Anterior uveitis occurs in association with a variety of systemic conditions. Since the clinical features present on ophthalmic examination may not point toward a specific cause, the emphasis on general medical history and physical examination, the use of directed laboratory testing, and a referral to a pediatric rheumatologist, are appropriate.[1, 2]
In this article, anterior uveitis associated with juvenile idiopathic arthritis (JIA) and entities related to human leukocyte antigen B27 (HLA-B27) are covered, including juvenile ankylosing spondylitis (AS), reactive arthritis (also referred to as Reiter syndrome), and inflammatory bowel disease. Also included are sarcoidosis, which may present with a nongranulomatous anterior uveitis, Blau syndrome, acute tubulointerstitial nephritis and uveitis, and Kawasaki disease. Brief coverage is given to uveitis related to systemic viral infections.
The pathophysiology of these entities is diverse, and the specific entities are covered in more detail below. For example, poorly controlled uveitis related to JIA may progress to band keratopathy, hypotony, and phthisis, whereas the iritis related to Kawasaki disease is self-limited and generally benign.
Causes of anterior uveitis in children may be classified broadly as infectious and noninfectious. The common and important infectious causes are due to viruses (eg, herpes simplex, herpes zoster) and following systemic viral syndromes (eg, mumps). Uveitis associated with herpes simplex often is accompanied by keratitis, making the diagnosis straightforward. Uveitis in children with herpes zoster usually occurs in the setting of immune suppression, such as AIDS.[3, 4, 5]
Noninfectious causes of childhood anterior uveitis are more common; the strongest association is with JIA. In JIA, the patient may be asymptomatic as the process quietly proceeds to band keratopathy, cataract, and glaucoma. Spondyloarthropathies (eg, AS, psoriatic arthritis, reactive arthritis, inflammatory bowel disease) also are associated strongly with nongranulomatous anterior uveitis. Sarcoidosis is an important cause of panuveitis but may present as an isolated nongranulomatous anterior uveitis.
United States
Approximately 6% of all cases of uveitis occur in children, with most cases occurring in association with JIA and the spondyloarthropathies. Uveitis can occur in 4 of the 7 categories of JIA, including oligoarthritis, rheumatoid factor (RF)-negative polyarthritis, enthesitis-related arthritis, and psoriatic arthritis.
Oligoarthritis affects 4 or fewer joints and typically occurs in young girls. Oligoarthritis is the most common type of JIA in Europe and North America. Uveitis most often accompanies this form of the disease and is seen in about 10-30% of patients. Antinuclear antibodies are common in this group of children. Uveitis occurs in up to 10% of children with RF-negative polyarthritis JIA. Enthesitis-related arthritis affects the attachments of ligaments and tendons to the bone. This form of JIA typically affects older boys. Uveitis is often unilateral with a sudden onset; children are often symptomatic. Approximately 10% of children with psoriatic arthritis develop uveitis. In these children, the uveitis is usually chronic and asymptomatic.
Of patients with AS, 20-30% develop uveitis; of patients with reactive arthritis, 12-37% develop uveitis; and, of patients with inflammatory bowel disease, 2-9% develop uveitis.
Uveitis associated with sarcoidosis is significantly less common in children compared to JIA-related causes and uveitis related to spondyloarthropathy. In one large series of childhood uveitis, it accounted for less than 1% of cases.
International
Uveitis in children and adolescents is less common than in adults. However, the reported percentage of children affected varies widely, ranging from 2.2-33.1% of all patients with uveitis. In a large study from Israel, anterior uveitis accounted for 13.4% of all cases of uveitis affecting children and adolescents.
Morbidity in childhood anterior uveitis may result from lack of treatment or from overzealous treatment.
The primary causes of ocular and visual morbidity in pediatric anterior uveitis are similar among the various entities, with the primary differences related to severity, chronicity, treatment success, complications, and age of onset.
Acute episodes of inflammation may be self-limited and benign or may cause anterior and posterior synechiae, with secondary glaucoma. Chronic anterior uveitis additionally may cause band keratopathy, cataract, spillover anterior vitreitis, and cystoid macular edema. Severe glaucoma and phthisis are the most feared complications.
