Uveitis: A search for a cause

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Review article

Uveitis: A search for a cause

Arshee S. Ahmed

*

_{, Jyotirmay Biswas}

Sankara Nethralaya, 18 College Road, Nungambakkam, Chennai 600 006, Tamil Nadu, India

a r t i c l e i n f o

Article history:

Received 13 August 2013 Received in revised form 28 August 2013

Accepted 1 September 2013 Available online 9 October 2013 Keywords:

angiography autoﬂuorescence optical coherence polymerase chain reaction uveitis

a b s t r a c t

This article aims to review the current literature to identify the various laboratory and investigative modalities that can be used to aid in the diagnosis of patients with uveitis. Although laboratory tests such as erythrocyte sedimentation rate, serum angiotensin-converting enzyme levels, and human leukocyte antigen typing among others have limited utility in the diagnosis of uveitis, they provide supportive evidence. Results of serological tests such as enzyme-linked immunosorbent assay have proven to be of significant importance in diagnosing diseases such as toxoplasmosis, and the use of ocular samples such as aqueous and vitreous has greatly increased the diagnostic reliability. Imaging techniques play a major role in the diagnosis of posterior uveitis. Fundusfluorescein angiography, indocyanine green angiography and lately, autofluorescence and optical coherence tomography provide information about the diagnosis of uveitis disorders and are also useful for monitoring progression, complications, and response to treatment. The use of ultrasonography and ultrasound biomicroscopy provides useful information in eyes with chronic uveitis where complications such as retinal detachment and cyclitic membranes are sus-pected and hazy media precludes a thorough clinical examination. Radiological investigations such as computerized tomography aid in the diagnosis and management of systemic disorders such as tuber-culosis or sarcoidosis.

“Diagnosis is not the end, but the beginning of practice.”

Martin H. Fischer Rarely has a_ﬁeld of medicine been more challenging than the

field of intraocular inflammation. The study of uveitic entities presents great challenges to the treating ophthalmologists because the list of differential diagnosis ever grows to encompass a range of diseases from infectious to immunological to malignant. To the trained eye, though, a methodical system of clinical examination and a pick of the most useful investigative modalities would lead to a definitive diagnosis in a majority of cases. In this article, we present a fresh look at the plethora of investigations at our disposal and the usefulness of these in arriving at a diagnosis.

Uveitis has been classified into various subdivisions according to the Standardization of Uveitis Nomenclature and International Uveitis Study Group classification.1 It could be anterior, interme-diate, posterior, or a panuveitis depending on the primary site of inflammation. It could also be classified based on etiology as

infectious, noninfectious, or a masquerade. The list of differentials under each category is mind-boggling and many times similar clinical pictures can pose diagnostic challenges. Therefore, here lies the usefulness of investigative modalities to narrow down the search for a cause. The role of these tests lies in obtaining diagnostic and prognostic information and in taking a therapeutic direction. A logical sequence of events would be to compare clinical charac-teristic with known uveitic entities and shortlist etiological possi-bilities. Then ﬁrst order relevant laboratory investigations and order extensive investigations if refractory to treatment.

Simple tests such as a complete blood count, erythrocyte sedi-mentation rate (ESR), and C-reactive protein may give information about the nature of the underlying disease. The ESR is a simple and inexpensive laboratory test. It is commonly used to assess the acute-phase response. For example, a raised ESR is seen in conditions such as tuberculosis, syphilis, sarcoidosis, and collagen vascular disorders. Levels of serum angiotensin-converting enzyme (ACE) have an important prognostic role to play in the diagnosis and management of sarcoidosis. Elevated levels often favor the disease, and response to treatment can be assessed by decreasing levels of ACE. However, patients on systemic steroids and ACE inhibitors may have false-negative values.2This test is indicated in all patients with granu-lomatous uveitis, intermediate uveitis, vasculitis, and those

The authors have no conﬂicts of interest relevant to this article.

*Corresponding author. Sankara Nethralaya, 18 College Road, Nungambakkam, Chennai 600 006, Tamil Nadu, India.

E-mail address:drarshee@gmail.com(A.S. Ahmed).

