Uveitis: Diagnostic Approach and Ancillary Analysis
Unni K. Nair
Emmett T. Cunningham Jr.
Acknowledgement
Supported in part by The Pacific Vision Foundation and The San Francisco Retina Foundation.
There is a strong tendency for most ophthalmologists to rely heavily on ancillary testing to search for and 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.1,2,3,4,5,6,7 This information helps direct the physician in 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 uveitis:
History, including demographic and geographic history, chief complaint, history of present illness, past ocular history, past medical and surgical history, personal history, and family history
Review of systems
Physical examination, both systemic and ocular
Naming
Meshing
Clinical laboratory investigations, special tests and procedures, and subspecialist consultation, as determined by steps 1 through 5
Uveitic diagnosis, as determined by steps 1 through 6
Patient management, based on the known course and prognosis of the identified uveitic entity as weighed against the potential risks of various treatments
HISTORY
DEMOGRAPHIC HISTORY
The most pertinent patient demographics are age, sex, and race.7,8,9,10,11,12,13,14 Of these, age is by far the most important. Most uveitic syndromes occur during the broad, middle-age group of 20 to 60 years,7,8,9,10,11,12,13,14 and virtually all diagnoses should be considered for patients in this category. Childhood uveitis encompasses a disproportionate number of cases of juvenile idiopathic arthritis (JIA),8,15,16,17 intermediate uveitis,18,19 toxocariasis,20,21 and toxoplasmosis.22,23,24,25 HLA-B27–related uveitis26,27 and Fuchs uveitis syndrome28,29 are seen primarily in older adolescents and young adults. Serpiginous30,31 and birdshot chorioretinopathy,32,33 in contrast, are more prevalent in those older than 50 years of age. Masquerade syndromes should be suspected at both ends of the age spectrum,34,35 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 JIA,15,16,17 which tends to affect young girls, and HLA-B27–related uveitis,26,27 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 HLA-B27–related uveitis26,27 and the so-called white-dot syndromes or inflammatory chorioretinopathies36,37 in whites; ocular sarcoidosis38,39,40 and systemic lupus erythematosus41,42 in those of African descent; Behçet syndrome43,44 in those of Mediterranean, Middle Eastern, and Asian descent; and Vogt-Koyanagi-Harada (VKH) syndrome45,46,47 in Asians, Asian Indians, and Native Americans.
GEOGRAPHIC HISTORY
A patient’s birthplace and history of travel and residence are important factors when considering the diagnosis of uveitis. 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,48,49 which occurs in the semiarid desert regions of the Southwest; with histoplasmosis,50,51 which is indigenous to the Mississippi and Ohio River valleys; and with Lyme disease,52,53 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, coccidioidomycosis48,49 and cysticercosis54,55 are found in Central and South America, whereas onchocerciasis56,57 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 less standardized.57,58,59,60 Toxoplasmosis is more frequent in parts of France24,61,62 and Brazil,24,63,64 where eating raw or undercooked meat is more common.
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 JIA,15,16,17 or so-called white iritis,65 in which pain, photophobia, and redness are frequently absent in the setting of significant, ongoing iridocyclitis. Symptomatic floaters suggest primary vitreous inflammation. Other localizing complaints include fixed scotomata, which suggest focal retinal damage, metamorphopsia or micropsia, which can occur in the setting of subretinal or intraretinal fluid or in association with retinal traction or distortion; and altitudinal or patchy visual field loss, 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 pigmentosa66 and retinal detachment,67,68 both of which may cause symptoms of floaters and show evidence of vitritis. Similarly, a history of herpes simplex keratitis69 or herpes zoster ophthalmicus70 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 toxoplasmosis22,23,24,25 or toxocariasis20,21 involving the macula. Past ocular trauma and surgery both increase the risk of endophthalmitis,71,72 lens-induced uveitis,73,74 and sympathetic ophthalmia.75,76 Last, a history of nonuveitic glaucoma is important for at least three reasons. First, some agents, such as β-blockers or prostaglandin agonists, can infrequently cause or worsen uveitis.77,78 Second, cholinomimetics, such as pilocarpine, tend to promote intraocular inflammation and should be avoided in patients with uveitis.79 Third, patients with glaucoma are at increased risk for having elevated intraocular pressure in response to local and systemic corticosteroids80,81 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 or antiviral agents, such as foscarnet. Last, some commonly used systemic medications have been associated with uveitis, including antibiotic sulfonamides,82 pamidronate disodium (an inhibitor of bone resorption),83 and rifabutin (used in patients with acquired immunodeficiency syndrome [AIDS] as prophylaxis against, and treatment for, Mycobacterium avium complex infection).84,85,86 In addition, the tumor necrosis factor inhibitor etanercept (Enbrel) has been implicated as a cause of uveitis in some patients.87
PERSONAL HISTORY
A thorough dietary, sexual, drug-use, pet, and contagion-exposure history should be elicited from every patient with uveitis.
