Special considerations in the evaluation and management of uveitis in children

PERSPECTIVE Special Considerations in the Evaluation and Management of Uveitis in Children GARY N. HOLLAND, MD, AND E. RICHARD STIEHM, MD

● PURPOSE:

To review issues related to the diagnosis, examination, and treatment of children with uveitis that are important for ophthalmologists. ● DESIGN: Literature review. ● METHODS: A review was made of pertinent reports from the medical literature, with commentary based on the authors’ experiences and on discussions at an international workshop. ● RESULTS: There are differences between children and adults in the differential diagnosis and manifestations of uveitis that should be considered during evaluation. There may be a higher risk of some ocular complications such as uveitic glaucoma, and the presence of other unique complications, such as amblyopia, in young patients during follow-up. With regard to treatment, children with uveitis may have unique dosing requirements and drug-associated risks such as growth retardation with systemic corticosteroids that must be considered. Examination and treatment may also be more difficult with children because of problems with patient cooperation. ● CONCLUSIONS: There are unique patient care issues associated with uveitis in children that must be considered by care providers. Attention to these issues will improve the well-being of this patient population. (Am J Ophthalmol 2003;135:867– 878. © 2003 by Elsevier Inc. All rights reserved.)

Accepted for publication March 12, 2003. InternetAdvance publication at ajo.com March 24, 2003. From the Ocular Inflammatory Disease Center, Jules Stein Eye Institute (G.N.H.), and the Departments of Ophthalmology (G.N.H.) and Pediatrics (E.R.S.), David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California. Doctor Holland was supported in part by Research to Prevent Blindness, Inc, New York, New York, the Skirball Foundation, Los Angeles, California, and the David May II Endowed Professorship, and is a recipient of a Research to Prevent Blindness Physician-Scientist Award. Inquiries to Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003; fax: (310) 794-7906; e-mail: [email protected] 0002-9394/03/$30.00 doi:10.1016/S0002-9394(03)00314-3

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HILDREN REPRESENT A UNIQUE POPULATION OF PA-

tients with regard to the evaluation and management of uveitis and other inflammatory diseases of the eye. The overall yearly incidence of uveitis among children in the general population of North America and Europe is estimated to be 4.3 to 6 in 100,000 population,1–3 which is lower than rates for adults. The same populationbased studies estimate the prevalence of uveitis in children to be approximately 30 cases in 100,000 population.2,3 Incidence and prevalence rates may be higher in developing countries.4 Based on these rates, children account for fewer than 10% of all patients with uveitis5; nevertheless, they deserve a disproportionate amount of attention because of various diagnostic and therapeutic challenges associated with this population. For example, the spectrum of disease, as well as disease manifestations, may differ between children and adults. There is some evidence that complications of disease occur at different rates in children and adults, and there are some complications of disease and treatment that are unique to children. Medical therapy for uveitis may be more difficult for a variety of reasons, including poor compliance. Side effects of treatment may be more troubling for children and less well tolerated. The risk of amblyopia in young children will infuence the management of media opacities. Loss of vision from uveitis in a child will have a greater impact over the lifespan of the patient than in an adult, in terms of financial burden and loss of productivity. There have been many reviews and case series dealing with uveitis in children but few large, well-designed, prospective studies to address specific problems encountered in this population. The purpose of this focused review is to identify these problems, and to provide evidence from the medical literature to support current recommendations regarding modifications in the way uveitis is evaluated and managed in children. In preparing this Perspective, we also drew upon discussions that occurred at an international multidisciplinary workshop on inflammatory eye disease in children, sponsored by the Ocular Inflammatory Disease Center, Jules Stein Eye Institute, and conducted at the University of

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California, Los Angeles, in March 2001. Workshop participants are listed in the Acknowledgments section.

more common than anterior uveitis in a review of nine large series: anterior uveitis accounted for 30% to 40% of cases; posterior uveitis, 40% to 50%; intermediate uveitis, 10% to 20%; and panuveitis, 5% to 10%. Most of these series have come from tertiary care facilities. In contrast, recent population-based studies suggest that the majority of children with uveitis have disease restricted to the anterior segment.1,2 Nevertheless, posterior uveitis does appear to account for a greater proportion of uveitis cases among children than among adults,6 especially very young children.9 Careful dilated examinations of the fundi are therefore important in this population. The frequency of various disorders is different in children than in adults. Most multisystem disorders, such as Vogt-Koyanagi-Harada disease, are much less common causes of uveitis in children than in adults.10 Uveitis attributable to Behcet disease, for example, is uncommon among young children, even in areas where the disease is a common cause of adult uveitis.11,12 Conversely, some noninfectious disorders that cause uveitis are more common among children; they include JIA and Kawasaki disease (mucocutaneous lymph node syndrome), a disorder in which patients can develop a mild, self-limited anterior uveitis.13 Primary ophthalmic syndromes (for example, Fuchs uveitis syndrome, birdshot retinochoroidopathy, other white dot syndromes) are much less common among children than adults. The prevalence of various diagnoses vary between centers based on the populations served, referral patterns, and the specific interests of practitioners at those centers. Nevertheless, most published series of children with uveitis over the past 4 decades have identified JIA (more commonly referred to as juvenile rheumatoid arthritis [JRA] in older American publications14) as the most common identifiable cause.1,5,7,8,12 Recent series from referral centers in North America and Europe have identified JIA in 41% to 67% of all children with uveitis1,8 (67% to 77% of anterior uveitis cases1,7,8). The proportion is probably lower in the general population of children with uveitis (21% to 36% of all uveitis cases).1,2 Proportions vary with geographic region; JIA accounts for only 12% to 15% of all uveitis cases in series from the Mediterranean region.11,12 The clinical features of JIA-associated uveitis have been described in numerous publications.15–30 Ophthalmologists should suspect JIA in children with chronic low-grade anterior uveitis. Although disease can cause macular edema as a complication, the presence of posterior uveitis (choroidal infiltrates, retinitis, retinal vasculitis) is not consistent with this diagnosis. The onset of anterior segment inflammation is indolent, and thus patients may not have redness, pain, or photophobia. Often, children will not be diagnosed until parents recognize complications of uveitis or strabismus associated with reduced vision. In most patients, uveitis develops after the onset of joint disease7; intervals range up to several years, but reported medians have been less than 1 year in several re-

