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Mistakes in ordering and interpreting diagnostic tests can lead to misdiagnosis and inappropriate therapy.
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Diagnostic tests should be ordered to narrow down the differential diagnosis.
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Clinicians must know the sensitivity and specificity of the diagnostic test to avoid misinterpretation of the results.
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A few diagnostic tests are both highly sensitive and highly specific and may therefore be useful as a screening test for patients with many forms of uveitis. The FTA-ABS test for syphilis is an example of a diagnostic test often used as a general screening for patients with uveitis.
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Assessing the likelihood of disease before the diagnostic test is crucial in determining the likelihood of disease after either a positive or a negative diagnostic test.
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Tests including fluorescein angiography and ocular coherence tomography are helpful in assessing response to therapy.
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Some diagnostic tests, such as bone mineral density studies, help to limit side effects of therapy and are now part of the standard care of patients on systemic antiinflammatory therapy.
What diagnostic tests should you order in the evaluation of the patient with uveitis? This is one of the most difficult questions we are asked. It is clear, however, that a nonselective approach to testing is costly and inefficient and provides information that is often irrelevant or, worse yet, that may lead to an incorrect diagnosis and inappropriate therapy. It is important to understand how to interpret diagnostic data because this information will help the clinician to order the appropriate tests.
Why does the clinician order diagnostic tests? Usually diagnostic tests are ordered to aid in making the correct diagnosis. Unfortunately, many clinicians are overly influenced when positive or negative results for a diagnostic test come back from the laboratory. A clinical example will serve to illustrate this point. A 34-year-old African-American woman from Texas presents with an intermediate uveitis in both eyes that has been present for the past 7 months. There is no history of rash, arthritis, or fever, but the patient does complain of wheezing and shortness of breath on exertion. The ophthalmologist orders a battery of diagnostic tests, including a serologic test for Lyme disease that has a positive result. Of course, the ophthalmologist is ecstatic in diagnosing the patient’s condition and treats her with a 2-week course of ceftriaxone. There are only three problems with this scenario: the patient probably does not have Lyme disease, did not need the expensive 2-week course of intravenous antibiotics, and more likely has sarcoidosis that is not being treated!
Before one can appropriately interpret the results of a diagnostic test, three pieces of information are needed. First, one needs to know the sensitivity of the diagnostic test ( Fig. 5-1 ). This is calculated by dividing the number of patients who actually have the disease and who on testing have a positive result, by the total number of patients with the disease who are tested. Another name given to patients with a disease who have a positive test result is true positives: they have a positive test result and actually have the disease. Patients who have the disease but who have a negative test result are called false negatives. Many of the commonly used serologic tests for Lyme disease have a sensitivity of 90%. What does that mean? It means that if 100 patients with Lyme disease were tested, 90 would have a positive result (true positives), but 10 would have a negative result (false negatives). Furthermore, many diagnostic tests have varying sensitivities based on the stage of the disease. For example, Lyme serologies are less sensitive during the acute stage of the disease.
The second piece of information you need to have to interpret a diagnostic test result is the specificity ( Fig. 5-1 ). The specificity of a diagnostic test is calculated by dividing the number of patients who do not have the disease in question and who have had an appropriately negative test result, by the total number of people without the disease who are tested. People who do not have the disease and who have a negative test result are called true negatives. Similarly, people who do not have the disease but who have a positive test result anyway are called false positives. In the case of the serologic test for Lyme disease, the specificity is also 90%. This means that if 100 patients without Lyme disease take this test, 90 will have an appropriately negative result, but 10 will have a misleading positive result!
Pretest likelihood of disease
The third and critical piece of information needed for test interpretation is often ignored by many doctors. This piece of information is called the pretest likelihood of the disease and is defined as the chance that the patient has a particular disease before the diagnostic test is ordered. The pretest likelihood can be based on a number of factors, such as the patient’s history and physical examination and the incidence of a particular disease in that area. This is the figure that most depends on the clinician’s prowess and ability: the more accurate the physician’s calculation of the pretest likelihood of disease, the more accurate the subsequent interpretation of the test result will be.
What is the pretest likelihood of Lyme disease in the case of the 34-year-old woman from San Antonio with intermediate uveitis who has no other symptoms and signs of Lyme disease and who does not live in an area endemic for the disease? The prevalence of Lyme disease in San Antonio, Texas, is probably less than 1 in 1000, and with no other evidence of the disease the pretest likelihood of the disease would probably be less than this. But let us be generous and say that the pretest likelihood of this patient having Lyme disease is 1 in 1000 or 0.1%. How do we interpret her positive test result for Lyme disease?