Sarcoidosis affects African Americans about 10 times more often than it affects whites. However, most young children with uveitis are white.
AS is 2-3 times more common in boys than in girls.
Reactive arthritis is at least 5 times more common in boys than in girls.
Sarcoidosis is slightly more common in girls than in boys.
Oligoarthritis JIA is more common in females than in boys, with a girl-to-boy ratio of 3-4:1.
Most children with oligoarthritis JIA are younger than 4 years, while children with RF-negative polyarthritis JIA are somewhat older. Enthesitis-related arthritis typically affects older boys.[6, 7]
Mean age of onset of AS is about 10 years and 10-11 years in psoriatic arthritis.
Children (and parents/guardians) with childhood anterior uveitis require prolonged education regarding the signs and symptoms of disease activity. It is important to stress the need for lifestyle changes to decrease and prevent exacerbations and to preserve current remaining vision and the need for appropriate pain management. Children complain less regarding visual symptoms and require regular eye visits to check for signs of ocular inflammation.
The main objective in taking the history in children with anterior uveitis is to narrow the differential diagnosis, to optimize laboratory testing, and to direct appropriate referrals.
The parents and the child, if appropriate, should be asked about the presence of arthritis, rashes or other dermatologic disorders, gastrointestinal disease, and asthma or other pulmonary conditions. The history is covered in more detail in the sections covering the specific causes of uveitis.
As in adult patients with uveitis, a complete examination of the eye and ocular adnexa is essential. Rarely, in younger patients or uncooperative patients, examination under anesthesia may be required.
Inspect and palpate the lacrimal gland because it may be enlarged in sarcoidosis and other infiltrative conditions. Similarly, palpate the lymph nodes of the head and neck.
When appropriate, inspect the skin of the entire body. Erythema nodosum is common in sarcoidosis but usually does not occur on the face. However, crops of papular eruptions may occur in a periocular distribution as a manifestation of sarcoidosis.
Blepharitis and blepharoconjunctivitis may be signs of herpes simplex virus (HSV) infection. Careful inspection of the conjunctiva for granulomata is obviously a key part of the evaluation of any patient with uveitis.
Yellow-orange periocular lesions may be a clue that intraocular inflammation is due to juvenile xanthogranuloma (JXG), as well as providing an easily accessible biopsy site.
Corneal band keratopathy is often seen in JIA-associated uveitis; it may be quite subtle and limited to the limbal areas of the 3-o'clock and 9-o'clock meridians.
Specifically seek evidence of geographic or stellate keratitis suggesting herpes infection; fluorescein or rose bengal staining helps to identify these signs.
Mutton-fat keratic precipitates (KP) may be present in granulomatous conditions, but smaller KP occur in JIA-associated and HLA-B27–associated uveitis. Assess anterior chamber cell and flare according to a standard grading scheme.
Examine the iris for Koeppe and Busacca nodules, which occur in granulomatous uveitis. Anterior and posterior synechiae suggest prior episodes or a prolonged course and indicate an increased likelihood of glaucoma.
Pseudohypopyon may indicate leukemia, retinoblastoma, and JXG.
Examine the vitreous for spillover inflammation, and exclude intermediate uveitis and pars planitis.
Optic disc edema is uncommon but can occur. The edema typically resolves but often lags behind improvement of the uveitis.[8]
Determination of the intraocular pressure is critical but usually does not help to narrow the differential diagnosis.
Arthritis and joint tenderness suggest JIA or spondyloarthropathy; limited torso flexion occurs in AS; and the development of a new heart murmur along with fever and rash may suggest Kawasaki disease.
JIA refers to arthritis of unknown cause in a child. The International League of Associations for Rheumatology (ILAR) classification of JIA includes 7 forms of the disease. Categories include systemic, oligoarticular, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undefined JIA. In the United States, JIA affects 60,000-70,000 children.