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age group of 30e40 years of age, with a nongranulomatous anterior

chamber reaction. It accounts for between 18% and 32% of all anterior uveitis cases in Western countries and between 6% and 13% of all anterior uveitis cases in Asia. The presence of HLA-B27 is also associated with other rheumatologic diseases such as ankylosing spondylitis.3

Another commonly performed HLA test is HLA-B51, for diag-nosing Behçet’s disease. It is considered to be a marker for more severe disease and may increase the risk for development of complications such as uveitis, erythema nodosum, and the full-blown syndrome.4,5

Rheumatoid factor is most often used for the diagnosis of rheumatoid arthritis although it can be positive in various other conditions such as systemic lupus erythematosus (SLE), sclero-derma, and dermatomyositis. It is indicated in the work-up of pa-tients who present with sclerouveitis.

Antinuclear antibodies are positive in up to 95% patients with SLE and scleroderma. Immunoﬂuorescence is commonly used to detect antinuclear antibodies and is considered to be the gold standard. ANA testing has 95% sensitivity for SLE. It carries low speciﬁcity and can be positive in various diseases.6

ANCA should be ordered in suspected cases of Wegener’s granulomatosis (WG). Sequential measurements of titers of cyto-plasmic ANCA (c-ANCA) may be useful to indicate the clinical course of patients with WG. Changes in titer of2 serial dilutions are considered signiﬁcant. Positivity for c-ANCA is a sensitive (88%) marker of active WG.7

ELISA is commonly performed to look for the presence of anti-gens or speciﬁc antibodies in the sera of patients. It is commonly performed for toxoplasmosis, human immunode_ﬁciency virus (HIV), and toxocariasis (Fig. 1).

Similarly, ELISA withToxocaraexcretory-secretory antigen has been shown to be highly speciﬁc forToxocarainfection.

Analysis of intraocularﬂuids has gained wide popularity for the diagnosis of both anterior and posterior uveitic entities, more so for posterior uveitis that poses diagnostic dilemmas. The most com-mon causes of infectious uveitis in immunocompetent individuals are herpes simplex virus types 1 and 2, varicellaezoster virus, and

the parasite T. gondii. PCR amplifies the deoxyribonucleic acid (DNA) or ribonucleic acid of pathogens, making them easier to detect, especially when present in small quantities. PCR is superior in terms of sensitivity, specificity, and rapidity of diagnosis. Analysis of a small sample of aqueous humor may be adequate to confirm a clinically suspected intraocular infection, in particular in the context of suspected viral retinitis. Anterior chamber paracentesis has the advantage of being quick, relatively straightforward to perform, and can be carried out in the outpatient setting. In cases of posterior uveitis, vitreous sampling is necessary. This can be ob-tained by either a vitreous cutter or by using a 23-G needle. Formal pars plana vitrectomy requires an operation and needs to be carried out by a skilled ophthalmic surgeon. This allows up to 2 mL of undiluted vitreous to be sampled and sent for analysis. The three main indications for sampling the vitreous are suspected intraoc-ular infection, suspected intraocintraoc-ular lymphoma, and an atypical response to therapy during the treatment of presumed autoim-mune intraocular inflammation.

Various study groups have characterized the relative merits of aqueous PCR and intraocular antibody testing (GoldmanneWitmer

coefﬁcient) in determining the diagnosis of immunocompromised and immunocompetent patients with uveitis. Theyﬁnd that the two approaches are complementary; for example, in the immu-nocompromised population, PCR is superior for detecting viral infection, whereas intraocular antibody assays are superior for the diagnosis of toxoplasmosis.10e12_{PCR for viral uveitis is indicated in}

atypical cases and testing is likely to be positive, including retinal vascular inﬂammation, extensive retinitis, optic nerve involvement, and immunocompromised state. It carries a sensitivity of 80.9% and a speciﬁcity of 97.4%.13

False-positive results are another marked pitfall to the routine use of PCR as the possibility of laboratory contamination or detection of latent DNA or DNA of normalﬂora becomes limiting.14 PCR for intraocular tuberculosis is extremely useful and various ocular tissues can be used for testing including aqueous humor, vitreous humor, subretinal_ﬂuid, and tissue obtained by chorior-etinal biopsy. Both real-time and nested PCR have been used in the diagnosis (Figs. 2and3).15e18

