Purpose
To describe an approach to diagnosing the uveitides, a collection of about 30 separate diseases characterized by intraocular inflammation.
Design
Perspective.
Methods
Integration of clinical approach with a more formal, informatics-derived approach to characterization and a Bayesian approach to laboratory testing.
Results
The patient’s uveitis is characterized along several dimensions: course, laterality, anatomic location of the inflammation, morphology, presence of active infection, and the host (age, presence of a systemic disease). Posterior uveitis can be characterized further by whether it is primarily a retinitis, choroiditis, or retinal vasculitis; by whether it is paucifocal or multifocal; and by the morphology of the lesions. This characterization narrows the differential diagnosis to 1 or, at most, a few diseases. Laboratory screening (ie, testing all patients) should be reserved for those diseases that can present as any type of uveitis, whereas targeted testing (ie, testing a subset with specific features) is used selectively. Laboratory testing should be used to identify an infection (which will alter therapy) or a systemic disease that will affect the patient’s health. A uveitis that is not one of the established diagnoses is designated as “undifferentiated” with the course, laterality, and anatomic location (eg, undifferentiated bilateral chronic anterior uveitis). We avoid the term “idiopathic” uveitis as most identified noninfectious uveitic diseases are idiopathic, and most systemic diseases associated with uveitis also are idiopathic (eg, juvenile idiopathic arthritis).
Conclusion
This approach should lead to the correct diagnosis of the specific uveitic disease in the large majority of cases without overuse of laboratory testing.
Uveitis refers to a collection of about 30 diseases characterized by intraocular inflammation ( Table 1 ). Traditionally these diseases have been grouped by the primary anatomic location of the inflammation as anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis. In the past, standardized “review of system” questionnaires often have been used to identify any symptoms of a systemic disease and a laboratory evaluation conducted to identify the “cause” of the uveitis, an approach often termed “the etiologic diagnosis of uveitis.” A refinement on this approach is the “naming-meshing” approach popularized by Smith and Nozik. If no underlying disease is found and a specific syndromic name cannot be given to the uveitis, it is termed “idiopathic.” This approach has problems and has led to tactics such as shotgun “uveitis survey” laboratory testing (a practice deplored by uveitis experts), the idea that one should only “work up” the second attack of uveitis (because of the low yield of shotgun laboratory testing), and exhaustive searches for laboratory evidence of sarcoidosis or other systemic diseases (often using tests with a low positive predictive value), even when there is no other evident organ involvement.
| Anatomic Location | Infectious | Systemic Disease | No Systemic Disease |
|---|---|---|---|
| Anterior uveitis | Cytomegalovirus anterior uveitis | HLA-B27-associated uveitis | Fuchs uveitis syndrome |
| Herpes simplex anterior uveitis | Juvenile idiopathic arthritis–associated uveitis | ||
| Varicella zoster anterior uveitis | Behçet disease | ||
| Syphilis | Sarcoidosis | ||
| Intermediate | Syphilis | Multiple sclerosis–associated uveitis | Pars planitis |
| Lyme disease | Sarcoidosis | ||
| Posterior uveitis | Toxoplasmic retinitis | Sarcoidosis | Serpiginous choroiditis |
| Cytomegalovirus retinitis | Acute posterior multifocal placoid pigment epitheliopathy | ||
| Acute retinal necrosis | Multiple evanescent white dot syndrome | ||
| Progressive outer retinal necrosis | Birdshot chorioretinitis | ||
| Diffuse unilateral subacute neuroretinitis | Multifocal choroiditis with panuveitis | ||
| Syphilis | Punctate inner choroiditis | ||
| Lyme disease | Relentless placoid choroiditis (“ampiginous”) | ||
| Tuberculosis | |||
| Bartonella neuroretinitis | |||
| Panuveitis | Syphilis | Behçet disease | Sympathetic ophthalmia |
| Lyme disease | Vögt-Koyanagi-Harada disease | ||
| Sarcoidosis |
Underlying these approaches is the flawed notion that uveitis typically is a manifestation of “something else” and that the “something else” must be identified regardless of cost. Also underlying this approach is the flawed concept that discovering an idiopathic systemic disease renders the uveitis not-idiopathic. For example, is chronic anterior uveitis in a child without an associated systemic disease idiopathic, but not idiopathic when present in a child with juvenile idiopathic arthritis? In fact, the etiology of most complex disorders is unknown (ie, idiopathic). Risk factors can be identified and pathogenesis inferred, but except for infectious diseases, Mendelian genetic disorders, and drug- or foreign substance–related toxic or allergic reactions, most disorders are not amenable to a simple identification of one “etiology.” Hence “the etiologic diagnosis of the uveitis” is a misleading concept.
