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Am Fam Physician. 2014;90(10):711-716

Author disclosure: No relevant financial affiliations.

Uveitis, or inflammation of the uveal tract (i.e., iris, ciliary body, and choroid), results from a heterogeneous collection of disorders of varying etiologies and pathogenic mechanisms. Uveitis is caused by a systemic disease in 30% to 45% of patients. Primary care physicians may be asked to evaluate patients with uveitis when an underlying systemic diagnosis is suspected but not apparent from eye examination or history. If the history, physical examination, and basic laboratory studies do not suggest an underlying cause, serologic tests for syphilis and chest radiography for sarcoidosis and tuberculosis are recommended. Typing for human leukocyte antigen-B27 is appropriate for patients with recurrent anterior uveitis. Because the prevalence of many rheumatologic and infectious diseases is low among persons with uveitis, Lyme serology, antinuclear antibody tests, serum angiotensin-converting enzyme tests, serum lysozyme tests, and tuberculin skin tests can result in false-positive results and are not routinely recommended. Drug-induced uveitis is rare and can occur from days to months after the time of initial exposure. Primary ocular lymphoma should be considered in persons older than 50 years with persistent intermediate or posterior uveitis that does not respond to anti-inflammatory therapy.

Uveitis, or inflammation of the uveal tract (i.e., iris, ciliary body, and choroid; Figure 1) is caused by a heterogeneous collection of disorders. The clinical diagnosis is often based on spillover inflammation (i.e., cells and protein flare) observed with a slit lamp in the aqueous or vitreous humors. Uveitis is classified according to the predominant site of inflammation: anterior (anterior chamber), intermediate (vitreous), or posterior (retina or choroid).1 Generalized intraocular inflammation is described as panuveitis, whereas inflammation centered in the optic nerve head with secondary peripapillary involvement is classified under posterior uveitis as neuroretinitis.1 When spillover inflammation from primary disease of the cornea or sclera occurs, the terms keratouveitis and sclerouveitis, respectively, are applicable. Classifying uveitis according to the predominant site of inflammation can help narrow the differential diagnosis.

Clinical recommendationEvidence ratingReferences
If the history, physical examination, and basic laboratory tests do not uncover a cause for uveitis, serologic tests for syphilis and chest radiography for sarcoidosis and tuberculosis are recommended.C11, 12, 15
Adults who have a single episode of mild anterior uveitis that responds to treatment and who have no systemic signs or symptoms do not need further laboratory studies.C11, 13
Routine radiography and serologic studies are not indicated for all patients with uveitis.C1315
Drug-induced uveitis should be considered in patients with unexplained uveitis beginning days to months after starting a new medication.C1719
Primary ocular lymphoma should be considered in patients older than 50 years with persistent unexplained intermediate or posterior uveitis that is unresponsive to anti-inflammatory therapy.C20

Most forms of uveitis not caused by accidental or surgical trauma are manifestations of infectious or immune-mediated disease. Approximately 30% to 45% of patients with uveitis have a causally associated systemic disease.2,3 Topical and systemic medications can cause secondary uveitis. This review provides a framework for primary care physicians who are asked to examine patients with uveitis when an underlying systemic diagnosis is suspected after ophthalmologic evaluation.

Epidemiology

The annual incidence of uveitis in North America ranges from 17 to 52 per 100,000 persons, and the prevalence ranges from 58 to 115 per 100,000 persons.47 Up to 35% of patients with uveitis have severe visual impairment, and roughly 10% are legally blind.8 Uveitis can occur at any age, but the peak incidence is between 20 and 59 years of age. Systemic diseases most often associated with uveitis in North America are the seronegative spondyloarthropathies, sarcoidosis, syphilis, rheumatoid arthritis, and reactive arthritis.47

Table 1 lists the main systemic disorders associated with uveitis, typical clinical findings, and suggested diagnostic studies.9,10 Anatomic classification of inflammation is helpful in reducing diagnostic possibilities, but the guidance it provides is limited. Disorders like the seronegative spondyloarthropathies and juvenile idiopathic uveitis usually involve the anterior segment of the eye, but other conditions like Behçet syndrome, syphilis, and sarcoidosis can affect any location.

