Classification
Related conditions
Anatomic
• Anterior—iritis, iridocyclitis, anterior cyclitis
• Intermediate—pars planitis, posterior cyclitis, vitritis/hyalitis
• Posterior—focal, multifocal, or diffuse choroiditis, chorioretinitis, retinitis, neuroretinitis
• Panuveitis—anterior, vitreous, retina, and choroid
Etiology
• Infectious—bacterial, viral, fungal, parasitic, and others
• Non-infectious—known versus unknown systemic association
• Masquerade syndromes—neoplastic, non-neoplastic
Additional dimensions
• Course—acute monophasic versus recurrent acute versus chronic
• Laterality—unilateral versus unilateral alternating versus bilateral asynchronous versus bilateral simultaneous
• Morphology—retinitis versus choroiditis paucifocal versus multifocal
• Host—child versus adult immunocompromised versus immunocompetent
In summary, based on the uveitis working groups described above each patient with uveitis should have a descriptive diagnosis based on anatomic location. Then using standardized examination reporting, additional disease dimensions (course, laterality, morphology, host, and immune status) should be assigned to create a differential of major uveitic diseases. Narrowing the possible diagnosis in this way will lead to a focused laboratory evaluation and greatly increase the utility of each test ordered.
The Importance of History and Examination
One cannot emphasize enough that ancillary testing should only be a supplement to the most important initial components of the uveitis work-up, the history and physical examination. In a busy ophthalmology practice it may be tempting to marginalize these steps and even have a reflex “uveitis panel” of testing regardless of the history and exam. This approach is costly, exposes patients to unnecessary testing, and may also produce testing results that confuse the diagnostic picture with false positives or negatives.
History: As with all aspects of clinical medicine, an essential first step when establishing a differential diagnosis is a thorough history [11, 12]. This becomes increasingly essential in our modern world of wide spread travel and globalization. We suggest utilizing a questionnaire for new patients with uveitis. This provides a thorough and time affective way to elicit important historical details that may otherwise be missed. An example of one such questionnaire is seen in Fig. 2.1a–d. To date, there has not been a standardized questionnaire established. Details such as age, gender, race, social history (residence, occupation, diet, travel, sexual history, drug abuse), past medical history, family history, and review of systems will help to narrow the differential diagnosis [13–20] (see Table 2.2).
Fig. 2.1
a–d Example questionnaire. Modified from questionnaire created by Dr. Stephen Foster at the Massachusetts eye and ear infirmary. Available at http://www.uveitis.org/uveitis-questionnaire
Table 2.2
Uveitic diseases by demographics
History | Related conditions |
|---|---|
Age | |
• Age < 5 • Age 5–25 • 25–45 • 45–65 • >65 | • Juvenile arthropathies, masquerade (retinoblastoma, juvenile xanthogranuloma) • Juvenile arthropathies, post-viral neuroretinitis, parasitic (e.g., toxocariasis), TINU, masquerade (retinoblastoma, juvenile xanthogranuloma), sarcoidosis, acute retinal necrosis, HLA-B27, toxoplasmosis, Fuch’s uveitis • HLA-B27, CMV retinitis, acute retinal necrosis, ankylosing spondylitis, Behcet’s, Vogt Koyanagi Harada’s (VKH), sarcoidosis, toxoplasmosis, serpiginous choroidopathy, white dot syndromes, idiopathic • HLA-B27, Behcet’s, birdshot retinochoroiditis, serpiginous choroidopathy, idiopathic • Serpiginous choroidopathy, masquerade syndromes (lymphoma), herpes zoster, idiopathic |
Gender | |
• Male • Female | • Ankylosing spondylitis, reactive arthritis, Behcet’s, sympathetic ophthalmia • Juvenile arthropathies |
Race/ancestry | |
• Caucasian • African American • Asian • Central/South America | • Ankylosing spondylitis, reactive arthritis • Sarcoidosis • VKH, Bechet’s • Toxoplasmosis, cysticercosis, onchocerciasis |
Social history | |
• Endemic location • Tick/insect or water borne • Animal exposure • Immunosuppresion | • Histoplasmosis, tuberculosis, toxoplasmosis, Lyme • Leptospirosis, treamtode granulomas, Lyme • Toxoplasmosis, toxocariasis, leptospirosis, cysticercosis • HIV, opportunistic infections |
Exam Findings: There is a tremendous amount of cross-over in exam findings between uveitic diseases. However, some diseases are clinically identifiable, and specific exam findings provide important clues into the possible diagnosis limiting the need for additional work-up. Particularly, a combination of specific findings may be syndromic for a specific diagnosis. For example, a patient with anterior uveitis, elevated intraocular pressure, and sectoral iris atrophy makes a diagnosis of herpetic uveitis very likely. Below, we highlight a few key exam findings that may help to further focus the work-up.