Uveitis can develop in children with oligoarthritis, RF-negative polyarthritis, enthesitis-related arthritis, and psoriatic JIA and can lead to long-term complications. A quiet, usually bilateral predominantly anterior uveitis is notorious for causing no symptoms in its early stages. As the inflammation continues, posterior synechiae, cataracts, glaucoma, and band keratopathy occur.
Males with JIA have a poorer visual prognosis. Children who develop uveitis prior to the onset of arthritis also have worse visual acuity during the first 3 years following the diagnosis of uveitis.[1, 9]
The classic description of reactive arthritis is that of a triad of urethritis, conjunctivitis, and arthritis.
Acute or chronic nongranulomatous anterior uveitis occurs in reactive arthritis in as many as 30% of cases. Recurrent acute attacks are typical; both eyes are affected but usually not simultaneously. Posterior synechiae, fibrinous exudates, hypopyon formation, and hypotony are common. Spillover vitritis and cystoid macular edema may be seen.
The attacks typically last from 2-3 months. In children, disease onset may occur following enteritis due to Salmonella, Shigella, Yersinia, or Campylobacter species. Antecedent chlamydial urethritis has a greater role in adult cases.
Approximately 60% of patients have the HLA-B27 haplotype, and males are affected at least 5 times more frequently than females. Within weeks following an inciting infection, a peripheral arthritis develops, typically asymmetrically involving the hands, feet, knees, ankles, and wrists. Other characteristic lesions include superficial oral ulcers, keratoderma blennorrhagica, and balanitis circinata.
AS is characterized by painful stiffening of the back caused by sacroiliitis and lumbosacral spondylitis. Lower back pain is the usual presenting symptom, although some patients have peripheral arthritis.
Of patients with AS, 90% have the HLA-B27 haplotype; however, unlike reactive arthritis, no other specific inciting cause is known.
Mean age of onset is 11.5 years, and males are 3 times more commonly affected than females. The uveitis is similar to that seen in reactive arthritis, as follows: recurrent, nongranulomatous anterior uveitis, frequently with fibrinous exudate, hypopyon formation, and posterior synechiae.
Compared to the previously discussed spondyloarthropathies, uveitis occurs less commonly in patients with inflammatory bowel disease. Overall, about 5% of patients develop iritis, which typically is mild anterior nongranulomatous. Patients often are asymptomatic.
Episcleritis also may occur in patients with inflammatory bowel disease. Whether the presence of uveitis parallels disease flare-ups is debated. Severe ocular sequelae are uncommon.
Sarcoidosis is a chronic multisystem disorder with variable clinical manifestations that is uncommon in children.
In children younger than 5 years, the clinical manifestations differ from older children with sarcoidosis. In these children, the most common clinical findings include a maculopapular, erythematous rash; uveitis; and polyarticular arthritis. Additionally, pulmonary involvement is uncommon in this group of children.
In children 5 years and older, the most common clinical findings include lymphadenopathy, pulmonary abnormalities, and uveitis. The clinical course in these children is similar to that seen in adults with sarcoidosis.
Ocular involvement is common in children with sarcoidosis. Anterior uveitis is the most common ocular manifestation in these children. The uveitis may be characterized as granulomatous or nongranulomatous. Ocular findings include KP, iris nodules, cells and flare, and posterior synechiae. Band keratopathy frequently is seen in children with chronic inflammation. Posterior uveitis and disc edema also can occur. Secondary glaucoma is not uncommon and can result in permanent visual loss.
Children who have findings suggestive of sarcoidosis should undergo a complete examination by a pediatrician. The examination should include a thorough evaluation of the lungs and a determination of serum and urine calcium levels. Additionally, these children should undergo complete examination by an ophthalmologist.
Kawasaki disease is a systemic disease of unknown cause affecting children and adolescents. Its major features are protracted fever, cervical lymph node swelling, strawberry tongue (prominence of tongue papillae), palmar erythema, erythematous rash, and bilateral conjunctival injection.
