AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

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 subspecialist, such as a rheumatologist, are appropriate.

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.

Pathophysiology

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.

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.

Frequency

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.

Mortality/Morbidity

• 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.

Race

Sarcoidosis affects African Americans about 10 times more often than it affects whites. However, most young children with uveitis are white.

Sex

• AS is 2-3 times more common in males than in females.
• Reactive arthritis is at least 5 times more common in males than in females.
• Sarcoidosis is slightly more common in females than in males.
• Oligoarthritis JIA is more common in females than in males, with a female-to-male ratio of 3-4:1.

Age

• 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.
• Mean age of onset of AS is about 10 years and 10-11 years in psoriatic arthritis.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

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.

Physical

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.¹ 
• 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.

Causes

• Juvenile idiopathic arthritis
• • 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.
• Reactive arthritis
• • 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.
• Ankylosing spondylitis
• • 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.
• Ulcerative colitis and Crohn disease
• • 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.
• Childhood sarcoidosis
• • 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
• • 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.
• Viral-associated diseases (eg, mumps, measles, varicella, mononucleosis): 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.
• Juvenile xanthogranuloma: 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.
• Leukemia: Anterior uveitis may rarely signal the onset of or a relapse of leukemia. A hypopyon may be present.
• Acute tubulointerstitial nephritis and uveitis
• • Initially described in adolescent females, acute tubulointerstitial nephritis and uveitis (TINU syndrome) consists of idiopathic tubulointerstitial nephritis and uveitis. Most patients are adolescents with a median age of 15 years, although middle-aged and elderly patients have been reported. No gender predominance has been established. Most patients exhibit proteinuria, elevated beta-2-microglobulin, and increased serum creatinine or decreased creatinine clearance. Additional findings in these patients include fever, weight loss, fatigue, anorexia, anemia, polyuria, glycosuria, and hypergammaglobulinemia.
  • Ocular manifestations of TINU syndrome include acute anterior uveitis, vitritis, disc edema, chorioretinitis, retinal perivascular sheathing, and panuveitis. The uveitis typically responds to treatment with corticosteroids but may become recurrent. 
• Poststreptococcal syndrome uveitis:  Rarely, bilateral nongranulomatous anterior uveitis can develop 1-8 weeks following group A streptococcal infection.  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).    
• Blau syndrome  
• • 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.
• Herpes simplex 
• • 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  
• • 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• 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.
• Antistreptococcal lysin O titers are indicated in patients with possible poststreptococcal syndrome uveitis.

Imaging Studies

• See Lab Studies.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• JIA-related uveitis: The mainstay of treatment currently is topical corticosteroids. The goal of treatment is to reduce the anterior chamber inflammation as much as possible. Sometimes brief courses of intensive treatment, with as frequent as hourly instillations, are needed. Some patients require prolonged courses of less frequent instillations to keep the inflammation in check. Short-acting cycloplegic agents often are prescribed to prevent synechiae. Severe or recalcitrant cases may require sub-Tenon corticosteroids or systemic corticosteroids. Long-term oral methotrexate is often an effective adjunct and may be an effective steroid-sparing therapy.
• HLA-B27–associated uveitis: The severity of uveitis in these conditions ranges widely, necessitating individualized and, in some cases, ongoing care. Milder cases related to Crohn disease or ulcerative colitis are treated with topical corticosteroids; more severe cases are treated with more intensive topical steroid treatment with the addition of cycloplegics. Treatment with sub-Tenon corticosteroids and systemic immunosuppressants expressly for the uveitis rarely is required.
• Sarcoidosis-associated uveitis: 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. However, when anterior disease predominates, treatment with topical corticosteroids and cycloplegics usually will suffice.
• Kawasaki disease and uveitis associated with systemic viral illness: 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.
• Blau syndrome: 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.
• Juvenile xanthogranuloma: Topical and systemic corticosteroids are often effective in treating this condition.

Surgical Care

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 (IOL) placement carries more risk of subsequent complications compared to leaving the patient aphakic; however, IOLs currently are being placed more often than in the past.

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.

Consultations

Depending on the patient, one or more of the following pediatric subspecialists may assist in the evaluation and treatment of patients:

• Rheumatologist
• Pulmonologist
• Infectious disease specialist
• Cardiologist
• Gastroenterologist
• Neurologist
• Oncologist

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The primary medications used in treating anterior uveitis in children are corticosteroids, topical cycloplegics, and, in certain cases of JIA-associated uveitis, methotrexate.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Cycloplegics

Instillation of a long-acting cycloplegic agent can relax ciliary muscle spasm that can cause a deep aching pain and photophobia.

Drug Category: Antimetabolites

Decrease inflammation; corticosteroid-sparing effect.

Drug Category: Immunomodulators

May be useful for uveitis associated with inflammatory bowel disease.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Outpatient Care

• 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.

In/Out Patient Meds

• See Medication.

Complications

• Band keratopathy
• Cataract
• Glaucoma
• Synechiae
• Cystoid macular edema
• Amblyopia
• Hypotony
• Phthisis

Prognosis

• 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Eye and Vision Center and Arthritis Center. Also, see eMedicine's patient education articles Anatomy of the Eye, Iritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis, and Inflammatory Bowel Disease.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• One common pitfall in the diagnosis of anterior uveitis in childhood and adolescence is concluding that an instance of uveitis is related to an early form of JIA, before excluding spondyloarthropathies, such as reactive arthritis, AS, and inflammatory bowel disease. However, the most common systemic association indeed is JIA.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor, Peter H Spiegel, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jan 5, 2008