approach to the uveitis workup

8/3/2019 Approach to the Uveitis Workup

1/13

Approach to the Uveitis Workup

For many years, uveitis was considered a single disease entity; therefore, the approach to treatmentvaried very little. As knowledge of the disease process grew and the sophistication of immunologic andmicrobiologic testing increased, the fact that uveitis entails a multitude of diseases became clear.

Although some diseases are local ocular immune phenomena, many of them are systemic diseases withocular manifestations. Because the spectrum of disease pathogenesis ranges from autoimmunity to

neoplasia to viruses, the practitioner of uveitis requires an understanding of internal medicine, infectiousdiseases, rheumatology, and immunology.

Patients with uveitis can present with some of the most challenging diagnostic dilemmas in all ofophthalmology. Because the treatment and prognosis of various uveitic entities varies greatly, accuratediagnosis is imperative. Many diseases, including Fuchs uveitis syndrome (formerly known as Fuchsheterochromic iridocyclitis), Behet disease,toxoplasmosis, cytomegalovirus (CMV) retinitis, ocularhistoplasmosis, andVogt-Koyanagi-Harada (VKH) disease, are clinical diagnoses that require little, if any,laboratory analysis. Likewise, the patient presenting with an initial episode of acute nongranulomatousanterior uveitis and an unremarkable review of systems and physical examination does not require alaboratory evaluation.

Laboratory tests are rarely useful as screening tools for this disease. In determining which tests to order,using clues from the history and physical examination and knowledge of the pretest probability of the

disease in question is helpful. This diagnostic process is important to avoid false-positive results andcostly and unnecessary testing. Consequently, no standard laboratory evaluation exists for the patientwith uveitis, except in screening for syphilis and possibly sarcoidosis, both of which can present in amyriad of ways. The key to the targeted and efficient patient evaluation is a thorough history, physicalexamination, and review of systems. With this information, the practitioner can generate a differentialdiagnosis and a subsequent strategy for laboratory evaluation.

For excellent patient education resources, visit eMedicine'sEye and Vision Center. Also, see eMedicine'spatient education articles Iritis andAnatomy of the Eye.

The lists below include some of the most common systemic findings in patients with uveitis.

Head/CNS

y Headaches - VKH disease, sarcoidosis, Behet disease,tuberculosis,herpes zoster, large celllymphoma, polyarteritis nodosa (PAN),Cryptococcus meningitis, toxoplasmosis, Lyme disease

y Auditory/vestibular - VKH disease, sarcoidosis, Wegener granulomatosis, Eales disease, syphilis

y Cranial neuropathy - Lyme disease, sarcoidosis,multiple sclerosis, syphilis,herpes simplex virus

y Psychosis - VKH disease, Behet disease,systemic lupus erythematosus (SLE)

y Cerebral vasculitis - Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), Behet disease,herpes simplex virus, herpes zoster virus, syphilis, Lyme disease

Ear/Nose/Throat

y Bilateral ear pinna inflammation - Relapsing polychondritis

y Saddle nose deformity - Syphilis, Wegener granulomatosis, relapsing polychondritis

y Oral ulcers - Behet disease, SLE, herpes simplex, Reiter syndrome,ulcerative colitis

y Sinusitis - Sarcoidosis, Wegener granulomatosis

y Salivary/lacrimal gland swelling - Sarcoidosis, lymphomay Lymphadenopathy- Lymphoma, HIV, toxoplasmosis

Gastrointestinal

y Diarrhea -Crohn disease, ulcerative colitis,Whipple disease

y Jaundice/hepatosplenomegaly -Brucellosis, CMV, sarcoidosis, infectious hepatitis, autoimmune hepatitis

ulmonary

y Cough, shortness of breath - Tuberculosis, sarcoidosis,Pneumocystis carinii, malignancy, Wegenergranulomatosis


2/13

y Nodules, hilar adenopathy, infiltrates - Ocular histoplasmosis, sarcoidosis (hilar adenopathy), malignancy,tuberculosis, Pcariniipneumonia

Genitourinary

y Genital ulcers - Behet disease, Reiter syndrome, syphilis

y Hematuria - Wegener granulomatosis, PAN, SLE

y Circinate balanitis -Ankylosing spondylitis, Reiter syndrome

y Urethral discharge - Reiter syndrome, syphilis

y Nephritis - PAN, Wegener granulomatosis, tubulointerstitial nephritis and uveitis (TINU)

y Epididymitis - PAN, Behet disease, Reiter syndrome

Dermatologic

y Alopecia - VKH disease, syphilis

y Vitiligo, poliosis - VKH disease

y Nodules - Sarcoidosis, SLE, leprosy, Crohn disease, ulcerative colitis

y Rash - Syphilis, Lyme disease, Reiter syndrome, leprosy, sarcoidosis, herpes zoster, Behet disease,psoriasis, SLE, Kawasaki disease

y Keratoderma blennorrhagicum - Reiter syndrome, ankylosing spondylitis

y Erythema nodosum - Behet disease, sarcoidosis, APMPPE

usculoskeletal

y Arthralgias/arthritis - Behet disease, sarcoidosis, SLE, juvenile idiopathic arthritis (JIA), Lyme disease,syphilis, psoriatic arthritis, Reiter syndrome, ulcerative colitis

y Sacroiliitis - Ankylosing spondylitis, Reiter syndrome, inflammatory bowel disease