DisorderSite of predominant inflammationPercentage of patients with uveitisSystemic findingsDiagnostic studiesComment
Ankylosing spondylitisAnterior40SacroiliitisRadiology studiesTraditional HLA-B27 spondyloarthropathy
Behçet syndromeAny location60 to 80Oral and genital ulcers, erythema nodosum, arthritis, epididymitis, gastrointestinal ulcersPositive pathergy test, HLA-B51Rapid onset of ocular symptoms can mimic endogenous infection
Bloodborne infectionAny locationUnknownVaries with clinical context; persons with indwelling venous catheters and intravenous drug users at high riskBlood cultureMay have no systemic symptoms by the time eye symptoms develop
Cat-scratch disease (bartonellosis)NeuroretinitisUnknownInfluenza-like illness, regional lymphadenopathySerologic studies for Bartonella henselaeHistory of cat exposure
Drug-related uveitisAny locationRareCan be associated with inflammation of conjunctiva and scleraWithdrawal of medication; re-challenge if causation is equivocal and risk/benefit is acceptableMost definite associations based on challenge/re-challenge test
Granulomatosis with polyangiitisUsually anteriorUnknownSinusitis, pulmonary lesions, glomerulonephritisc-ANCA serologyInflammation is usually spillover from scleritis or peripheral keratitis
Immunocompromised state or disorderAny locationVaries based on underlying disorderVaries based on type of opportunistic infectionStudies to assess degree of immune dysfunction; studies to identify opportunistic organism
Inflammatory bowel diseaseAnterior15 to 55Diarrhea, oral ulcer, arthritisEndoscopy
Juvenile idiopathic arthritisAnterior< 50Pauciarticular arthritis, fever93% are ANA positive5:1 girl-to-boy ratio; ocular inflammation with minimal or no symptoms
Lyme diseaseAny locationUnknownErythema chronicum migrans, arthritis, other organ involvement possibleELISA IgM and IgG, followed by Western blot testTick exposure history, seasonal variation
Multiple sclerosisIntermediate30Multifocal disease of white matter of brain; chronic remitting and relapsing courseMRI, CSF examination
Psoriatic arthritisAnterior7Psoriatic skin lesions, arthritis
Reactive arthritisAnterior7Sacroiliitis, keratoderma blennorrhagicum, oral-genital ulcers
Relapsing polychondritisAnteriorUnknownInflammation of cartilaginous tissuesOften associated with scleritis, spillover inflammation
Rheumatoid arthritisUsually anterior, spillover from scleritis or peripheral keratitis< 5Usually signs of extra-articular diseaseRheumatoid factorOften associated with scleritis or peripheral keratitis
SarcoidosisAny locationUnknownVaries depending on organ system involvedChest radiography or CT; serum ACE levelConjunctival biopsy variable yield but low risk
SyphilisAny location< 5Varies depending on stage and immune statusSyphilis serology; CSF-VDRL testNontreponemal and treponemal serologic tests are needed
Systemic lupus erythematosusAny location< 1Skin lesions, renal disease, multiple organ involvement possibleANA or anti-dsDNA antibodies
ToxocariasisPosteriorUnknownIsolated eye problem not associated with visceral larvae stage of infectionELISA titer > 1:8; peripheral eosinophilia occasionally notedUnilateral; usually occurs before 14 years of age; ova and parasite examination has no value
TuberculosisAny location< 1Varies depending on immune statusPPD skin test; interferon gamma release assay; chest radiographyConsider if patients traveled where disease is endemic
Tubular interstitial nephritisAnteriorUnknownFever, arthralgias, rash, nephritisUrinalysis, renal function studiesOcular symptoms can precede renal disease
Vogt-Koyanagi-Harada syndromePosterior100Vitiligo, poliosis, alopecia, meningismus, tinnitusLumbar puncture for pleocytosisProbable autoimmune disease; incidence varies worldwide

Clinical Presentation

Symptoms of uveitis are nonspecific, consisting of various combinations of blurred or reduced vision, visual floaters, eye discomfort or pain, and intolerance to light. Secondary headache or brow ache is common. Occasionally, a patient has no symptoms to report, which is more common in children. The onset of uveitis can be sudden or insidious. The clinical distinction between acute and chronic uveitis has been arbitrarily set at three months. Recurrent uveitis is defined as repeat episodes occurring after three months of disease inactivity without treatment.1

Most eyes with anterior uveitis display conjunctival injection, often associated with a blush of limbal vessels. The iris may be difficult to visualize clearly because of corneal edema or cells and protein suspended in the aqueous. Pupils may react poorly to light if the iris has become adherent to the anterior lens capsule (Figure 2). Occasionally, large clumps of inflammatory cells can be seen on the back surface of the cornea (Figure 3). When inflammation is severe, white blood cells settle in the anterior chamber forming a white interface with the overlying aqueous, a condition referred to as hypopyon (Figure 4). Children with juvenile idiopathic arthritis and anterior uveitis tend to have deceptively quiet eyes despite considerable inflammation internally. Intermediate and posterior uveitis can present with little or no evidence of inflammation on the surface of the eye. The accumulation of inflammatory cells and protein flare in the vitreous prevents clear inspection of the retina, as if the view is obscured by fog (Figure 5). Although inflammatory cells suspended in the aqueous or vitreous humors are the diagnostic hallmark of uveitis, they require brightly focused illumination and slit lamp magnification for visualization.

