Uveitis: Diagnostic Approach and Ancillary Analysis
EMMETT T. CUNNINGHAM JR. and ROBERT A. NOZIK
Table Of Contents
REVIEW OF SYSTEMS
SPECIAL TESTS AND PROCEDURES
|There is a strong tendency for most ophthalmologists to rely heavily on
ancillary testing to establish a diagnosis in patients with uveitis. Although
such testing is often useful, most authorities agree that the
vast majority of information required to make a diagnosis in patients
with uveitis is obtained from the history, review of systems, and physical
examination.1–7 This information helps direct the physician toward choosing the appropriate
laboratory tests and special studies to confirm or exclude those
few uveitic syndromes suspected on clinical grounds. We take the following
steps when evaluating and treating patients with uveitis2:|
The most pertinent patient demographics are age, sex, and race.7–14 Of these, age is by far the most important. The majority of uveitic syndromes tend to occur during the broad, middle-age group of 20 to 60,7–14 and virtually all diagnoses should be considered for patients in this category. Childhood uveitis encompasses a disproportionate number of cases of juvenile rheumatoid arthritis (JRA),15,16 pars planitis,17,18 toxocariasis,19,20 and toxoplasmosis.21–23 HLA-B27-related uveitis,24,25 pars planitis,17,18 and Fuchs' heterochromic iridocyclitis26,27 are seen primarily in older adolescents and young adults. Serpiginous28,29 and birdshot chorioretinopathy,30,31 in contrast, are more prevalent in those over 50. Masquerade syndromes should be suspected at both ends of the spectrum,32,33 with retinoblastoma, leukemia, and juvenile xanthogranuloma occurring in the very young, and intraocular lymphoma, uveal melanoma, metastatic carcinoma, ocular ischemia, and paraneoplastic syndromes presenting more often in the elderly.
With the exception of JRA,15,16 which tends to affect young girls, and HLA-B27-related uveitis,24,25 which tends to affect young men, the most common uveitic syndromes are more or less evenly distributed between the sexes.
A few uveitic syndromes do have a racial predilection. For example, there is an increased prevalence of (1) HLA-B27-related uveitis24,25 and the so-called white-dot syndromes or inflammatory chorioretinopathies34,35 in whites; (2) ocular sarcoidosis36–38 and systemic lupus erythematosus39,40 in blacks; (3) Behçet's syndrome41,42 in those of Mediterranean, Middle Eastern, and Asian descent; and (4) Vogt-Koyanagi-Harada (VKH) syndrome43–45 in Asians, Asian Indians, and Native Americans.
A patient's birthplace and history of travel and residence are important factors when considering uveitic diagnoses. Uveitic syndromes are segregated along geographic boundaries for at least three reasons. First, as mentioned earlier, a few uveitic entities occur more commonly among certain races, presumably reflecting genetic susceptibility. Second, the intermediate hosts and environmental factors preferred by some infectious agents limit their spread to certain parts of the world. In the United States, this is seen with coccidioidomycosis,46,47 which occurs in the semiarid desert regions of the Southwest; with histoplasmosis,48,49 which is indigenous to the Mississippi river valley; and with Lyme disease,50,51 which is prevalent in the Northeast from Massachusetts to Maryland, in the Midwest (especially Wisconsin and Minnesota), and on the West coast (particularly California and Oregon). Similarly, coccidioidomycosis46,47 and cysticercosis52,53 are found in Central and South America, whereas onchocerciasis54,55 occurs in Central America and West Africa. Third, socioeconomic factors that promote the spread of infection vary from region to region. Infectious causes of uveitis, for example, are more common in the developing world, where population densities are high and sanitation is relatively poor.56–58 Toxoplasmosis is more frequent in parts of France59,60 and Brazil,61,62 where eating raw or undercooked meat is commonplace.
CHIEF COMPLAINT AND HISTORY OF PRESENT ILLNESS
Recognition of a specific chief complaint allows the physician to identify that aspect of the patient's disorder that he or she finds most bothersome or problematic. In the case of uveitis, the chief complaint is usually voiced as unilateral or bilateral pain, photophobia, redness, floaters, or blurred or decreased vision, either alone or in combination. Although blurred or decreased vision is the most common and, unfortunately, least localizing symptom reported by patients with uveitis, other symptoms can suggest a primary site of intraocular inflammation. Pain, photophobia, and redness, for example, most often reflect iritis, iridocyclitis, elevated intraocular pressure, or corneoscleral disease. One notable exception in this regard is JRA,15,16 or so-called white iritis,63 in which pain, photophobia, and redness are frequently absent in the setting of significant, ongoing iridocyclitis. Symptomatic floaters can occur in virtually all forms of uveitis, but in the absence of pain, redness, and photophobia, floaters suggest primary vitreous inflammation. Other localizing complaints include fixed scotomata, which suggest focal retinal damage, metamorphopsia, or micropsia, which can occur with subretinal or intraretinal fluid; and altitudinal or patchy visual field loss, which is frequently seen with optic neuritis.
The history of present illness should address the severity, time of onset, and course of the patient's ocular complaints, including specific mention of whether the presentation was acute, chronic, or recurrent. In characterizing the course of the complaints, we consider a 3-month duration of symptoms to constitute a transition from acute uveitis to chronic uveitis.
Special note should be made of past treatment successes and failures. Most forms of endogenous uveitis respond to local or systemic immunosuppressants, such as corticosteroids. Masquerade syndromes, in contrast, show little response to such treatments, whereas intraocular infections paradoxically worsen with immunosuppressive therapy.
PAST OCULAR HISTORY
Pertinent past ocular history should be noted in all patients with uveitis, including refractive error, past or present ocular diseases, and any history of ocular trauma or surgery. High myopia, for example, is associated with retinitis pigmentosa64 and retinal detachment,65 both of which may cause symptoms of floaters and show evidence of vitritis. Similarly, a history of herpes simplex keratitis66 or herpes zoster ophthalmicus67 might suggest the diagnosis in a patient with anterior uveitis and elevated intraocular pressure, whereas a history of amblyopia or strabismus might represent monocular vision loss during early childhood, as can occur with toxoplasmosis21–23 or toxocariasis19,20 involving the macula. Past ocular trauma and surgery both increase the risk of endophthalmitis,68,69 lens-induced uveitis,70,71 and sympathetic ophthalmia.72,73 Lastly, a history of nonuveitic glaucoma is important for at least three reasons. First, β-blockers can infrequently cause drug-related uveitis.74,75 Second, cholinomimetics, such as pilocarpine, promote intraocular inflammation and should be avoided in patients with uveitis.76 Third, patients with glaucoma are at increased risk for having elevated intraocular pressure in response to local and systemic corticosteroids77,78 and so should be followed closely during treatment.