Constitutional

y Fever - Reiter syndrome, Behet disease, PAN, inflammatory bowel disease, HIV, tuberculosis,coccidioidomycosis, Whipple disease

y Night sweats - Malignancy, tuberculosis, sarcoidosis, coccidioidomycosis

y Flulike symptoms - APMPPE, multiple evanescent white dot syndrome (MEWDS)Opremcak advocates a differential-based diagnostic system that primarily uses 3 clinical features, asfollows: (1) location of the inflammation in the eye (corneoscleral, anterior, intermediate, posterior, ordiffuse uveitis), (2) type of inflammation (granulomatous vs nongranulomatous), and (3) associatedsystemic symptoms from the review of systems.[1]

Smith and Nozik recommend a strategy called "name meshing."[2] The naming process involves extractingrelevant clinical and historical information and creating a case profile (eg, acute unilateralnongranulomatous anterior uveitis in a 35-year-old white male with stiffness in the lower back). Thisinformation is meshed with clinical characteristics of known ocular inflammatory diseases. Using thisinformation, the practitioner can generate a list of differential diagnoses and then order laboratory testsbased on the likelihood that one of those diseases is present.

Although these systems work well, they are by no means foolproof. As the disease becomes chronic, theinflammation may change from nongranulomatous to granulomatous, the pattern of ocular involvementmay change, and systemic features that were not initially present may become apparent. Because of thedynamic nature of uveitis, updating the review of systems and categorizing the ocular inflammationaccordingly are important. Laboratory tests are no substitute for a systematic approach and careful

observation in treating patients with uveitis.

Choosing the Correct Diagnostic Test

Ordering a standard series of tests in every patient with uveitis is rarely useful, can be costly, and canoften confuse the diagnostic process. Rosenbaum and Wernick emphasize the futility of indiscriminatetesting.[3]The value of the test varies with the probability of the suspected disease (pretest probability).The test is most helpful in raising diagnostic probability to rule in levels when the history and physicalexamination findings create a pretest probability of 40-60%. Bayes theorem can be used to assess the


3/13

use of positive results by evaluating the sensitivity and specificity of a diagnostic test combined with thepretest probability of disease to calculate the posttest probability of disease.

Responsible clinical physicians decide which diagnostic tests to order for patients based on the bestpossible evidence. Sackett and colleagues coined the term evidence-based medicine, which is "theconscientious, explicit and judicious use of the current best evidence in making decisions about the careof individuals."[4] Evidence-based medicine is a lifelong learning process, incorporating sound clinical skills

with a proficiency for a critical appraisal of the medical literature. The following section is based on theexcellent work by Sackett and colleagues; the reader is encouraged to consult the References section.[4]

Evidence-based Medicine Approach to the Diagnosis of Uveitis

When a patient presents with intraocular inflammation, the diagnostic workup begins with the signs andsymptoms. Each facet of the history and physical examination serves to either increase or decrease theprobability of a target disorder being present. Unequivocally, the power of the clinical examination inestablishing a diagnosis is far greater than the laboratory evaluation. Sandler discovered that after thehistory, a correct diagnosis was established in 56% of patients in a general medical clinic; it increased to73% after the physical examination.[5]Routine laboratory evaluation helped to establish a diagnosis in only5% of patients; not surprisingly, it also added substantial cost.

One strategy used by nearly all clinicians is the formulation of a list of potential diagnoses from a brief

interaction with the patient, followed by a focused history and physical examination, and then anappropriate diagnostic evaluation that shortens the list of diagnostic possibilities. This strategy is termedthe hypothetico-deductive approach by Sackett and colleagues.[4] In evaluating patients with uveitis,revisiting certain aspects of the history is common once particular facets of the examination becomeapparent. For example, after an initial interaction with a 34-year-old black woman with symptoms ofredness, pain, and photophobia, the clinician discovers that she has mutton-fat keratic precipitates andiris nodules. Further questioning is directed toward the various entities that cause granulomatousinflammation, with the appropriate diagnostic tests ordered accordingly.

To understand the value of a particular diagnostic test, the concepts of pretest and posttest probability,sensitivity, specificity, and likelihood ratios (LRs) need to be introduced. Pretest probability, defined as theodds that a given disease exists in a specific patient with a particular constellation of signs andsymptoms, greatly influences which diagnostic tests are ordered. Very few published pretest probability

values exist for the various uveitic entities. Consequently, they usually are derived from the practitioner'sclinical experience and intuition. Alternatively, colleagues can be consulted about their experiences,thereby generating a pretest probability by consensus.

A diagnostic test is only useful if it can confidently rule in or rule out disease. In other words, a reliabletest is one that is positive in nearly all patients with the disease, giving the clinician confidence that theindividual is disease free when the test result is negative (for that disease).

Some commonly used parameters for determining whether the evidence for a diagnostic test is importantinclude the sensitivity and specificity of the test and the newer, more powerful concept of LRs. Sensitivityis the proportion of patients with the target disorder who have a positive test result (true positives),whereas specificity represents the proportion of patients without the target disorder who have a negativetest result (true negatives). By using Bayes theorem, the posttest probability of disease (ie, likelihood thata disease is present after a test result is known) can be calculated, given the sensitivity and specificity of

the diagnostic test and the pretest probability of the disease.