Occurrence of uveitis was not recognized in the early descriptions of Kawasaki disease but a self-limited, nongranulomatous anterior uveitis is very common, particularly in the early stages of the disease.
Mild, bilateral nongranulomatous, anterior uveitis is common in systemic viral illnesses such as those noted above. Patients typically are asymptomatic, and the uveitis is self-limited.
Chronic anterior uveitis with stellate keratic precipitates may occur in unvaccinated children. Cataract is not uncommon in these children.[10]
Intraocular JXG, usually presenting as an iris mass, may produce a picture resembling anterior uveitis. Characteristic yellow-cream lesions of the skin may be present, providing a convenient site to biopsy. Spontaneous hyphema also may occur.
Anterior uveitis may rarely signal the onset of or a relapse of leukemia. A hypopyon may be present.
Acute tubulointerstitial nephritis and uveitis (TINU syndrome) consists of acute interstitial nephritis and uveitis. Most patients are adolescents with a median age of 15 years, although middle-aged and elderly patients have been reported. Most patients exhibit proteinuria, elevated urine beta-2-microglobulin, glucosuria, and sterile pyuria. Serum creatinine is also elevated. Additional findings include fever, weight loss, fatigue, anorexia, anemia, and hypergammaglobulinemia.
The most common ocular manifestation of TINU syndrome is an acute bilateral anterior uveitis. The uveitis typically responds to treatment with corticosteroids but may become recurrent. Less common manifestations include vitritis, panuveitis, retinal vasculitis with perivascular sheathing, and rarely multifocal choroiditis.
To establish a diagnosis of TINU, the onset of uveitis should occur within a year of the development of acute interstitial nephritis.[11]
Rarely, bilateral nongranulomatous anterior uveitis can develop 1-8 weeks following group A streptococcal infection.[12] Posterior segment involvement has been reported but is much less common. Antistreptococcal lysin O titers are elevated. Management with pediatric subspecialists is essential (see Consultations).
Familial granulomatous arthritis, iritis, and rash (Blau syndrome) is an autosomal dominant multisystem inflammatory disease first described in 1985.
Clinical manifestations of Blau syndrome include arthritis, synovial cysts, camptodactyly, erythematous rash, and uveitis. Clinical findings are similar to those seen in childhood sarcoidosis; however, synovial cysts and camptodactyly have not been described in children with sarcoidosis. Additionally, pulmonary involvement has not been described in children or adults with Blau syndrome.
The rash seen in Blau syndrome is a granulomatous erythematous papular eruption described as painless, tiny, red dots often in a generalized distribution. Onset usually is in early childhood, but it can occur as early as age 4 months. In most cases, the rash resolves spontaneously.
Joint manifestations typically develop during childhood and often before age 10 years. The earliest joint changes are insidious in onset and include synovial cysts and boutonniere deformities. Painless synovial cysts may develop on the wrists, ankles, or dorsum of the foot. Boutonniere deformities of the fingers are a characteristic finding in these children. These early lesions often progress to camptodactyly and cystic swelling of the wrists, elbows, knees, and ankles.
Ocular involvement appears to be the most serious complication of Blau syndrome. Uveitis can develop in childhood or during the early adult years. In most cases, the uveitis initially manifests as a nongranulomatous anterior uveitis; however, the disease often is recurrent and eventually develops into a chronic anterior uveitis. Later in the clinical course, posterior uveitis can occur with vitritis, disc edema, and chorioretinal lesions. Secondary glaucoma is not uncommon and may lead to devastating visual loss.
Uveitis associated with herpes simplex often is accompanied by keratitis, making diagnosis relatively straightforward. Whether the inflammation represents active infection or an immune reaction is an unsettled question.
The inflammation may be severe, with pain, KP, and hypopyon formation. Trabeculitis with secondary glaucoma is an important complication.
Varicella zoster in children usually occurs in the setting of immunosuppression, such as in acquired immunodeficiency syndrome (AIDS).
Keratitis usually is seen with the uveitis that may occur. The uveitis is believed to result from vasculitis, with resultant vascular occlusion and ischemia.