Skin testing is commonly performed for diseases such as tuberculosis. The most commonly performed of these tests is the Mantoux test, which involves intradermal injection of puriﬁed protein derivative and assessing the resulting induration. It is based on the hypersensitive reaction toward the mycobacterial antigens. Its disadvantages are that it is not speciﬁc for Mycobacterium tuberculosis and does not distinguish latent infection from the

Fig. 1.A 42-year-old male patient with toxoplasmosis in the left eye. Enzyme-linked immunosorbent assay of aqueous sample was positive forToxoplasma.

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disease. It may be positive with cases involving Bacillus Calmettee

Guérin (BCG) vaccination/exposure to atypical mycobacteria and may be negative in immunosuppressed states/children/extrap-ulmonary or miliary tuberculosis. Its value is now becoming limited in endemic countries such as India because 30e69% of healthy

adults would test positive and it could be negative or weakly pos-itive in up to 33% of patients with tuberculosis.19,20

Interferon-gamma release assays are tests that measure the interferon-

g

release afterin vitrostimulation of patients’ lympho-cytes withM. tuberculosis-specific antigens. These are more specific markers of M. tuberculosis infection/previous exposure. The ad-vantages are that it is not influenced by BCG vaccination or expo-sure to atypical mycobacteria and not as subject to biases and errors of placement and reading as the tuberculin skin-sensitivity tests. Disadvantages are the higher cost and limited availability. It is possibly the most sensitive to detect latent infection than tuber-culin skin tests but does not distinguish it from active disease. It may also be negative or indeterminate in immunosuppressed states.21e24

Fundusfluorescein angiography (FFA) is invaluable in patients with uveitis as it demonstrates changes secondary to intraocular inflammation and helps in monitoring the response to therapy (Fig. 4). It aids in the diagnosis of cystoid macular edema, which is one of the most common causes of visual morbidity in patients suffering from uveitis. Classically, it appears as a fl ower-petal-shaped leakage of dye from the macular capillaries. Yannuzzi et al25classified macular edema intofive grades depending on the extent of hyperfluorescence noted.

FFA is useful in demonstrating the extent of retinal vasculitis by showing leakage of dye and staining of the walls of major retinal vessels in the areas of localized inﬂammation.26,27Conditions such

as intermediate uveitis, sarcoidosis, and Behçet’s disease are frequently associated with vasculitis. Neovascularization of the disc and elsewhere is very well demonstrated by FFA as it shows extensive dye leakage from the fragile vessels.26In conditions such as Eales disease, extensive areas of capillary nonperfusion also may be made out.

FFA is characteristic in patients with VogteKoyanagieHarada’s

(VKH) syndrome with exudative retinal detachment, showing multiple, pin-head leaks at the level of the retinal pigment epithelium (RPE) and the presence of subretinalﬂuid. Disc leakage is considered to be an important sign of activity. Exudative retinal detachments occurring at the posterior pole are also seen in pos-terior scleritis.28

FFAfindings in the so-called white dot syndromes are charac-teristic as they show early hypofluorescence followed by late hyperfluorescence seen in acute posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy, and serpigi-nous choroiditis.29e33 _{However, lesions in multiple evanescent}

white dot syndrome show early-phase FA, demonstrating punctate hyperﬂuorescence corresponding to the white dots seen clinically, which persist into the late phase. There is also leakage of the optic disc in most cases.34

Choroidal neovascularization (CNV) can complicate many of the uveitic diseases, and is most commonly seen in multifocal choroi-ditis, punctuate inner choroidopathy, serpiginous choroichoroi-ditis, and presumed ocular histoplasmosis syndrome (Figs. 5and6). It can also occur in toxoplasmic retinochoroiditis, VKH syndrome, bird-shot chorioretinopathy, and in various other entities.35

Discrepant FFA and optical coherence tomography (OCT)ﬁ nd-ings were noted in 46% of uveitic eyes in one study, predominantly occurring in eyes with mild macular edema. Although the FFAþ/

Fig. 2.A 48-year-old male presented with decreased vision in both eyes after a bout of febrile illness. Fundusﬁndings included multiple exudates and hemorrhages. Real-time polymerase chain reaction from aqueous tested positive for Chikungunya virus.