Knowing the posttest probability provides the clinician with objective evidence about a diagnosticconclusion or determines whether the clinician pursues further laboratory evaluation. Calculating theposttest probability from Bayes theorem is cumbersome and not always practical. Fortunately, an easiermethod using a nomogram, which interprets a diagnostic test result by using a newer concept (ie, LRs), isavailable. This attribute of a particular test indicates the probability that a given test result would beexpected in a patient with the target disorder, compared to the probability that the same result would bepresent in a patient without the target disorder. Any valid article on diagnostic testing should provide


4/13

information regarding the sensitivity and specificity of the test, and, if that is all that is given, then the LRcan be calculated easily.

The LR for a positive test result is LR+ = sensitivity/1-specificity; the LR for a negative test result is LR- =1-sensitivity/specificity. For example, a patient presents with retinal vasculitis and other signs andsymptoms suggestive of Wegener granulomatosis. Literature is searched, and an article about the use ofantineutrophil cytoplasmic antibodies (C-ANCA) with a cytoplasmic staining pattern in testing for Wegener

granulomatosis is found. According to the article, 90% of patients with biopsy-proven disease had apositive C-ANCA (sensitivity), and 10% of patients had a positive test but other causes of systemicvasculitis (false positives or 1-specificity). Therefore, in this example, the LR+ is .9/.1 or 9. In other words,the positive C-ANCA in this patient is 9 times more likely to be observed in an individual with Wegenergranulomatosis than without the disease.

By consulting the Fagan nomogram (conveniently located in the pocket guideEvidence-Based Medicine:How to Practice and Teach EBMby Sackett et al), the posttest probability of disease can becalculated.[4] For example, if a patient has a 50% chance of being diagnosed with the disease before thetest, the LR of 9 translates into a posttest probability of 92%, suggesting that the C-ANCA was a veryuseful test.

More and more investigators are realizing the value of the LR as a measure of diagnostic accuracy and

incorporating it in their reports. In addition to calculating the posttest probability, the LR has otheradvantages over the sensitivity and specificity; it is less likely to vary with the prevalence of the targetdisease, and it can be calculated for several levels of the diagnostic test, symptom, or sign (ie, verypositive to weakly positive).

Ultimately, the usefulness of a diagnostic test is determined by whether it helps doctors in caring for theirpatients (ie, test results changing the management of patients with uveitis, patients benefiting as a resultof the test). In the above example, the diagnosis of Wegener granulomatosis was crucial becausetreatment with cyclophosphamide favorably impacts the mortality rate and ocular complications. Thissection briefly introduced some concepts that are important to the diagnostic approach, particularly indiagnosing uveitis. The authors believe that implementing the principles of evidence-based medicine inthe daily practice of medicine makes better clinicians and, more importantly, better doctors for patients.

Diagnostic Approach to Specific Uveitic Entities

In an effort to better organize the classification and grading of various uveitic entities, the Standardizationof Uveitis Nomenclature (SUN) Working Group published a consensus report in 2005.[6] This reportprovides clarification of the anatomical classification of uveitis. The reader is referred to this document asthe prevailing methodology for the classification, descriptors, and terminology in the care of patients withuveitis.

Anterior uveitis

Patients with anterior uveitis present with a wide range of symptoms. These symptoms vary from a mildblurring of the vision with an otherwise normal-looking eye (ie, juvenile idiopathic arthritis [JIA]) to severepain, photophobia, and loss of vision associated with intense injection and hypopyon. Factors other thanocular signs and symptoms can help in diagnosing anterior uveitis. The onset, duration, and severity ofany symptom, as well as unilaterality or bilaterality of the disease, should be known. The patient's age,racial background, and ocular history should be taken into consideration. A detailed history and review ofsystems are of immeasurable value in the diagnostic approach to patients with uveitis.

An important element of any classification system for uveitis is defining what part of the eye is involved.The presence of white cells confined solely to the anterior chamber is called iritis. When the cellularactivity involves the retrolental vitreous, the inflammatory process is believed to include the ciliary bodyand iris and is known as iridocyclitis. Corneal or scleral involvement plus anterior chamber inflammation iscalled keratouveitis or sclerouveitis, respectively.


5/13

Multiple etiologies are noted for anterior uveitis. Most types of anterior uveitis are sterile inflammatoryreactions, as opposed to many of the posterior uveitic syndromes that are caused by infections. Thepercentage of idiopathic anterior uveitis ranges from approximately 38% to more than 70%; this is by farthe most common cause of anterior uveitis.[7, 8] The next most common etiology is the sudden-onsethuman leukocyte antigen (HLA)-B27positive or HLA-B27associated disease.

McCannel reports that both community-based patients and university-based patients have similar

incidence rates (about 17%).[9]After that, differences are observed in the probability of the variousetiologies, depending on the clinical setting. For community-based patients, trauma is the third mostcommon cause of anterior uveitis (5.7%); trauma was not observed in the university setting. Althoughherpes simplex virus is uncommon in community-based patients (1.9%), it was the third most likelydiagnosis in the university setting (12.4%). Varicella-zoster infection occasionally was observed in bothsettings (5-6%).

Pain, redness, and photophobia comprise the classic presentation of acute anterior uveitis. The painusually is described as a dull ache in and around the eye, but anterior uveitis can cause little or nodiscomfort. Vision can be normal or slightly decreased. Often, the eye is extremely sensitive to light(photophobia). The patient may notice redness in one or both eyes or no change at all in the look of theeye.

The conjunctiva classically shows perilimbal injection (known as ciliary flush). The cornea may havekeratic precipitates, which are clusters of WBCs collected on the endothelium. The type of keraticprecipitate can provide a clue to the classification of anterior uveitis. Mutton-fat keratic precipitates arecharacteristic of granulomatous uveitis. Diffuse stellate keratic precipitates classically are seen in Fuchsuveitis syndrome. Interstitial keratitis commonly is seen in patients with syphilis and herpetic disease.

