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recurrent chalazia must be biopsied for pathologic evaluation. The lesion can mimic benign ocular diseases such as chronic blepharoconjunctivitis, corneal pannus, and superior limbic keratitis. Patients who do not respond to treatment should be biopsied, especially those with loss of lashes and destruction of meibomian gland orifices.

18.How is the biopsy performed? How is the specimen sent to the lab? What stains should be requested?

Sebaceous cell carcinoma is multicentric and undergoes pagetoid spread. Multiple sites must be biopsied, including bulbar and palpebral conjunctiva, even if they appear uninvolved. A full-thickness eyelid biopsy may be necessary to make the diagnosis because the lesion originates deep in the tissues. The tissue should not be placed in alcohol, which will dissolve the fat from the specimen and make the diagnosis more difficult. Oil red O stain will stain the fat red.

19.How are patients with sebaceous cell carcinoma treated?

Because sebaceous cell carcinoma is an aggressive and potentially fatal disease, wide surgical excision is mandatory. Some physicians prefer exenteration as a primary treatment. Mohs’ microsurgery should be used with caution because the disease is multicentric with skip areas and some lesions may be missed. The tumor may spread hematogenously, lymphatically, or by direct extension.

20.What is the most common type of malignant melanoma of the eyelid?

Superficial spreading melanoma accounts for 80% of cases; lentigo maligna and nodular melanoma each occur in 10% of cases. However, all are rare and represent less than 1% of eyelid tumors. Superficial spreading melanoma occurs both in sun-exposed and in nonexposed areas. Lentigo maligna, also known as melanotic freckle of Hutchinson, is sun induced. Both have a long horizontal growth phase before invading the deeper tissues. Nodular melanoma is more aggressive with earlier vertical invasion. Treatment is wide surgical excision and lymph node dissection if microscopic evidence of lymphatic or vascular involvement is noted.

21.How do you follow a patient who has had an eyelid malignancy?

Once the patient has healed from the initial treatment, reevaluate every 6 to 12 months. Patients are at risk for additional malignancies. A thorough examination by a dermatologist may reveal cutaneous malignancies elsewhere. Patients with a history of cutaneous malignant melanoma and squamous cell carcinoma need periodic systemic evaluations for possible metastasis.

Bibliography

Albert DM, Jakobiec FA: ed 3, Principles and practice of ophthalmology, vol 3. Philadelphia, 2008, W.B. Saunders. American Academy of Ophthalmology: Basic and clinical science course on orbit, eyelids, and lacrimal system, San

Francisco. 2012.

Gerstenblith AT, Rabinowitz MP: The Wills eye manual, ed 6, Philadelphia, Lippincott, 2012, Williams & Wilkins.

1.What is uveitis?

Inflammation of the uvea, the pigmented layer of the eye, is classified as follows:

•Anterior uveitis, anterior segment inflammation predominantly affecting the iris

•Intermediate uveitis, or inflammation of the ciliary body and vitreous with associated vitreous cells but no retinal or choroidal involvement

•Posterior uveitis, or inflammation of the retina and/or choroid or sclera

•Panuveitis, or inflammation of both the anterior and the posterior segment

The incidence of various types of uveitis may differ among populations. This chapter focuses on uveitis in the Western world.

2.Describe the presenting symptoms of anterior uveitis.

Acute or sudden-onset anterior uveitis typically presents with pain, redness, and photophobia (sensitivity to light). Nonacute forms of anterior uveitis present with fewer symptoms and may be asymptomatic.

3.Name and describe the typical clinical signs of anterior uveitis.

The typical clinical signs of anterior uveitis (iritis) are cell and flare in the aqueous fluid in the anterior chamber and keratic precipitates (KPs). Flare is leakage of protein into the aqueous secondary to increased permeability of iris vessels. Keratic precipitates are accumulations of white blood cells on the endothelial surface of the cornea that may vary in size and location. Depending on the duration and severity of uveitis, adhesions can develop between the iris and the lens surface (posterior synechiae [PS]) and between the iris and the peripheral cornea (peripheral anterior synechiae [PAS]).