Intraocular Pressure: Both ocular hypertension and hypotony can result from intraocular inflammation. Elevated intraocular pressure in uveitis has been estimated to occur in nearly 42 % of patients [21]. Diseases thought to have a higher rate of ocular hypertension include Fuch’s heterochromic iridocyclitis (FHIC), glaucomatocyclitic crisis or Posner-Schlossman syndrome, sarcoidosis, juvenile rheumatoid arthritis, VKH, toxoplasmosis, and herpetic keratouveitis.
Keratic precipitates—The presence of keratic precipitates may be helpful in defining between acute versus chronic inflammation, and based on the appearance, may also give clues into the pathogenesis [1]. Fine precipitates are thought to be more common in spondyloarthropathies and juvenile arthropathies. Stellate precipitates that may be seen involving the superior cornea (as opposed to the typical inferior corneal base down triangular appearance of most precipitates) are often seen with Fuch’s heterochromic iridocyclitis. “Mutton fat” prescipitates are larger and are formed from macrophages and epithelioid cells. These may be indicative of a granulomatous disease (see Table 2.3).
Table 2.3
Conditions causing granulomatous inflammation
Sarcoidosis |
Sympathetic ophthalmia |
Vogt-Koyanagi-Harada syndrome |
Syphilis |
Tuberculosis |
Herpetic |
Uveitis associated with multiple sclerosis |
Intraocular foreign body |
Hypopyon—This layering of leukocytes is indicative of not only the number of cells in the anterior chamber, but also the presence of enough fibrin to cause the cells to clump. A limited number of etiologies may present with a hypopyon. The most common etiologies include infectious (both bacterial and viral), HLA-B27 associated uveitis, and Behcet’s disease. With infectious endophthalmitis the patient will typically have a history of recent surgery, trauma, or have risk factors for endogenous infection (e.g., intravenous drug use). Ocular involvement in these patients will typically be diffuse. Very fibrinous aqueous exudate and dense hypopyon are more commonly seen with infections and HLA-B27-associated disease. In contrast, the hypopyon seen with Behcet’s typically has much less fibrin and may shift with the patient’s head position. A hypopyon may also be seen in patients with rifabutin toxicity [22, 23]. Pseudohypopyon, composed of tumor cells and debris can occur in some of the masquerade syndromes. Triamcinolone layering may also present as a pseudohypopyon.
Iris Changes—Sectoral iris atrophy is more commonly seen with herpes simplex, varicella zoster, and cytomegalovirus infections. As mentioned above, if accompanied by elevated intraocular pressure one should be suspicious of a herpetic etiology. Nodule formation from the accumulation of inflammatory cells on or within the iris is more commonly seen with diseases causing granulomatous inflammation (see Table 2.3). Heterochromic iris changes are often, but not always, observed in Fuch’s heterochromic uveitis.
Retinal/Choroidal findings—The diagnosis of posterior uveitis may be recognizable clinically based on vascular and chorioretinal lesion characteristics. Ocular imaging techniques such as fluorescein angiogram are essential in characterizing these changes. Pattern recognition is important and a few key findings may be seen more commonly with specific diagnosis. Serous retinal detachments are classically associated with VKH syndrome (particularly if bilateral). Dalen-Fuchs nodules (small, discrete, deep, yellow-white chorioretinal lesions) may be associated with VKH and sympathetic ophthalmia. Acute retinal necrosis (ARN) is a type of necrotizing retinitis most commonly caused by herpetic viruses (HSV, VZV). The classic posterior appearance includes vitritis, retinal vascular arteriolitis, and peripheral retinitis. Typically, the retinitis begins as peripheral areas of multifocal retinal yellowing, often flat with scalloped edges. This can eventually progress into confluent whitening extending into the posterior pole. Cytomegalovirus (CMV) retinitis may also be identified clinically and should be suspected in patients that are immunosuppressed. The classic exam findings in CMV retinitis are peripheral or posterior yellow-white lesions that follow the retinal vasculature centripetally, vasculitis with a “frosted branch” appearance, and retinal hemorrhages. This constellation of findings has been described as a “scrambled eggs or cottage cheese with ketchup” appearance. There may be little to no vitritis, given the immunocompromised state of these patients. Classic toxoplasmosis lesions present as focal and white with overlying vitritis with a “headlight in the fog” appearance, often with adjacent pigmented retinochoroidal scarring. Other diagnosis that may be clinically identifiable include white dot syndromes, ocular histoplasmosis syndrome, and serpiginous choroidopathy.