By definition, the anterior chamber has variable amounts of white cells floating in the aqueous. Often,protein also is visible in the anterior chamber as flare. If enough white cells deposit on the bottom of thechamber, a hypopyon results. This finding is suggestive of HLA-B27 disease, Behet disease, orendophthalmitis.

The intraocular pressure (IOP) is often low in acute cases of anterior uveitis (with the exception ofherpetic uveitis) but may be elevated in chronic cases.

The iris can provide additional information about the possible etiology or chronicity of the disease. Long-standing inflammation can cause posterior synechiae. Inflammatory nodules on the iris suggestgranulomatous uveitis. Heterochromia is the classic finding in Fuchs uveitis syndrome. Atrophy of the irismay point to herpes zoster as the infection responsible for the inflammation.

The lens may show signs of cataractous change, which may suggest repeated bouts of iritis, orinflammatory precipitates may be present on the anterior lens capsule.

The anterior vitreous may have some cells that have "spilled over" from the anterior chamber. Some HLA-B27 diseases have varying amounts of vitritis and posterior pole involvement.

Papillitis or disc edema may be seen in Vogt-Koyanagi-Harada (VKH) disease, sarcoidosis, tuberculosis,Lyme disease, multiple sclerosis, toxoplasmosis, and toxocariasis.

In terms of testing, HLA-B27 is a genotype located on the short arm of chromosome 6 and is sometimesassociated with specific rheumatologic diseases. HLA-B27 is present in 1.4-8% of the general population;however, it is present in as many as 50-60% of patients with acute iritis. The HLA-B27 test should beconsidered in patients with recurrent anterior nongranulomatous uveitis. These so-called seronegativespondyloarthropathies are associated strongly with both acute anterior uveitis and a positive HLA-B27test. By definition, patients with these disorders do not have a positive rheumatoid factor. Some examplesinclude ankylosing spondylitis, Reiter syndrome, inflammatory bowel disease, psoriatic arthritis, andpostinfectious arthritis.


6/13

A thorough review of systems frequently directs the clinician toward the correct diagnosis. The possibilityalways exists of other systemic inflammatory disorders, some of which can be cured or at least managed.Syphilis, tuberculosis, Lyme disease, and herpes viruses are infectious diseases that can present as ananterior uveitis.

History is important in determining risk factors, but laboratory evidence of the disease is necessary soproper antibiotic therapy can be initiated quickly. Sarcoidosis is a systemic disease that classically

manifests as an anterior granulomatous uveitis but can present as any type of uveitis. Judicious use oflaboratory tests should help to better define the etiology of any anterior uveitis.

Table 1 is provided as a guide to the various clinical scenarios that may be confronted by the clinician.Beginning with knowledge of the type of inflammation, eliciting some associated factors should lead to apossible disease. Then, confirmatory laboratory tests can be used to establish a diagnosis. In general, aworkup is required if the anterior uveitis is bilateral, severe, recurrent, or granulomatous or if the posteriorsegment is involved. Minimal laboratory testing should include CBC count, urinalysis, ACE, VenerealDisease Research Laboratory (VDRL) test, and fluorescent treponemal antibody absorption (FTA-ABS)test. Chest radiography should also be performed.

Table 1. Various Clinical Scenarios Encountered by Practitioner of Uveitis(Open Table in a new window)

Type of Inflammation Associated Factors Suspected Disease Laboratory Tests

Acute/sudden onset,

severe with or without

fibrin membrane or

hypopyon

Arthritis, back pain,

GI/genitourinary symptoms

Seronegative

spondyloarthropathies

HLA-B27, sacroiliac

films

Aphthous ulcers Behet disease HLA-B5, HLA-B51

Postsurgical, posttraumatic Infectious endophthalmitis Vitreous tap, vitrectomy

Medication induced Rifabutin None

None Idiopathic Possibly HLA-B27

Moderate severity of

pain and redness

Shortness of breath, African

descent, subcutaneous

nodules

Sarcoidosis Serum ACE, lysozyme,

chest radiograph or chest

CT scan, gallium scan,

biopsy

Posttraumatic Traumatic iritis ...

Increased IOP, sectorial iris

atrophy, corneal dendriteHerpetic iritis ...

Poor response to steroid,

manifestations of 2 or 3syphilis, HIV

Syphilis Rapid plasma reagent

(RPR) or VDRL, FTA-ABS

Postcataract extraction, white

plaque on posterior capsule

Endophthalmitis, intraocular

lens (IOL)- related iritis

Vitrectomy and/or culture,

consider anaerobic and

fungal cultures

Medication induced Etidronate (Didronel),


7/13

metipranolol (OptiPranolol),

latanoprost (Xalatan)

History of HIV, alcohol

abuse, exposure to infected

individuals, residence in

endemic regions

Tuberculosis Purified protein derivative

(PPD), chest radiograph,

referral to infectious

disease specialist

None Idiopathic ...

