Uveitis is a common ocular disease that has a multitude of etiologies. Clinically, it can be difficult to decide what diagnostic tests or lab work should be ordered to discover the underlying cause. In addition, false positives and false negatives can complicate the search further.
This article will discuss how to design a targeted work-up for the uveitis patient based on case history and clinical findings.
Uveitis presentation
Uveitis is defined as inflammation of the uvea—composed of the iris, ciliary body, and choroid. In most cases, only one or two components of the uvea will be inflamed; however, in panuveitis, inflammation can be present in all three areas. The primary location of inflammation will typically determine the visual/ocular symptoms that a patient experiences.
- Anterior uveitis: Inflammation of the iris (iritis), ciliary body (cyclitis), or both (iridocyclitis). Patients with anterior uveitis often present with an acute onset of ocular ache/pain, redness, blurred vision, and photophobia. These are the patients who present to the office wearing sunglasses indoors (e.g., extreme ocular pain/photophobia).
- Clinical examination will reveal conjunctival hyperemia (often concentrated around the limbus), keratic precipitates, anterior chamber cell and flare, hypopyon, and posterior synechiae.
- Intraocular pressure can be normal, elevated (often due to inflammatory debris clogging the trabecular meshwork or trabeculitis), or decreased (due to ciliary body shutdown).
- Not all patients will present with all of these symptoms and signs. The particular presentation of the patient can help in tailoring the work-up.
- Intermediate uveitis: Inflammation confined primarily to the pars plana and vitreous. It tends to present with a new onset of floaters and blurred vision. Decreased vision can be due to vitreous cells accumulating in the visual axis or, in severe cases, macular edema.
- The pain and photophobia of anterior uveitis are generally not present with cases of intermediate uveitis.
- Posterior uveitis: A broad category of conditions involving inflammation of the choroid and often the retina. Patients can present with symptoms of blurred vision, metamorphopsia, and floaters.
- Posterior uveitis is best managed or co-managed with a retina/uveitis specialist and the patient’s primary care physician (PCP), given the potential for significant ocular morbidity and systemic etiology.
How the presentation will guide the work-up
Before ordering tests, the nature of your patient’s uveitis needs to be defined. Is it unilateral or bilateral? Granulomatous or non-granulomatous? Is the primary site of inflammation anterior, intermediate, or posterior, or does it involve the entire uveal tract? What are your patient’s age and ethnicity? Where do they live? What are their visual symptoms? By answering these questions (via thorough case history and clinical exam), you can tailor your approach and eliminate unnecessary and expensive tests.
Anatomic location of uveitis
Anterior uveitis is by far the most common presentation of uveitis and has numerous potential underlying causes. It is helpful to categorize them as infectious, inflammatory, traumatic, neoplastic, medication-induced, or idiopathic. It is important to note that idiopathic anterior uveitis is common.
A study conducted among white New Englanders found that approximately 35% of patients at a tertiary care center had idiopathic uveitis.1 Inflammatory causes (seronegative spondyloarthropathies, systemic lupus erythematosus, sarcoidosis, etc.) were the second-most common cause of anterior uveitis in that study.
Infectious anterior uveitis
Infectious causes of anterior uveitis are myriad. The typical causes of infectious uveitis are tuberculosis, syphilis, Lyme disease, varicella zoster virus (VZV), and herpes simplex virus (HSV). Testing measures for some of these conditions are discussed below. Posterior uveitis can be caused by Toxoplasma gondii, Toxocara canis, HSV, VZV, and others.
Traumatic anterior uveitis
Traumatic uveitis is typically a straightforward diagnosis that does not require further testing. The patient will usually report a recent history of blunt ocular trauma and will be present with anterior uveitis (typically unilateral). A careful dilated fundus examination is important to rule out retinal breaks and other posterior segment sequelae.
Medication-induced anterior uveitis
Medication-induced anterior uveitis can also be a straightforward diagnosis if the patient recently started a new medication and subsequently presents with uveitis. However, a tailored work-up is still recommended to rule out other causes.
There are numerous medications associated with anterior uveitis. These include bisphosphonates, rifabutin, TNF-alpha inhibitors, and sulfonamides. Topical prostaglandin analogs used in the treatment of glaucoma have also been associated with uveitis and cystoid macular edema.
Neoplastic anterior uveitis
Neoplastic disease can cause uveitis as well as pseudo-uveitis. Intraocular lymphoma can present with neoplastic cells in the anterior chamber and vitreous, mimicking the appearance of uveitis. In pediatric patients, retinoblastoma can present with a pseudohypopyon with anterior chamber flare.