PAST MEDICAL AND SURGICAL HISTORY
A detailed past medical and surgical history will often disclose systemic illnesses associated with intraocular inflammation, most commonly collagen vascular diseases, autoimmune or hypersensitivity syndromes, or infections. We find that a thorough uveitis questionnaire, to be filled out by the patient before his or her visit, is quite helpful in obtaining this information.4,5 In addition, some systemic conditions complicate the use of immunosuppressants in patients with uveitis. A history of tuberculosis, diabetes mellitus, peptic ulcer disease, or systemic hypertension, for example, must be weighed carefully against the treatment benefits when considering the use of systemic corticosteroids. Likewise, a history of renal insufficiency might weigh against the use of systemic cyclosporine (Cyclosporin A) or antiviral agents, such as foscarnet or ganciclovir. Lastly, some commonly used systemic medications have been associated with uveitis, including antibiotic sulfonamides,79 pamidronate disodium (an inhibitor of bone resorption),80 and rifabutin,81–83 used in patients with acquired immunodeficiency syndrome (AIDS) as prophylaxis against, and treatment for, Mycobacterium avium complex infection.
A thorough dietary, sexual, drug-use, pet, and contagion-exposure history should be elicited from every patient with uveitis.
Pica, a practice common among children, increases the risk for both toxocariasis19,20 and toxoplasmosis.21–23 Similarly, eating raw or incompletely cooked meat can lead to toxoplasmosis21–23 or cysticercosis,52,53 and drinking unpasteurized milk can transmit tuberculosis84,85 or brucellosis.86,87 Curiously, and for unknown reasons, eating English walnuts has been associated with the formation of oral aphthae in patients with Behçet's syndrome.2
Unprotected sexual relations put patients at risk for a host of sexually transmitted diseases, many of which have been associated with uveitis. These diseases and pathogens include herpes simplex virus,66 herpes zoster virus,67 cytomegalovirus (CMV),88,89 syphilis,90,91 chlamydia,92 human T-cell leukemia virus,93,94 and human immunodeficiency virus (HIV).95–100 Interestingly, HIV-infected patients experience a dramatically altered spectrum of uveitic disorders,95–100 such that CMV retinitis,88,89 Pneumocystis carinii choroiditis,101,102 and cryptococcal uveitis103,104—diseases that were once rare and seen only in patients with profound immunosuppression from systemic medications or malignancy—are now encountered frequently in these patients. Other important risk factors for contracting HIV include intravenous drug use or a history of blood-product transfusion.
Diseases passed from animals to humans, termed zoonoses, have become increasingly recognized in ophthalmology. For example, cats can transmit both Toxoplasma gondii,21–23 which causes toxoplasmosis, and Bartonella henselae,107,108 the causative organism for cat-scratch disease. Dogs, especially puppies, can shed Toxocara canis.19,20
The most important non-sexually transmitted contagious causes of uveitis in immunocompetent patients are tuberculosis84,85 and toxoplasmosis,21–23 which are of particular importance in developing countries. TORCH infections (toxoplasmosis,109 other [including syphilis110], rubella,111 CMV,112 and herpes simplex virus)113 can be transmitted from mother to fetus.
Once an infectious cause of uveitis is documented, a detailed history regarding the type, dosage, and duration of medical therapy should be obtained. In addition, state and local laws require that many contagious diseases be reported to the public health department.
With rare exceptions,114–120 uveitic syndromes are not believed to have a classic mendelian inheritance (i.e., recessive, dominant, or X-linked). Genetics, however, does appear to play a role in some forms of uveitis, as evidenced by their increased association with race or human leukocyte antigen (HLA). The two most notable associations in this regard are (1) HLA-B27 with anterior uveitis (particularly in whites), often occurring together with ankylosing spondylitis, Reiter's syndrome, psoriasis, or inflammatory bowel disease24,25; and (2) HLA-A29 with birdshot chorioretinopathy.30,31 Other HLA associations of note include HLA-B51 and HLA-B12 with Behçet's syndrome41,42; and HLA-B53, HLA-DR4, and HLA-DRw53 with VKH syndrome.43–45
|REVIEW OF SYSTEMS|
|A thorough, systematic review of systems serves at least two purposes in
patients with uveitis:|
A directed systemic examination should be part of the uveitis workup. Special attention should be paid to examination of the mucocutaneous, musculoskeletal, cardiopulmonary, gastrointestinal, and neurologic systems, because many systemic disorders associated with uveitis can affect these organs. For example, syphilitic uveitis can be accompanied by psoriasis of the palms and soles90,91; VKH syndrome can produce meningismus, vitiligo, poliosis, alopecia, and hearing loss43–45; and toxocariasis19,20 is occasionally associated with a restrictive airway disease that can mimic asthma.
Patients with uveitis require a complete eye examination, with special attention to the following.
A careful refraction is required to provide an accurate assessment of the patient's best-corrected visual acuity. Both intraocular inflammation and corticosteroids accelerate cataract formation, frequently producing a significant myopic shift. Recognition of such refractive changes can substantially improve a patient's vision and is especially important when trying to weigh the relative risks and benefits of therapeutic interventions, such as cataract removal or posterior sub-Tenon's corticosteroid injection for cystoid macular edema.
Any form of uveitis can be complicated by glaucoma if its course is chronic or recurrent.76 In contrast, acute uveitis is typically associated with a lowered intraocular pressure. Notable exceptions to this rule of acute uveitic hypotony include sarcoidosis36–38 herpes simplex keratouveitis,66 herpes zoster keratouveitis,67 toxoplasmosis,21–23 and Posner-Schlossman syndrome (also termed glaucomatocyclitic crisis),123 all of which may be accompanied by acutely elevated intraocular pressure.