Fig. 3.A 34-year-old male patient with serpiginous-like choroiditis. In addition, the quantitation report of the real-time polymerase chain reaction on aqueous sample revealed Mycobacterium tuberculosisDNA.

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OCTþconsistency was noted frequently in active uveitis, the FFA/ OCTþdiscrepancy was common in eyes with inactive uveitis. These results show that FFA and OCT are complementary investigations, each revealing different aspects of the pathophysiological features of uveitic macular edema, and this may inﬂuence the therapeutic decisions.36

Fundus autofluorescence (FAF) is a new technique that allows topographic mapping of lipofuscin distribution in the retinal pigment epithelium cell monolayer as well as of otherfluorophores that may occur with disease in the outer retina and the sub-neurosensory space. FAF imaging gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, FA, and OCT. Its clinical value coupled with its simple, efficient, and noninvasive nature is increasingly appreci-ated.37 In patients with serpiginous choroiditis, increased

auto-fluorescence (hyperfluorescence) may be seen in acute phases. During the resolution stages of inflammation, the pigment in the lesion becomes slate gray. With this change comes a decrease in the amount of visible autofluorescence. Regressed or inactive lesions show hyperfluorescence. Slate or neutral gray-black areas frequently have a complete absence of autofluorescence. Secondary CNV often is easy to recognize by FAF imaging because the sur-rounding hyperplastic RPE is hyperautofluorescent and neatly outlines the neovascularization. This hyperautofluorescence per-sists for years after the CNV has formed. After treatment, CNV may contract and leave a zone of absent RPE in a manner similar to that of inflammatory lesions.38

Indocyanine green angiography (ICGA) was _ﬁrst described in 1973 and since then has been a better imaging modality for viewing the choroidal vasculature than FA.39The major application of ICGA is in disorders involving the choriocapillaris and the choroid. ICG is more protein bound, and therefore, leakage from the fenestrations of the choriocapillaris is reduced, enabling better visualization of

the choroidal circulation. Most information is obtained from the late phases of the study. Recently, these disorders have been clas-sified into two groups based onfindings revealed by ICGA. Type 1 is the inflammatory choriocapillaropathies and appears as

hypo-fluorescence in both the mid and late phases of the ICGA study. Examples of this are the various white dot syndromes (Fig. 7). Type 2 represents stromal inflammatory vasculopathies and is charac-terized by late leakage of ICG dye from inflamed choroidal vessels. Sarcoidosis, tuberculosis, VKH disease, sympathetic ophthalmia, birdshot chorioretinopathy, Behçet’s disease, and posterior scleritis are examples of stromal involvement.40

The ICGA study is helpful in differentiating an inactive chorior-etinal scar from active CNV. Scars appear hypoﬂuorescent throughout the angiogram, whereas the CNV may present as a hot spot of hyperﬂuorescence in the midphase of the study, with late leakage.41

OCT is a noninvasive, noncontact tool, which uses the principle of low coherence interferometry to take axial and transverse scans of the retina using a light source (Fig. 8).42It is very useful in the diagnosis and follow-up of macular disorders such as cystoid macular edema due to uveitis, epiretinal membranes, vitre-omacular traction, and even choroidal neovascular membranes.43 Various studies have studied the role of OCT in uveitic eyes and have tried to assess the correlation between visual acuity and OCT

ﬁndings. Some suggest a strong correlation, whereas others suggest weak correlation. One study described three patterns of macular edema in patients with uveitis: diffuse macular edema, cystoid macular edema, and retinal detachment.44_{It is especially useful for}

the diagnosis of macular detachment, which is difﬁcult to pick up on FFA. Recently, newer techniques such as enhanced-depth im-agingeOCT have allowed us to measure choroidal thickness, which

may serve as a marker for degree of choroidal inﬂammation in acute VKH disease.45

Fig. 4.Fundus photo andﬂuorescein angiogram reveal uveitic macular edema in a patient with pars planitis.