4.How is granulomatous uveitis distinguished from nongranulomatous uveitis?

Uveitis may be classified as granulomatous or nongranulomatous based on pathologic features. Histopathologically, granulomatous uveitis is characterized by nodular collections of epithelioid cells and giant cells surrounded by lymphocytes. Nongranulomatous uveitis is characterized by diffuse infiltration of lymphocytes and plasma cells. Both of these entities have relatively distinct clinical appearances.

5.What are the distinctive clinical features of granulomatous anterior uveitis?

Granulomatous uveitis is often chronic (greater than 4 months duration). Anterior segment examination may reveal “mutton-fat” (large, “greasy”) KPs, nodules on the iris surface (Busacca nodules), and PAS. Anterior chamber cell and flare are also present (Table 39-1).

6.What are the clinical features of nongranulomatous anterior uveitis?

Nongranulomatous anterior uveitis (NGAU) is typically acute with an abrupt onset of symptoms and selflimited course less than 4 months duration. Clinical signs include fine KPs usually located on the inferior cornea, anterior chamber cells, and flare. PS may or may not be present, depending on the duration and severity of the inflammation. Certain forms of NGAU may present with hypopyon (Table 39-1).

7.Can iris nodules occur in nongranulomatous anterior uveitis?

Koeppe nodules are grayish-white nodules that appear at the pupillary margin. They may be present in either granulomatous or nongranulomatous anterior uveitis.

8.Can the distribution of keratic precipitates be helpful in narrowing a differential diagnosis?

Yes. The typical location for KPs is on the inferior cornea, an area referred to as the Arlt triangle (Fig. 39-1). In Fuchs’ heterochromic iridocyclitis, the fine “stellate” KPs are found scattered diffusely on the entire posterior surface of the cornea. In herpes simplex keratouveitis, KPs are localized to the area of corneal involvement.

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Table 39-1.  Features of Granulomatous and Nongranulomatous Anterior Uveitis

Figure 39-1.  Granulomatous KPs in the Arlt’s triangle.

9.Is a dilated fundus examination indicated in all patients with anterior uveitis?

Yes. All patients who appear to have anterior uveitis require a dilated examination to identify potentially blinding posterior segment disease.

10.What is the most common cause of nongranulomatous anterior uveitis?

Human leukocyte antigen (HLA)-B27-associated conditions account for approximately 45% of acute NGAU. Although this HLA marker can be seen associated with NGAU without systemic inflammatory disease, inflammatory spondylarthropathies including ankylosing spondylitis (AS), Reiter disease, psoriatic arthritis, and inflammatory bowel disease are present in 50 to 80% of patients with HLA- B27-positive NGAU. A review of systems aids differentiation (Table 39-2).1,2

11.Describe the typical nongranulomatous anterior uveitis seen in HLA-B27 disease.

The anterior uveitis is unilateral and self-limited. It is usually recurrent and may be present in alternate eyes over time. A fibrinous response in the anterior chamber and, in some cases, hypopyon may occur.

12.What is the incidence of HLA-B27 in the general population?

The incidence of HLA-B27 in the general population is 8%. In contrast, it is present in 90% of patients with AS and 80% of those with Reiter’s disease.

13.What other conditions are in the differential diagnosis of acute nongranulomatous anterior uveitis?

More than 50% of cases are idiopathic. Other uveitides that may present with clinical findings consistent with NGAU are listed in Tables 39-3 and 39-4. Note that some forms of granulomatous uveitis (e.g., sarcoidosis, syphilis, Lyme disease, and toxoplasmosis) may present with nongranulomatous features. However, nongranulomatous conditions do not present in a granulomatous fashion.

14.Discuss the most common cause of uveitis in children

Juvenile idiopathic arthritis (JIA) is the most common identifiable cause of uveitis in children. The uveitis is anterior and chronic and can lead to serious vision loss. The eye is white and quiet so that children often do not complain of symptoms. For these reasons, diagnosis may be delayed.

