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Anterior Uveitis
Key Concepts
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Anterior uveitis is the most common form of uveitis, with an annual incidence of 8:100,000 population, and is the least likely to be referred to a uveitis specialist.
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Although anterior uveitis is usually the most easily managed form, associated complications, such as glaucoma, may result in severe visual loss.
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Many disorders that can cause panuveitis, such as sarcoidosis, Behçet disease, bacterial endophthalmitis, and ocular malignancies, start as anterior uveitis. As with all cases of uveitis, it is important to diagnose infection and malignancy so that prompt and appropriate therapy can be started.
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Diagnostic evaluation should be based on the medical history and clinical examination findings and used to narrow the differential diagnosis.
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Anterior uveitis is associated with systemic disease in about half the patients. Diagnosis of the underlying condition is important to ensure proper treatment of both uveitis and the systemic disease.
Anterior uveitis is the most common form of uveitis and the least likely to be referred to a uveitis specialist. The diagnosis of anterior uveitis is based on inflammation limited to the anterior chamber. Because many patients have only a single episode of disease without recurrence or complications, there is debate as to the right approach to evaluate and treat patients with newly diagnosed anterior uveitis. Although anterior uveitis is usually the most easily managed form, associated complications, such as glaucoma, may result in severe visual loss. In addition, many disorders that can cause a sight-threatening panuveitis, such as sarcoidosis, Behçet disease, and bacterial endophthalmitis, can start as anterior uveitis. Furthermore, ocular malignancies, such as leukemia, can masquerade as anterior uveitis. Therefore the approach to patients with anterior uveitis requires careful thought and planning.
As we learn more about the pathophysiology of uveitis, it is becoming increasingly clear that many forms of uveitis may be triggered by microbial agents. There are numerous conditions in which the line between infectious and noninfectious causes becomes blurred. Therefore this chapter is included in the section on noninfectious uveitic conditions. Infectious causes of anterior uveitis are reviewed in other relevant chapters in this text.
Epidemiology
Anterior uveitis accounts for approximately three-quarters of cases of uveitis, with an annual incidence rate of about eight per 100,000 population. Most cases have no identifiable cause and are classified as idiopathic; however, in some series, human leukocyte antigen (HLA)-B27 is associated with the disease in one-third to almost two-thirds of patients. , Furthermore, in a single center series of patients with spondyloarthritis, the prevalence of uveitis at the time of diagnosis was 11.5%, and 20 years after diagnosis, it reached nearly 40%.
Clinical Description
Anterior uveitis includes diseases previously categorized as both iritis (inflammation of the iris) and iridocyclitis (inflammation of the iris and ciliary body). Patients with anterior uveitis often complain of redness, pain, and photophobia; some are relatively asymptomatic. Tearing may occur, but ocular discharge is rare. Some patients with severe anterior uveitis may also complain of blurred vision. Conjunctival injection is frequently noted on examination. Ciliary flush, that is, conjunctival injection in the perilimbal area, is characteristic of many forms of the disease. Pupillary miosis, posterior synechiae, and dilated iris vessels are common findings in all forms of anterior uveitis. However, sector abnormalities of the iris may suggest herpes zoster ophthalmicus as an underlying cause. The iris may also adhere to the trabecular meshwork, forming peripheral anterior synechiae (PAS). These PAS should be looked for on gonioscopic examination because patients with severe PAS are at increased risk for secondary glaucoma. In addition, patients with severe posterior synechiae, that is, iris adhesions to the lens, can develop pupillary block and may require prophylactic iridectomy.