Lids, Conjunctiva, Sclera, and Cornea
The lids, palpebral and bulbar conjunctiva, and sclera should be examined carefully for nodules suggesting granulomatous disease, as can occur with sarcoidosis36–38 or tuberculosis.84,85 Ciliary injection often accompanies iritis, whereas injection of deep episcleral vessels with edema usually represents scleritis. Scleral thinning, as manifested by increased visualization of uveal pigment, suggests prior episodes of severe, necrotizing scleritis,124,125 seen with rheumatoid arthritis or less common systemic vasculitides (e.g., Wegener's granulomatosis, polyarteritis nodosa, relapsing polychondritis). Evidence of past or present keratitis may be related to a number of infectious organisms, but herpes simplex66 and herpes zoster67 should be considered when corneal sensation is decreased or intraocular pressure elevated.76 Band keratopathy results from longstanding uveitis and is seen frequently in JRA15,16 and sarcoidosis.36–38 Inferior corneal thickening and nummular stromal infiltrates have been described in patients with sarcoidosis,126 as well as idiopathic intermediate uveitis.127
Keratic precipitates should be described with regard to number, distribution, appearance, and size.2,4 Most are found on the inferior corneal endothelium between 4 and 8 o'clock, an area termed Arlt's triangle. Keratic precipitates are characterized as follows:
Pigmented: Often old and inactive
The angle should be examined for granulomas, termed Berlin's nodules, as well as anterior synechiae and neovascularization, both of which may occur with recurrent or chronic intraocular inflammation.
Anterior chamber shallowing in the patient with uveitis may result from extensive anterior synechiae formation with contraction, extensive posterior synechiae formation with iris seclusion, or inflammatory infiltration of the anterior choroid producing anterior displacement of the lens-iris diaphragm. The presence of cells and flare in the anterior chamber should be graded carefully. We use the system of 0 to 4+ proposed by Hogan and associates,128 although other grading systems are available (Table 1).1,4,5 Hypopyon formation signifies severe anterior inflammation and may be seen in HLA-B27-related uveitis,24,25 Behçet's syndrome,41,42 and endophthalmitis,105 or in association with keratitis, particularly herpetic.66,67 A pseudohypopyon may represent tumor cells, either from a primary intraocular malignancy, such as retinoblastoma, or from a metastatic carcinoma.32,33 The occurrence of a hemorrhagic hypopyon with chronic uveitis suggests the possibility of iris or angle neovascularization,129 whereas anterior chamber bleeding in the setting of acute uveitis is seen most often with herpetic uveitis or with masquerade syndromes such as retinoblastoma or juvenile xanthogranuloma.32,33
* Schlaegel recommended using a “wide beam and narrow slit.” We and others4,5 recommend a 1 × 1 mm maximal intensity beam, set at an incident angle of approximately 45°. Some authors have provided intermediate grades, and have described fewer than 5 cells per high-power field as rare, trace, or occasional. We record the actual number of cells per high-power field when inflammation is less than 1+ .
The iris is typically miotic in the inflamed eye, but may be irregular if synechiae are present, or there is a history of trauma or herpes virus infection with damage to the sphincter muscle. Iris precipitates are seen in granulomatous uveitis2,4,5 and are located either at the pupillary margin (Koeppe nodules) or between the pupillary margin and angle (Busacca nodules). Posterior synechiae tend to occur in recurrent or chronic uveitis and, when extensive, may result in seclusion with secondary angle closure glaucoma. Iris atrophy, commonly seen with Fuchs' heterochromic iridocyclitis26,27 and herpes zoster uveitis,67 is best visualized with retroillumination. Herpes zoster uveitis, in particular, can cause sector iris atrophy. Rubeosis can occur in chronic anterior uveitis, although its presence in the setting of diffuse uveitis should prompt a search for retinal nonperfusion or ocular ischemia.
Anterior lens capsule pigment clumps may represent broken posterior synechiae from old bouts of uveitis. Cataract formation, particularly posterior subcapsular opacification, is a common complication of both uveitis and its therapy, corticosteroids. When a pseudophakus is present, the capsular bag should be examined carefully for the presence of residual lens material, suggesting lens-induced uveitis, and for white plaques representing possible infection with a slowly growing organism, such as Propionibacterium acnes or Staphylococcus epidermidis.130,131
Vitreous inflammation may be anterior, posterior, or diffuse. Anterior vitreous cells are often seen in the setting of iridocyclitis, where they represent “spillover” from the anterior segment. Best seen with a slit beam, anterior vitreous cells should be graded on a 0 to 4+ scale, similar to that used for anterior chamber cells (see Table 1). Posterior vitritis occurs with retinal, choroidal, or optic nerve head inflammation. Posterior vitritis is best seen with a Hruby or contact fundus lens by focusing just in front of the area of inflammation, which serves as a pale relief against which the small, dark, cellular silhouettes are readily visualized. Diffuse vitreous cells obscure the view of the posterior pole and should be graded on a 0 to 4+ scale using either a direct ophthalmoscope or Hruby lens, as suggested by Kimura and associates,132 or an indirect ophthalmoscope, as described by Nussenblatt and colleagues133 (see Table 1). Vitreous cells may aggregate to form “snowballs,” “strings of pearls,” or “snowmen,” or they may organize to form an opaque band at the inferior periphery, termed “snowbank,” which is seen most typically in intermediate uveitis.
Retinitis can be manifested as retinal whitening, hemorrhage, or vasculitis. When examining areas of retinitis, the depth of the inflammation is particularly important. CMV88,89 and toxoplasmosis,21–23 for example, typically produce full-thickness inflammation, whereas the focal inflammation that occurs with neuroretinitis108 or acute multifocal retinitis134 tends to be superficial. Conditions such as acute multifocal placoid pigment epitheliopathy,34,35 acute retinal pigment epitheliitis,34,35 multiple evanescent white-dot syndrome,34,35 and progressive outer retinal necrosis syndrome,135 described in patients with AIDS, affect primarily the outer retina, including the retinal pigment epithelium (RPE).28,29 The location and extent of the retinitis should also be noted carefully, particularly with regard to major retinal landmarks, such as the arcade vessels, optic disc, and fovea.
Retinal vasculitis may affect predominantly the arterioles, causing arteriolitis, or the venules, producing venulitis or phlebitis. Certain forms of uveitis, such as the acute retinal necrosis136 and Behçet's41,42 syndromes, tend to produce arteriolitis, whereas other forms, such as sarcoidosis,36–38 syphilis,90,91 and toxoplasmosis,21–23 primarily produce retinal phlebitis. In addition, the vasculitis may be either exudative, seen as sheathing, or occlusive. In general, arteriolitis tends more often to be occlusive than does phlebitis, whereas phlebitis is more commonly associated with sheathing and, on occasion, hemorrhage. The classic example of exudative phlebitis is seen with sarcoidosis and is termed tache de bougie, or candle wax drippings. Inflammation of the small retinal capillaries, termed microvasculitis, produces cotton-wool spots and intraretinal hemorrhages. Microvasculitis is most characteristic of collagen-vascular diseases137 and Behçet's syndrome.41,42
Retinal neovascularization occurs in response to both intraocular inflammation and retinal ischemia. New blood vessels typically arise from the optic nerve head or arcade vessels, although neovascularization may occur in the midperiphery as well. It is important to recognize that the development of neovascular fronds requires an adherent posterior hyaloid surface to act as a scaffolding, and so the presence of a posterior vitreous detachment can allow rubeosis to develop in the absence of visible retinal neovascularization.