Other uveitis risk factors to consider
- Granulomatous vs. non-granulomatous: The presence of granulomatous uveitis, indicated by bilateral, large “mutton fat” keratic precipitates, suggests systemic inflammatory causes such as sarcoidosis or systemic infection such as tuberculosis, syphilis, Lyme disease, or chronic herpetic infection. These patients will need a systemic work-up to determine the underlying etiology.
- Laterality: Bilateral anterior uveitis is more likely to be associated with a systemic condition and therefore requires a work-up. Some clinicians will also work up patients with unilateral anterior uveitis in recurrent/chronic cases.
- Patient age and ethnicity: The age and ethnicity of the patient also help guide our decision-making. Uveitis in a pediatric patient should prompt suspicion of juvenile idiopathic arthritis (JIA). An elderly patient presenting with their first case of uveitis should raise suspicion for a neoplastic masquerade syndrome.
- Ethnicity is important because certain conditions are more common in patients of certain genetic backgrounds. For example, African American patients are at higher risk of sarcoidosis, whereas patients of middle eastern or Mediterranean descent are at higher risk of Behçet’s disease.
- Geography: Geographic demographics are important because infectious causes of uveitis tend to have a geographic distribution. Lyme disease is more common in the American northeast and upper midwest, while tuberculosis is more prevalent in Asia and the developing world. Knowing what diseases are endemic in a specific area and the travel patterns of the patient can help tailor the work-up.
- Intraocular pressure (IOP): Frequently, the IOP in acute anterior uveitis is decreased due to ciliary body shut down. The presence of elevated intraocular pressure can be a helpful clinical sign to narrow the differential diagnosis.
- Herpes simplex uveitis frequently presents with markedly elevated intraocular pressure. Glaucomatocyclitic crisis, AKA Posner-Schlossman Syndrome, also presents with very high intraocular pressure with a minimal anterior chamber reaction.
- While intraocular pressure can be elevated with any anterior uveitis, the presence of markedly elevated IOP should prompt the clinician to consider HSV if the patient is displaying the typical symptoms of uveitis or cases of glaucomatocyclitic crisis with a very mild uveitis.
Putting together a uveitis work-up
Once the patient’s uveitis has been characterized using the abovementioned criteria, a work-up can be planned. It is very tempting to have a routine work-up that all patients with uveitis will receive. However, many uveitis specialists recommend ordering only tests that are most likely to yield useful data.2
Ordering a wide-ranging battery of tests may seem like a good idea ("cover all the bases"), but it can be expensive and time-consuming. Additionally, no test is perfect and false positives can lead the clinician astray. Thus, it is best to be familiar with the common causes of uveitis, their presentations, and their systemic symptoms. You can then narrow your search for an underlying diagnosis.
There are two tests that should always be ordered; the first is a complete blood count (CBC) with differential (CBC with differential) and the second is a test for syphilis.
A CBC is a fast and inexpensive test that gives you an overall accounting of the patient’s red blood cells, platelets, and white blood cells. This can also be helpful in screening for neoplastic causes of uveitis. Syphilis is a curable disease that can cause significant systemic disease if untreated; testing all uveitis patients for syphilis should be performed. A positive syphilis test should prompt a referral to an infectious disease specialist or other clinician experienced in treating syphilis. In addition, HIV testing is warranted for syphilis patients, given that it is a common co-infection.
“The patient demographics and clinical presentation should guide all further testing.”
Below, Table 1 is a list of common inflammatory causes of uveitis along with their typical clinical presentation, Table 2 is a list of common infectious causes, and Table 3 is a list of lab tests associated with these conditions. Following these tables is a detailed discussion breaking down the different lab tests and how to interpret them.
Table 1 features common inflammatory uveitic diseases with their corresponding typical clinical presentations.
| Inflammatory condition | Location | Laterality | Granulomatous | Patient demographics | Additional data |
|---|---|---|---|---|---|
| Ankylosing spondylitis | Anterior | Unilateral (bilateral rare) | No | Young adults | Lower back pain |
| Reactive arthritis | Anterior | Unilateral | No | Male, 20 to 50 years old | Previous bacterial infection, urethritis, arthritis |
| Crohn's/ulcerative colitis | Anterior | Unilateral or bilateral | No | Usually 15 to 35 years old | Bowel dysfunction |
| Sarcoidosis | Anterior | Bilateral | Yes | Adult, African American | Respiratory dysfunction |
| Systemic lupus erythematosus | Anterior | Unilateral | No | Adult | Fatigue, fever, arthralgia |
| Juvenile idiopathic arthritis | Anterior | Bilateral | No | Children, teenager, female | Arthritis, asymptomatic uveitis |
| Behçet's disease | Anterior, posterior, panuveitis | Bilateral | No | Mediterranean or Asian ethnicity, age up to 30s | Oral and genital ulcers, vasculitis |
Table 2 lists common infectious causes of uveitis to consider when doing a work-up.