Optic Nerve—Disc hyperemia, papillitis or papilledema can occur in many uveitic disorders, However, classically prominent disc hyperemia is noted in VKH.
Principles of Diagnostic Testing
As emphasized above, all testing should be complementary to the history and exam, not an alternative. Patient work-up should focus on ruling out infectious diseases that may respond to antimicrobial therapy and systemic disorders that may affect the patients overall health.
It is important to understand several key concepts when discussing diagnostic testing. Knowing how pre- and post-test probabilities and predictive values change based on Bayesian principles can help direct when a test should be ordered. Additionally, the utility of each test can be clarified by acknowledging the difference between targeted versus screening tests as well as understanding when different tests are helpful for ruling in disease versus ruling out disease.
Pre–test probability is defined as the likelihood that a patient has the disease in question prior to testing. It can be estimated based on history, exam, the incidence of disease in the population, and the sensitivity and specificity of the test (see Fig. 2.2). To illustrate how this value changes from patient to patient we will use the example of a male patient with no risk factors, from a non-endemic area presenting with intermediate uveitis. The clinician is considering sending Lyme testing (specificity 50–95 %, sensitivity 99–100 % [24, 25]). For purposes of this illustration we will say the overall incidence for the patient’s geographic location is 1:1000. The patient has no risk factors on history and no other findings on exam so we would estimate the pre-test probability to be approximately 1:1000 (0.1 %). Using a specificity and sensitivity of 90 %, we can calculate the post-test probability using the formula in Fig. 2.2. This calculation estimates the post-test probability as only 0.9 %. In other words, if this patient’s serology testing came back positive, there would still only be a 0.9 % chance of having Lyme disease and ultimately a positive value may be misleading. Testing may likewise be unhelpful if the pre-test probability is very high (i.e., the patient recently went hiking in the northeast, was bitten by a tick, and has a new “bulls-eye” rash). In this case, the post-test probability would nearly equal the pre-test probability. This also makes the test minimally useful as the patient would likely receive treatment regardless of the results.
Fig. 2.2
Post-test probability formula
Positive predictive value defines the likelihood that a person with a positive test has the disease in question. It is a function of the test itself and is also dependent on disease prevalence in the population being tested. Thus, if a test is performed on a population with a very low prevalence of disease, the positive predictive value declines substantially. The alternative is true, the more prevalent the disease, the more likely a positive test accurately indicates that the patient has the disease in question (high positive predictive value). An example of this can be demonstrated with tuberculosis testing. In the general population of the United States, tuberculosis accounts for 0.1–0.5 % of uveitis cases [26–29]. The reported sensitivity and specificity of purified protein derivative (PPD) ranges from 75–89 % and 85–86 %, and for Quantiferon-gold 70–81 %, 97–99 % [27–30], respectively. If all patients are screened for tuberculosis, the positive predictive value is 1 % for the PPD test and 11 % for Quantiferon-gold [26, 27]. However, in a patient from an endemic area with exam findings concerning for possible tuberculosis (e.g., differential of serpiginous choroiditis vs. serpiginous-like choroiditis) the positive predictive value of the PPD and Quantiferon-gold increase to 82 and 96 %, respectively [1, 31]. Thus the utility of each test can vary remarkably based on which patients are tested. The same concept applies when defining disease by anatomical location of the inflammation (see below). For example, the utility of HLA-B27 testing in a patient with bilateral posterior uveitis is poor and a positive test would confuse the diagnostic picture and likely represent a false positive (can be positive in up to 8 % of Caucasians and 4 % of African Americans [32]) and should, in general, be performed only in patients with acute, recurrent anterior uveitis. Likewise, positive HLA-A29 or toxoplasmosis testing will likely represent false positivity in a patient with anterior uveitis and should generally be restricted to selective cases with posterior uveitis. Table 2.4 illustrates how positive predictive values are affected by disease prevalence.
