Pediatric Uveitis
Grace T. Liu
Alex V. Levin
INTRODUCTION
Uveitis in the pediatric population is a significant cause of ophthalmic morbidity. Approximately 2% to 14% of patients seen in uveitis clinics are children (1,2,3). Unique to the pediatric age group in the management and timely diagnosis of uveitis is the threat of amblyopia. In addition, the associated systemic disease profile is much different than that seen in adults. Children more often (71%) have an associated systemic illness than adults (55%) (4). Although juvenile idiopathic arthritis (JIA) is the predominant cause of anterior uveitis in children (5,6), it is important to recognize that uveitis in a child can be due to a wide range of etiologies, including serious life-threatening masquerade syndromes such as retinoblastoma and leukemia. Presenting signs and symptoms are often not recognized until advanced stages, and the disorder may even be entirely asymptomatic until irreversible ocular damage has been sustained (Fig. 13.1). The child may be unable to verbalize his/her symptoms, and can often function normally with visual acuity well below 20/20 for activities of daily living, especially when the disease is unilateral and the child is younger. The approach to pediatric uveitis requires the understanding that early recognition through screening, where appropriate, can be of utmost importance.
Table 13.1 summarizes the diagnostic approach to the child with pediatric uveitis.
EPIDEMIOLOGY
The frequency and etiology of childhood uveitis is in part dependent on geography. Widespread globalization may also affect the current distribution of the disease. A meta-analysis of worldwide studies showed that 7% of patients with uveitis are children. Parasitic anterior uveitis (49.3%) is the most common etiology globally, with idiopathic being the second most common (25.5%) (7). A group from Saudi Arabia reported idiopathic anterior non-granulomatous uveitis as the most common type of uveitis in children (26%) (8). A report from Israel found infectious diseases to be the primary etiology of uveitis in children and adolescents (31.2%) (1).
To the contrary, a study from the US National Eye Institute found that idiopathic uveitis (28.8%) was the leading etiology in the United States, followed by JIA (20.9%), and pars planitis (17.1%). A retrospective study characterizing disease characteristics and visual outcome of 527 children in the United States with uveitis, found that 54% were female; 62% White, 15% Hispanic, 12% Black, 3% Asian, and 2% multiracial (9). The median age at diagnosis was 9.4 years.
CLASSIFICATION
Although consortium-driven classification systems have been proposed, they may be difficult to use in the clinical setting. The Standardization of Uveitis Nomenclature (SUN) criteria were developed for classification and description of uveitis by anatomic location (Table 13.2). Specific grading criteria, such as quantitative grading of inflammation, were also elaborated (10). Morphologic classification, according to cell type, for example granulomatous versus nongranulomatous, may be less useful in children. A broader classification might separate etiologies into exogenous, representing any external injury or invasion of microorganisms from outside the globe, versus endogenous, resulting from factors that originate within the patient.
TREATMENT AND COMPLICATIONS
Topical Medical Therapy
Even with low-grade iritis, the goal is early, aggressive treatment to suppress inflammation maximally, in hopes of preventing the development of vision-threatening complications (11,12,13,14). When inflammation is more severe, topical corticosteroids may be indicated as frequently as every 1 to 2 hours. Follow-up within 1 to 2 weeks after initiating treatment is critical to ensure improvement. Perhaps the most common reason for recalcitrant and recurrent uveitis is the too rapid tapering of topical steroids. Although a fairly rapid taper may be appropriate on the first episode, any indication of iritis recurrence during the taper should be met with a change to a slow taper. It may take weeks, months, or even
years to accomplish a full taper in some children. Although there are certainly risks of steroid-induced cataract or glaucoma, the risk of these complications from inadequately treated uveitis is even greater. Our experience with high dose and chronic topical steroid use actually shows a reduction in such complications and better vision outcomes (15).
years to accomplish a full taper in some children. Although there are certainly risks of steroid-induced cataract or glaucoma, the risk of these complications from inadequately treated uveitis is even greater. Our experience with high dose and chronic topical steroid use actually shows a reduction in such complications and better vision outcomes (15).
 FIGURE 13.1. Child with asymptomatic oligoarticular juvenile idiopathic arthritis who did not present until visual loss was noted by which time she had a dense white cataract, multiple posterior synechiae, and active anterior uveitis. Note the absence of conjunctival inflammation. |
Table 13.1 EVALUATION AND TESTING FOR PEDIATRIC UVEITIS | |||||||||||||||||||||||||||||||
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Cycloplegic agents are also important, given the increased tendency of children to form synechiae. Many different regimens have been suggested (16). We prefer a minimum of one dose of cyclopentolate 1% at bedtime. It is also important to consider (and treat with glasses if needed) the blur induced by cycloplegia, especially in school-aged children.
A recent study specifically on the use of difluprednate in pediatric uveitis demonstrated its use to be effective for anterior segment inflammation and reduction of cystoid macular edema (CME) when used as an adjuvant to systemic immunomodulatory therapy, but it was not without risks (17). Glaucoma
and cataract were both observed at significant rates, and the authors recommend close monitoring of pediatric patients on this medication.
and cataract were both observed at significant rates, and the authors recommend close monitoring of pediatric patients on this medication.