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Ultrasonography (B scan) is useful in demonstrating vitreous opacities, choroidal thickening, retinal detachment, or cyclitic membrane formation, particularly if media opacities preclude a view of the posterior segment. This may be the result of the pres-ence of corneal opaciﬁcation, anterior chamber hyphema or hypopyon, pupillary miosis, cataract, lenticular membranes, or vitreous hemorrhage or inﬂammation (Figs. 9and10).

B-scan ultrasound is useful in quantifying scleral thickness. Highly reﬂective echoes with thickening of the uvea and sclera are usually present. Scleral edema associated withﬂuid within Tenon’s space results in an echolucent region just posterior to the sclera, the so-called T sign. This is considered virtually diagnostic of posterior scleritis.46,47

Ultrasound biomicroscopy (UBM) uses high-frequency ultra-sound waves (40e60 MHz) to allow high-resolution examination of

the anterior segment, ciliary body, and pars plana region. In pa-tients with intermediate uveitis, UBM allows the documentation of pars plana exudates and membranes in eyes with hazy media or

small pupil. It is also useful for assessing the severity and extent of involvement in patients with peripheral toxocariasis. In eyes with chronic hypotony, UBM gives clues as to the presence of chronic ciliary membranes resulting in ciliary body shutdown.48e50

Radiological investigations such as high-resolution computer-ized tomography (HRCT) are useful for suspected cases of uveitis secondary to systemic diseases such as tuberculosis and sarcoid-osis. According to one study, 81% of uveitis patients referred for chest HRCT demonstrated signs suggestive of tuberculosis, 8.6% patients showed signs suggestive of sarcoidosis, and 10.3% patients showed normal chest HRCT. Chest HRCT was found to be a useful tool in the diagnosis of granulomatous uveitis, especially tuberculosis-associated uveitis, and can aid in therapeutic decisions.51

In conclusion, a modern approach to uveitic disorders is to look for speciﬁc uveitic entities rather than ordering a battery of tests. For example, in a patient with recurrent attacks of non-granulomatous anterior uveitis, it would be appropriate to order rheumatoid factor, antinuclear antibodies, and ESR. In addition, based on medical history, one could look for HLA-B27, venereal disease research laboratory (VDRL), Treponema pallidum hemag-glutination assay (TPHA), and a chest X-ray along with the Mantoux test to rule out tuberculosis. Similarly for a granulomatous anterior uveitis, tests for sarcoidosis should also be advised. Likewise, for intermediate uveitis, tests for tuberculosis, sarcoidosis, and even multiple sclerosis may be needed along with ancillary tests such as OCT to track structural changes (e.g., cystoid macular edema), which are a major cause of drop in visual acuity in these patients. In patients suffering from posterior uveitis, the commonly performed tests are ELISA for Toxoplasma, Mantoux test, serum ACE and lysozyme levels, VDRL, and TPHA. Tests for HIV should be included whenever there is a high clinical suspicion of the disease. Ancillary tests should include FFA, ICG, OCT, and ultrasonography as

Fig. 6.Active serpiginous choroiditis with typical fundus autoﬂuorescence showing hyperﬂuorescent borders suggestive of activity.

Fig. 7.Fundus photograph,fluorescein angiography, and indocyanine green angiography (ICGA) in a patient with multiple evanescent white dot syndrome. The ICGA highlights the multiple hypofluorescent spots that are not picked up on fundusfluorescein angiography.

Fig. 8.Optical coherence tomography in a patient with chronic pars planitis showing typical cystic spaces suggestive of cystoid macular edema.

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indicated. Established entities such as Behçet_’s disease, sympa-thetic ophthalmia, or VKH syndrome require a clinical diagnosis and no speciﬁc diagnostic test is needed. To conclude, arriving at a diagnosis is possible in a majority of the patients with uveitis using a targeted approach. Detailed initial examination and keeping in mind the various differentials can lead to selection of appropriate laboratory and ancillary tests.

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