Table 2.4
The affect of disease prevalence on positive predictive value
Disease prevalence (%) | Positive predictive value (%) |
|---|---|
1 | 16 |
10 | 68 |
20 | 83 |
50 | 95 |
Targeted versus Screening tests—After addressing the importance of a focused or targeted laboratory work-up, it is important to acknowledge that there are a few infectious uveitic diseases that cannot be defined by their clinical findings and may present in various anatomical locations. These are important to highlight as they are not treated with immunomodulators, and if left untreated can lead to a poor visual and in some cases systemic prognosis. Generally, these diseases include Lyme disease, syphilis, and tuberculosis. The appropriate timing for Lyme testing can be elicited by the patient’s history and risk factors, and thus should not be ordered on every patient. We do, however, suggest that it may be warranted to send a screening syphilis test on all patients requiring laboratory work-up. Although this infection is rare, the incidence of primary and secondary disease has doubled in the US since 2000 [33]. Screening is warranted given that risk factors may be difficult to illicit, testing is inexpensive and very sensitive and specific, it is easily treatable, and there is significant morbidity associated if left untreated. There are differing opinions on whether or not tuberculosis testing should be sent as a screening test on all patients. Rosenbaum et al. [26] concluded that routine screening in the general US population with purified protein derivative (PPD) is not warranted based on the low positive predictive value. Hong et al. [34] more recently suggested that screening in certain geographic areas in the US that are known to have a large immigrant population (such as the Los Angeles County hospital cited in the study) may be useful. It is important to highlight that in the latter study the only risk factor found to significantly predict PPD positivity was a history of being born outside of the United States. Thus, a thorough history may help guide the decision about screening for tuberculosis. In practice, many uveitis specialists advocate for screening tuberculosis testing citing the importance of confirming negativity prior to starting systemic immune modulation therapy, especially if an anti-TNF (anti-Tissue Necrosis Factor) medication may be utilized [35].
Several non-specific tests may also be appropriate as screening tools. A complete blood count (CBC) with differential may be useful for identifying more urgent diagnosis such as patients with systemic infection (leukocytosis or eosinophilia), malignancy (leukemia), or who are immunocompromised. Likewise, a comprehensive metabolic panel (CMP) and urinalysis (UA) may reveal renal or hepatic dysfunction or hyperglycemia. This information may also be important when making decisions about starting oral immunomodulators.
Tests that rule in disease versus ruling out disease—In some cases, a test being negative may be just as important as positive testing. An example is seen with toxoplasmosis titers. A positive value does not mean a patient has toxoplasma retinochoroiditis, since nearly 30 % of the population may have been exposed to toxoplasma at some point in their life. Specifically, seropositivity in the US has been reported as >20 % (higher in males, nonhispanic blacks, those not born in the US, elderly) [36, 37]. In contrast, a negative test is sensitive for the exclusion of toxoplasmosis. HLA-A29 is another test that, if negative, may be helpful in ruling out Birdshot chorioretinopathy in patients with multiple white chorioretinal lesions.
Individual Tests
We will now briefly review the sensitivities and specificities of commonly ordered diagnostic testing. It is important to keep in mind the above concepts that despite sensitivity and specificity, the utility of each test may vary greatly dependent on the patient’s risk factors, population prevalence, and exam findings. A summary of the discussed tests including their estimated costs, sensitivities, and specificities can be found in Table 2.5. Additionally, it is important to note that much of the research regarding sensitivity and specificities of the following tests are based on non-ophthalmologic literature.