The likelihood that the diagnosis of Lyme disease is correct in this patient can be calculated because we now have the sensitivity of the test (90%), the specificity of the test (90%), and the pretest likelihood of the disease (0.1%). This calculation of what is called the post-test likelihood of disease is carried out with the use of a formula derived by the mathematician Bayes and is called Bayes’ theorem. The standard form of Bayes’ theorem states the following:
Post-test probability=Pretest probability×sensitivity(Pretest probability×sensitivity)+(1−pretest probability)(1−specificity)
Bayes’ theorem has been understood for two centuries but has only been applied to clinical reasoning over the past 30 years. Although formulas may appear daunting to some clinicians, computer programs and nomograms have been developed to help the clinician interpret the data. , So what is the likelihood that our patient has Lyme disease, given her positive laboratory test result? With Bayes’ theorem the chance that she has Lyme disease is still only 0.9%, or a chance of 9 out of 1000! Although this represents an almost 10-fold increase in likelihood compared with the pretest likelihood, because there was a very small chance that she had Lyme disease before the test, she still probably does not have the disease. Knowing that the post-test likelihood of the patient having Lyme disease is less than 1%, the clinician probably would not opt to treat her with antibiotics.
Diagnostic tests are also not as useful if there is a very strong likelihood that a patient has the disease before the test is ordered. If this same patient came from Lyme, Connecticut, had a history of a tick bite followed by an erythematous, round rash, and now presented with an intermediate uveitis and arthritis, even without testing she would probably have a greater than 99% chance of having the disease. Even if the result of her serologic test for Lyme disease was negative, after applying Bayes’ theorem the patient would still have about a 99% chance of having the disease!
Diagnostic tests are most helpful when the pretest likelihood of the disease is about 50%. For our patient with intermediate uveitis, if after our initial assessment we thought that her chance of having Lyme disease was 50%, a positive serologic test result would increase the post-test likelihood of the disease to 90%. So in this case, we start with a 50 : 50 chance of Lyme disease but end up with Lyme disease being by far the most likely diagnosis.
Receiver operating characteristic (ROC) curve
Many diagnostic tests involve establishing a numerical cut-off, above which a patient is felt to have a ‘positive’ test and hence is more likely to have the disease. Where you set that cut-off affects the sensitivity and specificity of the test and determines the number of false positive and false negative test results. Unless a test is 100% sensitive and 100% specific, the more sensitive it is the more likely you are to get false positives. The sensitivity of a test can be graphed against 1-specificity of the test to obtain what is called the receiver operating characteristic (ROC) curve ( Fig. 5-2 ). The performance of a diagnostic test can be quantified by calculating the area under the ROC curve. Importantly, the ability of two continous variables to diagnose a disease can be distinguished by comparing the two ROC curves and the area under these curves, and determining whether this difference is statistically significant. , If so, the test with the greater area under the ROC curve may be more discriminating.
It is also important to critically assess the quality of the data underlying the sensitivity and specificity numbers you use. Data usually come from a number of clinical trials that use the given test. A meta-analysis of these studies can be used to assess diagnostic test accuracy by graphing the results on the ROC curve.
So now that you have the knowledge to analyze data, it should be easy to interpret your patients’ test data, right? Unfortunately, it is not that easy. It is difficult to obtain the sensitivities and specificities for many of the common diagnostic tests we order. Many laboratories are considering providing a nomogram listing the post-test likelihood of the disease for differing pretest likelihoods because they already know the current sensitivity and specificity for that test. But how do we know the sensitivity or specificity of a chest X-ray for the diagnosis of sarcoidosis, or of a diagnostic vitrectomy for intraocular lymphoma? These figures are difficult to obtain and may vary tremendously from institution to institution. More and more, however, articles are being published on the sensitivity and specificity of diagnostic procedures and tests. In addition, the clinician can do the calculations on the basis of hypothetical numbers. For example, one might ask this question: given a 95% sensitivity and a 95% specificity for a test in a patient who I think has a 10% chance of having the disease, what is the post-test likelihood of the disease? It is surprising how much such calculations can help you to decide on a diagnostic or therapeutic approach to patients with complicated conditions. Rosenbaum and Wernick have written a review on how to apply Bayes’ theorem to the evaluation of patients with uveitis, and this should be useful to many clinicians.