| Infectious condition | Location | Laterality | Granulomatous | Patient demographics | Additional data |
|---|---|---|---|---|---|
| Lyme disease | Any | Any | Either | Any | Northeast or upper midwest US, patient history of recent tick bite |
| Syphilis | Any | Any | Either | Any, usually adult males | HIV co-infection is common |
| Tuberculosis | Any | Any | Yes | Travel to endemic areas | Pulmonary dysfunction |
Table 3 highlights a list of lab tests for specific diseases that could cause uveitis.
| Disease | Test |
|---|---|
| Ankylosing spondylitis | HLA-B27 |
| Reactive arthritis | HLA-B27 |
| Crohn's disease/ulcerative colitis | HLA-B27 |
| Sarcoidosis | ACE, chest X-ray |
| Systemic lupus erythematosus | ANA, RF |
| Juvenile idiopathic arthritis | ANA |
| Behçet's disease | HLA-B51 |
| Lyme disease | Western blot |
| Syphilis | RPR/VDRL + FTA-ABS/MHA |
| Tuberculosis | PPD or QuantiFERON Gold |
Available testing for a uveitis work-up
Angiotensin-converting enzyme
Angiotensin-converting enzyme (ACE) is an enzyme that predominantly helps regulate systemic blood pressure via the renin-angiotensin pathway. It is also an indirect marker of sarcoidosis, a common cause of uveitis. Sarcoidosis causes granuloma formation, particularly in the lungs and lymphatic system. Epithelioid cells, which are a component of granulomas, produce ACE. Thus, ACE levels will increase in the presence of active sarcoid granulomas.
“However, ACE testing can be prone to false positives because ACE levels are not specific to sarcoidosis.”
ACE can be elevated in active histoplasmosis infection, diabetes mellitus, hyperthyroidism, amyloidosis, active tuberculosis infection, and scleroderma. It is also elevated normally in pediatric patients. Patients taking ACE inhibitors or systemic prednisone will have lower levels of ACE, leading to false negatives.
Also, if the patient has localized sarcoidosis, there may not be enough granuloma formation to lead to elevated ACE levels—thus causing a false negative. Given the limitations of ACE testing, adding a chest X-ray to the work-up is advised for patients with suspected sarcoidosis.
Antinuclear antibodies
Antinuclear antibodies (ANA) are autoantibodies that react against nuclear material found in leukocytes. Antinuclear antibodies are often present in normal patients at low levels, but elevated ANA levels can indicate autoimmune disease, especially systemic lupus erythematosus (SLE). Laboratories measure the amount of ANA by diluting a blood sample until ANAs are no longer detectable. The highest dilution that still produces detectable levels of ANAs is called the “ANA titer.”
“A positive ANA test is very sensitive for diagnosing SLE however it is not very specific for SLE.”
Other disorders that can cause elevated ANA levels are systemic sclerosis, scleroderma, rheumatoid arthritis, myasthenia gravis, leukemia, ulcerative colitis, and infectious mononucleosis. In addition, certain medications can elevate ANA levels; these include penicillin, tetracycline, acetazolamide, thiazides, and oral contraceptives.
If ANA testing is positive, testing for specific autoantibodies should be conducted. These autoantibodies are called anti-double-stranded-DNA (anti-dsDNA), anti-Ro, anti-La, anti-Sm, and anti-RNP. SLE is associated with elevated anti-dsDNA, anti-Sm, and anti-RNP. Sjogren’s syndrome is associated with anti-Ro and anti-La autoantibodies.
Interpretation of ANA test results should be done with caution. Since ANA testing can be very sensitive, a positive ANA with a low titer (1:40, for example) could be due to normal levels of ANAs and not be indicative of autoimmune disease. There is also uncertainty about the relevance of a positive ANA test with a high titer (1:160 or more) in the absence of any other systemic symptoms.
Some uveitis specialists recommend not testing for ANA unless other symptoms suggestive of SLE exist.2 However, a negative ANA test strongly suggests that the patient does not have SLE, so ANA testing can be helpful in eliminating SLE as a differential diagnosis.