DIETARY HISTORY
Pica, a practice common among children, increases the risk for both toxocariasis20,21) and toxoplasmosis.22,23,24,25 Similarly, eating raw or incompletely cooked meat can lead to toxoplasmosis22,23,24,25 or cysticercosis,54,55 and drinking unpasteurized milk can transmit tuberculosis88,89 or brucellosis.90,91 Curiously, and for unknown reasons, eating English walnuts has been associated with the formation of oral aphthae in patients with Behçet syndrome.2
SEXUAL HISTORY
Unprotected sexual relations put patients at risk for a host of sexually transmitted diseases, many of which have been associated with uveitis. Common sexually transmitted pathogens include herpes simplex virus,69 herpes zoster virus,70 cytomegalovirus (CMV),92,93 syphilis,94,95 chlamydia,96 human T-cell leukemia virus,97,98 and human immunodeficiency virus (HIV).99,100,101,102,103 HIV-infected patients can experience a dramatically altered spectrum of uveitic disorders,99,100,101,102,103 such as an increased risk of syphilitic uveitis,104 CMV retinitis,92,93 Pneumocystis carinii choroiditis,105,106 and cryptococcal choroiditis107,108—diseases that were once rare and seen only in patients with profound immunosuppression from systemic medications or malignancy. Other important risk factors for contracting HIV include intravenous drug use or a history of blood-product transfusion.
DRUG-USE HISTORY
PET HISTORY
Diseases passed from animals to humans, termed zoonoses, have become increasingly recognized in ophthalmology. For example, cats can transmit both Toxoplasma gondii,22,23,24,25 which causes toxoplasmosis, and Bartonella henselae,111,112 the causative organism for catscratch disease. Dogs, especially puppies, can shed Toxocara canis.20,21
CONTAGION-EXPOSURE HISTORY
The most important nonsexually transmitted contagious causes of uveitis in immunocompetent patients are tuberculosis88,89 and toxoplasmosis,22–25 which are of particular importance in developing countries. TORCH infections113 (toxoplasmosis,114 other [including syphilis115], rubella,116 CMV,117 and herpes simplex virus118) 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, such as syphilis, be reported to the public health department.
FAMILY HISTORY
With rare exceptions,119,120,121,122,123,124,125,126, uveitic syndromes are not believed to have a classic mendelian inheritance (i.e., recessive, dominant, or X-linked). Genetics does appear to play a role in some forms of uveitis, however, as evidenced by their increased association with race or a particular human leukocyte antigen (HLA) subtype. The two most notable associations in this regard are, first, HLA-B27 with anterior uveitis (particularly in whites), often occurring together with ankylosing spondylitis, Reiter syndrome, inflammatory bowel disease, or psoriatic arthritis26,27; and second, HLA-A29 with birdshot chorioretinopathy.32,33 Other HLA associations of note include HLA-B51 and HLA-B12 with Behçet syndrome;43,44;nd HLA-B53, HLA-DR4, and HLA-DRw53 with VKH disease.45,46,47 Blau syndrome, a familial form of granulomatous inflammation characterized by uveitis, dermatitis, and arthritis, is associated with a mutation in the caspase recruitment domain (CARD15) gene.127,128
REVIEW OF SYSTEMS
A thorough, systematic review of systems serves at least two purposes in patients with uveitis:
It identifies specific signs and symptoms that might indicate the presence of a systemic disease previously unrecognized by the patient. Examples include the arthritis that occurs with JIA,15,16,17 the diarrhea of inflammatory bowel disease,129,130 and the fevers and night sweats that occur with tuberculosis.88,89
PHYSICAL EXAMINATION
SYSTEMIC EXAMINATION
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 a psoriasis-like rash on the palms and soles;94,95;KH disease can produce meningismus, vitiligo, poliosis, alopecia, and dysacousis;45,46,47;nd toxocariasis20,21 is occasionally associated with a restrictive airway disease that can mimic asthma.
