Practical Diagnostic Approach to Uveitis

Anthony Grillo; Ralph D Levinson; Lynn K Gordon

Disclosures

Expert Rev Ophthalmol. 2011;6(4):449-459. 

In This Article

Anterior Uveitis

The majority of patients with a nongranulomatous AAU has either an idiopathic cause or are associated with HLA-B27.[46,47] However, the differential diagnosis includes multiple infectious and other noninfectious etiologies.[13,19,22,29,46–48] Cases associated with HLA-B27 are frequent and may be associated with seronegative spondyloarthropathies such as ankylosing spondylitis, reactive arthritis, IBD and psoriatic arthritis.[19,49,50] It is therefore important to return to the history and clearly define associated symptoms that may help to diagnose underlying, previously undiagnosed systemic inflammatory conditions. Referral to medical subspecialists for evaluation of the associated systemic conditions is important in patients with an appropriate history. HLA-B27 evaluation may be warranted if the clinical history is supportive for a systemic inflammatory syndrome or in the case of recurrent episodes of AAU.[50] However, HLA-B27 gene frequencies occur in significant percentages of the normal population (varying according to ethnicity, ranging from 0 to 50%, but is 8% in the UK)[51] and approximately one-third of patients with AAU are HLA-B27 negative.[46,52] The presence of HLA-B27 alone adds limited value in diagnostic testing for patients who present with uveitis, but may be helpful in predicting the disease course over time.

A picture resembling HLA-B27-associated AAU may also be observed following trauma, may be the initial presentation of endophthalmitis or may be observed following cataract extraction either associated with retained lens fragments or with a low-grade infectious endophthalmitis.

In the setting of anterior, often chronic, uveitis there are multiple other potential etiologies. In unilateral anterior uveitis (AU), considerations would include an underlying viral infection, FHI or idiopathic etiology.[26,53–55] Viral etiologies for AU include herpes zoster, Herpes simplex and cytomegalovirus (CMV). Many of these cases would previously have been labeled as idiopathic, but recent advances in diagnostic techniques, most notably PCR, are quickly identifying a variety of viral organisms in association with uveitis.[7,22,39,41,42,56] Findings that support an underlying viral infection include: increased intraocular pressure prior to corticosteroid initiation; diffuse KP, or KP not in Arlt's triangle; endothelial changes or corneal edema without severe inflammation or other reason for corneal endothelial dysfunction; iris atrophy without previous intraocular surgery; and a history of herpes zoster in the V1 dermatomal distribution. Studies have demonstrated that aqueous and vitreous aspiration can be performed in outpatient settings and have high sensitivity and specificity in clinical studies, although false-positive and -negative results remain challenging.[57,58] In the setting of an AAU, this type of testing would probably be considered too invasive. The one exception would be CMV-associated AU, as it can be specifically treated using oral valganciclovir. However, antiviral agents have risks for systemic toxicity and must be used judiciously; a topic that is beyond the scope of this discussion.

Fuch's heterochromic iridocyclitis is typically a chronic, unilateral (>90%) AU associated with minimal pain, redness and anterior chamber cell/flare.[26,55] Some of the unique features of FHI are the small, scattered KP that are not confined to the inferior portion of the cornea and the iris atrophy that leads to a secondary, acquired heterochromia. Koeppe nodules may be observed, but rarely, if ever, is there associated posterior synechiae or, in the absence of prior surgery, cystoid macular edema. Recent research has demonstrated a strong link between this condition and infection with the rubella virus, and CMV has also been implicated, but the diagnosis is clinically based on hallmark findings.[59,60]

Behçet's disease is a recurrent, systemic small-vessel vasculitis that can affect all organ systems.[21] Oral and genital aphthous ulcerations are very common. Behçet's disease may initially present with AAU in 18–44% cases and may be accompanied by hypopyon.[29,61] Although initial ocular involvement may be unilateral and similar to other AAU syndromes, it is important to recognize this disease as it may become bilateral, severe and sight threatening with posterior segment involvement. The diagnosis is based on clinical findings and major diagnostic criteria that include recurrent oral aphthous ulcers, skin lesions including erythema nodosum, recurrent genital ulcers and ocular inflammatory disease. Minor diagnostic criteria include arthritis, gastrointestinal ulceration, epididymitis, systemic vasculitis and neurologic involvement.[61,62] Although there is an association between Behçet's disease and HLA-B5 and HLA-B51, the positive-predictive value is not strong enough (0.3) to justify HLA typing for diagnostic purposes (Table 1).[52] Furthermore, HLA is not part of the published diagnostic criteria.

Bilateral AU is associated with multiple systemic diseases and in some cases the disease becomes chronic or the associated ocular disease may extend beyond the anterior chamber. Although this condition may be idiopathic, systemic associations include Behçet's disease, JIA, sarcoidosis, syphilis, tubulointerstitial nephritis and uveitis (TINU) and, rarely, Lyme disease.[8,21,23,63–66] Judicious use of diagnostic testing is dictated by the clinical history and examination (Table 2).