Diagnostic Approach

There is no universally accepted approach to the evaluation of uveitis.3,11,12 If the history, physical examination, and basic laboratory tests do not suggest a specific diagnosis, serologic studies for syphilis and chest radiography for sarcoidosis and tuberculosis are recommended2,3,11 (Table 19,10 ). Basic laboratory studies include complete blood count with differential, basic metabolic panel, urinalysis, and erythrocyte sedimentation rate. However, adults who have a single episode of mild anterior uveitis that resolves with a short course of topical corticosteroids, and who have no other suggestive clinical history, usually do not require laboratory studies.13 Typing for human leukocyte antigen-B27 is appropriate for patients with recurrent anterior uveitis, and can be positive in the absence of signs or symptoms of spondylitis. Routine radiology and serologic studies are not indicated for all patients.1315 Given the relatively low prevalence of many systemic diseases among persons with uveitis, the positive predictive values for Lyme serology, antinuclear antibody, serum angiotensin-converting enzyme, serum lysozyme, and tuberculin skin tests are generally too low to order these studies routinely.1416

DRUG-INDUCED UVEITIS

Drug-induced uveitis is rare. Symptoms, which overlap those in other forms of uveitis, usually begin days to months after exposure.1719 Although some drugs can cause concurrent inflammation of the conjunctiva or sclera, drug-induced uveitis essentially mimics infectious and immune-mediated uveitis. For reasons not understood, use of systemic medications can result in unilateral eye involvement. Establishing causal associations can be difficult, and has historically depended on such maneuvers as drug withdrawal and re-challenge.17 Table 2 lists drugs and vaccines that have been associated with uveitis.1719

MedicationSite of intraocular inflammationRisk of uveitisOnset after exposureEvidence of association
Anti-VEGF, intravitrealIntermediate in treated eye1% to 5% of treated eyesUnknownDefinite
BisphosphonatesAnterior< 1%Days to monthsDefinite
Brimonidine, topicalAnterior, treated eyeRare11 to 15 monthsDefinite
Cidofovir (Vistide), intravenousAnterior17% to 89%Days to weeksDefinite
Cidofovir, intravitrealAnterior26% to 52%Days to weeksDefinite
Metipranolol (Optipranolol), topicalAnterior, treated eyeRareUnknownDefinite
Moxifloxacin (Avelox), oralAnteriorRare1 to 20 daysProbable
Prostaglandin analogues, topicalAnterior, cystic macular edema, treated eye0.9% to 4.9%Weeks to monthsDefinite
Rifabutin (Mycobutin)Any location14% to 64%2 weeks to 7 monthsDefinite
SulfonamidesAnteriorRareDays to weeksDefinite
Vaccines
Bacille Calmette-Guérin (tuberculosis)Any locationRareWeeksDefinite
Hepatitis BAny locationRareDaysProbable
InfluenzaAny locationRareWeeksProbable
Measles, mumps, rubellaAny locationRareWeeksProbable
VaricellaAnterior, posteriorRareUnknownPossible

MASQUERADE SYNDROMES AND DIAGNOSTIC CAVEATS

Neoplastic cells may simulate intraocular inflammation. Primary ocular lymphoma should be considered in persons older than 50 years with persistent intermediate or posterior uveitis that does not respond to anti-inflammatory therapy.20

Although intermediate and posterior uveitis caused by bloodborne infection usually occur in the context of severe illness, patients can present with endogenous endophthalmitis and not appear acutely ill. Smoldering intraocular infections can develop secondary to transient septicemia from a fungus or low-virulence bacterium after removal of a chronic indwelling venous catheter or after recreational intravenous drug use. Visual symptoms usually develop days or weeks later when persons are afebrile and may otherwise feel well. Another clinical setting in which persons may not feel seriously ill involves Klebsiella pneumoniae infection; many of these patients also have diabetes mellitus.21 Specific serotypes of Klebsiella have a predilection to seed the eye, even when primary sites of infection appear under control. Delays in diagnosis have resulted in devastating visual outcomes, including loss of an eye.22

Data Sources: PubMed was searched using the terms anterior uveitis, intermediate uveitis, posterior uveitis, choroiditis, retinochoroiditis, chorioretinitis, and neuroretinitis. Major textbooks of ophthalmology, infectious disease, and rheumatology were reviewed for relevant source material. The Cochrane Database of Systematic Reviews, the Agency for Healthcare Research and Quality, and the American Academy of Ophthalmology's Basic and Clinical Sciences Course books were also searched. Search dates: June and July 2013; September 2013; and July 2014.

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