Diagnostic tests for uveitis
After your initial differential diagnosis is generated, diagnostic tests should be ordered to help discern among the most likely disorders. Remember that diagnostic tests will have the most utility in confirming or rejecting diagnoses that start with about a 50% chance of being correct. Table 5-1 and Box 5-1 list the common diagnostic tests useful for the evaluation of patients with uveitis. In addition to helping the clinician make the correct diagnosis, diagnostic tests are ordered in two other clinical settings. The first of these involves ordering tests to help the practitioner exclude the diagnosis of tumor and infection, because these disorders require specific therapy and would be exacerbated by antiinflammatory treatment. The second is to determine why a patient’s vision has decreased and whether this change is reversible. In eyes with complicated uveitis, the reasons for poor vision may be multifactorial, and the clinician needs as much information as possible.
| Tests | Conditions/Comments |
|---|---|
| Angiotensin-converting enzyme | Sarcoidosis; may be elevated in children without sarcoidosis |
| Antiphospholipid Ab (lupus anticoagulant and anticardiolipin Ab) | Thrombosis, CNS disease, and spontaneous abortions in patients with systemic lupus erythematosus |
| ANA | Systemic lupus erythematosus and other rheumatic diseases |
| Antifungal Ab | Fungal disease |
| ANCA | Wegener’s granulomatosis (cANCA) |
| Polyarteritis nodosa (pANCA) | |
| Antitoxoplasma Ab | Toxoplasmosis |
| Antiviral Ab | Viral infection |
| Calcium | Sarcoidosis |
| Chlamydia complement-fixation test | Chlamydia |
| C-reactive protein | Underlying inflammatory disease (i.e., rheumatic disease) |
| Cultures | Bacterial, fungal, mycobacterial, and viral diseases |
| Erythrocyte sedimentation rate | Underlying systemic diseases (i.e, rheumatic disease, malignancy) |
| Complete blood cell count | Underlying systemic disease |
| HIV ELISA | HIV |
| HTLV-1 | HTLV-1 infection |
| HLA typing | (Specific HLA types associated with specific diseases) |
| Immune complexes | Rarely useful |
| Liver function tests | Sarcoidosis, hepatitis |
| Lumbar function for cell count | APMPPE, VKH, Infection, Malignancy |
| Lumbar puncture for CSF VDRL | Syphilis |
| Lumbar puncture for culture and Gram stain | Infection |
| Lumbar puncture for cytology | CNS lymphoma |
| Lyme serology | Lyme disease (be aware of false-positive results) |
| Rheumatoid factor (RF) | Rheumatoid arthritis; girls with JRA and uveitis often RF negative but ANA positive |
| Stool for ova and parasites | Parasitic disease |
| T-cell subsets | (Low CD4+ count predisposes patient for opportunistic infections) |
| Thyroid function tests | Increased incidence of thyroid disease in patients with uveitis |
| Urinalysis | (Blood suggests rheumatic disease) |
| VDRL/FTA-ABS | Syphilis |
IMAGING TESTS
CT scan of head
CT scan of sinuses
Gallium scan
Hand X-ray
MRI of head
Sacroiliac X-ray
SKIN TESTING
Allergy testing
Anergy testing
Behçetin
Histoplasmin
Pathergy
PPD
ANCILLARY OPHTHALMIC TESTING
Color vision testing
Contrast sensitivity
Electroretinogram
Electrooculogram
Fluorescein angiography
Indocyanine green angiography
Laser interferometry
Laser flare photometry
Manifest refraction
Optical coherence tomography
Ultrasound of orbit
Ultrasound of retina
Visual evoked potentials
Visual field testing
BIOPSY SPECIMENS
Conjunctiva
Lacrimal gland
Aqueous humor
Vitreous
Choroid and retina
Skin
The number of diagnostic tests available to the ophthalmologist has increased tremendously over the last decade. Many tests are expensive yet yield little useful information; others are critical for the appropriate management of patients. These tests can be arbitrarily grouped into laboratory tests, imaging techniques, skin testing, surgical specimens, and ancillary ophthalmic tests. Many of the tests listed in Table 5-1 and Box 5-1 are more thoroughly discussed in later chapters on specific diseases; however, several points for each group of diagnostic tests deserve comment here.