Chronic, minimal signs

of redness or pain

Child, especially with

arthritis

JIA-related iridocyclitis Antinuclear antibody

(ANA), erythrocyte

sedimentation rate (ESR)

Heterochromia, diffuse

stellate keratic precipitate,

unilateral

Fuchs uveitis syndrome None

Postsurgical Low-grade endophthalmitis,IOL

Vitrectomy, capsulectomywith culture

None Idiopathic Lyme titers (possibly)

Intermediate uveitis

Intermediate uveitis is an anatomical term suggested by the SUN Working Group. Intermediate uveitis isdefined as intraocular inflammation that predominantly involves the peripheral retina, pars plana, andvitreous. Other terms used in the literature include chronic cyclitis, peripheral uveitis, and pars planitis.The term pars planitis is reserved to describe a subgroup of patients with idiopathic intermediate uveitiswith snowbanking and/or snowball formation.

Intermediate uveitis accounts for approximately 8-15% of patients with uveitis in tertiary referral centers inthe United States. Because characterization of this disease (and terminology associated with it) has beenambiguous, the conclusions of some older epidemiologic studies have been called into question.However, the report by Rodriguez et al used IUSG criteria and found that 162 of 1237 patients (13%) hadintermediate uveitis, essentially confirming other studies.[7]

Patients typically present with painless blurred vision and floaters. Photophobia and redness are unusual.

Ocular findings include mild-to-moderate anterior segment inflammation, although anterior cellular activitymay be more pronounced in children and in patients with multiple sclerosis. Presence of anterior vitreouscells is the sin qua non of this disorder, and, occasionally, the vitritis is severe enough to cause profoundloss of vision. White clumps of inflammatory cells (called snowballs) tend to accumulate at the vitreousbase where perivascular exudation and neovascularization may be present. The presence of a whitishyellow exudative material on the peripheral retina and the pars plana (called snowbanking) is commonly

seen. The presence of this material facilitates the diagnosis but is not required to establish a diagnosis ofintermediate uveitis. This finding is more consistent in patients with idiopathic intermediate uveitis and inchildren.

Because intermediate uveitis has been described in association with several systemic disorders, the initialdiagnostic evaluation should exclude masquerade syndromes and infectious diseases in whichimmunosuppression may be ineffective or contraindicated. The diagnostic approach to intermediateuveitis should focus on the history and clinical examination. As stated by Henderly et al and also byRodriguez et al, approximately two thirds of patients have idiopathic intermediate uveitis (pars planitis).[10,7] Of the 162 patients with intermediate uveitis described by Rodriguez et al, 69% of them were idiopathic,


8/13

sarcoidosis was diagnosed in 22% of them, multiple sclerosis was diagnosed in 8% of patients, and Lymedisease was diagnosed in only 1 patient.[7] Other entities have been reported to cause or to be confusedwith intermediate uveitis (see Table 2).

The authors' efforts focus on excluding sarcoidosis and multiple sclerosis with a thorough review ofsystems. Generally, the authors order an ACE level and a chest radiography for all patients to rule outsubclinical sarcoidosis. The presence of neurologic symptoms or a history of optic neuritis may

necessitate an MRI of the brain with subsequent neurologic consultation to rule out multiple sclerosis.

Patients from endemic areas for Lyme disease with a history of a rash typical of erythema migrans,chronic arthritis, or cranial nerve palsies undergo testing for antibodies toBorrelia burgdorferi. Theauthors seek consultation with a gastroenterologist for those patients with symptoms suggestive ofinflammatory bowel disease or Whipple disease (if the diagnosis has not already been established). Olderpatients presenting with vitreous cells may be indicative of intraocular large cell lymphoma. Diagnosticvitrectomy, cytological evaluation of cerebrospinal fluid (CSF), and neuroimaging may be necessary.

Table 2. Other Entities Reported to Cause or Confused With Intermediate Uveitis(Open Table in a newwindow)

Clinical Entity Diagnostic Tests

Idiopathic (pars

planitis)

None

Sarcoidosis ACE, chest radiography, gallium scan, biopsy (possibly)

Multiple sclerosis MRI and neurologic consultation if history of neurologic symptoms or optic neuritis, HLA-

DR2

Lyme disease Lyme serology (immunoglobulin [Ig]G/IgM Western immunoblot testing) if from endemic

area and/or presence of systemic signs

Syphilis VDRL, FTA-ABS

Inflammatory bowel

disease

GI consultation

Whipple disease GI consultation

Lymphoma Vitreous cytology with immunophenotyping, lumbar puncturefor cytology, neuroimaging

Retinal vasculitis

Conditions causing retinal vasculitis are a heterogeneous group of disorders that include some of themost devastating medical diseases encountered by the ophthalmologist. The term vasculitis impliesprimary retinal vascular inflammation (ie, immune complex deposition due to type III hypersensitivity), asseen in Behet disease, but vasculitis is commonly a sign of intraocular inflammation from other causeswith secondary vascular involvement (eg, toxoplasmosis).

Some noninflammatory retinal vascular diseases can be associated with perivascular exudation, such asdiabetic retinopathy, radiation retinopathy, sickle cell retinopathy, venous occlusive disease, and Coatdisease. The differential diagnosis of retinal vasculitis can be subdivided broadly into those diseases thathave systemic involvement and those diseases that are confined to the eye, as outlined below.


9/13

y Systemic diseases associated with retinal vasculitiso Behet diseaseo Syphiliso Systemic lupus erythematosus (SLE)o Tuberculosiso Sarcoidosiso Wegener granulomatosiso Toxoplasmosiso Cytomegalovirus (CMV)o Polyarteritis nodosa (PAN)o Candidiasiso Multiple sclerosiso Herpes zoster/herpes simplexo Giant cell arteritiso Lyme diseaseo Crohn diseaseo Rickettsiao Whipple diseaseo Large cell lymphomao Polymyositis/dermatomyositis

y Ocular diseases associated with retinal vasculitiso Eales diseaseo Frosted branch angiitiso Acute retinal necrosiso Retinal arteritis and aneurysmso Birdshot choroiditiso Toxoplasmosiso Pars planitisCommon presenting ocular symptoms include painless blurred vision or severe visual loss, floaters, andscotomata.