The major indicators of anterior uveitis are the presence of cells and flare in the anterior chamber. Anterior chamber inflammation is assessed on slit-lamp biomicroscopic examination and is discussed in detail in Chapter 3 . These cells and flare represent extravasated inflammatory cells and protein as a result of a breakdown of the blood–aqueous barrier. The clinical examination remains the gold standard in assessing anterior segment uveitis. A commercial device using laser photometry to objectively assess anterior chamber flare is available, although it is not routinely used in clinical practice. Guex-Crosier et al. used laser flare-cell photometry to demonstrate that disruption of the blood–aqueous barrier was very pronounced in idiopathic anterior uveitis and acute retinal necrosis but minimal in patients with toxoplasmosis or Fuchs heterochromic cyclitis. These authors have suggested that laser flare-cell photometry provides quantitative and sensitive assessment of anterior segment inflammation and may be useful in the management of patients with uveitis.
Fibrin may accumulate in the anterior chamber and may cause the once-mobile cells that circulate in the aqueous to become frozen. This plasmoid aqueous is a sign of severe anterior uveitis, which requires aggressive therapy. Another sign of severe anterior uveitis is a hypopyon composed of layered leukocytes. A hypopyon can be seen in a number of forms of anterior uveitis, but it is frequently associated with Behçet disease or infectious endophthalmitis. Anterior uveitis, including some cases with hypopyons, has been described in patients with acquired immunodeficiency syndrome (AIDS) receiving the drug rifabutin as treatment or prophylaxis for mycobacterial infection. Also, hyphema may occur in patients with anterior uveitis, but it usually resolves without permanent damage.
Inflammatory cells may also collect and adhere to the corneal endothelium and form keratic precipitates (KPs). The mechanism appears to involve the expression of cell adhesion molecules that are upregulated in the presence of inflammatory cytokines, such as interleukin-1 (IL-1). Large, greasy-appearing KPs are suggestive of a granulomatous inflammation and may help in determining the cause of the uveitis (see Chapter 4 ). In vivo confocal microscopy of keratic precipitates showed heterogeneous features of KPs and may have diagnostic relevance. Furthermore, anterior segment inflammation can damage the corneal endothelium and may lead to long-term damage, particularly with intraocular surgery.
During the acute inflammatory episode, intraocular pressure (IOP) is often reduced because of ciliary body shutdown and reduced aqueous fluid production. As the inflammation subsides, however, IOP may rapidly increase, especially in patients with severe PAS. In some patients, it is difficult to determine whether the increased IOP is a result of underlying inflammation or a response to the corticosteroids used to control the disease. In secondary glaucoma caused by active inflammatory disease, increased corticosteroid therapy leads to a reduction in IOP.
Although some of the clinical symptoms and signs of anterior uveitis are specific for certain diseases, most disorders are differentiated by their associated systemic findings. The clinical findings of the common disorders that cause anterior uveitis are summarized in Table 20.1 . Some disorders, such as postsurgical inflammation, infectious uveitis, Behçet disease, sarcoidosis, and masquerade syndromes, are discussed in separate chapters.
TABLE 20.1
Syndromes of Anterior Uveitis
| Disease | Age (years) | Sex | Ocular Redness | HLA-B27 | Systemic Findings | Steroid Response |
|---|---|---|---|---|---|---|
| Idiopathic | Any | Either | Yes | No | None | Yes |
| HLA-B27, ocular only | 15–40 | M > F | Yes | Yes | None | Yes |
| Ankylosing spondylitis | 15–40 | M > F | Yes | Yes | Spondylitis, sacroiliitis | Yes |
| Reactive arthritis | 15–40 | M > F | Yes | Yes | Arthritis, urethritis, mucocutaneous lesions | Yes |
| Juvenile rheumatoid arthritis | 3–16 | F > M | No | No | Pauciarticular arthritis, ANA-positive, RF-negative | Yes |
| Fuchs iridocyclitis | Any | Either | No | No | None | Yes/no |
| Posner-Schlossman syndrome | Adult | Either | No | No | None | Yes |
| Schwartz syndrome | Adult | Either | No | No | None | No |
| Ocular ischemia | >50 | Either | Yes | No | Carotid insufficiency | No |
| Kawasaki disease | 1–18 | Either | Yes | No | Skin rash, lymphadenopathy fever, cardiac lesions | Yes |
ANA, antinuclear antibody; RF, rheumatoid factor.
