Uveitis in patients with systemic sarcoidosis is common in people of any race, gender, or age but is particularly more prevalent in pigmented people than in whites. In Japanese people, uveitis in association with sarcoidosis is very common and is ranked as one of the three major uveitides, the other two being Behçet's disease and Vogt-Koyanagi-Harada disease. Uveitis of sarcoidosis accounts for 15% of all uveitis cases in Japanese patients.
Sarcoidosis is an immunological and systemic disease and involves all organs in the body—the lymph nodes, lungs, liver, spleen, skin, eyes, muscles, and so on. We found an ocular manifestation of disease in 60% of patients in whom sarcoidosis was diagnosed systemically by specialists. In most patients, systemic sarcoidosis was asymptomatic and silent but, in those with systemic involvement, ocular disorders were the most severe complication and led to severe visual loss. Among all sarcoid uveitis cases, 15% of patients showed an unfavorable visual outcome (visual acuity <0.2), owing to the development of ocular complications.
In this chapter, we describe our experience with the clinical features, characteristics, and visual prognosis of sarcoid uveitis in Japanese patients.
Sarcoid uveitis may involve persons of any age and either gender, although it is most prevalent in middle-aged and elderly women (>30 years). The disease appears in an acute and a chronic form. In elderly people, the chronic form is more common, whereas in youths, no gender prevalence is noted and the acute form prevails. Acute panuveitis occurs in the acute, aggressive form of sarcoidosis, usually in association with Herrfordt syndrome, with uveoparotid fever in both boys and girls. Beyond middle age, women are four times as likely to be affected as are men. In general, female patients with sarcoid uveitis are twice as prevalent as male patients with this disease. Ninety percent of patients with sarcoid uveitis are affected bilaterally.
Sarcoidosis is characterized by the formation of noncaseating epithelioid cell granuloma involving all the organs in the body. Affected anatomical regions are the lymph nodes, lungs, liver, spleen, heart, muscles, skin, and eyes. Inflammatory granuloma response consists of a centrally located collection of epithelioid cells surrounded by scattered lymphocytes (Fig 1).
These pathological findings bear a strong resemblance to granuloma in tuberculosis, except that the latter is caseating. Giant cells or asteroid bodies sometimes are seen in the lesion.
The systemic manifestations of sarcoidosis are generally mild. However, the eye is one of the predominantly involved organs, becoming severely inflamed and involving intraocular tissue also. In the eye, epithelioid cell granulomas are seen in any tissue, such as in the ciliary body (see Fig 1), iris, choroid, retina (Fig 2), vitreous, optic nerve, sclera, episclera, and extraocular muscle.
Characteristically, some large conglomerates of inflammatory cells consisting of epithelioid cell granuloma take up residence in the vitreous or on the surface of the ciliary body (see Fig 1). The plasma membrane of epithelioid cells is so sticky that each cell easily adheres to another and so is transformed into large nodular cell collections, which correspond with snowball vitreous opacities and so-called strings of pearls in the vitreous. These cell collections then migrate to the anterior chamber, adhere to the back surface of the cornea, and become mutton-fat keratic precipitates. Thus, mutton-fat keratic precipitates, snowball opacities, and strings of pearls are characteristic signs in sarcoidosis—as is granulomatous uveitis—but they are not pathognomonic. Presence of these findings indicates that the cause of uveitis is granulomatous and implicates sarcoidosis.
The etiology of systemic sarcoidosis is unknown. However, the disease is presumed to be initiated by an infectious agent, probably Propionibacterium acnes. Cellular immunity is suppressed in this disease. There is abnormality of the host-parasite relationship.
The inflammatory response in sarcoid uveitis is mostly mild. Subjective symptoms too are mild. In the chronic form, onset is insidious, and the disease develops gradually without subjective symptoms. Only at the time that complications of cataract or glaucoma develop do patients notice illness of the eye. When inflammation is remarkable, blurring of vision, reduced visual acuity, and myodesopsia occur. In the acute form, slight redness of the bulbar conjunctive and blurring of vision occur.
At the lower fornix of the conjunctiva, hard nodular follicles sometimes are seen in sarcoidosis. These follicles consist of sarcoid granuloma. The sclera and episclera are sometimes reddish and swollen, as seen in scleritis and episcleritis. Injection of the bulbar conjuctiva, if present, is slight. The cornea is clear but sometimes affected with band keratopathy.
So-called mutton-fat keratic precipitates frequently appear (Fig 3). The number of precipitates depends on the grade of inflammation. These precipitates consist of conglomerates of epithelioid cells that migrate from the ciliary body. In the anterior chamber, large inflammatory cells float, but hypopyon does not appear.
On the iris surface and at the pupillary margin of the iris, grayish white, small nodular exudates frequently are seen (Busacca's nodule, Koeppe nodule) (Fig 4). Posterior synechiae of the iris are very frequently seen.
At the chamber angle, small, grayish white nodular exudates are seen frequently on the trabecular meshwork. Tentlike, small peripheral anterior synechiae or goniosynechiae also are frequently seen. These findings in the chamber angle are termed trabecular sarcoidosis.