Laboratory tests
Laboratory tests usually are the first diagnostic tests that most physicians order. Although we have emphasized that laboratory tests should not be routinely used to screen patients with uveitis for disease, and that tests should be ordered only to discern among likely diagnoses, there is one exception: practically all patients with uveitis should be tested for syphilis. There are a number of factors that support the use of laboratory tests to screen for syphilis in most patients with uveitis. Syphilis remains a common cause of uveitis and is easily treatable. Patients with untreated ocular syphilis often have devastating visual outcomes. Importantly, the fluorescent treponemal antibody absorption (FTA-ABS) test for syphilis is both extremely sensitive and specific. For patients with late syphilis – the stage of disease – associated with uveitis, the sensitivity and specificity of the FTA-ABS test are both 99%. With this combination of a treatable, common disease; poor outcome in untreated patients; and a highly sensitive and specific diagnostic test with little risk and moderate cost, screening becomes useful. It is important to note, however, that other laboratory tests for syphilis are not as good for screening for late syphilis (see Chapter 10 ). The Venereal Disease Research Laboratory (VDRL) test, for example, has a sensitivity of only 70% for late syphilis. Therefore the clinician should insist on an FTA-ABS test in evaluation of the patient with uveitis. Also, the incidence of syphilis in patients with AIDS is increasing. , As a result, all patients with syphilis who have uveitis should also be tested for human immunodeficiency virus (HIV) infection, and vice versa.
A number of tests are used for research purposes but are commercially available. Many practitioners order these tests but do not know what to do with the results when they come back. Standardization of many of these tests is subpar, and many of these tests are better left unordered. One example is testing for circulating immune complexes. Circulating immune complexes were first thought to be the mechanism underlying the destruction of the eye in various forms of uveitis. Tests for circulating immune complexes were ordered, and if present they were assumed to be the cause of the disease. However, it is no longer clear that immune complexes are the cause of many occurrences of uveitis. Circulating immune complexes are found in many persons, and the evidence to date suggests that their presence in ocular inflammatory disease may be protective rather than destructive (see Chapter 1 ).
A number of laboratory tests are used in the evaluation of patients with possible rheumatic diseases. Acute-phase reactants include a number of proteins produced by the liver in reponse to stress, and signal underlying inflammation. The most commonly used tests for acute-phase reactants are the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Rheumatoid factor (RF) is an autoantibody against the Fc portion of human IgG. The test is relatively sensitive for rheumatoid arthritis, and may also be positive in patients with other rheumatic diseases, including Sjögren’s syndrome and systemic lupus erythematosis (SLE). However, RF may also be positive in patients with chronic inflammatory diseases or malignancy and is also seen in normal subjects. Antinuclear antibodies are another test indicative of underlying connective tissue diseases. They are extremely senstive for SLE, and depending on the immunofluorescence pattern of the test, can indicate specific disorders such as polymyositis, dermatomyositic, or CREST (calcinosis, Raynaud’s phenomenon, esophogeal dysmotility, sclerodactyly, and telangiectasis).
The antineutrophil cytoplasmic antibody (ANCA) test has been very helpful in the diagnosis of Wegener’s granulomatosis, a systemic vasculitis characterized by a necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, a focal necrotizing glomerulonephritis, and systemic small vessel vasculitis involving a number of organ systems, and in follow-up of patients with this disease. Ocular involvement including uveitis, scleritis, and retinal vasculitis occurs in about 16% of patients. Young described 98 patients with uveitis tested for the presence of ANCAs by an indirect immunofluorescence method and found a positive ANCA test result in patients with chronic uveitis from various causes. A cytoplasmic pattern of staining (cANCA) is felt to be more specific for Wegener’s granulomatosis than a peripheral pattern (pANCA). Soukasian and colleagues reported that ANCA test results were positive in seven patients with scleritis caused by Wegener’s granulomatosis but negative in 54 patients with other ocular inflammatory diseases; this suggests that the test is both sensitive and specific. High specificity of the cANCA test for Wegener’s granulomatosis in patients with ocular inflammatory disease has been reported by other investigators as well. The ANCA test may also be useful in guiding immunosuppressive therapy. Failure of ANCA titers to revert to normal levels may be associated with an increased risk of relapse. These patients may benefit from more aggressive immunosuppressive therapy.