OCULAR EXAMINATION
Patients with uveitis require a complete eye examination, with special attention to the following.
Refraction
A careful refraction is necessary to provide an accurate assessment of the patient’s best-corrected visual acuity. Both intraocular inflammation and corticosteroids accelerate cataract formation, frequently producing a “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 corticosteroid injection for the treatment of cystoid macular edema.
Intraocular Pressure
Any form of uveitis can be complicated by ocular hypertension or glaucoma if chronic or recurrent.79 In contrast, acute uveitis is typically associated with a lowered intraocular pressure. Notable exceptions to this rule of acute uveitic hypotony include sarcoidosis38,39,40 herpes simplex keratouveitis,69 herpes zoster keratouveitis,70 CMV-associated anterior uveitis,131,132 toxoplasmosis,22,23,24,25 syphilis,133 and Posner-Schlossman syndrome (also termed glaucomatocyclitic crisis),134 all of which may be accompanied by an acute elevation in 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 sarcoidosis38,39,40 or tuberculosis.89,90 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,135,136 seen with rheumatoid arthritis or less common systemic vasculitides (e.g., Wegener granulomatosis, polyarteritis nodosa, relapsing polychondritis). Evidence of past or present keratitis may be related to various infectious organisms, but herpes simplex69 and herpes zoster70 should be considered when corneal sensation is decreased or intraocular pressure elevated.79 Band keratopathy results from long-standing uveitis and is seen frequently in JIA15,16,17 and sarcoidosis.38,39,40 Inferior corneal thickening and nummular stromal infiltrates have been described in patients with sarcoidosis,137 as well as idiopathic intermediate uveitis.138
Keratic precipitates should be described with regard to number, distribution, appearance, and size.2,3,4 Most are found on the inferior corneal endothelium between 4 and 8 o’clock, an area termed the Arlt triangle. Keratic precipitates are characterized as follows: pigmented, often old and inactive; white or yellow, recently or currently active; granulomatous, larger and frequently greasy in appearance; nongranulomatous, smaller; stellate, often distributed over the entire endothelial surface. They;ccur most commonly with herpetic uveitis, Fuchs uveitis syndrome, toxoplasmosis, and sarcoidosis.2
Gonioscopy
The angle should be examined for granulomas, termed Berlin nodules, as well as anterior synechiae and neovascularization, both of which may occur with recurrent or chronic intraocular inflammation.
Anterior Chamber
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 rotation of the ciliary body and iris root. 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 et al,139 although other grading systems are available (Table 37-1).1,4,5 However, some variation may exist in grading anterior chamber cells and flare.140 A standardized anterior chamber grading system has recently been introduced by the Standardization of Uveitis Nomenclature (SUN) working group.141 Hypopyon formation signifies severe anterior inflammation and may be seen in HLA-B27-related uveitis,26,27 Behçet syndrome,43,44 and endophthalmitis,109,110 or in association with keratitis, particularly herpetic infection.69 In the developing world, leptospirosis is a recognized cause of hypopyon.142 A pseudohypopyon may represent tumor cells, either from a primary intraocular malignancy, such as retinoblastoma, or from a metastatic carcinoma.34,35 The occurrence of a hemorrhagic hypopyon with chronic uveitis suggests the possibility of iris or angle neovascularization,143 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.34,35
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