PATIENT POPULATIONS CHILDREN WITH UVEITIS ACTUALLY REPRESENT A HETERO-

geneous group of patients. Issues of importance vary with the age of the patient; among other factors, stages of growth and development, metabolism, cooperation, and exposures vary greatly between birth and adulthood. Subpopulations include neonates and infants; young children, during the period of risk for amblyopia; older children; and adolescents. Examination may be difficult in very young patients, and in some cases, examination under anesthesia will be required. Medical therapy may also be difficult in young children, who may not cooperate with instillation of drops or administration of oral medications, and who will require general anesthesia for periocular injections of corticosteroid. Administration of medications away from home is more difficult in school-age children, and compliance problems are common among adolescents. The incidence of uveitis increases with age during the childhood years.1,5 The proportion of various categories of uveitis and diagnoses also vary with age groups.1,5,6 Edelsten and associates1 found no cases of acute uveitis (uveitis of sudden onset) in patients younger than 4 years; this category of disease increased in frequency with age, and was the most common type of uveitis in older teenagers, as in adults. Other issues that vary with the age of the patient are so noted in the sections below. There is no specific upper age limit at which children should be considered adults with regard to evaluation and management of uveitis. Typically, published series of children with uveitis include patients up to the age of 16 years.2,5,7,8 There may also be sex differences. Girls appear to be more commonly affected by uveitis than boys.5,9 Different prevalence rates may, in part, reflect the fact that girls are more likely than boys to develop juvenile idiopathic arthritis (JIA), a common cause of childhood uveitis, as described below. In addition, however, chronic idiopathic anterior uveitis is more common among girls as well.

DIFFERENTIAL DIAGNOSIS AS WITH ADULTS, THERE ARE MANY CAUSES OF CHILD-

hood uveitis, and a differential diagnosis depends on the region of the eye involved and the characteristics of disease. The distribution of cases between anatomic categories of disease (anterior, intermediate, posterior, and panuveitis) in children varies with age1,3 and varies between reported series, in part because of a different spectrum of diseases seen in different geographic areas. Cunningham4 found that posterior uveitis was slightly 868

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ports.22,23,26 Thus, ophthalmologists should encourage parents to continue bringing their children in for routine screening eye examinations according to current guidelines.14,17,31 The severity of eye disease does not necessarily relate to the severity of joint involvement.7 At our institution, JRA-associated uveitis is also the most common identifiable systemic disease association, but children with chronic, idiopathic anterior uveitis who do not have joint disease that fulfills American College of Rheumatology criteria for diagnosis of JRA outnumber children with JRA-associated uveitis (unpublished data). Published series have also identified a high rate of chronic, idiopathic anterior uveitis.1,5,12,32 The clinical features of disease are similar to those of JIA-associated uveitis, and management of the two conditions can be approached in a similar manner. There are laboratory differences between these groups of patients, however. Ohno and associates29 found that tests for antinuclear antibodies (ANA) were positive in 71% of patients with JRA-associated uveitis, but were positive in only 32% of patients with chronic idiopathic anterior uveitis. Some investigators have labeled such cases “chronic iridiocyclitis in young girls,”5,7,29 but there is no evidence that these cases represent a distinct, homogeneous clinical entity. While some investigators have found these cases to be more common among girls,5,29 others have found no sex differences.2 Sarcoidosis is a well-known cause of uveitis in children, but it accounts for only a small proportion of cases, and it is substantially less common than JIA-associated uveitis. In a series of 340 children with anterior uveitis who were known to have a systemic disease, Kanski and Shun-Shin7 described 277 patients with juvenile chronic arthritis but only three with sarcoidosis. Likewise, Tugal-Tutken and associates8 described 130 children with various forms of uveitis, 54 of whom were diagnosed with JRA, but only three of whom had sarcoidosis. Sarcoidosis deserves to be highlighted as a cause of uveitis in children, however, because its presentation in children tends to be different than in adults. Young children with sarcoidosis are less likely than adults to have pulmonary involvement, and more likely to have skin involvement and arthritis.33,34 Chest roentgenograms are thus less likely to be of value in evaluating children for possible sarcoidosis.33 Serum angiotensin-converting enzyme levels can also be misleading, as children tend to have higher normal values than adults.33,34 If sarcoidosis is suspected, children should undergo careful rheumatological evaluation for systemic disease including skin and joint changes; roentgenograms of the hands may be helpful. Eye involvement is more common among younger children with sarcoidosis than among older children or adults.34 Anterior uveitis is the most common manifestation of intraocular sarcoidosis in children.35 When uveitis is restricted to the anterior segment in a child with sarcoidosis and arthritis, it can be confused with JIAassociated uveitis. Unlike JIA-associated uveitis, however, VOL. 135, NO. 6