In pediatric patients with uveitis, ANA should be ordered as it strongly correlates with juvenile idiopathic arthritis. JIA is the most common cause of pediatric uveitis, particularly chronic uveitis. Any child or teenager presenting with uveitis should have their ANA levels checked.
C-reactive protein
C-reactive protein (CRP), like the erythrocyte sedimentation rate, is a nonspecific marker of systemic inflammation. It is produced by the liver and is elevated during systemic inflammation. CRP rises and falls quickly in response to changes in inflammation, and chronically elevated CRP can be seen in conditions such as rheumatoid arthritis.
“In cases of isolated uveitis, the CRP is not likely to be elevated.”
Its value in a work-up for uveitis is limited, given its nonspecific nature. However, a positive CRP, particularly if it is significantly elevated, can alert the clinician to the presence of an underlying systemic inflammatory or infectious disease.
Complete blood count with differential
All patients should get a complete blood count with differential (CBC with diff). This test overviews the patient’s red blood cell count, platelet levels, hemoglobin levels, and white blood cell count. While non-specific in diagnosing disease, the CBC with differential is an inexpensive test that can give insight into the patient’s overall health.
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR) is a nonspecific marker of systemic inflammation. It is measured by placing a blood sample in a test tube, adding an anticoagulant, and then measuring the rate at which red blood cells settle to the bottom of the tube over the course of 1 hour. This is referred to as the “sedimentation rate.”
In the presence of systemic inflammation, there is an increase in plasma proteins which causes red blood cells to clump together. These heavy clumps of red blood cells (“rouleaux”) fall to the bottom of the tube faster, and thus the sedimentation rate increases.
An elevated ESR does not indicate the presence of any particular condition. It simply indicates an elevated level of systemic inflammation, which can have many different causes.
Uveitis in isolation is unlikely to raise the ESR; thus, the ESR may be of little value in a uveitis work-up. However, in patients with additional systemic symptoms or a pre-existing autoimmune/inflammatory disease diagnosis, the ESR can serve as an indicator of overall systemic inflammation. It is also important to know that certain conditions can lower an ESR. Hyperviscosity syndromes, such as polycythemia vera and sickle cell disease, can decrease the ESR.
Human leukocyte antigen typing
Human leukocyte antigen (HLA) genes are located on chromosome 6 within a region known as the major histocompatibility complex (MHC). These genes code for cell-surface proteins, which function in antigen presentation. They are classified into classes I, II, and III, and class I has three subclasses (A, B, and C). There are numerous variants of these genes, denoted by number.
“One particular variant, known as HLA-B27, is highly associated with several conditions known as seronegative spondyloarthropathies.”
They are called “seronegative” because these patients' rheumatoid factor (RF) is not elevated. These conditions can present with uveitis, particularly in young adults. Two other HLA variants of importance in uveitis are HLA-B51 and HLA-A29, which are associated with Behçet’s disease and birdshot chorioretinopathy, respectively.
Lyme testing
Lyme disease is a rare cause of uveitis. Serologic testing for Lyme disease involves a two-step process. A screening test is performed to check for the presence of antibodies against B. burgdorferi. A Western blot is used to confirm the diagnosis if the screening test is positive.
These tests can remain positive for years after the infection and thus can lead to false positives. Hence, Lyme disease testing can easily be misleading in a uveitis work-up unless other findings suggestive of Lyme disease exist.
Purified protein derivative and QuantiFERON Gold
There are two screening tests for tuberculosis. The first is the tuberculin skin test, whereby a solution of M. tuberculosis antigens, called a purified protein derivative (PPD), is intradermally injected into the skin of the forearm. After 48 to 72 hours, the injection site is inspected for a reaction.
A positive test in an asymptomatic patient is considered evidence of latent tuberculosis. On the other hand, a positive test in a symptomatic patient requires further evaluation. Both scenarios require treatment. False positives are possible in patients who have received the bacille Calmette-Guérin (BCG) vaccine due to cross-reactivity.
The second test is the QuantiFERON Gold test. In this test, a sample of the patient’s blood is mixed with M. tuberculosis antigens, and the immune response is measured. The advantage of the QuantiFERON Gold test over the skin test is that it does not require a follow-up visit and is not affected by prior BCG vaccination.
Tuberculosis testing is indicated for uveitis patients with possible exposure to tuberculosis or who have been to areas where tuberculosis is endemic. It is also recommended for patients starting anti-TNF treatment due to the possibility of activating a latent tuberculosis infection.