Finally, there is now interest in exploring the use of artificial intelligence to improve the diagnosis and treatment of many disorders, including anterior uveitis. For example, machine learning has been employed in the selection of intraocular lenses and the analysis of photographic and optical coherence tomography (OCT) images in the diagnosis of retinal diseases. Algorithms and networks to aid in differential diagnoses and treatment approaches help with the application of artificial intelligence to diagnoses of specific disease entities and are specifically being developed for anterior uveitis. It is hoped that these tools will help clinicians improve outcomes in patients with anterior uveitis.
Idiopathic Anterior Uveitis
After a thorough medical history and ocular and general physical examinations, almost 50% of patients are found to have anterior segment inflammation that is not associated with other defined clinical syndromes. This form of anterior uveitis is referred to as idiopathic anterior uveitis. To diagnose idiopathic anterior uveitis, patients must not only lack systemic disease associations but also cannot have the HLA-B27 haplotype, which is associated with anterior segment inflammatory disease. In one study, 47% of patients with anterior uveitis had HLA-B27-associated anterior uveitis ; however, about one-quarter of these patients also had underlying systemic disorders, including ankylosing spondylitis and Reiter syndrome. Nevertheless, the diagnosis of idiopathic anterior uveitis depends greatly on the extent of the evaluation for an underlying condition. Many patients initially diagnosed with idiopathic anterior uveitis are later found to have a specific disorder causing their ocular inflammatory disease.
Importantly, one should rule out masquerade syndromes that present with anterior uveitis (see Chapter 31 ). Some conditions, including the presence of intraocular foreign bodies; malignancies, including leukemia and lymphoma; ocular infections, such as postsurgical infections; and pigment dispersion syndrome, can all be misdiagnosed as idiopathic anterior uveitis. Medications, including rifabutin, sulfonamides, topical prostaglandin analogues for glaucoma and ocular hypertension, and vaccines, have been associated with anterior uveitis. , Nevertheless, even after a thorough evaluation, a specific etiology cannot be determined in many patients. It has been hypothesized that these patients may have an immune responsiveness that may explain the development of anterior segment inflammation. In a study, patients with a history of acute anterior uveitis but no signs of ocular inflammation at the time of recruitment showed a high innate immune responsiveness compared with control subjects. In a whole blood culture assay, levels of tumor necrosis factor-α and cross-reactive protein (CRP) were significantly higher in patients with a history of anterior uveitis than in control subjects.
Diagnostic Workup
How should you evaluate a patient with a first episode of anterior uveitis? This is a controversial topic among uveitis specialists. Some have suggested that no evaluation is needed. Others have stated that a long list of laboratory tests and diagnostic procedures should be ordered on every patient. The prudent approach probably lies somewhere in the middle, and, as discussed in Chapter 5 , a complete medical history and a thorough examination can help focus the workup. For example, if the patient complains of lower back pain, a diagnosis of ankylosing spondylitis is suggested and the evaluation might consist solely of sacroiliac joint radiography and HLA-B27 testing. Similarly, for a child with anterior uveitis with band keratopathy and a history of arthritis, a diagnosis of juvenile rheumatoid arthritis is suggested, and a targeted evaluation consisting of tests for antinuclear antibody (ANA) and rheumatoid factor with a referral to a pediatric rheumatologist may be appropriate.