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juvenile sarcoidosis can involve all segments of the eye.35,36 Patients can have retinal vasculitis, destructive chorioretinal disease, or primary optic nerve inflammation. Subretinal neovascular membrane formation can be a complication of sarcoidosis in children. Familial juvenile systemic granulomatosis can result in ocular disease identical to that seen in children with sarcoidosis.37 Evaluation of children with uveitis and joint disease should include questions about family members with similar joint problems. In both very young and elderly patients, infections and neoplastic masquerade syndromes are relatively more common causes of uveitis than in other age groups. If newborns are found to have intraocular inflammation, congenital infections of the TORCH complex (toxoplasmosis; “other,” including syphilis; rubella; cytomegalovirus disease; herpes simplex virus infection) should be considered. The noninfectious forms of uveitis typical of older children and adults are not seen in newborns. These congenital infections and their sequellae can result in persistent or recurrent uveitis later in childhood. Nearly all published series have identified toxoplasmosis (congenital or acquired) as the most common cause of posterior uveitis in all age groups.1,2,4,5,8,9,11 Clinicians should be aware, however, that lymphocytic choriomeningitis virus chorioretinitis can mimic toxoplasmic retinochoroiditis in young children.38 It is becoming the standard of care to treat newborns with toxoplasmosis using chronic antiparasitic therapy for the first year of life to reduce the rate and severity of ocular involvement.39 Older children are at risk of acquiring infections while playing outdoors that can lead to uveitis.40 Toxocariasis, for example, is a classic form of childhood uveitis that should be suspected in patients with focal granulomata.6 It is seen most commonly in older children (late in the first decade), but remains an uncommon form of uveitis regardless of age in most published series.4,8 Children are also at risk for endogenous infections. Candidiasis is an important cause of infection in children with specific risk factors.41 Endogenous bacterial endophthalmitis is an uncommon cause of intraocular inflammation, but it can occur in children with minimal or no signs of systemic infection.42 At our institution, endogenous bacterial endophthalmitis has been seen more frequently than the endophthalmitis form of toxocariasis, with which it can be confused (unpublished data). An important masquerade syndrome in children is acute lymphocytic leukemia, which typically results in a “pseudohypopyon.” In contrast to the layered hypopyon of neutrophils that can be seen with severe noninfectious anterior uveitis of sudden onset, a pseudohypopyon of neoplastic cells will appear somewhat “lumpy” and remain persistent despite treatment. There may be no other manifestations of leukemia, especially with early disease recurrences; in such cases, diagnosis may require aqueous humor paracentesis for cytologic examination. A mistake

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Although band keratopathy can occur at any age, it is considered by many to be a hallmark of childhood uveitis. The high prevalence of band keratopathy in children with uveitis may reflect the chronicity and severity of many forms of uveitis seen in this age group, such as JIAassociated disease. In a cross-sectional study, however, Perkins5 found that band keratopathy was more common among younger children with uveitis, suggesting that it is not related to chronicity of disease alone. Band keratopathy can be particularly severe in children. If it affects the visual axis in young children, it can lead to amblyopia. If it is present in a child with cataracts who is not a candidate for intraocular lens (IOL) implantation, it may preclude successful aphakic contact lens wear. The presence of complications at initial examination appears to be an important risk factor for development of subsequent complications, regardless of therapy.18,19,47 The nature of this association is not completely understood; while early complications are a marker for severe underlying disease, which may place patients at an ongoing risk for complications, it is possible that the complications themselves change the ocular milieu, fostering development of further complications. The most common complications to occur during treatment include cataract and glaucoma,47 which may be attributable, in part, to corticosteroid use. It is suspected, but not proved, that better control of inflammation early in the course of disease will reduce the rate of complications.46 It is also rational to assume that prevention of early complications of any type will improve long-term outcomes. Unfortunately, current screening programs have not been successful at identifying all children with JIA-associated uveitis before the development of complications.15

sometimes made by pediatricians is to assume that such children have intraocular opportunistic infections because of immunosuppression from chemotherapy. In general, masquerade syndromes will be more slowly progressive than intraocular infections. Other masquerade syndromes in children include juvenile xanthogranuloma43 and posttransplant lymphoproliferative disorder.44 Intraocular neoplasms can be accompanied by an inflammatory response; thus, the presence of retinal vasculitis, keratic precipitates, or a partial response to corticosteroid therapy does not exclude the possibility of a masquerade syndrome.

COMPLICATIONS OF DISEASE IT IS GENERALLY BELIEVED THAT CHILDREN WITH UVEITIS

are at greater risk than adults for development of complications,4 although there is no definitive proof of that. The higher prevalence of complications among children with uveitis may be attributable to longer delays before diagnosis and treatment or to the spectrum of diseases seen in children. Complications include band keratopathy, secondary glaucoma, posterior synechiae, secondary cataract formation, inflammatory membranes, macular edema, hypotony, and phthisis.4,7,8 Unique to young children is the possibility of developing amblyopia from media opacities or macular edema. In a large series of children with anterior uveitis, Kanski and Shun-Shin7 found that 46% had secondary cataracts, which may be related to chronic inflammation, corticosteroid use, or both. They also observed that children developed more severe glaucoma than their adult counterparts. Children with JIA-associated uveitis appear to be at a higher risk of complications than those with other forms of uveitis.1 Foster and Barrett45 found that, even with aggressive therapy to control inflammation, 18% of patients with JIA-associated uveitis who had at least 1 year of follow-up developed secondary cataracts. Foster and associates46 also found that uveitic glaucoma or elevated intraocular pressure occurred in 42% of patients with JIA-associated uveitis at intervals ranging from 0.6 to 58 years after the onset of uveitis (mean 9.2 years). They found no relation between the development of complications and the course of a patient’s arthritis. Particularly devastating is the development of ciliary membranes, which can place traction on the ciliary body, leading to its detachment. Uveitis associated with JIA can also lead to ciliary body atrophy with hypotony, even in the absence of tractional detachment, presumably through the effects of chronic inflammation. Ultrasonographic biomicroscopy is an important technique for evaluating the status of the ciliary body and identifying the presence of ciliary membranes, but may be difficult to perform in young children because of the large fluid chamber placed over the eye, and the need for patient cooperation. 870