Examination reveals perivascular exudation or cuffing that predominantly involves the arteries, the veins,or both; varying degrees of anterior chamber cell and flare; and vitritis. These findings may be

accompanied by retinal hemorrhages, cotton-wool spots, exudates, cystoid macular edema (CME),neovascularization, vitreous hemorrhage, or disc edema.

The history and clinical examination are by far the most powerful diagnostic tools in evaluating thiscomplex group of diseases. After a thorough review of systems and physical examination, the lack offindings indicating a systemic disease makes the pretest probability of disease very low and, thus,reduces the predicative value of any diagnostic tests.

Some investigators have shown that patients with retinal vasculitis presenting with symptoms and signsconfined to the eye needlessly undergo exhaustive and expensive diagnostic evaluation. When George etal reviewed a series of patients with primary retinal vasculitis, they found that 96% of them had a negativereview of systems; however, all patients underwent an exhaustive battery of tests.[11]A diagnosis wasestablished in only 1 patient; false-positive results were obtained in 21% of patients. The shotgunapproach has no place in evaluating a patient with retinal vasculitis. It invariably results in false-positive

results, which, in turn, leads to more unnecessary testing, cost, and inconvenience to the patient.

Fluorescein angiography is an important aspect of the evaluation process. Findings may include stainingof the vessel walls, beaded vessels, microaneurysms, telangiectatic vessels, capillary nonperfusion,neovascularization, and CME. Fluorescein angiography helps to classify the vasculitic process as eitherocclusive or nonocclusive. Perhaps more importantly, fluorescein angiography aids in making thedetermination as to whether a noninflammatory retinal vascular disease is present.

Numerous tests are ordered for all patients with intraocular inflammation, primarily to rule out masqueradesyndromes and to evaluate the status of the patient's health. Such a limited workup includes CBC count,


10/13

urinalysis, FTA-ABS, ACE, and chest radiography. Tests for syphilis and sarcoidosis help to rule in or ruleout these 2 readily treatable diseases, which can present as any type of intraocular inflammation. Fromhere, aspects of the history and clinical examination are used to formulate a differential diagnosis. If thepretest probability of disease is sufficiently high (but not too high), then further testing should beperformed accordingly or treatment initiated if a clinical diagnosis is established.

A flowchart summarizing the diagnostic approach to retinal vasculitis is provided in the image below.

Flowchart for the evaluation of retinal vasculitis.This chart is intended to serve as a guide for the thought process involved in approaching the diagnosisof retinal vasculitis. Implicit in this diagnostic approach is the need for consultation with an internist andpossibly a rheumatologist or an infectious disease specialist. Most cases are idiopathic (sometimes calledEales disease), and many of the systemic diseases are clinical diagnoses (eg, Behet disease, SLE). Inthese cases, laboratory tests are supportive but not diagnostic.

Inflammatory chorioretinopathies

This diverse group of choroidal inflammatory disorders is named because of their association withmultiple, well-circumscribed, whitish yellow lesions affecting the choroid and choriocapillaris-retinalpigment epithelium (RPE) complex. Certain well-defined ocular inflammatory and infectious conditions,such as sarcoidosis, VKH disease, sympathetic ophthalmia, mycobacterium avium complex, andPcariniichoroiditis, can be associated with well-circumscribed choroidal lesions. These clinical entities

nearly always are associated with other ocular and extraocular manifestations, thereby posing littlediagnostic dilemma. However, intraocular large cell lymphoma commonly presents with multiple punctatesubretinal infiltrates that can be confused easily with an inflammatory process.

This discussion is limited to those disorders that are idiopathic and inflammatory in nature. The term whitedot syndromes is intentionally vague because of the lack of understanding of their pathogenesis.Consequently, most of the diseases have descriptive terms attached to them, such as evanescent andplacoid, implying ignorance as to their etiology. Some of these entities have overlapping clinical findings,prompting a debate as to whether they represent parts of a spectrum of a single disease or whether theyare distinct clinical disorders.

These diseases are all clinical diagnoses; therefore, the clinical presentation and, to a larger degree, theocular findings are vital in the diagnostic evaluation. Several of these diseases have an acute onset (eg,multiple evanescent white dot syndrome [MEWDS], acute posterior multifocal placoid pigmentepitheliopathy [APMPPE]), whereas others are insidious in onset (eg, birdshot retinochoroiditis). Most ofthese diseases have little, if any, anterior or vitreous cellular activity, except birdshot retinochoroiditis,which can be associated with significant vitritis (without snowbanking), retinal vasculitis, and CME. Afundus finding, such as a granular appearance of the macula, is pathognomonic for MEWDS, whereasthe lesions of other diseases occasionally can be confused with each other. The authors have foundfluorescein angiography to be a helpful test in evaluating these patients.

Table 3 outlines clinical features and tests that are useful in the diagnostic approach to white dotsyndromes.


11/13

Laboratory investigation of these patients is uniformly unproductive with the exception of birdshotretinochoroiditis. The association between this disease and the HLA-A29 phenotype is very strong.Testing for the HLA-A29 antigen is both sensitive and specific and has a relative risk of 132 to 157.Patients with a moderately high pretest probability of disease benefit from HLA typing because the resultmay rule in or rule out disease.