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Table 39-2.  Differentiation of HLA-B27-Associated Conditions

HLA, Human leukocyte antigen; NGAU, nongranulomatous anterior uveitis.

Table 39-3.  More Common Infectious Causes of Uveitis

*May also have nongranulomatous anterior uveitis.

Young girls (age 4 years) with pauciarticular JIA who are rheumatoid factor-negative and antinuclear antibody-positive are at highest risk. These children should be screened every few months for uveitis. Boys may develop more acute recurrent inflammation at a later age (9 years). A majority of these children with later onset JIA are HLA-B27-positive and may develop AS later in life.

15.What condition may produce spontaneous hyphema in a child?

Juvenile xanthogranuloma is a systemic condition that consists of one or more nonmalignant inflammatory tumors. Ocular lesions include iris xanthogranuloma masses, recurrent anterior chamber cellular reaction, and spontaneous hyphema (Fig. 39-2). Diagnosis is made with iris biopsy or by finding similar lesions on the skin.3,4

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Table 39-4.  More Common Noninfectious Causes of Uveitis

APMPPE, Acute posterior multifocal placoid pigment epitheliopathy; CNVM, choroidal neovascular membrane; IVFA, fluorescein angiography; JIA, juvenile idiopathic arthritis; MEWDS, multiple evanescent­ white dot syndrome; MS, multiple sclerosis; PAS, peripheral anterior synechiae; PS, posterior synechiae; TINU, tubulointerstitial nephritis–uveitis.

16.What is the most common cause of granulomatous anterior uveitis?

Sarcoidosis is the most common cause of granulomatous anterior uveitis in adults. Differential diagnosis includes syphilis, Lyme disease, Propionibacterium acnes (pseudophakic patients), tuberculosis, and herpesvirus infection. Other more common causes are also listed in Tables 39-3 and 39-4.5

CHAPTER 39  UVEITIS  307

Figure 39-2.  Large, solitary juvenile xanthogranuloma that had given rise to a spontaneous hyphema in a 7-month-old patient. (From Shields JA, Shields CL: Intraocular Tumors: A Text and Atlas, Philadelphia, W.B. Saunders, 1992.)

17.What is the leading cause of blindness in the world?

Onchocerciasis (river blindness) is the most common cause of blindness in the world. It is caused by Onchocerca volvulus and transmitted by the bite of a Simulium black fly. Sclerosing keratitis and

extensive chorioretinal and optic atrophy cause severe visual impairment. The disease predominantly affects people in western and central Africa and Central America. Treatment of at-risk populations with antifilarial agents such as ivermectin can dramatically reduce disease.6

18.When is a systemic workup indicated in uveitis?

A systemic evaluation should be performed in patients with granulomatous uveitis, a second episode of nongranulomatous uveitis, posterior uveitis, a positive review of systems, or severe disease that may require systemic immunosuppression.

19.What studies should be ordered?

A chest x-ray for sarcoidosis, fluorescent treponemal antibody absorption (FTA–ABS) or rapid plasmin reagin (RPR) test, urinalysis, and complete blood count should be ordered in all patients. HLA-B27 titers should be ordered in patients with NGAU. Additional diagnostic tests may be appropriate based on clinical history and ocular and physical examination and positive review of systems.

20.When ocular tests are helpful?

Ocular tests including intravenous fluorescein angiography, indocyanine green angiography, B-scan ultrasound, and ocular coherence tomography may help to characterize uveitis with posterior segment findings, as well as to detect cystoid macular edema.

21.What may confound interpretation of serology for infectious agents?

Because of its localized nature, an active intraocular infection is not always accompanied by a significant rise in systemic antibody titers. Furthermore, serology may be unreliable in immunocompromised patients or negative in masquerade syndrome. In cases of progressive sight-threatening uveitis in one or both eyes that is unresponsive to therapy or when unusual infections or masquerade syndrome are suspected and systemic antibody titers are not diagnostic, specimens from the iris, aqueous, vitreous, retina, or choroid may be obtained for evaluation, including antibody titers, polymerase chain reaction (PCR), histopathology, and flow cytometry.