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THERAPY TRADITIONALLY, CORTICOSTEROIDS HAVE BEEN THE MAIN-

stay of treatment for noninfectious forms of uveitis. In recent years, there has been a trend to earlier and more aggressive use of immunomodulatory agents for adults and children to treat noninfectious forms of uveitis, both to prevent development of complications and to avoid local and systemic side effects of corticosteroids. The more traditional approach of waiting until vision drops or complications develop before beginning immunomodulatory therapy is no longer considered to be an appropriate management strategy by most uveitis specialists. Needed is a better understanding of the risk factors for development of complications so that early immunomodulatory therapy can be used selectively for those patients who require it. Children receiving systemic corticosteroids or immunosuppressive drugs require special attention because of the effect of these agents on growth, nutrition, school and recreational activities, infectious diseases, and fertility. The use of systemic corticosteroids and immunosuppressive OF

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agents for treatment of uveitis has been reviewed in detail elsewhere.48,49 Highlighted below are issues specifically related to the treatment of children. Parents often ask how long uveitis will last and how long treatment will be needed. The course of disease depends on the type of uveitis. Some disorders (HLA-B27-associated uveitis; active infections, such as toxoplasmic retinochoroiditis) can resolve completely with treatment. Some cases of idiopathic disease and some forms of uveitis associated with systemic disorders (Kawasaki disease, poststreptococcal syndrome50) will be mild and transient. Clinicians should assume, however, that most cases of uveitis characterized by prominent inflammatory signs or complications will persist for long durations, and plan treatment accordingly. The chronic anterior uveitis seen in children with JIA may decrease in severity over time, but is likely to persist into adulthood; it is not unusual for joint inflammation to subside while iridocyclitis persists. It is sometimes said that pars planitis syndrome will “burn out,” but we have observed numerous children whose disease has persisted for many years; while the proportion of such cases in our practices may be high because of referral bias, one should not assume that disease will resolve when counseling parents. ● ANTIMETABOLITES: Methotrexate is the most common immunosuppressive agent used in children. It is generally safe, well tolerated, and easily administered. It does not affect future reproductive potential. Methotrexate therapy is substantially safer for long-term treatment of children than oral corticosteroids. Methotrexate is an effective treatment for joint disease in children with JIA,51 and is believed to be an effective therapy for JIA-associated uveitis and chronic, idiopathic anterior uveitis of childhood. The use of methotrexate for treatment of childhood uveitis has not been investigated in well-designed, prospective trials. Furthermore, despite the many articles written about the use of methotrexate to treat uveitis in children, there have been few specific data published about response rates.52 Based on workshop discussions, it seems to be the clinical impression of many uveitis specialists that methotrexate is effective in at least 60% of children with chronic uveitis, which is comparable with published response rates for treatment of arthritis.51 Methotrexate is cleared more rapidly from children than from adults, and thus, doses must be higher on a per-mass basis in children. It is usually given once weekly at an oral dose of 10 to 30 mg/m2.53 Because children are smaller, total weekly doses generally are in the same range as those given to adults. Absorption is variable in children and subcutaneous injection of methotrexate should be considered before assuming that methotrexate is ineffective. Subcutaneous injections may also be better tolerated than oral administration in children who experience stomach upset.

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There is less experience with the use of other antimetabolites (azathioprine, mycophenolate mofetil, leflunomide) for treatment of uveitis in children, although there appears to be growing interest in mycophenolate mofetil as an alternative medication for children intolerant of methotrexate. ● CYCLOSPORINE:

Cyclosporine has been used successfully to treat various forms of uveitis in children.8,54,55 In one report,8 all treatment failures were in children with JIA-associated uveitis, but other investigators have not had similar problems in treating children with this disease.55 Cyclosporine is generally given to children with uveitis in the same dosage range (3 to 5 mg/kg daily) used in adults. Cyclosporine has no effect on growth or gonadal function. ● CYTOTOXIC AGENTS: Cyclophosphamide and chlorambucil have been used in children for the treatment of such disorders as severe systemic lupus erythematosis, amyloidosis, Behcet disease, or other systemic vasculitides. The potential for serious long-term side effects has limited their use for nonlife-threatening diseases, and thus, there is little experience in the treatment of ocular inflammatory disease in children with these drugs.56,57 ● BIOLOGICS: Cytokine inhibitors are being used, in some cases with dramatic success, to treat various forms of arthritis in children.58 With that experience, the use of these drugs has been considered in the management of inflammatory eye disease in children as well. Two agents that inhibit tumor necrosis factor (TNF) have undergone some evaluation in patients with uveitis: etanercept (Enbrel, Immunex Corporation, Seattle, Washington, USA), a fusion protein containing a portion of the TNF receptor, which binds with TNF before it can activate cells; and infliximab (Remicade, Centocor, Inc., Malvern, Pennsylvania, USA), a monoclonal antibody against TNF. Reiff and associates59 used etanercept to treat chronic anterior uveitis in 10 children, seven of whom had JRA. Over a 6-month period, they noted substantial improvement in inflammation in 10 of 16 treated eyes, with improvement of vision in four of 10 eyes that had decreased vision at baseline. Only one patient had an exacerbation of inflammation. Smith and associates60 compiled a series of 16 patients from multiple centers who were treated with etanercept or infliximab for various indications including uveitis, scleritis, and arthritis. They were less enthusiastic about the results of treatment; their report emphasized the differential response to drug between nonocular and ocular tissues. Joint inflammation improved in all 12 patients who had arthritis, whereas ocular inflammation improved in only six of the 16 patients. Because etanercept and infliximab have different mechanisms of action, there has been discussion about whether