However, when thorough history taking and physical examination fail to suggest specific diagnoses, what tests should be ordered? Many uveitis specialists will do a limited workup of all patients with anterior uveitis even if it is their first episode. If the uveitis is nongranulomatous, I request testing for syphilis serology because syphilis is a frequently missed diagnosis, and early treatment can prevent long-term complications. Similarly, I request a complete blood cell count and urinalysis to rule out an underlying systemic disorder, such as connective tissue disease, because the associated renal disease or anemia may be asymptomatic and yet warrant therapy. If the inflammation is granulomatous, a number of other disorders are suggested (see Chapter 4 ). For granulomatous anterior uveitis, I will also request a purified protein derivative test, chest x-ray, serum and urine calcium test, and serum angiotensin-converting enzyme level measurement to rule out asymptomatic tuberculosis or sarcoidosis. Although it is important to rule out infection as a cause of idiopathic anterior uveitis, anterior chamber paracentesis with polymerase chain reaction (PCR) has a relatively low diagnostic utility. Importantly, most of my evaluation is based on using the tests to discern among the diseases in my differential diagnosis based on medical history and clinical examination. Without knowing the pretest probability of a disease, even relatively sensitive and specific diagnostic test results can mislead the clinician (see Chapters 4 and 5 on Differential Diagnosis and Diagnostic Testing).
Treatment
The breakthrough in the treatment of ocular inflammation came with the discovery of corticosteroids. In 1949, Hench et al. reported the beneficial effects of 17-hydroxy-11-dehydrocorticosterone and pituitary adrenocorticotropic hormone in patients with rheumatoid arthritis. During the subsequent year, two reports were published in the Journal of the American Medical Association (JAMA) on their effects on ocular inflammatory disease. , A vast improvement was seen compared with the outcomes of previous therapies. Earlier in the twentieth century, patients with ocular inflammation were treated by inducing hyperpyrexia. Early on, patients were placed in steam baths in which their temperature was raised to 40–41° C for 4 to 6 hours. In some patients, the inflammation subsided, but many patients experienced severe complications. Later, patients were injected with milk protein or typhoid toxin to induce fever. Despite complications with their use, corticosteroids were a welcome advancement in the treatment of inflammation.
Patients with idiopathic anterior uveitis tend to have nongranulomatous inflammation that responds well to topical corticosteroid therapy. Acetate preparations of topical corticosteroids tend to penetrate the cornea better compared with other preparations, especially if the epithelium is intact, and many clinicians tend to use prednisolone acetate 1%. Prednisolone acetate can be used hourly to treat severe anterior segment inflammation. Difluprednate 0.05% has been approved by the U.S. Food and Drug Administration (FDA) to treat endogenous anterior uveitis. In a phase III, multicenter, randomized controlled trial (RCT), difluprednate 0.05% four times daily was shown to be not inferior to prednisolone acetate 1% given eight times daily with decreasing anterior chamber cells at 14 days in patients with anterior uveitis. The study also showed that complete clearing of anterior chamber cells was greater in difluprednate-treated patients and that increased IOP was also more common with difluprednate treatment.
To prevent the development of posterior synechiae and to reduce pain and photophobia caused by inflammation of the ciliary muscle, mydriasis and cycloplegia are indicated. Scopolamine 0.25% given twice daily is usually sufficient. For resistant disease, periocular injections of corticosteroids may be useful. Systemic corticosteroids or other systemic anti-inflammatory drugs are rarely needed to treat anterior uveitis. However, patients with anterior uveitis may develop posterior segment disease. These patients frequently require more aggressive anti-inflammatory therapy, including periocular or systemic corticosteroids, or other immunosuppressive therapy. Local corticosteroid therapy, such as periocular injections, may also be warranted for severe or recalcitrant anterior uveitis with inadequate response to topical therapy. In some patients, topical nonsteroidal anti-inflammatory drugs are used to taper topical corticosteroids. Systemic anti-inflammatory drugs, including the biologics, are more frequently used when there is an underlying systemic disease requiring therapy.
Hla-B27–Associated Anterior Uveitis
HLA-B27–associated anterior uveitis appears to be a distinct clinical disorder. This form of the disease has frequent associations with systemic diseases, including ankylosing spondylitis, Reiter syndrome, inflammatory bowel disease, Whipple disease, and psoriatic arthritis. Nevertheless, as stated earlier, many patients with the HLA-B27 haplotype and anterior uveitis have no associated systemic illness, and not all patients with the HLA-B27 haplotype have uveitis; the prevalence of HLA-B27 is about 7% in North American whites.