Table 3. Clinical Features and Tests Useful in Diagnostic Approach to White Dot Syndromes(Open Table

in a new window)

Clinical Presentation Cellular Activity Fundus Lesions FluoresceinAngiography Other Tests

Birdshot retinochoroiditis Insidious onset, middle age, F>M,

bilateral (90%)

Mild anterior chamber cells,

mild-to-moderate vitritis

100-300 m, cream colored,

indistinct, posterior pole to equator

Early hyperfluorescence, macular and disc

leakage

HLA-A29+ (90%), electroretinography (ERG)

findings abnormal

APMPPE Acute onset, viral prodrome, young,

M=F, bilateral, CNS symptoms

1+ anterior chamber cells,

mild vitreous cells

Large, flat, cream colored, placoid,

primarily in posterior pole

Early hypofluorescence with late staining Cerebrospinal fluid (CSF) pleocytosis, ERG and

electroretinography (EOG) findings negative

MEWDS Acute onset, young, F>M, unilateral(90%), viral prodrome

mild vitreous cells Many, discrete, white, 100-200 m,posterior pole, granular macula

Wreath pattern of hyperfluorescence with latestaining

ERG and EOG findings very abnormal

Serpiginous choroidopathy Insidious onset, middle age, M=F,

bilateral

Mild anterior chamber and

vitreous cells

Large geographic, starts peripapillary

with helicoid progression

Window defects, loss of choriocapillaris, acute

lesion shows blocked fluorescence

...

Punctate inner choroidopathy

(PIC)

Insidious onset, young, myopic, F>M,

bilateral

Quiet 100-300 m, white, punctate,

posterior pole

Block early, stain late ERG and EOG findings normal

Multifocal choroiditis withpanuveitis (MCP)

Insidious onset, young, myopic, F>M,bilateral (80%)

Mild anterior chambercells, vitreous cells (100%)

100-300 m, multifocal, punched-out Early hyperfluorescence, late staining ERG and EOG findings normal

Acute retinal pigment

epitheliitis (ARPE)

Acute onset, young, M=F, unilateral

(75%)

Quiet Small black spots with halo around

fovea

Early blockage with halo of hyperfluorescence

and late staining

EOG findings negative

Surgical Management of Patient With Uveitis

Background

Surgical indications in the management of uveitis include visual rehabilitation, diagnostic biopsy whenfindings may change the treatment plan, and removal of media opacities to monitor the posteriorsegment. Despite advances in anti-inflammatory and immunomodulatory therapy, permanent structuralchanges can occur in the eye that are best managed with surgery (eg, cataract formation, secondary

glaucoma due to pupillary block or angle closure, retinal detachment).

In preparing the eye for surgery, medical treatment should be intensified for a minimum of 3 months toachieve complete quiescence of inflammation (ie, complete eradication of anterior chamber cells, activevitreous cells). Generally, beginning 24-48 hours preoperatively, topical prednisolone acetate 1% isadministered every 1-2 hours (while awake) with prednisone (1 mg/kg) depending on the nature of theinflammation. Intraocular and/or periocular steroids may be administered intraoperatively. Systemic andtopical medications are tapered slowly postoperatively depending on the degree of inflammation.

Table 4. Specific Surgical Conditions Possibly Encountered by Practitioner of Uveitis(Open Table in anew window)

Condition Common Etiologies Surgical Procedure Comment

Corneal opacification Herpetic keratitis, peripheral

ulcerative keratitis

Penetrating keratoplasty High risk of rejection or recurrence

Band keratopathy Juvenile idiopathic arthritis (JIA) Chelation, excimer laser May require general anesthesia

Cataract Any type of uveitis Phacoemulsification intraocular lens (IOL),

vitrectomy and lensectomy

See below (Cataract surgery in patient

with uveitis)

IOL precipitates Chronic anterior uveitis YAG laser "polishing" May be recurrent and require long-


12/13

term topical steroid use

Pupillary membranes JIA YAG laser, pars plana vitrectomy (PPV) High YAG laser energy mayexacerbate uveitis

Glaucoma, pupillary block, 2

angle closure

Chronic anterior uveitis, herpetic

uveitis, Fuchs heterochromic

iridocyclitis

Laser iridectomy, filtering surgery with mitomycin

vs aqueous drainage tube

Consider performing laser peripheral

iridectomy when 270 or more of

posterior synechiae

Vitreous opacification Intermediate uveitis, sarcoidosis,

vitreous hemorrhage, intraocular

lymphoma

PPV See indications for vitrectomy in

patient with uveitis.

Epiretinal membrane Intermediate uveitis, any posterioruveitis

PPV/membrane peeling See indications for vitrectomy inpatient with uveitis.

Retinal detachment Intermediate uveitis,

cytomegalovirus (CMV) retinitis,

acute retinal necrosis (ARN)

PPV scleral buckle, long-acting gas, or silicone oil See indications for vitrectomy in

patient with uveitis.