Behçet disease is a systemic vasculitis characterized by recurrent oral aphthous ulcers, genital ulcers, and uveitis. Additional manifestations are variable but may include skin lesions, venous thrombosis, arthritis, and central nervous system symptoms. Most affected patients are aged 25-35 years. However, children can be affected.
Children with Behçet disease may develop anterior uveitis, posterior uveitis, or panuveitis. A retrospective report from Turkey found that among children, 33% had anterior uveitis.[13]
If JIA is suspected, obtain an antinuclear antibody test to classify the condition and to determine the risk of recurrent and severe disease.
In patients suspected of having AS, reactive arthritis, or inflammatory bowel disease, perform testing for the HLA-B27 haplotype. Sacroiliac joint films may demonstrate evidence of joint involvement in AS and reactive arthritis.
Sarcoid uveitis is investigated with determination of the angiotensin-converting enzyme (ACE) level, with or without serum lysozyme testing, chest roentgenograms, and gallium scanning. Remember that normal ACE values in children are higher than those in adults. Definitive diagnosis requires histopathologic demonstration of noncaseating granulomatous inflammation, in the absence of another possible cause.
If symptoms suggest TINU, urinalysis, serum creatinine, and urine beta-2-microglubulin testing is indicated.
Antistreptococcal lysin O titers are indicated in patients with possible poststreptococcal syndrome uveitis.
In these children, the ultimate goal of treatment is to eliminate all anterior chamber cells if possible.
Initial therapy typically includes topical and systemic corticosteroids. Children treated with topical corticosteroids have an increased risk of developing cataracts, especially those treated more than 3 times daily.[14] Short-acting cycloplegic agents often are prescribed to prevent posterior synechiae.
In many patients, corticosteroids alone are not sufficient to control the inflammation, and immunomodulatory therapy will be necessary. Use of immunomodulatory therapy may result in improved outcomes in children with JIA-associated uveitis.[15] Long-term oral methotrexate is often an effective steroid-sparing therapy. Children treated with methotrexate for at least 3 years prior to discontinuation may have a longer relapse-free interval.[16] Cyclosporine, azathioprine, and mycophenolate mofetil have also been useful steroid-sparing therapies.[17, 18]
Biologic response modifiers may be useful for children with persistent inflammation despite standard immunomodulator therapy. Among these agents, etanercept may be less effective in the treatment of uveitis.[19, 20, 21, 22, 23, 24]
The severity of uveitis in these conditions ranges widely, necessitating individualized and, in some cases, ongoing care. Milder cases are treated with topical corticosteroids while moderately severe cases are treated with more intensive topical steroid treatment with the addition of cycloplegics. Treatment with sub-Tenon corticosteroids may also be useful for severe flares and/or cystoid macular edema. In recalcitrant cases, immunomodulatory therapy may be necessary to control the inflammation.
Keep in mind that the particular tissues involved, the severity of the inflammation, and the degree of visual loss drives treatment decisions in most cases. When anterior disease predominates, treatment with topical corticosteroids and cycloplegics usually will suffice. However, severe refractory cases may require systemic immunomodulatory therapy.
Treatment rarely is required in these self-limited conditions; topical steroids may be given in symptomatic cases. More severe cases may be treated with topical corticosteroids and cycloplegics.
Topical corticosteroids are the mainstay of therapy for patients with anterior uveitis. Cycloplegics may be used for patients with photophobia and to prevent posterior synechiae formation. Severe exacerbations may require periocular corticosteroids to control the inflammation. Patients with posterior uveitis require systemic corticosteroids and/or immunosuppressive therapy.
Topical and systemic corticosteroids are often effective in treating this condition.
Surgery is required to treat the complications of severe or chronic inflammation. For example, in JIA-associated uveitis, cataract often develops and the eye should be quiet for at least 3 months prior to surgery. Perioperative systemic corticosteroids have been advocated to reduce postoperative inflammation. Intraocular lens placement is still somewhat controversial; however, intensive medical therapy to control inflammation is essential for patients receiving intraocular lenses.[25]
Severe band keratopathy, as seen in JIA, may require treatment with Ca EDTA chelation. Development of glaucoma may require trabeculectomy or placement of a drainage implant.