Table 2.5
Summary of important testing modalities
Test | % Positivity (in uveitis patients) | aEstimated cost | Sensitivity/specificity disease prevalence dependent | Possible indications |
|---|---|---|---|---|
Tuberculin skin test | 0.2–1 % | $18 | 75–89 %/85–86 % | Tuberculosis, immunomodulatory therapy |
Interferon gamma release assay—Quantiferon-gold | $243 | 70–81 %/97–99 % | Tuberculosis, immunomodulatory therapy | |
Lyme serology | Geographic dependent | $56-screening $193-confirmatory | 59–99 %/81–100 %b | Lyme disease |
Angiotensin converting enzyme | 3-7 % | $56 | 60–90 %/83–95 %d | Sarcoidosis |
Lysozyme | $75 | 60 %/76 % | Sarcoidosis | |
Antinuclear antibodies | 0.1–1 % | $48 | 95 %/68–97 %e | JIA, vasculitis, connective tissue disease |
VDRL | 1.6–4.5 % | $27 | Primary 78–86 %/85–99 % Secondary 100 %/85–99 % Tertiary 95–98 %/85–99 % Neurosyphilis/ocular 69 %/85–99 % | Syphilis |
FTA-ABS | $60 | Primary 84 %/96 % Other stages 100 %/96 % | Syphilis | |
HLA-B27 | 50–80 % of acute anterior uveitis | $105 | 99 %/99 % | Seronegative spondyloarthropathy |
Complete blood count | $27 | Overall health, immunomodulatory therapy, masquerade syndromes | ||
Complete metabolic panel | $92 | Overall health, immunomodulatory therapy, sarcoidosis, masquerade syndromes | ||
Urinalysis | $40 | Vasculitis, TINU | ||
Chest X-ray—Sarcoidosis | $156c | 79 %/99 % | Sarcoidosis, tuberculosis, Wegener’s | |
Chest X-ray—Tuberculosis | $156c | 86.8 %/89.4 % | ||
Chest computed tomography—Sarcoidosis | $975c | 85–95 %/53 % | Sarcoidosis | |
Magnetic resonance imaging—head | $2,785c | Multiple sclerosis, CNS lymphoma, cysticercosis | ||
Gallium scan | $695c | Sarcoidosis |
Laboratory
Tuberculin Skin Test and Interferon Gamma Release Assays
Tuberculin is a glycerol extract derived from the precipitate of sterilized, concentrated cultures of the tubercle bacillus. The skin test, also known as the purified protein derivative (PPD), or Mantoux skin test, is performed when tuberculin is injected intradermally and then skin induration is measured at 24–48 h based on a host type IV Hypersensitivity reaction. The extent of skin induration indicates test positivity (see Table 2.6). It is important to note that certain conditions can suppress this reaction leading to false negative results (see Table 2.7). The test was established in 1908 and remained the foremost means of screening for tuberculosis for nearly a century. In 2005, the CDC released guidelines for use of FDA approved interferon gamma release assays. These tests are ELISA assays that measure the interferon gamma produced when the patient’s peripheral blood leukocytes are purified and mixed with three different tuberculosis antigens from a whole blood sample. There are currently two FDA approved tests, the Quantiferon TB-gold test, and the T-SPOT TB test. A recent head-to-head prospective study demonstrated the Quantiferon TB-gold test to be more specific but slightly less sensitive than the T-SPOT TB [38, 39]. However, the Quantiferon test was significantly more accurate in identifying true-positive tuberculous uveitis than T-SPOT TB in discordant cases (98 % vs. 76 %) [39]. The Quantiferon-gold is more readily available and used more extensively in the US. Latent versus active TB cannot be differentiated from a positive result for skin testing or for ELISA assays. It is not recommended that these be used as the sole method for diagnosis. Microbiologic sampling remains the gold standard for diagnosis. However, culture or tissue sampling is often difficult to obtain in an ocular specimen and analysis may be limited in its availability.