Cystoid macular edema is the most common cause of visual loss in patients with uveitis138 and is believed to reflect the degree of vitritis and/or the proximity of associated retinal or optic nerve head inflammation. Foveal cysts are best assessed with a Hruby or fundus contact lens, but when the edema is mild or the view limited, fluorescein angiography may be required to make the diagnosis.
Exudative retinal detachments occur infrequently in patients with uveitis. When present, however, subretinal fluid is usually secondary to choroidal inflammation, as can occur with VKH syndrome,43–45 posterior scleritis,139 or sympathetic ophthalmia.72,73 As exudative retinal detachments resolve, widespread RPE mottling and atrophy may remain, a common occurrence in patients with VKH syndrome termed “sunset-glow fundus.”
Active choroidal inflammation is usually white or yellow, dependent largely on the amount of overlying choroidal and RPE pigmentation. Typical causes of choroiditis in immunocompetent patients include sarcoidosis,36–38 tuberculosis,84,85 syphilis,90,91 and sympathetic ophthalmia.72,73 Immunosuppressed patients, in contrast, are more likely to have an opportunistic infection of the choroid, such as pneumocysticosis,101,102 histoplasmosis,140 or cryptococcosis.103,104
Choroidal neovascularization is an uncommon finding in patients with uveitis131 but does occur, particularly when the inflammation is chronic and involves the outer retina and choroid.
Optic disc edema is a common finding in patients with uveitis. Most often, optic nerve swelling is secondary to adjacent vitritis, as in intermediate uveitis17,18 or surrounding choroiditis, which are seen with VKH syndrome43–45 or posterior scleritis.132 We term such secondary optic disc edema “uveitic papillopathy.” This is distinct from primary inflammation of the optic disc, which is termed “optic neuritis” or “papillitis,” and is distinguished by objective evidence of optic nerve dysfunction, such as an afferent pupillary defect or color vision loss.
|To categorize or subdivide uveitic syndromes, a number of schemes have
been used based on demographics, severity, chronology, laterality, pathology, location
and pattern of intraocular inflammation, associated ocular
and systemic findings, and when applicable, predisposing factors
or events (Table 2). In isolation, none of these classification schemes is wholly adequate, because
by focusing on information intrinsic to any one categorizing
system, important information may be inappropriately de-emphasized or
overlooked. We therefore recommend what we refer to as “naming”—the
process by which all information for each of the above-mentioned
categories is combined to form a synoptic description of
the patient with uveitis. In most cases the naming step alone narrows
considerably the range of diagnostic possibilities, usually to three or
four. The template is as follows:|
A [age]-year-old [race] [sex] with [severity], [chronicity], [laterality], [pathology], [location and pattern] uveitis associated with [ocular and systemic findings], who [predisposing factors and events].
The following are examples of patient descriptions using the naming approach:
|The naming step generates a succinct description, or profile, of the patient
with uveitis, constructed entirely from the patient history, review
of systems, and physical examination. This clinical picture is then
compared with the known profiles of the 40 to 50 common uveitic syndromes (Table 3) in a process we term “meshing,” whereby a short differential
diagnosis is generated. Unfortunately, meshing is based almost entirely
on clinical experience, and clinical experience varies from clinic
to clinic and country to country. Hence, infectious causes of uveitis
are seen much more commonly in patients with AIDS95–100 and in third-world countries.56–58 Similarly, VKH syndrome43–45 and Behçet's syndrome41,42 are much more common in Asia and the Middle East, respectively. However, these
caveats notwithstanding, Table 3 can be used to generate a differential diagnosis in most settings. Our
meshing for the five naming examples given above is as follows:|
*Any chronic uveitis may be complicated by cataract formation or glaucoma.
† Baseline workup includes (1) syphilis serologies (RPR or VDRL. and treponernal antibody titers); (2) chest x-ray to rule-out Granulomatous disease, such as sarcoidosis and tuberculosis; (3) skin testing with PPD, as well as mumps and Candida to rule out anergy; and (4) serum angiotensin-converting enzyme (ACE) and/or lysozyme levels for sarcoidosis.
A, Asian; ANA, antinuclear antibody; ANCA, antineutrophil cycloplasmic antibodies; B, Black; CBC, complete blood count; CME, cystoid macular edema; CMV, cytomegalovirus; CNS, central nervous system; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; EOG, electro-oculogram; ERG, electroretinogram; ESR, erythrocyte sedimentation rate; FA, Fluorescein angiogram; GI, gastrointestinal; LP, lumbar puncture; PAN, polyarteritis nodosa; PCR, polymerase chain reaction; PPD, purified protein derivative; RF, rheumatoid factor; RPE, retinal pigment epithelium; RPR, rapid plasma reagin; SLE, systemic lupus erethematosus; VDRL, Venereal Disease Research Laboratory; VZV, varicella zoster virus; W, White.