In the vitreous, numerous small inflammatory cells and large collections of such cells float. Particularly on the lower periphery of the retina, typical snowball opacities and strings of pearls usually are found (Fig 5).
The papillae sometimes are hyperemic and the margin blurred. In a few eyes, the papillae swell in a choked-disc appearance owing to granuloma formation in the optic disc.
In the retina, segmental periphlebitis is seen most often at the equator, sometimes in the periphery, and rarely in the posterior pole. Phlebitis usually is associated with “candle-wax drippings” (Fig 6) and sometimes with arteritis. Nodular exudates as well as punched-out lesions in the deep retina and choroid sometimes are seen in the periphery. These manifestations mimic birdshot chorioretinopathy.
In the acute form, massive yellowish white exudates appear in the posterior pole, showing a Coats' disease–like appearance. In chronic cases, persistent mild inflammation leads to retinal edema and cystoid macular edema. In rare cases, retinal and vitreal hemorrhages from retinal neovascularization occur.
Clinical Characteristics in Sarcoid Uveitis
Sarcoid uveitis generally is bilateral (90%), and both eyes manifest similar findings, and a similar clinical course. The typical findings are mutton-fat keratic precipitates, posterior iris synechiae, Koeppe nodules, trabecular sarcoidosis, snowball opacity and strings of pearls in the vitreous, segmental periphlebitis, and candle-wax drippings. These findings are a result of granuloma formation in the tissues and are manifestations of nodular uveitis.
The presence of ocular signs and clinical features as just outlined strongly suggests a diagnosis of sarcoidosis. To confirm a suspicious diagnosis, we perform systemic investigations as follows:
- Erythrocyte sedimentation rate
- Mantoux skin test
- Serum angiotensin-converting enzyme level
- Chest radiography (to search for bilateral hylar lymphadenopathy)
- Lymph node biopsy (subclavian, mediastinum)
A negative Mantoux test indicates delayed cellular hypersensitivity and strongly suggests sarcoidosis. Particularly in patients in whom a Mantoux test result previously was positive and a current test proves negative, sarcoidosis is strongly suggested. The results of these systemic tests can support the diagnosis of sarcoidosis, but any one of these tests is not pathognomonic for that disease.
When manifestations of uveitis correspond perfectly with ocular manifestations of sarcoidosis but all systemic tests are negative, can we make a diagnosis of sarcoidosis? Some papers from Japan have reported that, in such patients, sarcoidosis was confirmed histologically by mediastinoscopy of the hilar lymph node. Given those reports, we accept the argument that uveitis may exist with sarcoidosis even in the face of negative systemic tests.
Sarcoid uveitis should be differentiated from both tuberculosis and Vogt-Koyanagi-Harada disease. A positive Mantoux skin test and chest radiograph should distinguish tuberculosis cases. Vogt-Koyanagi-Harada disease manifests in the early stage with flat or bullous retinal detachment. In late-stage disease, a sunset fundus appearance with a Dalen-Fuchs' spot and recurrent iridocyclitis with mutton-fat keratic precipitates and posterior synechiae of the iris are present. The patient generally is HLA-DR4-positive.
Clinical Course and Visual Outcome
Usually, uveitis exhibits such long-term, persistent inflammation that many associated complications occur. In uveitis alone, inflammation is mild and visual outcome is favorable. When uveitis lasts for a long period, cystoid macular edema, iris bombé due to the formation of posterior synechiae, and secondary angle-closure glaucoma due to peripheral anterior synechiae frequently develop. Long-lasting uveitis leads to cataract formation. Development of glaucoma and cataract results in visual loss.
Fifteen percent of eyes with sarcoid uveitis have shown severe visual loss (visual acuity <0.2). The main cause of severe visual loss was the development of various complications. Vitreol retinal hemorrhage is a rare complication of sarcoid uveitis.
Sarcoidosis can be treated with corticosteroids. In severe cases, oral steroids are necessary, whereas mild uveitis can be treated with a topical steroid or via sub-Tenon's steroid injection. Steroids should be given for a sufficiently long term, until at least 3 months after the disappearance of uveitis. The initial steroid dose is 8 mg oral prednisolone. Interruption of steroid administration after a short term invites uveitis rebound. Steroid use must continue over a long period if recurrent uveitis is to be prevented.
Topical use of cycloplegia (mydriatics) is also necessary. In the case of cataract formation, cataract surgery must be performed. Should glaucoma develop, topical use of a β-blocker or, if necessary, surgical management is appropriate. In the case of chronic uveitis, cystoid macular edema, epiretinal membrane, or a persistent, dense vitreous opacity, vitreous surgery (cataract surgery, vitrectomy, inner limiting membrane removal, epiretinal membrane excision) may be performed. The outcomes of these operations are usually favorable.
Sarcoid uveitis is common, mostly in a chronic form, and is prevalent in women past middle age. The onset is insidious. Infammation is commonly mild but persists for a long period and then is complicated by the development of macular edema, cataract, and glaucoma, resulting in visual loss. The diagnosis is made according to characteristic ocular signs and systemic investigations. Effective treatment consists primarily of long-term use of steroids. Nonetheless, 15% of cases of sarcoid uveitis demonstrate an unfavorable visual outcome.