Depending on the patient, one or more of the following pediatric subspecialists may assist in the evaluation and treatment of patients:
The primary medications used in treating anterior uveitis in children are corticosteroids, topical cycloplegics, and, in certain cases of JIA-associated uveitis, methotrexate.[26, 27] In cases of recalcitrant inflammation, other immunosuppressives and biologic agents have been used with variable success.
Clinical Context: Inhibits phospholipase A and Fc receptor expression, reduces cytokine production, suppresses lymphocyte function, and redistributes circulating leukocytes.
Clinical Context: Potent topical corticosteroid used to treat anterior segment inflammation. Initial dosage is determined by the degree of inflammation.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: Useful in treating pain from ciliary spasm and decreasing formation of synechiae.
Instillation of a long-acting cycloplegic agent can relax ciliary muscle spasm that can cause a deep aching pain and photophobia.
Clinical Context: Useful in patients with JIA-associated uveitis, where it may reduce inflammation in patients who do not adequately respond to corticosteroid treatment.
Clinical Context: Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of the parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and the liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after it is taken.
Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. The mechanism whereby azathioprine affects autoimmune diseases is unknown. It works primarily on T cells. It suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. It works very slowly and may require 6-12 months of trial prior to effect. Up to 10% of patients may have an idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/µL or lymphocyte count to drop below 1000/µL.
Azathioprine is available in tablet form for oral administration or in 100-mg vials for intravenous injection.
These agents may be useful as a single agent or in combination with systemic corticosteroids and/or other immunosuppressive agents.
Clinical Context: Recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Reduce inflammation and inhibit progression of structural damage.
Clinical Context: Neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Mix in 250-mL normal saline for infusion over 2 h. Must use with low-protein-binding filter (1.2 µm or less). Several investigational reports have described use in childhood uveitis.
Follow-up care is on a case-by-case basis and depends on the cause of the uveitis, the severity of the uveitis, and the medications used in treatment.
In the short term, adequate control of the inflammation must be assessed and monitored. Intraocular pressure must be monitored as elevations may result from inflammation, corticosteroid treatment, or both.
Longer term follow-up care additionally focuses on the formation of cataracts, cystoid macular edema, angle-closure glaucoma, and band keratopathy, in addition to the previously mentioned areas.
General medical evaluations are required for those patients on systemic immunosuppressants, such as prednisone and methotrexate.
The German Uveitis in Children Study Group recommends screening examinations for children with JIA as outlined below.
Children with JIA and no previous history of uveitis
Oligoarthritis, RF-negative polyarthritis, or early childhood psoriatic arthritis: Screening examinations should be conducted at 6-week intervals for 2 years, then every 3 months for the next 5 years.
Systemic arthritis or RF-positive polyarthritis: Screening examinations should be conducted every 3 months for 7 years.
Enthesitis-associated arthritis or late onset psoriatic arthritis: Screening examinations should be conducted every 6 months.
Children with JIA and a history of uveitis
The intervals of screening examinations should be adjusted based upon the activity and the treatment of the uveitis.
Complications of uveitis may include the following:
Prognosis in juvenile anterior uveitis varies greatly for the different causes. Systemic infections and Kawasaki disease have relatively benign courses. Uveitis associated with inflammatory bowel disease may be very mild or recurrent and of moderate severity. Reactive arthritis and AS may cause severe recurrent episodes of fibrinous inflammation.
Prognosis in sarcoid uveitis may vary widely; intractable cases leading to blindness do occur.
Uveitis related to JIA requires aggressive and careful follow-up, as it continues to be a blinding condition. Aggressive and persistent treatment of uveitis is required to avoid the severe complications, which may evolve insidiously.
For patient education resources, see the Eye and Vision Center and Arthritis Center, as well as Anatomy of the Eye, Iritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis, and Inflammatory Bowel Disease.