One important point is that tuberculosis, syphilis, and sarcoidosis are found on virtually all lists of differential diagnoses, because these diseases, known to be “great imitators,” may present as virtually any form of uveitis. In addition, syphilis, tuberculosis, and sarcoidosis are largely treatable, further emphasizing the need for accurate diagnosis. We therefore test specifically for these entities in virtually every patient with uveitis. Our baseline workup includes the following: (1) syphilis serologies, including both a rapid plasma reagin (RPR) or Venereal Diseases Research Laboratory (VDRL) test and a specific treponemal antibody test (FTA-ABS or MHATP); (2) a routine chest x-ray to look for evidence of granulomatous or infiltrative disease; and (3) skin testing for tuberculosis (purified protein derivative; PPD), as well as for mumps antigen and Candida to test for anergy.
|The selection of laboratory tests in patients with uveitis should be tailored
to confirm or eliminate those few diagnostic possibilities generated
by the naming and meshing steps discussed earlier.141,142 In general, we treat empirically without further testing for first episodes
of acute, unilateral, mild to moderately severe, nongranulomatous
iritis or iridocyclitis in otherwise healthy, young to middle-aged adults; we
call this presentation “simple anterior uveitis.” If, however, patients
with simple anterior uveitis (have a change in
their presentation, such that the ocular inflammation becomes recurrent, bilateral, severe, or
granulomatous, or if the patient fails to respond
promptly to standard treatment with intensive topical corticosteroids
and cycloplegia, we proceed to a baseline workup, as described earlier. Moreover, if
signs or symptoms suggest an underlying systemic
disease, additional testing is requested (see Table 3). The following is a discussion of some of the more commonly ordered laboratory
ANGIOTENSIN-CONVERTING ENZYME LEVEL
Angiotensin-converting enzyme (ACE) cleaves two amino acids from the C-terminus of the decapeptide angiotensin I to produce the much more potently vasoactive angiotensin II, an octapeptide. ACE is produced primarily by capillary endothelial cells, abundant in both lung and liver, and by secretory monocytes, especially macrophages. For this reason, a number of pulmonary, hepatic, and lymphoproliferative disorders are associated with an elevated ACE level. Clinically, ACE levels are ordered almost exclusively to aid in the diagnosis of sarcoidosis, because circulating levels are elevated in more than two thirds of patients with active disease.143,144 Moreover, although ACE levels may be elevated in a number of conditions, very few of these disorders are associated with uveitis and a negative skin test for tuberculosis. Therefore, in the setting of uveitis and a negative PPD, we interpret an elevated ACE as fairly specific for sarcoidosis. This stated, it is important to realize that ACE levels are elevated in childhood and may be lowered by prolonged use of systemic corticosteroids or by systemic ACE inhibitors used to lower blood pressure.
Antinuclear antibodies (ANAs) are directed against proteins, nucleic acids, and/or nucleoprotein complexes normally confined to cellular nuclei. The ANA test is typically performed by applying serial dilutions of the patient's serum to cultured tumor cells and then titrating for the presence and pattern of nuclear autoantibody staining. The ANA test is generally used to confirm what is already a strong clinical suspicion, based on the history, review of systems, and physical examination, that the patient has a collagen-vascular disease, particularly systemic lupus erythematosus or juvenile rheumatoid arthritis.141,142 Other rheumatic diseases that are also associated with elevated ANA titers include Sjögren's syndrome, rheumatoid arthritis, scleroderma, Raynaud's disease, periarteritis nodosa, and dermatomyositis. More than 15% of normal patients, particularly elderly women, also have a mildly elevated ANA, making markedly elevated titers most useful in determining the diagnosis. When the suspicion of collagen-vascular disease is high and the ANA is elevated to greater than 1:80, antibodies to more specific antinuclear antigens should be considered: for example, anti-Ro/SSA and anti-La/SSB/Ha antibodies for Sjögren's syndrome and systemic lupus erythematosus; anti-dsDNA, anti-ssDNA, anti-nRNP, and anti-Sm antibodies for systemic lupus erythematosus; or antihistone antibodies for rheumatoid arthritis or mixed connective tissue disease.145,146
ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
Antineutrophil cytoplasmic antibodies (ANCAs) are IgG autoantibodies directed against cytoplasmic antigens of human polymorphonuclear cells. ANCAs are sensitive for the presence of severe small-vessel vasculitis, such as Wegener's granulomatosis, microscopic polyarteritis nodosa, and segmental necrotizing glomerulonephritis. ANCAs can also be positive in arthritides, inflammatory bowel disease, and HIV infection. Two types of ANCAs have been described based on the cytoplasmic distribution of autoantibodies. A cytoplasmic pattern of staining, termed cANCA, is most often directed against proteinase 3, a neutral serine protease present in polymorphonuclear cells. cANCA is approximately 90% sensitive and specific for Wegener's granulomatosis. A perinuclear staining pattern, termed pANCA, is less specific for disease type and represents autoantibodies to a number of polymorphonuclear antigens. In general, we reserve ANCA testing for patients with uveitis accompanied by severe scleritis, retinal vasculitis, or optic neuritis, particularly when systemic signs or symptoms suggest concurrent renal or respiratory tract disease.147–150 It should be noted, however, that elevated ANCA titers have been demonstrated in 10% to 20% of patients with chronic, idiopathic uveitis in the absence of either ocular or systemic vasculitis.147,151 Some authors have suggested using ANCA titers to monitor disease activity and response to treatment.150,151
COMPLETE BLOOD CELL COUNT WITH DIFFERENTIAL
A complete blood cell count with differential can determine whether an elevated white blood cell count is due to systemic infection or leukemia. In addition, systemic eosinophilia can be found in systemic toxocara infections, atopy, and allergic granulomatous angiitis (or Churg-Strauss syndrome).152,153 Lastly, it is good general practice to obtain a complete blood cell count before initiating systemic therapy with either corticosteroids or other immunosuppressive agents, particularly alkylating agents such as cyclophosphamide and chlorambucil, the effects of which are titrated to total white blood cell count.
ERYTHROCYTE SEDIMENTATION RATE
The erythrocyte sedimentation rate (ESR) is a nonspecific indicator of plasma fibrinogen and globulin levels and may be elevated in systemic infection or inflammation or in the presence of malignancy or paraproteinemias. Using the Westergren method, a normal ESR should be less than 10 mm/h for children, 15 mm/h for men, and 20 mm/h for women. These values may increase to 20 mm/h and 30 mm/h, respectively, for men and women older than 50. Miller and associates154 studied more than 28,000 healthy men and 1000 healthy women aged 20 to 65 and found that for men, 98% of the ESRs would be less than age/2, whereas for women the 98% cutoff could be estimated by (age + 10)/2. These formulas were less reliable for subjects older than 70.