Rheumatoid factor
The rheumatoid factors (RF) are a family of antibodies that are directed against immunoglobulin G (IgG). While there is a clear association between RF and rheumatoid arthritis, these antibodies are also seen in patients with other rheumatic diseases, such as Sjogren syndrome and systemic lupus erythematosus.
“Chronic infections, such as hepatitis C and tuberculosis, can also elevate RF values.”
Rheumatoid arthritis is not a cause of anterior uveitis and given the nonspecific nature of RF testing, routine testing for RF in uveitis patients without other systemic symptoms is not necessary.
RPR/VDRL + FTA-ABS/MHA
Testing for syphilis is always recommended for uveitis patients because syphilis has significant morbidity and can be cured. Testing for syphilis is divided into two stages—non-treponemal tests and treponemal tests. The non-treponemal tests rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) screen for the presence of antibodies against cardiolipin and are useful as inexpensive initial tests for syphilis.
A positive non-treponemal test, due to its non-specificity, requires a confirmatory treponemal test, such as the fluorescent treponemal antibody absorption test (FTA-ABS) or microhemagglutination assay (MHA). The treponemal tests are positive for life and thus cannot be used to track disease activity.
Uveitis case examples
Case 1
A 21-year-old white male presents with pain, photophobia, and blurred vision in the right eye of 1-day duration. He has no medical history and takes no medications. Family history is negative for uveitis. He reports no recent illnesses or international travel. Further questioning of the patient revealed that he has been experiencing lower back pain for the past several months. He denied any respiratory, bowel, or dermatologic symptoms.
Uncorrected visual acuity is 20/30 OD (no improvement with pinhole) and 20/20 OS. Extraocular movement testing is smooth and full OU, confrontation fields are FTFC OU, and pupils are equal, round, and reactive to light with no afferent pupillary defect.
A slit lamp examination of the right eye reveals normal lids and lashes, grade 3 conjunctival hyperemia, a clear cornea with fine keratic precipitates on the endothelium, grade 3 cell in the anterior chamber, no posterior synechiae, and a clear crystalline lens. A slit lamp exam of the left eye was normal. Intraocular pressure, measured via Goldmann applanation tonometry, was 12 OD and 17 OS. Gonioscopy showed open angles with no anterior synechiae. Dilated fundus exam was unremarkable.
The patient was diagnosed with an acute, unilateral, non-granulomatous anterior uveitis of the right eye. Given the patient’s clinical presentation and history of lower back pain, ankylosing spondylitis is high on the list of differential diagnoses. A targeted work-up was ordered—complete blood count with differential, syphilis testing, and HLA-B27. The patient was started on topical corticosteroids and cycloplegics.
Testing confirmed the presence of HLA-B27 and the patient was referred to rheumatology for further evaluation.
Case 2
A 52-year-old African American female presented with bilateral ocular pain and intense photophobia of 2-day duration. Her medical history is significant for essential hypertension and hypercholesterolemia, for which she takes lisinopril and atorvastatin. Family history is significant for glaucoma. She reports no recent international travel or recent illnesses. She reports a recent history of mild cough and feeling tired.
The corrected visual acuity was 20/25 OD and OS. All other entrance tests were normal. A slit lamp exam revealed bilateral findings of conjunctival hyperemia, mutton-fat keratic precipitates, and grade 3 cell and flare. The IOP was 11mmHg OU. Dilated fundus examination was unremarkable.
The patient was diagnosed with a bilateral, granulomatous anterior uveitis. At the top of the differential list is sarcoidosis. Lab testing for serum ACE, CBC with differential, and syphilis testing was ordered. A chest x-ray was also ordered. The uveitis was treated with topical corticosteroids and cycloplegics.
The lab testing came back borderline positive for ACE and the chest X-ray showed bilateral enlargement of the mediastinal lymph nodes. A diagnosis of likely sarcoidosis was made and a referral to pulmonology was made.
Conclusion
The diagnosis of an underlying cause for uveitis can be complicated by the myriad of tests available and their inherent imperfections. It is important to conduct a thorough case history, as well as perform a detailed clinical examination with dilated fundus evaluation.
“The clinician can then design a tailored work-up for the patient and avoid costly and time-consuming testing that may not be necessary.”
Primary eyecare providers can have a big impact when caring for patients with uveitis. Through patient education, appropriate testing, treatment, and co-management, these patients can feel well-cared for and avoid irreversible vision loss.