A more modern approach is to recognize that the goal of the clinician is to make the diagnosis of a specific uveitic disease. The likely diagnosis can be derived from the history, examination, and, for posterior uveitides, sometimes the imaging studies. Laboratory testing then is used to identify infectious diseases that cannot be identified by the morphologic picture and systemic diseases with an impact on the patient’s health. Making the correct diagnosis of a specific uveitic entity is critical to management; each disease has its own course, treatment, and prognosis. The import of this approach is shown in Table 2 , which lists selected posterior uveitides. Several are infectious (in this article infectious uveitides are those in which there are replicating infectious organisms) and require antimicrobial or antiviral treatment; some are spontaneously remitting diseases with a good prognosis, requiring no treatment; and several are presumed to be autoimmune (or autoinflammatory), chronic, eye-limited disorders, requiring systemic immunosuppression. Even if one restricts the discussion of management decisions to noninfectious posterior uveitis, the management varies substantially, depending on the specific disease diagnosed.
| Disease | Pathogenesis | Course | Treatment |
|---|---|---|---|
| Toxoplasmic retinitis | Parasitic infection | Recurrent acute | Antimicrobial agents |
| Cytomegalovirus retinitis | Viral infection | Chronic | Antiviral agents |
| Acute retinal necrosis | Viral infection | Monophasic acute | Antiviral agents |
| Serpiginous-like tuberculous choroiditis | Mycobacterial infection | Chronic | Antimicrobial agents |
| Acute posterior multifocal placoid pigment epitheliopathy | Unknown | Self-limited | None, good prognosis |
| Multiple evanescent white dot syndrome | Unknown | Self-limited | None, good prognosis |
| Serpiginous choroiditis | Presumed immune-mediated | Chronic | Immunosuppression |
| Birdshot chorioretinitis | Presumed immune-mediated | Chronic | Immunosuppression |
| Multifocal choroiditis with panuveitis | Presumed immune-mediated | Chronic | Immunosuppression |
| Punctate inner choroiditis | Presumed immune-mediated | Monophasic acute, recurrent acute, or chronic | Variable, none to immunosuppression |
Characterization of the Uveitis
The diagnosis of a uveitic entity is begun by carefully characterizing it along several dimensions ( Table 3 ) based on the history, examination, and, in selected diseases, imaging. These dimensions have been derived from the Standardization of Uveitis Nomenclature (SUN) Project, which is developing classification criteria (criteria used for research reporting) for the major uveitic diseases, and adapted to clinical care. The course of the disease is determined by its onset (sudden or insidious) and duration (limited or persistent). Sudden-onset disease of limited duration is considered acute disease, whereas chronic disease typically is insidious in onset but with a persistent duration. Acute disease may be monophasic, with a single, limited-in-duration episode (for research purposes, defined as less than 3 months), or recurrent. The key feature of recurrent acute disease is the presence of episodes of active inflammation separated by periods of no inflammation when not on therapy. Conversely, chronic disease relapses promptly when therapy is discontinued. If these terms are used precisely, the often seen term “chronic/recurrent uveitis” has no meaning. Furthermore, precise characterization will guide therapy. Recurrent acute disease may need only treatment of acute attacks, whereas chronic disease is likely to need chronic suppressive therapy.
| Dimension | Examples |
|---|---|
| Course | Acute, monophasic vs recurrent acute vs chronic |
| Laterality | Unilateral vs unilateral alternating vs bilateral asynchronous vs bilateral simultaneous |
| Anatomic | Anterior vs intermediate vs posterior vs panuveitis |
| Morphology | Retinitis vs choroiditis Paucifocal vs multifocal |
| Infection | Toxoplasmosis vs cytomegalovirus vs herpes simplex virus vs varicella zoster virus vs syphilis vs Lyme disease vs Bartonella |
| Host/systemic disease | Child vs adult Immunocompromised (eg, AIDS, transplant) vs immunocompetent |
The second dimension is the laterality. Uveitides may be unilateral, unilateral alternating, bilateral simultaneous, or bilateral asynchronous. In unilateral alternating disease, either eye may be affected by an attack, but only one eye is affected at a time, and the attacks are episodic and recurrent in nature. Conversely, in bilateral asynchronous disease, the onset in the 2 eyes is not simultaneous, but both eyes remain affected after involvement begins in the second eye, and the disease typically is chronic in nature.
The third dimension is the anatomic type of uveitis: anterior, intermediate, posterior, or panuveitis. The anatomic class of uveitis is based on the primary location of the inflammatory reaction, but not on the location of any structural complications, such as macular edema. In anterior uveitis, cells are seen primarily in the anterior chamber; there may be some retrolenticular cells present (iridocyclitis), but inflammation does not extend all the way posteriorly through the vitreous. Inflammation primarily in the vitreous is termed intermediate uveitis; there may be a mild anterior chamber reaction, but there should not be anterior segment structural complications, such as posterior synechiae or peripheral anterior synechiae. If there is a substantial anterior chamber reaction with structural complications, the uveitis should be classified as both an anterior and intermediate uveitis. In posterior uveitis there are chorioretinal inflammatory lesions, and in some diseases there is an accompanying vitreous inflammatory reaction. In a panuveitis, inflammation affects the anterior chamber, vitreous, and retina/choroid, but no one location predominates. As with any classification system, there is some arbitrariness in classification and apparent inconsistencies based on historical naming of the syndrome. Hence multifocal choroiditis with panuveitis is considered a posterior uveitis because the primary inflammation is in the choroid and the accompanying anterior chamber or vitreous reaction typically is mild.