Appropriate diagnostic testing in patients with a suspicious clinical history might include Lyme serology, serum evaluation for ACE and lysozyme, CBC and urinalysis. Syphilis serology is typically always recommended. In cases with a high clinical suspicion for sarcoidosis, chest radiograph is abnormal in 70–90% of patients but computed tomography (CT) imaging may be more sensitive (Table 3).[2,8,67–70] Gallium scans or PET with CT (PET-CT) may also be highly sensitive in cases of suspected sarcoidosis but ultimate diagnosis is made by tissue histopathology of biopsies from conjunctiva, lymph nodes, skin or the lung. Despite appropriate diagnostic testing, many of these will remain idiopathic even after extensive work-up.

In the setting of pediatric patients with sudden onset symptomatic bilateral AU, TINU is diagnosed in up to one-third of patients.[63] The history must include specific attention to constitutional and urinary-tract symptoms. The onset of TINU can occur at any age and most often presents initially with a systemic febrile illness, which may be mild. Uveitis may present months later and an association with the preceding illness may not be recalled.[71] Laboratory testing includes CBC with differential, erythrocyte sedimentation rate (which can be very high, even close to 100 mm/h), C reactive protein, renal function tests and urinary analysis, including β-2-microglobulin. β-2-microglobulin will be abnormal during the period of the acute interstitial nephritis, but will usually become normal over weeks to months.

Juvenile idiopathic arthritis patients may develop an insidious onset bilateral nongranulomatous uveitis.[23–25] Risk factors for uveitis in these patients include pauciarticular or oligoarticular joint disease, antinuclear antibody seropositivity, rheumatoid factor seronegativity, HLA-DR5 and disease onset at a young age. However, obtaining HLA in this context is not helpful either for diagnosis or prognosis. Patients with JIA must be referred for scheduled, regular ophthalmologic examination, as ocular symptoms of uveitis may be mild. Concordantly, if a pediatric patient presents with bilateral chronic AU and a history of arthritic complaints, it is imperative to refer the patient to rheumatology for a thorough diagnostic evaluation. A rheumatologist should manage the laboratory evaluation and definitive diagnosis of JIA.

Granulomatous Anterior Uveitis

The hallmark clinical evidence for granulomatous AU includes inflammatory nodules, in particular the Busacca nodules, which are located on the iris surface. KPs in granulomatous AU are typically larger, have a greasy appearance and are generally present in the lower half of the cornea. In the setting of suspected granulomatous AU, a careful examination of the posterior segment must be performed to evaluate for choroidal or retinal lesions, vasculitis or optic disk involvement. Granulomatous AU is often chronic and may be unilateral or bilateral. The differential diagnosis for granulomatous AU is large and includes idiopathic etiology, sarcoidosis, syphilis, tuberculosis, Lyme disease (in endemic areas), multiple sclerosis, viral infections (Herpes zoster, Herpes simplex and CMV), fungal disease (coccidiodomycosis) and unusual bacterial diseases (leprosy and brucellosis).[8,14,20,48,53,67,72,73]

Sarcoidosis accounts for 10–20% of chronic AU at tertiary care centers in the USA.[65–68,74] When sarcoidosis is suspected, a chest x-ray (CXR) should be performed to identify bilateral hilar lymphadenopathy (Table 3). Although high-resolution CT of the chest is more sensitive than a CXR in diagnosing hilar lymphadenopathy, the cost and radiation exposure should limit the use of CT to cases in which the clinical suspicion is high but the CXR is negative.[2] Serum ACE or lysozyme levels can also be helpful in the diagnosis of sarcoidosis. However, ACE, which may be elevated in up to 80% of patients with systemic sarcoidosis, may only be elevated in 40% of patients with only ocular involvement.[2] In addition, ACE may be elevated in multiple other diseases and may be low secondary to medical therapy with ACE inhibitors for control of hypertension. The gold standard for diagnosis of sarcoidosis is biopsy showing noncaseating granulomas, which may be present in the conjunctiva or lacrimal gland. Evaluations for tuberculosis using purified protein derivative or the IFN-γ-release assay and for syphilis using a specific anti-treponemal test should always be performed in cases of granulomatous uveitis to rule out these prevalent infectious diseases.[20] In the setting of recurrent disease, TINU may also demonstrate granulomatous findings.

In cases of granulomatous AU in which the routine testing is unrevealing, considerations should be made for other diagnoses. Evaluation for Lyme serology should be reserved for individuals with an appropriate history of travel to an endemic area, history of a tick bite, or systemic symptoms consistent with Lyme disease. Wegener's granulomatosis can rarely cause uveitis; however, in the presence of systemic signs or symptoms suggestive of the disease or in the setting of isolated retinal vasculitis, it should be evaluated by serologic testing for antineutrophil cytoplasmic antibodies, as this test has strong specificity for this serious disease.[75]

Masquerade syndromes must be considered in the differential diagnosis of chronic uveitis and these include foreign body reaction, intraocular lymphoma, leukemias, retinoblastoma and juvenile xanthogranulomas (abnormal iris findings may be mistaken for uveitic nodules) (Table 4).[10,76] Additional studies are required for diagnosis of masquerade syndromes and should be dictated by the clinical presentation and findings on examination. These may include vitreous biopsy, lumbar puncture and evaluation of cerebrospinal fluid, brain imaging with MRI or full-body CT, or PET–CT.[11]

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