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particularly troubling for adolescents who are more likely to have a heightened concern about their body images. Elevation of intraocular pressure caused by topical corticosteroids is more common and more severe in children than in adults and is dose dependent.64,65 In our experience periocular injections of corticosteroids are more likely to result in elevated intraocular pressure in children than in adults. For example, in a study of 20 patients with intermediate uveitis who received posterior subtenon injections of corticosteroid, we found that three of the six who had corticosteroid-induced elevation of intraocular pressure were 11 years old or younger, despite the fact that most patients in the series were adults.66 Communicable diseases are a concern for children receiving immunosuppressive therapy because of their increased exposure to infectious agents from other children. Children receiving high-dose corticosteroids or immunosuppressive drugs should not receive live virus vaccines (mumps-measles-rubella vaccine, varicella-zoster virus vaccine, oral polio vaccine, BCG) while on therapy or for 3 months after stopping therapy. Varicella-zoster vaccine should therefore be given before start of immunosuppressive therapy. Children receiving only prednisone at doses less than 2 mg/kg daily or 20 mg daily maximum can be given live virus vaccines, however. Most immunosuppressive drugs interfere with cellular, rather than antibody-mediated, immunity; thus, children receiving these drugs are not particularly susceptible to respiratory infections, and do not need to be isolated from other children. Nevertheless, because these children are more likely to develop systemic viral diseases, they should receive a yearly influenza vaccine, and if susceptible, varicella-zoster virus immune globulin upon close exposure to chickenpox. Children who develop varicella are at increased risk of disease-related complications. If the CD4⫹ T-lymphocyte count is less than 200 cells/␮l, consideration should be given to placing the child on prophylaxis against Pneumocystis carinii pneumonia. In general, children receiving chronic corticosteroid or immunosuppressive drug therapy can participate in routine school and recreational activities. Although immunosuppressive drugs, notably methotrexate, may result in poor wound healing, most children do not have major problems with healing during treatment. Methotrexate is generally stopped for 2 weeks before and 2 weeks after major surgery, such as an orthopedic procedure, because of concerns regarding wound healing. It is not necessary to stop methotrexate for children undergoing eye surgery, however. Prepubertal children given cytotoxic agents are at lower risk for sterility later in life than adolescents and adults. If cyclophosphamide or chlorambucil are used in older children, the possibility of sterility should be discussed with parents or guardians. Cryopreservation of sperm or eggs can be considered. An alternative approach under investigation for female patients of reproductive age is concom-

one drug might be more effective than the other for treatment of uveitis in children. Anecdotal reports suggest that infliximab may be more effective, but it should be noted that infliximab has a higher rate of complications, including increased risk of tuberculosis and development of antibodies to the drug. Also, it is difficult to predict the effects of biologic agents that target only one factor in the complex dynamics of the immune response. In addition to affecting disease differently in various tissues of the body, these agents may affect various forms of uveitis differently. ● NONSTEROIDAL ANTI-INFLAMMATORY DRUGS:

Oral nonsteroidal anti-inflammatory drugs are an important component in the management of joint disease in children with JIA. Their use has also been advocated as adjuncts to other anti-inflammatory drugs in the management of uveitis in children,8,21,27,28,30,61 but there is little objective evidence of their beneficial effect for this indication.48,61 Although Dana and associates21 found a relationship between use of systemic nonsteroidal anti-inflammatory drugs and better visual outcomes in children with JIAassociated uveitis, their study could not confirm a causal relationship. In our experience, neither oral nor topical formulations of these drugs are effective for treatment of uveitis. ● DRUG SIDE EFFECTS:

The risks associated with various immunosuppressive drugs are discussed in detail elsewhere.48,49 With regard to methotrexate, toxicities are similar in both children and adults. With regard to cyclosporine, children can develop nephrotoxicity and hypertension with treatment, but these problems are less common in children than in adults. Unique to children, especially those who are very young, is the suppressive effect of corticosteroids on growth and development.62 Suppression of linear growth by corticosteroids is dose-related; growth can be affected by doses greater than 0.4 mg/kg daily,63 and can cease completely at very high doses. Prednisone given as a single dose on alternate days will have less effect on growth potential, but will be less effective for control of inflammation than daily administration. Growth suppression cannot be reversed with human growth hormone. Other drugs can also interfere with growth indirectly by causing nausea, abdominal pain, or anorexia, and thus affecting nutrition. All children receiving systemic anti-inflammatory drugs should have height and weight checked at 3-month intervals and recorded on a growth curve. Children are also susceptible to the mydriad other effects of corticosteroids including osteoporosis, adrenal suppression, and secondary Cushing syndrome. As with adults, children receiving corticosteroids should be given calcium and vitamin D to reduce bone mineral loss. Certain of the adverse effects of systemic corticosteroid use, such as weight gain, acne, and mood swings, may be 872

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itant gonadotropin-releasing hormone agonist therapy to limit gonadotoxicity and prevent sterility.67 Adolescent patients being treated with methotrexate should be counseled about its teratogenicity and the need for birth control while taking the drug. ● AN APPROACH TO MEDICAL TREATMENT:

Both the goals and risks of medical treatment must be considered in the management of uveitis during childhood. While elimination of all cells from the anterior chamber is an appropriate target when starting treatment, it is not always possible to do so. Furthermore, it is likely that not all patients with a given level of cells will be at the same risk for vision-limiting complications. Thus, the side effects of drug therapy must also be considered when planning long-term treatment strategies. In consideration of these treatment issues, we outline below our general approach to the medical management of noninfectious forms of uveitis in children. At initial examination of patients with active anterior segment inflammation, we generally initiate a trial of intense topical corticosteroids (prednisolone acetate 1% at a frequency of one drop every 1 or 2 hours while awake), regardless of the level of anterior chamber cells. Children will be reassessed in 1 or 2 weeks for response to treatment. If some response is seen, but the patient still has 1⫹ cells or more, we will continue treatment at the same frequency for as long as several weeks, in the hope of seeing continued slow resolution of inflammation. Once inflammation appears to be at its best level of control (fewer than 1⫹ cells, with no iris nodules or keratic precipitates), the frequency of drug instillation will be tapered slowly to the fewest number of drops that will maintain inflammation at its best level of control. In some cases, total elimination of cells from the anterior chamber is not achieved nor are we able to discontinue medication completely. If control can be maintained with fewer than four drops daily, topical treatment is continued in preference to oral therapy. Over time, the need for continued therapy is reassessed, and further tapering is attempted. If the level of anterior chamber cells increases as we taper the frequency of drops below four times daily, we will add a systemic corticosteroid-sparing agent, usually methotrexate. Once a commitment is made to use methotrexate, we will continue treatment for 1 to 2 years, if it is found to be effective and is well tolerated; an attempt is then made to taper and discontinue its use. If, conversely, there has been little or no response to initial anti-inflammatory therapy, no vision loss, and no complications, we will reconsider the need for aggressive therapy in view of the potential for drug-related side effects. It has been our experience that there is a subgroup of patients with low aqueous humor protein levels by laser flare photometry, who present with normal vision and no complications, and who remain complication free for long periods of time without intense topical or systemic therapy,