22.What is the most common cause of intermediate uveitis?

Pars planitis, an inflammation of unknown etiology, is the most common cause of intermediate uveitis. It is recognized by the typical inflammatory “snow bank” in the inferior pars plana. The clinical course is variable. Approximately 16% of patients may develop multiple sclerosis (MS). HLA-DR15 may play a role in both diseases. Granulomatous anterior uveitis may be present in MS-associated uveitis.7,8

23.What are the causes of vision loss in pars planitis?

Cystoid macular edema is the most common cause of vision loss. Other causes include cataract, glaucoma, vitreous hemorrhage, epiretinal membrane, and tractional retinal detachment.

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24.What are the indications for treatment in pars planitis?

Indications for treatment include cystoid macular edema with associated vision loss.

25.Describe the most common causes of posterior uveitis.

Ocular toxoplasmosis is the most common cause of posterior uveitis. It is most often a recurrent infection, characterized by necrotizing retinochoroiditis, appearing as a white infiltrate adjacent to a pigmented retinal scar. A diffuse vitritis may make the retinitis appear as a “headlight in the fog.” In immunocompromised patients, including the elderly, the retinitis may be multifocal and bilateral and may not be associated with a scar.9

26.How is the diagnosis of ocular toxoplasmosis made?

Diagnosis usually is based on clinical history and fundus examination. Positive IgG or IgM titers, even in very low concentrations (undiluted serum), are supportive of the diagnosis. IgG indicates

congenital or previous infection, whereas IgM indicates recently acquired infection. Interpretation may be confounded by a high prevalence of positive titers in the population. A negative titer excludes the diagnosis except in immunosuppressed patients.10

27.How is ocular toxoplasmosis managed?

Treatment is recommended for active lesions that threaten the macula or optic nerve and for severe vitritis. Although sulfonamides, clindamycin, pyrimethamine, folinic acid, and corticosteroids have been used in various combinations, there is no universally accepted treatment regimen, and the effectiveness of toxoplasmosis therapy has been questioned. Duration of treatment is typically 4 to 6 weeks and treatment does not prevent recurrences. Observation is recommended for small peripheral lesions.11,12

28.What serious side effects may occur with oral antibiotic therapy for toxoplasmosis?

•Pseudomembranous colitis (clindamycin)

•Hematologic toxicity (pyrimethamine)

•Erythema multiforme and Stevens-Johnson’s reaction (sulfonamides)

29.What are the features of ocular sarcoidosis?

The eye is involved in approximately 20% of individuals. Uveitis is the most common ocular manifestation. Anterior segment inflammation is classically bilateral, chronic, and granulomatous, although acute and asymmetric anterior uveitis may occur. Posterior segment inflammation including choroidal or optic nerve granulomas, vitritis, retinal vasculitis or vascular occlusions, and neovascularization are less common, but do threaten sight. Conjunctival and eyelid nodules and enlarged lacrimal glands may be noted and are useful tissues for confirmatory biopsy.

30.How does the presentation of sarcoidosis differ with age?

In children younger than 5 years, uveitis, arthritis, and skin rash are typical and the presentation may resemble JIA. In patients 20 to 40 years of age, bilateral chronic granulomatous iritis or panuveitis and hilar adenopathy are most common, whereas in elderly patients, lesions resembling multifocal choroiditis or birdshot chorioretinitis and interstitial lung disease may be seen.13,14

31.What testing may be helpful in making the diagnosis of sarcoidosis?

•Chest x-ray is positive in 90% of patients with sarcoidosis.

•Angiotensin-converting enzyme and lysozyme are sensitive but not specific indicators of sarcoidosis.

•In cases with high suspicion and a negative chest x-ray, gallium scan and computed tomographic (CT) scan of the chest may be considered.