Table 2.6
Positivity classification of the tuberculin skin test reaction
Diameter of induration | Persons for whom reaction is considered positive |
|---|---|
Induration of >5 mm | HIV infected, recent contact of person with TB, fibrotic changes on X-ray consistent with prior TB, immunosuppressed (history of organ transplant, taking the equivalent of >15 mg/day of prednisone for >1 month; taking TNF-α antagonists) |
Induration of >10 mm | Recent immigrants (<5 years) from high prevalence countries, Injection drug users, Nursing home/correctional facility residents and employees, healthcare workers, Mycobacteriology laboratory personnel, Age >70 or <18 years old, medical condition associated with increased TB risk (diabetes, corticosteroid use, gastrectomy, malabsorption, silicosis, malnutrition) |
Induration of >15 mm | All others |
Table 2.7
Conditions that suppress PPD hypersensitivity reaction
Infectious mononucleosis |
Live virus vaccine—if given within 3 weeks of testing |
Sarcoidosis |
Hodgkin’s disease |
Corticosteroids/immune suppression |
Malnutrition |
Upper respiratory tract infection |
There are certain limitations to both the tuberculin skin test and ELISA assays. Skin testing is limited by poor inter-reader reliability (e.g., 9 mm negative vs. 10 mm positive), low specificity (e.g., prior BCG vaccination), poor predictive value in low prevalence populations (see example mentioned above), and it requires patient reliability to return to read the test. Thus, interferon gamma release assays may be more useful for poorly reliable patients or immigrants from endemic areas that may have a false positive PPD from previous BCG vaccination. There are conflicting reports about the sensitivities and specificities of purified protein derivative versus Quantiferon-gold. Reported sensitivities and specificities range from 75–89 % and 85–86 % for the PPD test and 70–81 %, 97–99 % for Quantiferon-gold, respectively [27–30]. Another recent study by McMullen et al. indicates that in the correct population, PPD screening is still highly specific with a specificity of 99.7 % versus 91.4 % for Quantiferon-gold (p < 0.0001) [40]. Cost continues to be an important disparity between these two screening methods. One study focusing on the cost-effectiveness of Quantiferon versus PPD measured the number of averted TB cases in two years. This study estimated the cost for the screening of latent TB and treatment of a hypothetical cohort to be $16,021 per averted case for PPD versus $227,977 per averted TB case for Quantiferon [41].
As mentioned above, the role of tuberculosis testing as a screening tool for all patients is debated among uveitis specialists. Given the varied population presenting at our clinic, it is generally our practice to selectively send this as a screening test for patients with intermediate or posterior/panuveitis, any patient with suggestive exposure history or risk, and those we are anticipating the initiation of systemic immune modulation therapy (especially with TNF alpha inhibitors).
Syphilis Testing (Non-specific and Specific)
Syphilis is rarely diagnosed by dark field microscopy or immunofluorescence from a tissue biopsy. Thus, the mainstays of testing are specific (direct) and non-specific (indirect) treponemal antibody tests. Indirect tests such as the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) measure IgG and IgM antibodies directed to cardiolipin that is released during cellular damage that occurs during active infection. These antibodies are not specific for Treponemal pallidum. These tests typically become non-reactive with time and following adequate treatment. The sensitivities for the indirect tests for syphilis are reported to be 78–86 % for detecting primary syphilis, 100 % for detecting secondary syphilis, and 95–98 % for detecting tertiary syphilis [42]. Sensitivity, however, decreases significantly for detection of neurosyphilis to 69 % [43]. Specificity ranges from 85 to 99 %. False positives can be seen with systemic lupus erythematosus, biliary cirrhosis, rheumatoid arthritis, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, Lyme, HIV, hepatitis, viral diseases. Confirmation for any positive or equivocal non-treponemal test result are traditionally followed with a specific or direct treponemal test, such as the fluorescent treponemal antibody absorption (FTA-ABS), quantitative VDRL/RPR, microhemagglutination assay T. pallidum (MHA-TP), T. pallidum hemagglutination (TPHA), or T. pallidum particle agglutination (TPPA) test. Direct treponemal tests detect antibodies specific to T. pallidum (and a few other treponemal subspecies that are rarely seen in the US). This test stays reactive for life and indicates that infection has occurred but does not distinguish active versus latent or treated infection. Thus, a positive direct test will indicate whether the patient has been exposed to syphilis in the past and a positive indirect test such as the RPR or VDRL will indicate active untreated infection. FTA-ABS is the most commonly used confirmatory test following positive VDRL or RPR test findings. FTA-ABS has a sensitivity of 84 % for detecting primary syphilis infection and almost 100 % sensitivity for detecting syphilis infection in other stages. Its specificity is 96 % [42]. Possible causes for a positive direct test and negative indirect are latent syphilis, previously treated infection, neurosyphilis, or false positive direct test.
Of note, it has been reported that nearly 30 % of ocular syphilis cases test negative to non-specific testing [44]. Thus, we strongly advocate using direct testing for initial screening. Many laboratory protocols have been trending toward this approach as well. Treponemal Enzyme Immunoassays (EIA) are a type of automated direct treponemal test, where reactive results are subsequently followed by indirect testing. Reports indicate that this approach is highly cost effective, slightly decreases the sensitivity, but improves specificity [45–47]. This protocol is now the standard at many academic laboratories, including ours. Ophthalmologists should become familiar with their local laboratory testing algorithm for syphilis, so if needed, it can be specified that you would like direct testing done first.
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