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even if there is persistence of some cells in the anterior chamber.47 Such patients deserve very close follow-up, however, to be sure that complications do not develop, and treatment should be reconsidered if there is any change in the patient’s status. These patients constitute a minority of the cases that we see, however. In general, the uveitis seen in these patients is idiopathic in nature, and is not associated with systemic diseases. For most patients, we agree with the recommendations of C. Stephen Foster, MD (described in various publications8,27,28,30) that patients should be treated with early, aggressive anti-inflammatory therapy to suppress inflammation maximally, in hopes of preventing development of vision-threatening complications, even if the patients have only low-grade anterior chamber cellular reactions at presentation. This approach is especially important for children with JIA-associated uveitis and other disorders of comparable severity. Intense treatment is administered to any patient with keratic precipitates or iris nodules. In our experience, a common mistake among referring clinicians is to undertreat patients, which allows persistence of smoldering inflammation and the eventual development of complications. For patients with intermediate and posterior uveitis, periocular injections of corticosteroid can be used to quiet disease initially, and for short-term management of disease exacerbations, but repeated injections are probably not an appropriate strategy for long-term control, especially in young children. We generally treat such cases with methotrexate, as described above. Methotrexate and other immunosuppressive agents will not have an immediate onset of action, and even young children may need an initial course of oral corticosteroids. We try not to continue oral corticosteroids for longer than 1 month, however. Patients with panuveitis who have a prominent anterior component of inflammation may need both systemic and topical therapy. If monotherapy with an immunosuppressive agent is not able to bring disease under control, treatment strategies include drug switching and supplementation with a second agent. We generally switch from one agent to another single agent only if there has been a lack of response, drug intolerance, or substantial treatment side effects. If some treatment effect has been demonstrated, but disease is not at its best level of control, we will generally choose to add a second drug. Most often we will add cyclosporine to an existing regimen of methotrexate. For some patients who require surgery, we will use combination therapy only in the perioperative period, when control of inflammation is most critical, but can be most difficult. ● MANAGEMENT OF COMPLICATIONS: Urgent surgery may be necessary for vision-threatening complications, such as ciliary membrane formation with ciliary body detachment, retinal detachment, or uncontrolled elevations of intraocular pressure. In contrast, cataract extraction and other elective surgeries should be deferred until

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inflammation will be at its best level of control for at least 3 to 4 months, as with adults who have uveitis. Some parents will request that surgery be scheduled to coincide with summer vacations or holidays, to minimize the child’s time away from school. Such accommodations should be made only if inflammation is controlled at that point in time. Deferral of surgery may require that children have special educational arrangements, such as low vision aids or tutors, until surgery can be performed. The medical advantages of deferral should be weighed against the risks of amblyopia in very young patients with unilateral cataracts, however.

high rate of complications.72–74 In a series of seven patients with JRA who underwent cataract extraction and intraocular lens implantation, Probst and Holland73 described less favorable results among the children in their series when compared with the adults; problems included elevated intraocular pressure, posterior synechiae formation, and pupillary membrane formation. Lundvall and Zetterstrom72 described 10 eyes of seven children with uveitis that underwent IOL implantation. In seven of 10 eyes, inflammatory membrane formation required that reoperations be performed. In contrast, Lam and associates68 more recently described IOL implantation in six eyes of five patients with JIA, none of whom developed vision-limiting complications, despite longer periods of follow-up (median 43.5 months, range 17 to 69) than for patients in previous series. They attributed their good results to meticulous control of inflammation, with immunosuppressive drug therapy in most cases. Even with intensive anti-inflammatory therapy and well-controlled disease at the time of surgery, inflammatory membranes and other complications can eventually develop that require explantation of IOLs, however.76 Such complications occur most commonly in patients with JIA and those who have inflammation in the intermediate portion of the eye, as seen with pars planitis syndrome. Thus, without more experience and longer periods of follow-up for children with uveitis who have already undergone IOL implantation, it is difficult to recommend this procedure as routine in all cases. Rehabilitation of vision with aphakic spectacles or contact lenses is most successful when children with uveitis are aphakic in both eyes.74 In contrast, failure of aphakic contact lens rehabilitation is especially high in young children with uveitis who undergo unilateral surgery and have good visual acuity in the other, phakic eye74; such children may be the most appropriate candidates for IOL implantation at this time. Opacification of the posterior lens capsule has been a common sequella of cataract extraction in children with uveitis.68,72–74 Young age is a risk factor for postoperative capsular opacification, even in children without uveitis, and capsular opacification can lead to amblyopia.77 Postoperative laser capsulotomies can be difficult or impossible to perform in young children, because of the need for patient cooperation. For these reasons, some clinicians advocate primary posterior capsulotomy with anterior vitrectomy at the time of surgery, when cataract extraction is performed through an anterior approach, as a means of maintaining a clear visual axis.72,74,77 This procedure does not preclude the implantation of an IOL. Central posterior capsulotomy and anterior vitrectomy does not necessarily prevent formation of retrolenticular membranes in children with uveitis, however.74 Pars plana vitrectomy with removal of all lens material through a posterior approach has been advocated as a means of preventing ciliary membrane formation by total elimination of the scaffolding upon which such membranes

● CATARACT EXTRACTION:

