of the eye. Prostaglandins cause a marked increase in protein content of the aqueous humor and mild smooth muscle contraction (pupillary miosis). Certain prostaglandins lower IOP, and others (E₁ and E₂) may increase it. The increased permeability of the ciliary epithelium may be a critical factor in inducing increased IOP secondary to prostaglandin release. All should be taken with meals.

Immunosuppressive agents. Immunosuppressive drugs usually should not be prescribed by a non–uveitis trained ophthalmologist alone, but in concert with an uveitis speciliast, rheumatologist, or primary care physician who is familiar with them and confident in their management. In making a decision as to which patient should receive immunosuppressive therapy, the physician must remember that the use of these drugs for non-neoplastic and non–life-threatening illness is a great clinical responsibility. To date there appear to have been very few severe complications from the combined regimen of corticosteroids and immunosuppressive agents, probably because of the lower dosages used and the better general health of the ophthalmic patients receiving them. Patients should be fully informed as to potential risks and benefits. A signed consent form or chart note to that effect is advisable.