Chronic CME Any type of uveitis PPV (possibly), intravitreal triamcinolone and/or

bevacizumab

Quality of evidence is weak

Choroidal neovascular

membrane

Multifocal choroiditis, punctate

inner choroiditis, ocular

histoplasmosis syndrome

Thermal laser (extrafoveal), photodynamic therapy

(ocular histoplasmosis syndrome [OHS]),

intravitreal bevacizumab, submacular surgery

Trial of aggressive anti-inflammatory

or immunosuppressive therapy first if

possible

Retinal/optic disc

neovascularization

Sarcoidosis, intermediate uveitis,

Behet disease

Photocoagulation, cryopexy, intravitreal

bevacizumab

May respond to corticosteroids

Progressive unresponsivechorioretinal lesions of

unknown etiology

Neoplastic and infectious diseases Chorioretinal biopsy Referral to institutions familiar withprocedure and expertise in

interpretation of specimen

Medically unresponsiveintermediate uveitis

Pars planitis, sarcoidosis Pars plana cryopexy or laser photocoagulation

PPV

Double freeze thaw to area of parsplana exudate

Indications for vitrectomy in patient with uveitis

Posterior and intermediate uveitis may be associated with significant vitreous opacification that isunresponsive to medical therapy. Visually disabling opacities may occur with intermediate uveitis. Retinalor optic disc neovascularization may complicate conditions associated with vasculitis or vascularocclusion (eg, pars planitis, Behet disease, sarcoidosis), resulting in vitreous hemorrhage. Modernvitrectomy offers a therapeutic option in these situations.

Mediators of intraocular inflammation stimulate fibrous tissue proliferation, thus predisposing the eye toepiretinal membrane formation. No prospective clinical trials in the literature exist comparing outcomes of

membrane peeling in eyes with uveitis and those with idiopathic causes. However, Dev et al reportedfavorable visual results in a group of patients with pars planitis.[20]The investigators also noted apostoperative improvement in the level of vitritis in all patients. Because the macula may already haveirreversible damage (eg, scaring, chronic cystoid macular edema [CME], macular hole, capillarynonperfusion), proper patient selection and realistic patient expectations are important.

Conditions resulting in large areas of thin and atrophic retina (eg, CMV retinitis, ARN) commonly arecomplicated by retinal detachment. These types of retinal detachments usually are associated withatrophic posterior breaks. Vitrectomy with long-acting gas or silicone tamponade commonly is used withor without scleral buckling. Scleral buckling alone usually is not successful.


13/13

At times, potentially life-threatening malignant processes or infectious uveitis may be mistaken forimmune-mediated intraocular inflammation. A thorough review of systems and knowledge of response toprior therapy are critical. Vitrectomy or needle aspiration for diagnostic and therapeutic reasons isindicated whenever the intraocular inflammation responds poorly or incompletely to appropriate therapyor if clinical suspicion is raised for intraocular neoplasia or infection. Common masquerade syndromes inpatients with vitritis include intraocular large cell lymphoma, chronic fungal or anaerobic endophthalmitis,and retinal detachment. Whenever the diagnosis of lymphoma is entertained, the threshold to performvitrectomy should be low; it is better to have a high number of negative biopsy results rather than to missthe diagnosis of this lethal condition. Proper specimen retrieval and handling and communication with thecytopathologist or microbiology laboratory are critical.

Several reports are available in the ophthalmic literature (all of them are retrospective and uncontrolled)that address the issue of therapeutic vitrectomy as a means of moderating intraocular inflammation.Vitrectomy may debulk the antigenic stimulus in the eye, thus reducing intraocular inflammation andCME, and allow tapering or elimination of systemic therapy. While the theoretical advantages ofvitrectomy in chronic uveitis seem apparent, and although the body of evidence is growing, the quality ofthe evidence is weak. The role of vitrectomy in the management of uveitis will likely expand to include theplacement of intraocular sustained-release drug delivery devices as well as to modulate the inflammatoryresponse. Likewise, as polymerase chain reaction (PCR) becomes more widely used, diagnosticvitrectomy will be performed more regularly to confirm or establish a diagnosis and to guide therapy.

Cataract surgery in patient with uveitis

Cataracts occur in most patients with chronic or recurrent uveitis likely due to inflammatory mediators andcorticosteroid-induced mechanisms. Indications for cataract surgery include the following: (1) visuallysignificant lens opacity with good visual potential, (2) in combination with vitreoretinal surgery to bettervisualize the posterior segment, (3) lens-induced uveitis, and (4) impairment of fundus assessment.Prognosis is strongly dependent on preoperative control of all intraocular inflammation for a minimum of 3months but preferably 3-6 months. Use aggressive topical, periocular, and oral steroid regimens incombination with immunomodulatory therapy if needed. Bringing the eye into a state of quiescence is keyto a favorable outcome.

Modern techniques have improved surgical outcomes. Evidence suggests that phacoemulsification inconjunction with small incision surgery causes less breakdown of the blood-aqueous barrier compared

with extracapsular techniques. Similarly, other investigators have found that clear corneal incisions areless likely to cause early postoperative inflammation than sclerocorneal tunnels. The optimal lensbiomaterial has yet to be found, but some evidence exists in the literature that heparin-modified IOLs mayprovoke less inflammation than other materials. Until a superior biomaterial is discovered, placement ofan all polymethyl methacrylate (PMMA) lens in the capsular bag with attention to meticulous corticalcleanup is recommended.

Cataract extraction and IOL placement is probably safe in patients with Fuchs heterochromic iridocyclitis,pars planitis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), ocular histoplasmosis,and chronic well-controlled anterior uveitis. Consider vitrectomy/lensectomy in patients with JIA,panuveitis, and granulomatous diseases. Placement of an IOL in children with JIA probably should beavoided, although some reports offer encouraging results with IOL implantation in this otherwisecomplicated form of uveitis.

approach to the uveitis workup

Documents