Cataract surgery in children with uveitis can be technically more difficult because of their small eyes, lack of scleral rigidity, and high rates of preexisting complications. Nevertheless, with modern surgical techniques and good perioperative control of inflammation, excellent visual results can be obtained; recent series report that 75% or more of children with uveitis achieve postoperative visual acuity of 20/40 or better after cataract extraction.45,68 In young children it may be appropriate to remove cataracts earlier in the course of vision loss than would be done in adults, to avoid amblyopia. A variety of surgical techniques have been described for removal of cataracts from children with uveitis. Most reported series describe surgery on children with JIA, but the principles described in these series are applicable to other disorders as well. Techniques have included lensectomy/vitrectomy69 –71; phacoemulsification through a limbal incision, followed by pars plana vitrectomy with removal of all lens material45; and standard phacoemulsification techniques, in some case combined with posterior capsulotomy and vitrectomy through an anterior approach, and in some cases with IOL implantation.68,72–74 Recent series have involved fewer than 20 patients each, and there have been no comparative studies to clarify the relative merits or disadvantages of each technique. The implantation of IOLs in children with uveitis has been a subject of controversy,75 with valid arguments both for and against their use. Until recently, most uveitis specialists have considered IOL implantation to be contraindicated in children with JIA-associated uveitis because IOLs may serve as scaffolding upon which inflammatory membranes could form.16 Conversely, visual rehabilitation with aphakic contact lenses can be difficult, especially in young children, because of poor compliance or intolerance.45 Contact lens wear may be impossible in patients with severe band keratopathy, and there may be an increased risk of contact lens-related infections in patients who require chronic topical corticosteroid therapy. Recently there have been several series describing the implantation of IOLs in children with uveitis, the majority of whom have had JIA.68,72–74 Initial reports described a 874

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could form.45,69 –71 Removal of lens cortex and nucleus through an anterior approach before pars plana vitrectomy may allow better management of the iris, especially in cases of extensive posterior synechiae45; the capsule is then removed during pars plana vitrectomy. These procedures preclude the use of IOLs. The basic safety and good results associated with vitrectomies that are performed in conjunction with cataract extraction in children have been shown in published case series,45,69,70 but the need for vitrectomy in all children with chronic uveitis and cataracts has not been proven. It seems appropriate to plan each surgery on a case-by-case basis, considering factors such as the ease with which inflammation is controlled, the existence of ciliary membranes, the tendency to form posterior synechiae, and the age of the patient. In our experience, patients without complications or vitreous humor changes, and whose inflammation is well controlled, can undergo routine cataract extraction with retention of the posterior capsule and vitreous humor and do well, with excellent long-term vision. In older published case series, hypotony at the time of surgery was associated with a substantial risk of phthisis after cataract extraction.71 BenEzra and Cohen74 found that children with JRA-associated uveitis had more postoperative problems after cataract surgery than children with other forms of uveitis, but patients with JRA in their series were also younger, which may have been a contributing factor to the poor outcomes. Even with good initial postoperative results, patients can have progressive loss of vision over time after cataract extraction. Fox and associates69 found that glaucoma and macular disease were the major reasons for vision loss. These problems may or may not be related to cataract extraction or the specific techniques used. ● GLAUCOMA MANAGEMENT: Tolerance of some glaucoma medications differs between children and adults. Acetazolamide is better tolerated in young patients, while topical brimonidine can cause somnolence and decreased alertness in many children, especially among the very young. Pilocarpine, although rarely used in the management of uveitic glaucoma, may not be tolerated in young patients because of pain. Foster and associates46 found that intraocular pressure could be controlled with topical medications in only seven (17%) of 41 patients with JIA and uveitic glaucoma; pressure could be controlled in 15 (37%) of 41 patients with a combination of topical medications and an oral carbonic anhydrase inhibitor. In all but one of the remaining children, intraocular pressure was controlled after surgery. Several published case series have specifically described the surgical management of glaucoma in children with uveitis.46,78 – 80 Techniques have included trabeculectomy with intraoperative application of mitomycin-C,46 standard goniotomy,78 trabeculodialysis (a modified goniotomy),79 and implantation of drainage devices.46,80 As with series describing cataract extraction in children with

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uveitis, most patients in these series have had JIA-associated uveitis. Long-term success rates range from 60% to 90%. It is hard to compare the efficacies of different reported techniques, as durations of follow-up have varied between series, and authors have used different definitions of success. In a high proportion of successful surgeries, children have continued to require topical glaucoma medications for optimum intraocular pressure control. Standard trabeculectomies are associated with a high rate of failure in children because of increased scarring. Trabeculectomy with intraoperative application of mitomycin-C has been more successful in children, but raises concerns about postoperative infection and bleb leaks over the long expected lifespans of these patients. For that reason, the use of drainage devices appears to be the most popular technique for surgical management of uveitic glaucoma in children currently.

MONITORING AND COMPLIANCE MONITORING OF DISEASE AND TREATMENT EFFECTS IS ES-

pecially important in children with uveitis, who may not report changes in vision, as would an adult. Particular attention should be paid to visual acuity of children at risk for amblyopia. As with adults, periodic examinations should be performed to assess levels of inflammation (anterior chamber cells and flare; vitreous humor cells and haze), signs of uncontrolled inflammation (keratic precipitates; iris nodules), the presence of complications, and evidence of drug toxicities. Kanski and Shun-Shin7 suggest that children be monitored more closely than adults for evidence of uveitic glaucoma. They noted that glaucomatous optic disk changes can progress rapidly in this population and recommended frequent dilated examinations of the optic discs. It may be impossible to monitor children reliably with visual fields. Patients with chronic anterior uveitis who had no systemic complaints at presentation should be asked about the development of joint symptoms during follow-up, as arthritis can develop after the onset of uveitis in a minority of children with JIA.7,23 Assessment of compliance with treatment regimens is also important, especially if children receive medications in school or are allowed to instill their own topical medications. Compliance may be a problem in long-term drug therapy of teenagers, who are notable for stopping their own medications. Parents or guardians must participate in the administration of medications to assure that doses are not missed.

