Uveitis in the Immunocompetent Patient
- 1.
What is uveitis?
Inflammation of the uvea, the pigmented layer of the eye, is classified as follows:
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Anterior uveitis, anterior segment inflammation predominantly affecting the iris
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Intermediate uveitis, or inflammation of the ciliary body and vitreous with associated vitreous cells but no retinal or choroidal involvement
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Posterior uveitis, or inflammation of the retina and/or choroid or sclera
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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.
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- 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 ).
Table 39-1
Features of Granulomatous and Nongranulomatous Anterior Uveitis
Features
Granulomatous
Nongranulomatous
Onset
Often insidious
Acute (usually)
Course
Chronic
Acute or chronic
Injection
+
+++ (usually)
Pain
+/−
+++ (usually)
Iris nodules
+++ (Busacca and Koeppe)
− (Koeppe on occasion)
Keratic precipitates
Large, mutton-fat
Small, fine
Other
Dense posterior synechiae
+/− posterior synechiae, hypopyon
+, Present; −, absent.
- 6.
What are the clinical features of nongranulomatous anterior uveitis?
Nongranulomatous anterior uveitis (NGAU) is typically acute with an abrupt onset of symptoms and self-limited 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.
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 ).
Table 39-2
Differentiation of HLA-B27-Associated Conditions
HLA-B27-Associated Disease
Symptoms
Systemic Clinical Findings
Ankylosing spondylitis
Stiffness and low back pain worsen with inactivity
Spinal fusion, sacroiliac joint disease; no skin findings; 25% develop NGAU
Reiter’s disease
Same plus painless mouth ulcers, heel pain, painful urination
Keratoderma blennorrhagica, circinate balanitis, urethritis, polyarthritis; conjunctivitis is typically bilateral and papillary
Psoriatic arthritis
Skin rash, arthritis
Psoriasis
Inflammatory bowel disease
Gastrointestinal symptoms
Erythema nodosum
HLA, Human leukocyte antigen; NGAU, nongranulomatous anterior uveitis.
- 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.
Table 39-3
More Common Infectious Causes of Uveitis
Disease
Granulomatous versus Nongranulomatous
Clinical Presentation
Infectious Agent
Syphilis
Granulomatous ∗
Anterior, pan, or posterior
Treponema pallidum
Acute retinal necrosis
Granulomatous
Panuveitis
Herpes simplex or zoster virus
Chronic postoperative endophthalmitis
Granulomatous
Anterior or intermediate
Propionibacterium acnes
Lyme disease
Granulomatous ∗
Predominantly intermediate
Borrelia burgdorferi via Ixodes tick bite
Tuberculosis
Granulomatous
Panuveitis
Mycobacterium tuberculosis
Toxoplasmosis
Granulomatous ∗
Pan or posterior
Toxoplasma gondii
Cat-scratch disease
Granulomatous
Panuveitis
Bartonella henselae
Toxocariasis
Granulomatous
Panuveitis
Toxocara canis
Onchocerciasis
Nongranulomatous
Panuveitis
Onchocerca volvulus
Ocular histoplasmosis
No anterior chamber or vitreous cells
Posterior
Histoplasma capsulatum
Fungal choroiditis
Granulomatous
Predominantly posterior
Cryptococcus, Aspergillus, Candida species
Diffuse unilateral subacute neuroretinitis
Nongranulomatous
Posterior
Baylisascaris procyonis
Table 39-4
More Common Noninfectious Causes of Uveitis
Disease
Granulomatous versus Nongranulomatous
Clinical Presentation
Secrets
JIA
Nongranulomatous
Anterior
See text
HLA-B27-associated uveitis
Nongranulomatous
Anterior
See text
Fuchs’ iridocyclitis
Nongranulomatous
Anterior
Iris heterochromia; no PAS/PS
Kawasaki syndrome
Nongranulomatous
Anterior
Rash, lymphadenopathy, fever, cardiac disease in children
TINU syndrome
Nongranulomatous
Anterior
Cellular casts in urine
Sarcoidosis
Chronic granulomatous; acute nongranulomatous
Anterior, posterior, or panuveitis
Clinical findings depend on age
Pars planitis
Nongranulomatous; if granulomatous, suspect MS
Intermediate
16% may develop MS
Juvenile xanthogranuloma
Nongranulomatous
Anterior or intermediate
See text
Phacoanaphylactic uveitis
Granulomatous
Intermediate uveitis
Autoimmunity to lens proteins after trauma or cataract surgery
Multifocal choroiditis
Nongranulomatous
Panuveitis
Myopia; 30% develop CNVM
Birdshot chorioretinitis
Nongranulomatous
Posterior or panuveitis
HLA-A29 in more than 90%
APMPPE
Nongranulomatous
Posterior or panuveitis
Young patients, viral prodrome, bilateral; recurrence and CNVM rare
MEWDS
Nongranulomatous
Posterior
IVFA wreath; hyperfluorescence
Serpiginous choroiditis
Nongranulomatous
Posterior
Older patients, lesions contiguous to disc, unilateral; recurrence common, CNVM 30%
Behᆕet’s disease
Nongranulomatous
Anterior, posterior, or panuveitis
Hypopyon iritis
Vogt-Koyanagi-Harada syndrome
Granulomatous
Panuveitis
Starry sky
Sympathetic ophthalmia
Granulomatous
Panuveitis
See text
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.
- 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. 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.
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.)
- 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 .
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 28.
What serious side effects may occur with oral antibiotic therapy for toxoplasmosis?
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Pseudomembranous colitis (clindamycin)
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Hematologic toxicity (pyrimethamine)
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Erythema multiforme and Stevens-Johnson’s reaction (sulfonamides)
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- 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.
- 31.
What testing may be helpful in making the diagnosis of sarcoidosis?
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Chest x-ray is positive in 90% of patients with sarcoidosis.
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Angiotensin-converting enzyme and lysozyme are sensitive but not specific indicators of sarcoidosis.
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In cases with high suspicion and a negative chest x-ray, gallium scan and computed tomographic (CT) scan of the chest may be considered.
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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.
Key Points: Most Common Forms of Uveitis
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