For ophthalmologists, an ESR is most often used to diagnose and monitor giant cell arteritis and polymyalgia rheumatica.155 Although less studied, the ESR may be helpful when systemic signs or symptoms suggest a vasculitis other than giant cell, especially in the setting of severe scleritis, retinal vasculitis, or optic neuritis. Although an elevated ESR does not provide a diagnosis, it strongly supports the presence of a systemic disorder and, as with giant cell arteritis, may be used to gauge the efficacy of systemic immunosuppressants.156,157 C-reactive protein, another circulating acute-phase reactant, provides comparable information.158
The prevalence of herpesvirus antibodies is so high in the general population that a positive antibody titer is virtually meaningless.159,160 A negative test, however, all but eliminates herpesvirus infection from the list of diagnostic possibilities, and therefore can be useful in selected instances. An example of the use of herpesvirus serology to rule out herpetic uveitis might be the young patient with anterior uveitis, elevated intraocular pressure, and iris atrophy who has no associated herpetiform dermatitis or keratitis. For this patient, negative serologic testing for herpes simplex and zoster would essentially confirm the diagnosis of Fuchs' heterochromic iridocyclitis. Serologic testing is available for antibodies against herpes simplex virus, herpes zoster virus, CMV, and Epstein-Barr virus. Herpesvirus serology should remain positive for life.
HUMAN IMMUNODEFICIENCY VIRUS ANTIBODIES
Human immunodeficiency virus antibodies are most commonly detected using an enzyme-linked immunoassay. Positive results are confirmed by a Western blot test.161,162 The predictive value of a positive result on both tests exceeds 99%. We order HIV testing in uveitis patients with (1) known HIV risk factors, (2) severe or bilateral retinitis or choroiditis, and (3) suspected herpes zoster uveitis when they are younger than 50 years of age. HIV testing requires patient consent.
HUMAN LEUKOCYTE ANTIGENS
Human leukocyte antigens (HLAs) are gene products derived from the major histocompatibility complex.163,164 HLA antigens are divided into class I, II, and III: Class I antigens include HLA-A, -B, and -C subtypes, are present on virtually every cell, and mediate the presentation of antigens to cytotoxic T-cells (CD8+ ), a phenomenon termed HLA restriction. Class I antigens are important for lysis of virally infected cells and mediate graft-versus-host disease. Class II antigens, including HLA-DR, HLA-DP, and HLA-DQ subtypes, are found preferentially on B-cells and macrophages, and mediate antigen presentation to helper T-cells (CD4+ ). Aberrant expression of class II antigens has been postulated as an autoimmune mechanism. Class III antigens circulate in the bloodstream, and include the second and fourth components of the classic complement pathway (C2 and C4), as well as properdin factor B of the alternative pathway.
HLA antigens are used for organ and bone marrow transplantation, choosing platelet donors for immunized recipients, and paternity testing, as well as to support the diagnosis of certain diseases known to have increased associations with certain HLA antigens. In the acute, anterior, nongranulomatous uveitis seen with ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, or Reiter's syndrome, more than 75% of cases are HLA-B27 positive, whereas only 5% to 10% of the general population carry this serotype.24,25 Similarly, more than 90% of patients with birdshot choroiditis are HLA-A29 positive.30,31 Other HLA associations of note include HLA-B51 and HLA-B12 with Behçet's syndrome41,42; and HLA-B53, HLA-DR4, and HLA-DRw53 with VKH syndrome.43–45
Lyme disease is a multisystem, tick-borne disorder caused by infection with the spirochete Borrelia burgdorferi.50,51 As with HIV, an enzyme-linked immunoassay in combination with a Western blot test offers the most sensitive and specific testing for serum antibodies against Borrelia burgdorferi.165,166 False-negative results may be obtained in the first few weeks after infection, especially if the patient has been treated with antibiotics, whereas false-positive results occur from cross-reactivity with other spirochetes, including Treponema pallidum,167 and in patients with collagen-vascular disorders.168 Positive testing is therefore most helpful in the setting of known risk factors, such as camping or hiking in wooded areas, or systemic findings suggesting Lyme disease, including migratory arthritis, erythema migrans, or isolated cranial neuropathies.
Like ACE, lysozyme is an enzyme produced by epithelioid cells, giant cells, and macrophages found in granulomas. Although lysozyme levels tend to parallel ACE levels, some authors have suggested that an elevated serum lysozyme level is a more sensitive indicator of active pulmonary sarcoidosis.169 As with ACE, however, studies have yet to address the sensitivity and specificity of an elevated lysozyme for sarcoidosis in a population of uveitis patients with a negative PPD. We generally obtain both ACE and lysozyme levels, because in the absence of a characteristic biopsy, the diagnosis of sarcoidosis is based on the cumulative weight of clinical and laboratory findings, and because studies to date has failed to provide evidence for a clear superiority of circulating ACE versus lysozyme levels in the setting of uveitis.
RHEUMATOID FACTOR TEST
Rheumatoid factor (RF) refers to a class of autoantibodies directed against the Fc fragment of human IgG.142,170 Most often, rheumatoid factor consists of IgM-anti-IgG, although IgG-anti-IgG does occur. About 80% of patients with rheumatoid arthritis are RF seropositive,170 defined as a titer of greater than 1:80. RF seropositivity is nonspecific, however, and may occur in a number of collagen-vascular disorders. RF is therefore best used to support a clinical diagnosis of rheumatoid arthritis, based primarily on age, sex, and the presence of arthritis and extra-articular manifestations, such as subcutaneous nodules or scleritis.141,142 Mildly elevated RF may be seen in acute infections and in the elderly.
Antitreponemal antibody tests, such as the FTA-ABS and MHATP, approach 100% sensitivity and specificity for syphilis, regardless of stage, and are therefore the preferred tests for prior exposure. Unfortunately, these tests remain positive for life and therefore do not reflect ongoing disease activity or the adequacy of prior treatment. The RPR and VDRL titers, in contrast, do reflect disease activity and are therefore used primarily to gauge disease activity and response to therapy. Both types of tests may be run on either serum or cerebrospinal fluid. RPR and VDRL may be falsely elevated in autoimmune disease and related spirochete infections, such as Lyme disease, yaws, and leprosy.171 Both indirect and direct tests for syphilis may be falsenegative in patients with AIDS.172
CD4+ and CD8+ T-lymphocyte counts and ratios have assumed considerable importance with the advent of AIDS, and the recognition that the number of CD4+ T-lymphocytes declines more rapidly than does the number of CD8+ T-lymphocytes during the course of HIV infection.173 As a general rule, children start with about 3000 CD4+ cells/mm3 and reach their normal circulating levels of 1500 cells/mm3 by adulthood. This number continues to decline with age, but should always be greater than 500 cells/mm3; counts less than 500 cells/mm3 are suggestive of immunosuppression. CD4+ cell counts vary considerably from day to day and may be elevated by stress. Splenectomy also elevates peripheral CD4+ counts but tends not to alter the CD4+ ÄCD8+ ratio.174
Once patients are found to be HIV positive, absolute CD4+ T-lymphocyte counts can provide considerable information about ocular disease susceptibility.173 For example, Kaposi's sarcoma, lymphoma, and tuberculosis tend to occur at CD4+ cell counts of between 200 and 500 cells/mm3, whereas pneumocystosis and toxoplasmosis are often seen at counts of 100 to 200 cells/mm3, and CMV retinitis, herpes zoster retinitis, and cryptococcal choroiditis are most prevalent at counts less than 100 cells/mm3.173
Several different tests are available to detect and quantify anti-Toxoplasma gondii antibodies, including the Sabin-Feldman dye test, the indirect fluorescent antibody (IFA) test, and the enzyme-linked immunosorbent assay (ELISA).21–23,175,176 Of these, the Sabin-Feldman dye test remains the most sensitive and specific and the standard against which all other tests are judged. However, the Sabin-Feldman dye test is technically difficult and of limited availability, whereas IFA and ELISA are relatively easy and economical and can be used to distinguish IgG from IgM anti-Toxoplasma gondii antibodies. Moreover, ELISA is available in convenient kits and appears to offer greater specificity at low antibody titers. When interpreting positive titers, it is important to remember that IgM anti-Toxoplasma gondii antibodies may be elevated for up to 1 year after infection, limiting the accuracy with which they can date acute infection, and that antibody titers are generally less reliable in patients with AIDS.