Epidemiology
Some studies suggest that as many as 50% of patients with acute anterior uveitis are HLA-B27 positive, and half of these have spondyloarthropathies. In a systematic review of 126 articles describing 29,877 patients with spondyloarthropathy, Zeboulon et al. reported a uveitis prevalence rate of 32.7%. This prevalence rate increased with the duration of disease. As noted earlier, in a series of 798 patients with anterior uveitis, 60% were HLA-B27 positive, and a total of 50% had axial spondyloarthritis.
Demographics and Clinical Findings
Patients with HLA-B27–associated anterior uveitis are more often males and tend to develop uveitis at a younger age compared with those who are HLA-B27 negative. Although some studies have indicated that the long-term visual prognosis is similar for both groups, data suggest that spondyloarthritis is more common in patients who are HLA-B27 positive.
In a retrospective cohort study of 177 patients with HLA-B27–associated uveitis, the average age at onset of acute anterior uveitis was 36 years, with no difference between males and females. HLA-B27–associated systemic disease developed earlier in males, and bilateral uveitis developed more frequently in females.
Should HLA typing be performed in all patients with anterior uveitis? We obtain HLA typing for male patients presenting with their first episode of acute anterior uveitis and in all patients if they have back pain or other systemic symptoms or signs. In addition, if patients have severe chronic anterior uveitis, we request HLA typing for the patient because the finding of the HLA-B27 haplotype often obviates the need for an extensive laboratory evaluation to rule out infectious or other treatable causes of the disease.
Etiology
The finding of the HLA-B27 haplotype is also of interest as a clue to the possible pathogenesis of both the spondyloarthropathies and anterior uveitis. We know that major histocompatibility complex (MHC) class I molecules, such as HLA-B27, are involved in antigen presentation and the initiation of an immune response. Some hypothesize that HLA-B27 interacts with certain endogenous antigens, leading to the development of inflammatory disease. HLA-B27 also has a tendency to misfold and may lead to a number of outcomes, including dimer formation with unique binding properties or activation of the IL-23–IL-17 axis, predisposing to inflammatory disease ( Fig. 20.1 ).
A number of studies have examined the associations among HLA-B27, infections, and the development of inflammatory disease. The role of gram-negative bacteria and their interaction with MHC class I antigens in triggering anterior uveitis has been of particular interest. , Helicobacter pylori has also been associated with anterior uveitis. Unfortunately, this possible link among microbial antigens, HLA-B27, and anterior uveitis remains speculative because antimicrobial agents have not been proven to affect the course of disease. This may be attributed to lack of efficacy of antimicrobial agents or the dearth of trials investigating this therapeutic approach. A possible explanation for the lack of efficacy of antimicrobial agents is that the infection induces inflammation through Toll-like receptors (TLRs), and the process becomes separate from the active infection.
Other immunologic studies have been performed in an attempt to determine the pathogenesis of anterior uveitis. Increased levels of complement and immunoglobulin G (IgG) compatible with breakdown of the blood–aqueous barrier can be detected in the aqueous of patients with anterior uveitis. There is also evidence of complement activation in the aqueous of patients with anterior uveitis, indicated by the presence of C3a, C4a, and C5a. Evidence of increased serum fibrin degradation products has suggested a pathogenic role of the clotting pathways. Increased expression of cell adhesion molecules has been associated with the development of intraocular inflammation. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in the irides of patients with uveitis has been reported, and expression of cell adhesion molecules in the anterior uvea has been shown to precede infiltration of inflammatory cells in animal models of acute anterior uveitis. , Polymorphisms within the tumor necrosis factor (TNF)-α promoter region have been identified, and individuals with these single-nucleotide polymorphisms (SNPs) show higher susceptibility to the development of uveitis.