Posterior involvement can be further subdivided based on the primary site of inflammation as a retinitis, a choroiditis, or a retinal vasculitis. Although there is some variability in the use of the term, in this context retinal vasculitis should involve inflammation of the retinal vessels, preferably with evidence of vascular occlusion. Mere leakage should not suffice; macular edema is not retinal vasculitis, even though there is vascular leakage. Retinitis and choroiditis can be further described as paucifocal (a few spots) or multifocal. Sometimes the term “focal” is used interchangeably with “paucifocal” and interpreted as distinct from “multifocal.” In immunologically normal hosts, retinitis typically is paucifocal and is nearly always infectious in nature (eg, toxoplasmic retinitis, acute retinal necrosis). Multifocal retinitis does occur, but it occurs in immunocompromised hosts and is infectious in nature. Choroiditis may be paucifocal or multifocal and may be either infectious or immune-mediated in nature. Although presumed immune-mediated multifocal choroidopathies occur in immunologically normal hosts (eg, birdshot chorioretinitis), infectious multifocal choroiditides typically are seen in immunocompromised hosts. The choroidal lesions of a multifocal choroiditis can be further described by a short phrase that leads to the likely diagnosis. For example, the lesions of serpiginous choroiditis are amoeboid or serpentine; those of acute posterior multifocal placoid pigment epitheliopathy, placoid; those of birdshot chorioretinitis, yellow-orange ovoid; those of multifocal choroiditis with panuveitis, “punched-out” atrophic; those of punctate inner choroiditis, punctate; and those of multiple evanescent white dot syndrome, evanescent and white.
The value of this approach (which is more structured and formalized but is somewhat akin to the “naming-meshing” approach) is suggested by Table 4 . The proper characterization of the uveitis along these dimensions leads to a limited differential. For example, studies of anterior uveitis have shown that although only 20% of all anterior uveitis is spondyloarthropathy-associated (also known as HLA-B27-associated), nearly 80% of patients with recurrent acute, unilateral alternating, anterior uveitis will have a spondyloarthropathy or be HLA-B27 positive. Of patients with HLA-B27-associated uveitis, about 60%-75% will have an associated spondyloarthropathy, and of these, in about one half, the spondyloarthropathy will be undiagnosed or misdiagnosed prior to the uveitis consultation. Hence the proper characterization of the uveitis can lead to the correct diagnosis of an associated systemic disease in about one third of the patients with this uveitic disease. Other features, such as the nature of the keratic precipitates, the severity of the anterior chamber inflammation (eg, presence of a hypopyon), the presence or absence of posterior synechiae, and the presence of other iris features (eg, atrophy, heterochromia), assist in the diagnosis of anterior uveitis ( Table 5 ). Fuchs heterochromic iridocyclitis (also known as Fuchs uveitis syndrome) practically is defined by the features of the “stellate” keratic precipitates, the absence of posterior synechiae, and the heterochromia. Although hypopyon uveitis is the classical anterior segment finding in Behçet uveitis, a hypopyon also can be seen in spondyloarthropathy-associated (HLA-B27-associated) uveitis and in certain drug reactions producing uveitis (eg, rifabutin). In fact, in the United States, because of the much greater prevalence of the spondyloarthropathies than of Behçet disease, a patient presenting with hypopyon uveitis is more likely to have spondyloarthropathy-associated uveitis. However, in the Middle East and the Far East, the situation is reversed because of the greater prevalence of Behcet disease. A study using anterior chamber paracentesis for polymerase chamber reaction (PCR) analysis for viral DNA demonstrated that classic-appearing “herpetic uveitis” with sectoral iris atrophy nearly always (>95%) was herpetic uveitis on PCR testing. Hence PCR testing will have value in uncertain cases, but in typical cases the diagnosis can be made on the clinical features.
| Course | Laterality | Anatomic Location | Morphology | Host | Disease Examples |
|---|---|---|---|---|---|
| Recurrent acute | Unilateral alternating | Anterior | Spondyloarthropathy-associated uveitis (HLA-B27-associated) | ||
| Chronic | Bilateral | Anterior | Child | Juvenile idiopathic arthritis–associated uveitis | |
| Chronic | Unilateral | Anterior | Heterochromia | Fuchs uveitis syndrome | |
| Chronic | Bilateral | Intermediate | Snowbank formation | Pars planitis | |
| Recurrent acute | Unilateral | Posterior | Paucifocal retinitis | Toxoplasmic retinitis | |
| Chronic | Unilateral or bilateral | Posterior | Paucifocal retinitis | Immunocompromised | Cytomegalovirus retinitis |
| Acute | Unilateral or bilateral | Posterior | Paucifocal peripheral retinitis | Immunocompetent | Acute retinal necrosis |
| Chronic | Bilateral | Posterior | Multifocal choroiditis | Immunocompetent | Birdshot chorioretinitis, multifocal choroiditis with panuveitis |
| Acute monophasic | Bilateral or unilateral | Posterior | Multifocal choroiditis | Immunocompetent | Acute posterior multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