Some investigators have suggested that anterior chamber paracentesis be used to compare the ratio of the circulating anti-Toxoplasma gondii antibody titer with that inside the eye, the so-called Witmer or Witmer-Goldmann coefficient. Here, a ratio of greater than 1 would support the diagnosis of active intraocular toxoplasmosis.21–23 In practice, collection of intraocular fluid for anti-Toxoplasma gondii antibody testing is rarely necessary and, for those few diagnostic dilemmas requiring paracentesis, has been largely supplanted by newer polymerase chain reaction-based assays.177–179
A number of immunodiagnostic approaches for the detection of anti-Toxocara canis antibodies have been developed, including hemagglutination, complement fixation, and IFA testing.19,20 None of these, however, has the sensitivity and specificity of ELISA, which exceeds 90% in most laboratories.180,181 Although a titer of greater than 1:8 is considered diagnostic for ocular toxocariasis, it is important to remember that ocular toxocariasis is primarily a clinical diagnosis and that a negative titer does not rule out the disease.
|SPECIAL TESTS AND PROCEDURES|
Chorioretinal biopsy is most helpful in patients with undiagnosed chorioretinal inflammatory disorders that are unresponsive to standard therapy. We usually consider intraocular biopsy only in poorly seeing eyes, particularly when the second eye shows similar and worsening inflammation.182
COLOR VISION TESTING
Color vision testing serves as an objective measure of optic nerve dysfunction. In addition, patients with birdshot chorioretinopathy30,31 can develop color vision loss disproportionate to their visual acuity or fundus findings, presumably reflecting the widespread outer retinal dysfunction believed to occur in this disease.
CONJUNCTIVAL AND LACRIMAL GLAND BIOPSY
Conjunctival and lacrimal gland biopsy should be reserved for those patients with visible conjunctival masses or lacrimal gland enlargement, as can occur with sarcoidosis,36–38 tuberculosis,84,85 or coccidioidomycosis.46,47 Blind conjunctival biopsies, although once popular in patients with suspected sarcoidosis, have a very low yield and should be avoided.183 Occasionally, a gallium scan will demonstrate lacrimal gland uptake and support the use of lacrimal gland biopsy.
Fluorescein angiography is most often used to diagnose uveitic cystoid macular edema, retinal or choroidal neovascularization, or retinal nonperfusion. Angiography is also useful in patients with neurosensory retinal detachments and outer retinal inflammations, particularly those involving the RPE.34,184
Lumbar puncture is most often used in patients with suspected intraocular lymphoma; atypical cells can be detected cytologically.32,33 Lumbar puncture should be done after a complete neurologic evaluation and imaging procedure (e.g., computed tomography [CT], magnetic resonance imaging [MRI]) to avoid unexpected shifting of intracranial contents. Lumbar puncture also is used to test for suspected meningitis, most often due to syphilis,90,91 tuberculosis,84,85 toxoplasmosis,21–23 cryptococcosis,103,104 or coccidioidomycosis.46,47
The greatest use of oral mucosal biopsy is for the diagnosis of Behçet's syndrome41,42; evidence of an occlusive vasculitis can greatly support the diagnosis. Similarly, characteristic inflammation of one of the minor salivary glands can confirm a clinical suspicion of Sjögren's disease,185 whereas inflammation of the intestinal mucosa can support the diagnosis of ulcerative colitis, Crohn's disease, or Whipple's disease.121,122
Although anterior chamber and vitreous paracenteses have limited utility with regard to determination of intraocular antibody titers (see earlier discussion), aqueous and vitreous samples are useful for polymerase chain reaction testing for toxoplasmosis177–179 and the herpesviruses,186–190 particularly in AIDS patients, in whom diagnosis can be difficult. Biopsy of the anterior and posterior chamber is also used in the following settings: (1) endophthalmitis, to obtain specimens for Gram's stain and culture or to give intraocular antibiotics191; and (2) suspected intraocular lymphoma, to obtain cells for cytologic examination.32,33,191
Intravenously injected gallium-67 citrate localizes to normal liver, spleen, and bone, as well as to areas of active inflammation, such as inflamed lymph nodes, parotid and lacrimal glands, and joints. Although any cause of inflammation can produce a positive test, the gallium scan is used most frequently to identify pulmonary hilar, or lacrimal, parotid, or submandibular gland inflammation—findings suggestive of sarcoidosis.36–38,192 It is interesting to note that although lacrimal, parotid, and salivary gland uptake is said to be less specific than hilar or paratracheal enhancement for sarcoidosis, there are fewer previous studies directly comparing regional uptake in patients with uveitis, and so the predictive value of lacrimal, parotid, and salivary gland uptake in patients with intraocular inflammation and a negative PPD remains unknown.
The sacroiliac joint is inflamed in 60% to 90% of patients with HLA-B27-related uveitis.24,25 Plain radiographs are quite useful for demonstrating inflammatory narrowing of the sacroiliac joints,193 and we order this study in any symptomatic patient with anterior, intermediate, or diffuse uveitis. CT194 and MRI195 offer increased sensitivity for documented sacroiliitis, but are considerably more expensive.