Hla-B27–Associated Anterior Uveitis With Systemic Disease
Ankylosing Spondylitis
Ankylosing spondylitis is chronic, inflammatory arthritis that primarily affects the spine and the sacroiliac joints. The disease was previously known as Bechterew disease and Marie-Strumpell disease and is now classified as a spondyloarthropathy. Without treatment, the disease can progress and result in fusion and rigidity of the spine, known as bamboo spine. Diagnosis of ankylosing spondylitis is usually based on imaging, with characteristic active inflammation seen on magnetic resonance imaging (MRI) or definite sacroiliitis on radiography, with at least one other clinical feature of the disease. Clinical features of ankylosing spondylitis include anterior uveitis, arthritis, inflammatory back pain, psoriasis, dactylitis, inflammatory bowel disease, heel enthesitis, a family history of spondyloarthropathies, presence of HLA-B27, elevated CRP, and good response to nonsteroidal anti-inflammatory drugs (NSAIDs).
Ocular involvement occurs in 25% of patients with ankylosing spondylitis. In 80% of patients, both eyes are involved but are rarely inflamed simultaneously. Although the ocular findings associated with ankylosing spondylitis include both iritis and conjunctivitis, iritis is the more significant manifestation. The disease course is quite variable. Recurrence of the ocular inflammation may occur as frequently as every 2 to 3 weeks. Some patients have fewer than one exacerbation per year. Interestingly, recurrence may be seasonal, although this variation appears to be more frequent in patients with idiopathic anterior uveitis.
The anterior uveitis associated with ankylosing spondylitis usually has a presentation similar to that of idiopathic disease, occurring as unilateral acute iritis with pain, photophobia, and redness ( Fig. 20.2A ). Patients often report onset of an attack 1 to 2 days before anterior chamber cell and flare are evident on slit-lamp biomicroscopy. The use of laser photometry may help determine when the initial breakdown of the blood–aqueous barrier occurs in relation to the development of symptoms and clinical signs of inflammation. Vision may decrease transiently during an acute episode as a result of anterior chamber inflammation or, less often, because of associated cystoid macular edema. A fibrin clot may form in the anterior chamber (see Fig. 20.2B ). Posterior synechiae commonly develop unless the attacks are treated promptly with corticosteroids and cycloplegic agents ( Fig. 20.3 ).
Ankylosing spondylitis has been reported to affect men 2.5 to three times more frequently in comparison with women. Women may have a milder disease that may present with more peripheral joint manifestations. It is a common disorder that affects 0.1% of white adults. Because the HLA-B27 antigen is dominantly inherited and expressed, 50% of offspring will carry the gene, but the disease will be manifest in only 10% of them. Approximately 96% of patients with ankylosing spondylitis have the HLA-B27 antigen compared with 6% to 14% of a control white population without ankylosing spondylitis. HLA-B27 is found in 0% to 4% of African Americans. Thus the relative risk for ankylosing spondylitis in patients with the HLA-B27 antigen is as high as 100. Nevertheless, only 1.3% of all HLA-B27–positive patients will have the disease.
Sacroiliitis may be asymptomatic early in the course of disease but may be associated with severe lower back pain and debilitating stiffness and decreased range of motion. X-rays of the sacroiliac joints show blurring of the joints, followed by sclerotic changes and eventually obliteration as the disease progresses (see Fig. 20.2C ). A common mistake in the initial evaluation of patients with possible ankylosing spondylitis is to order lumbosacral spine films instead of imaging of the sacroiliac joints. MRI of the sacroiliac joints often provides definitive evidence of active sacroiliitis and is useful in the diagnosis of ankylosing spondylitis.
As noted earlier, early diagnosis and treatment is imperative because of the risk of fusion of the spine, which begins in the lumbar region but can involve all parts of the spine. This leads to back pain and stiffness and, in severe disease, may cause pulmonary restriction and a stiff, flexed neck, making positioning for slit-lamp biomicroscopic examination difficult (see Fig. 20.2D ). Interestingly, the associated uveitis does not appear to correlate with the severity of the underlying spondylitis. Aortic insufficiency, cardiomegaly, and conduction defects are also associated with this disease.
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