SUMMARY THE EVALUATION AND MANAGEMENT OF CHILDREN WITH

uveitis is based on the same principles that apply to adults,

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7. Kanski JJ, Shun-Shin GA. Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 1984; 91:1247–1252. 8. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology 1996;103:375–383. 9. Kimura SJ, Hogan MJ. Uveitis in children: analysis of 274 cases. Trans Am Ophthalmol Soc 1964;62:173–192. 10. Jordan JF, Walter P, Ayertey HD, Brunner R. Intermediate uveitis in childhood preceding the diagnosis of multiple sclerosis: a 13-year follow-up. Am J Ophthalmol 2003;135: 885– 886. 11. Pivetti-Pezzi P. Uveitis in children. Eur J Ophthalmol 1996; 6:293–298. 12. BenEzra D, Cohen E, Maftzir G. Patterns of intraocular inflammation in children. Bull Soc Belge Ophtalmol 2001; 279:35–38. 13. Kumagai N, Ohno S. Kawasaki disease. In: Pepose JS, Holland GN, Wilhelmus KR, editors. Ocular infection & immunity. St. Louis: Mosby-Year Book, 1996:391–396. 14. Petty RE, Smith JR, Rosenbaum JT. Arthritis and uveitis in children: a pediatric rheumatology perspective. Am J Ophthalmol 2003;135:879 – 884. 15. Chia A, Lee V, Graham EM, Edelsten C. Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening program. Am J Ophthalmol 2003;135:757–762. 16. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol 1990;34:253–267. 17. Kanski JJ, Petty RE. Chronic childhood arthritis and uveitis. In: Pepose JS, Holland GN, Wilhelmus KR, editors. Ocular infection & immunity. St. Louis: Mosby-Year Book, 1996: 485–493. 18. Wolf MD, Lichter PR, Ragsdale CG. Prognostic factors in the uveitis of juvenile rheumatoid arthritis. Ophthalmology 1987;94:1242–1248. 19. Edelsten C, Lee V, Bentley CR, et al. An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood. Br J Ophthalmol 2002;86:51–56. 20. Chalom EC, Goldsmith DP, Koehler MA, et al. Prevalence and outcome of uveitis in a regional cohort of patients with juvenile rheumatoid arthritis. J Rheumatol 1997;24:2031– 2034. 21. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Visual outcomes prognosticators in juvenile rheumatoid arthritis-associated uveitis. Ophthalmology 1997;104:236 – 244. 22. Zulian F, Martini G, Falcini F, et al. Early predictors of severe course of uveitis in oligoarticular juvenile idiopathic arthritis. J Rheumatol 2002;29:2446 –2453. 23. Kotaniemi K, Kautiainen H, Karma A, Aho K. Occurrence of uveitis in recently diagnosed juvenile chronic arthritis: a prospective study. Ophthalmology 2001;108:2071–2075. 24. Oren B, Sehgal A, Simon JW, et al. The prevalence of uveitis in juvenile rheumatoid arthritis. J AAPOS 2001;5: 2–4. 25. Boone MI, Moore TL, Cruz OA. Screening for uveitis in juvenile rheumatoid arthritis. J Pediatr Ophthalmol Strabis 1998;35:41–43. 26. Kotaniemi K, Kaipiainen-Seppanen O, Savolainen A, Karma A. A population-based study on uveitis in juvenile rheumatoid arthritis. Clin Exp Rheumatol 1999;17:119 –122. 27. Ceisler EJ, Foster CS. Juvenile rheumatoid arthritis and uveitis: minimizing the blinding complications. Int Ophthalmol Clin 1996;36:91–107. 28. Hemady RK, Baer JC, Foster CS. Immunosuppressive drugs

with the caveat that there are additional special considerations when dealing with children. Examination and treatment are more challenging in young patients, and coordination of care with pediatricians experienced in the management of inflammatory diseases is important.14 Substantial progress has been made in this field over the past several decades, but even recent surveys demonstrate a higher rate of uveitis-associated complications and vision loss in children than in adults. It is the consensus of experts in the field that early and aggressive anti-inflammatory therapy is the best means to improve long-term outcomes for children with uveitis in the future. Opinions may vary regarding specific approaches to therapy, but attention to the issues raised in this Perspective should be an important component in formulating management strategies. ACKNOWLEDGMENTS

Additional participants in the workshop “Evaluation and Management of Inflammatory Eye Disease in Children” included: Emmett T. Cunningham, Jr., MD, PhD, MPH (New York, NY), Janet L. Davis, MD (Miami, FL), Joseph L. Demer, MD, PhD (Los Angeles, CA), Sean P. Donahue, MD, PhD (Nashville, TN), Clive Edelsten, MRCP, FRCOphth (London, England), C. Stephen Foster, MD (Boston, MA), Lynn K. Gordon, MD, PhD (Los Angeles, CA), Elizabeth M. Graham, FRCP, DO, FRCOphth (London, England), Sherwin J. Isenberg, MD (Los Angeles, CA), Ralph D. Levinson, MD (Los Angeles, CA), Marilyn B. Mets, MD (Chicago, IL), Bartly J. Mondino, MD (Los Angeles, CA), Ross E. Petty, MD, PhD (Vancouver, British Columbia, Canada), Narsing A. Rao, MD (Los Angeles, CA), Andreas A. Reiff, MD (Los Angeles, CA), Arthur L. Rosenbaum, MD (Los Angeles, CA), Jonathan C. Song, MD (Los Angeles, CA), and Justine R. Smith, MBBS, PhD (Portland, OR). The authors appreciate the contributions of each participant during the workshop; opinions and recommendations contained in this Perspective are those of the authors, however, and may or may not be shared by other workshop participants.

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