The Schlaegel test was originally proposed by Schlaegel and Weber196 as a 3-week therapeutic trial of oral isoniazid to treat presumed tuberculous uveitis. Improvement during or after treatment was viewed as a positive outcome. Early studies produced equivocal results, however, suggesting poor sensitivity.84,85 These studies notwithstanding, when skin testing supports the diagnosis of tuberculous uveitis and the remaining uveitis workup is negative, we still advocate a therapeutic trial with antituberculous medicines. We tend, however, to use two to four drugs and to treat for 2 to 6 months, depending on the patient's age and early response to the treatment.
Skin testing involves intradermal injection of 0.1 mL of antigen to elicit a delayed-type hypersensitivity reaction indicative of prior exposure. We test virtually all patients with uveitis for tuberculosis with 0.1 mL of 5 units of PPD. This includes patients with a prior bacille Calmette-Guérin (BCG) vaccination or a distant history of tuberculosis, because PPD positivity quickly reverts after BCG or adequate antituberculous therapy, and because a markedly positive test is much more supportive than 5 to 10 mm of induration.197,198 In addition, we place at least two control injections, typically Candida and mumps antigen, to rule out anergy, which can occur with sarcoidosis, AIDS, severe illness, advanced age, or pharmacologic immunosuppression.199,200
Patients with active Behçet's syndrome occasionally show increased dermal sensitivity, termed pathergy, which is manifested by formation of a local pustule in response to intradermal injection of 0.1 mL of sterile normal saline solution. This test should be performed with a 25-gauge needle and read 12 to 36 hours after injection. Although often discussed, the Behçet's skin test has limited sensitivity, even in the active phase of Behçet's syndrome.41,42
The Kveim-Siltzbach test involves intradermal injection of a suspension of spleen tissue obtained from a patient with biopsy-“proven” sarcoidosis.36–38 A biopsy specimen is obtained from the injection site at 6 weeks and examined for sarcoid granulomas, which indicates a positive test. This test is reported to be positive in up to 90% of patients with active pulmonary sarcoidosis and 25% to 50% of patients with extrapulmonary disease. Although of historical interest, the difficulty of obtaining suitable tissue, the inability to use systemic corticosteroids after placement, and concerns about transmitting infectious agents, particularly HIV, have made the test obsolete.
B-scan ultrasonography is used most commonly in patients with uveitis to investigate inflammatory choroidal and scleral thickening, as can occur with VKH syndrome,43–45 posterior scleritis,139 and sympathetic ophthalmia,72,73 and to evaluate the posterior segment in patients with dense cataracts or other media opacities.
|Our approach, consisting of a thorough history, review of systems, physical examination, thoughtful use of the naming and meshing techniques, and judicious choice of laboratory tests and special studies, should permit the practicing ophthalmologist to arrive at a diagnosis for the vast majority of patients with uveitis. Treatment options and prognoses, although outlined in Table 3, are covered more thoroughly in other sources.1–7|
3. Brockhurst RJ, Jakobiec FA (sect eds): Uveal tract. In Alberts DM, Jakobiec FA (vol eds): Principles and Practice of Ophthalmology. Vol 1, Clinical Practice, Sect 2, Chaps 21–37. Philadelphia, WB Saunders, 1994
62. Melamed J, Sebben JC, Maestri M et al: Epidemiology of ocular toxoplasmosis in Rio Grande do Sul, Brazil. In Dernouchamps JP, Verougstraete C, Caspers-Velu L (eds): Recent Advances in Uveitis: Proceedings of the Third International Symposium on Uveitis, Brussels, Belgium. Amsterdam, Kugler, 1993
72. Chan CC, Roberge FG, Whitcup SM, Nussenblatt RB: 32 cases of sympathetic ophthalmia: a retrospective study at the National Eye Institute, Bethesda, MD, from 1982-1992. Arch Ophthalmol 113:597, 1995
82. Saran BR, Maguire AM, Nichols C et al: Hypopyon uveitis in patients with acquired immunodeficiency syndrome treated for systemic Mycobacterium avium complex infection with rifabutin. Arch Ophthalmol 112:1159, 1994
89. Kuppermann BD, Pety JG, Richman DD et al: Correlation between CD4+ counts and the prevalence of cytomegalovirus retinitis and human immunodeficiency virus-related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Ophthalmol 115:575, 1993
93. Manabu M, Watanabe T, Yamaguchi K, Tajima K: Human T-lymphotrophic virus, type I associated disease. In Pepose JS, Holland GN, Wilhelmus KR (eds): Ocular Infection & Immunity, Chap 98, pp 1366–1387. St. Louis, Mosby, 1996
104. Kestelyn P, Taelman H, Bogaerts J et al: Ophthalmic manifestations of infections with Cryptococcus neoformans in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 116:721, 1993
106. Pettit TH, Edwards JE Jr, Purdy EP, Bullock JD: Endogenous fungal endophthalmitis. In Pepose JS, Holland GN, Wilhelmus KR (eds): Ocular Infection & Immunity, Chap 91, pp 1262–1286. St. Louis, Mosby, 1996
143. Ainsley GM, Benatar SR: Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extrathoracic involvement, radiographic type and therapy. Q J Med 55:253, 1985
158. Dinant GJ, De Kock CA, van Wersch JWJ: Diagnostic value of C-reactive protein measurement does not justify replacement of the erythrocyte sedimentation rate in daily general practice. Eur J Clin Invest 25:353, 1995
160. Lucht E, Sundqvist V-A, Linde A et al: Presence of autologous neutralizing antibodies against cytomegalovirus (CMV) in serum of human immunodeficiency virus type 1-infected patients shedding CMV in saliva. J Infect Dis 169:1096, 1994
173. Turner BJ, Hecht FM, Ismail RB: CD4+ T-lymphocyte measures in the treatment of individuals infected with human immunodeficiency virus type 1: a review for clinical practitioners. Arch Intern Med 154:1561, 1994
186. Cunningham ET Jr, Short GA, Irvine AR et al: Acquired immunodeficiency syndrome-associated herpes simplex virus retinitis: clinical description and use of a polymerase chain reaction-based assay as a diagnostic tool. Arch Ophthalmol 114:834, 1996
190. Short GA, Margolis TP, Kuppermann DB et al: A polymerase chain reaction based assay for diagnosing varicella-zoster virus retinitis in patients with acquired immunodeficiency syndrome. Am J Ophthalmol 123:157, 1997