•Biopsy of normal-appearing conjunctiva in patients with presumed sarcoidosis is positive in 12% of cases. Lacrimal biopsy in presumed sarcoidosis is positive in 22% of cases.15

KEY POINTS: MOST COMMON FORMS OF UVEITIS

1.Children—JIA (chronic iridocyclitis)

2.NGAU—HLA-B27

3.Granulomatous anterior uveitis—sarcoidosis

4.Intermediate uveitis—pars planitis

5.Posterior uveitis—toxoplasmosis

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42.What is unusual about the clinical course of Behҫet’s disease?

Behҫet’s disease is characterized by periodic relapse and spontaneous remission. Remissions may

be misunderstood as a therapeutic response to intermittent steroid therapy. Unlike most other causes of retinal vasculitis, including sarcoidosis, which may have similar clinical findings, Behҫet’s disease requires chronic systemic immunosuppression to prevent relapses that lead to blindness.

43.Describe the ocular features of Lyme disease

Ocular Lyme disease is usually bilateral. In stage 1, conjunctivitis may occur along with a migratory rash (erythema migrans) or arthritis. In later stages, an atypical intermediate uveitis with granulomatous KPs and PS may be present. Inflammation may affect almost any ocular tissue. Diagnosis requires a history of outdoor activity in an endemic area in the late spring or summer and positive indirect immunofluorescent antibody and/or enzyme-linked immunosorbent assay. Western blot, which is very specific, may be confirmatory. False-negative results occur in the early stages or following incomplete antibiotic treatment. The spirochete may be identified in skin rash biopsy or cerebrospinal fluid.21,22

44.Describe the most common features of ocular tuberculosis.

The most common feature of ocular tuberculosis is choroiditis. Inflammation is typically unilateral. Associated anterior uveitis is chronic and granulomatous. Ocular involvement may occur without signs of active pulmonary involvement.23,24

45.What form of uveitis may present with enlarged lymph glands?

Primary inoculation with Bartonella henselae produces regional lymphadenopathy and conjunctivitis (Parinaud’s oculoglandular syndrome). Additional findings may include Leber’s neuroretinitis and a retinal white-dot syndrome. Patients with sarcoidosis may also present with lymphadenopathy.25

46.Why do patients with uveitis develop glaucoma?

The most common mechanism of acute glaucoma is direct inflammation of the trabecular meshwork or trabeculitis. Chronic glaucoma may result from closure of the trabecular meshwork by peripheral anterior synechiae or angle-closure glaucoma from iris bombé (360 degrees of PS). In addition, topical, intraocular, and periocular corticosteroids can cause glaucoma.26

47.Name the uveitis entities that are associated with an acute elevation in intraocular pressure.

•Herpes simplex and zoster

•Toxoplasmosis

•Sarcoidosis

•Syphilis

48.What is the approach to the treatment for uveitis?

1.Identify and treat the underlying causes. This is especially important in immunocompromised individuals, in whom most uveitis cases are infectious.

2.Prevent vision-threatening complications. Anti-inflammatory agents are the mainstay of treatment to prevent or reverse vision-threatening complications, including retinal ischemia, retinal scarring, cataract, and macular edema, among others.

3.Relieve ocular discomfort and improve vision. Cycloplegic agents relax the ciliary body and reduce pain. In addition, they stabilize the blood aqueous barrier and help to break or prevent PS.

49.What should be the general approach to the use of steroids to treat uveitis?

High-dose corticosteroids should be used initially until inflammation is suppressed and then tapered. A common mistake is infrequent dosing initially, which results in a smoldering, extended course. Topical corticosteroids are best suited to anterior uveitis, as they do not reach the posterior segment in therapeutic levels. Prednisolone acetate achieves the highest anterior chamber concentrations. Posterior segment disease must be treated with periocular (posterior sub-Tenon or preseptal) or intravitreal injection, or intravitreal implant, and/or systemic corticosteroids. Systemic steroids are typically reserved for severe or bilateral disease. In patients unresponsive to steroids, one must suspect an infectious or neoplastic masquerade syndrome.

50.When are alternate immunosuppressives indicated to treat autoimmune uveitis?

•When the systemic steroids required to suppress ocular inflammation are higher than can be safely administered over extended periods. In these cases a steroid-sparing agent is indicated.

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