Image analysis
Although newer techniques provide the practitioner with high-resolution images, simple radiographic techniques, such as skull X-rays to evaluate patients with suspected congenital toxoplasmosis for calcifications, should not be overlooked. Chest X-rays should be obtained in patients suspected of having sarcoidosis or tuberculosis. A computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is indicated for patients with possible intraocular lymphoma (see Chapter 30 ). In contrast, sinus radiographs are frequently ordered as part of the evaluation of patients with uveitis; however, it is not clear that this test is helpful on a routine basis. Patients with a history of sinus disease and uveitis may have an underlying systemic vasculitis such as Wegener’s granulomatosis, but in these patients an ANCA test, consultation with an otolaryngologist, and possibly a CT scan of the sinuses may be more appropriate and useful than sinus radiographs.
Skin testing
Skin testing is often neglected by the practitioner, but these simple tests can give the observer a large amount of information. The purified protein derivative (PPD) and histoplasmin skin tests are easily performed and give important clinical data. The PPD test is important in the evaluation of the patient with uveitis with a history suggesting tuberculosis. In addition, patients should have a PPD test before they are given immunosuppressive therapy, because if the PPD test result is positive these patients will require antituberculous therapy before immunosuppressive therapy is begun. Patients with a history of possible tuberculosis or a positive reaction to a tuberculosis skin test should be tested with a lower-strength PPD, such as a 1 test unit dose, instead of the usual 5 test unit dose. If these test results are negative, then the higher test dose can be given. The histoplasmin skin test is useful in evaluating patients with presumed ocular histoplasmosis syndrome; however, the test may activate an old, inactive histoplasmosis lesion and should be avoided in patients with macular lesions.
Skin testing can also be used to document anergy. Patients with sarcoidosis are typically anergic and should have depressed responses to skin testing with control antigens such as tetanus. Systemic corticosteroid administration sometimes reverses anergy in these patients, whereas ciclosporin may prevent type IV hypersensitivity reactions in the skin and yield a negative result to the skin test. In the past, the Kveim test was commonly performed for sarcoidosis, but the result was very dependent on the batch of Kveim antigen that was used. Currently, Kveim antigen cannot be obtained, and the test is no longer used. The Behçetin skin test is also infrequently performed. In this test, patients with suspected Behçet’s disease are stuck with a sterile needle, and the skin is observed or samples are biopsied for evidence of a type IV reaction. The hypothesis is that patients with Behçet’s disease will display a positive delayed hypersensitivity response to the needlestick (pathergy). Although the test is rarely performed, a history of skin reactions to phlebotomy draws or after intravenous line placements may suggest pathergy and the diagnosis of Behçet’s disease.
Allergy testing was at one time a very important component in the evaluation of the patient with uveitis. The relevance of atopy or a specific allergy to uveitis is not clear. Hard evidence showing that type I hypersensitivity reactions are a major, underlying force in intraocular inflammatory disease is lacking: only anecdotal information suggests perhaps a secondary role. As a result, we only occasionally order allergy testing for our patients.
Tissue samples
The diagnosis of many forms of uveitis is based on the history and the typical appearance of the ocular disease. Nevertheless, the definitive diagnosis of many occurrences of uveitis requires histologic confirmation. No oncologist or radiation therapist would agree to treat a patient with presumed intraocular lymphoma without a tissue diagnosis. Similarly, the definitive diagnosis of sarcoidosis also requires histologic confirmation. In many other instances, analysis of ocular fluid or tissue can provide a wealth of information to the clinician. The information is, however, only as good as the evaluation of the specimen. It is imperative that the tissue is processed expeditiously by a person experienced in a variety of histologic and immunologic techniques, including immunohistochemical staining.
The evaluation of intraocular fluid is of great potential value. A condition for which the analysis of intraocular fluids has aided the clinician in diagnosis is toxoplasmosis. Problems arise when atypical lesions are noted in a patient with low levels of circulating antitoxoplasma antibody. Desmonts proposed that local (that is, intraocular) production of specific antitoxoplasmosis antibody strongly suggests an active ocular lesion as a result of toxoplasmosis. To demonstrate local production of antibody, the specific antibody in the eye is measured relative to the total amount of globulin in the eye. This led Desmonts to calculate the antibody coefficient (C). The formula for determining this value is:
C=Antibody titerAqueous humorSerum×ImmunoglobulinSerumAqueous humor
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