Systemic Medical Therapy
Methotrexate is usually the first-line systemic agent if topical therapy fails to control the iritis, or if chronic high frequency dosing of topical steroids is needed. Absorption of oral methotrexate in children can be variable, and subcutaneous injection may be more effective. GI upset is a common side effect of oral administration (18)
Table 13.2 THE SUN WORKING GROUP CLASSIFICATION OF UVEITIS (10) | |||||||||||||||||||||||||||||||||||||||
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Caution should be taken with use of chronic oral corticosteroids in children. The risks of growth retardation, osteoporosis, adrenal suppression, gastrointestinal upset, emotional lability, and susceptibility to infection must be
considered. Secondary glaucoma may occur more frequently in children than in adults (19,20). In general, oral corticosteroids are reserved for short course (<14 days) as an acute intervention, to test for steroid responsiveness, or perioperatively. Although nonsteroidal anti-inflammatory medications (NSAIDs) may be a useful adjunct in managing the systemic symptoms of JIA, and there has been some suggestion of ocular benefit, they play a minor role in the management of pediatric uveitis (21).
considered. Secondary glaucoma may occur more frequently in children than in adults (19,20). In general, oral corticosteroids are reserved for short course (<14 days) as an acute intervention, to test for steroid responsiveness, or perioperatively. Although nonsteroidal anti-inflammatory medications (NSAIDs) may be a useful adjunct in managing the systemic symptoms of JIA, and there has been some suggestion of ocular benefit, they play a minor role in the management of pediatric uveitis (21).
In recent years, the use of anti-tumor necrosis factor (anti-TNF) and other biologic agents has become the mainstay of second-line systemic therapeutics in uveitis management. These agents, along with methotrexate, may also assist as steroid-sparing interventions to reduce the risks of topical steroids.
Infliximab is approved for many autoimmune diseases, including ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, and JIA. It has good efficacy in children with oligo- or polyarthritis from JIA (22). It appears to be superior to etanercept (23). Infliximab should be considered as the first-line anti-TNF agent in treating pediatric uveitis refractive to topical treatment and methotrexate. During infliximab treatment, low dose methotrexate is usually continued. One disadvantage, however, of infliximab in addition to the high cost, is the need for in-hospital infusion and the risk of anaphylaxis.
Adalimumab is a subcutaneous injection approved for polyarticular JIA since 2008 with favorable results in pediatric uveitis (2-year study) (24). Adverse effects include injection site pain, reaction or burning, headache, respiratory or viral infection, trauma, and headache. Although usually given every other week, dosage intervals may be shortened to every week to improve uveitis control.
Etanercept is another TNF inhibitor that has been approved for the treatment of JIA and other autoimmune diseases. It has been studied especially for the treatment of polyarticular JIA (25,26,27,28). It is less effective than infliximab (23). It is administered subcutaneously, usually weekly. Compared to the other anti-TNFs in use for pediatric uveitis, etanercept may have lower rates for the development of malignancy (29).
Abatacept, a biologic disease-modifying antirheumatic drug, prevents the costimulatory signal for T cells to fully activate. It gained approval for treatment of polyarticular JIA in 2008 after an international, multicenter trial demonstrated a statistically significant difference in the time period to flare compared to placebo (30,31). There is less data available regarding its efficacy in pediatric uveitis (32).
Other Drugs
In patients who do not respond to the agents above (and switching amongst those agents may also be effective), anakinra, rilonacept (both interleukin-1 inhibitors) and tocilizumab (interleukin-6 inhibitor) have been used. Mycophenolate mofetil has been studied in children with uveitis. Because of its selective mechanism of action, its side effect profile is more tolerable (33,34). Doycheva and colleagues found a steroid-sparing effect and possible reduced relapse rates. Side effects include, gastrointestinal disturbances, headache, rash, leukopenia, and possible increase in opportunistic infection (35,36).
Surgical Treatment
Band Keratopathy
Cataract
Cataract can be secondary to the inflammation itself or the chronic use of corticosteroid drops. Most commonly, the opacity begins as a posterior subcapsular cataract, but this can progress, sometimes rapidly, to a total white cataract with or without lens intumescence. In the latter circumstance, phacomorphic or phacolytic glaucoma may rarely ensure.
Though controversy still exists over when and whether to place an intraocular lens (IOL), most physicians agree that a quiescent period is desirable before surgery. Perioperative and postoperative oral steroids are recommended along with intraoperative intravenous steroids. Some authors have recommended intracameral, in addition to the usual subconjunctival steroids at the end of surgery (37). We usually prescribe a 3-day course of oral prednisone at approximately 1 mg/kg/day prior to surgery. This
is continued for 7 to 10 days thereafter, along with a topical regimen of frequent prednisolone acetate (q1-2h) and a cycloplegic agent.
is continued for 7 to 10 days thereafter, along with a topical regimen of frequent prednisolone acetate (q1-2h) and a cycloplegic agent.
 FIGURE 13.2. Typical band keratopathy of chronic pediatric anterior uveitis. Usually starts at medial and temporal limbus and then spreads over interpalpebral cornea. |
The implantation of an IOL in an eye already predisposed to inflammation is known to potentially complicate the postoperative course. BenEzra and colleagues found that children with JIA-associated uveitis had more postoperative complications after cataract surgery than those with other forms of uveitis (38). Lund vall’s study of 10 eyes in children with uveitis who underwent IOL implantation showed that 7 required reoperation (39). There remains no agreement as to whether or not primary posterior capsulotomy is beneficial in these patients (38,39,40).
Glaucoma
The mechanism of glaucoma in pediatric uveitis may be due to “clogging” of the trabecular meshwork by inflammatory cells and/or fibrin, toxic or immunologic “poisoning” of meshwork cells, peripheral anterior synechiae, or the use of corticosteroids. Given the known complications of intraocular surgery in this population, medical management is recommended for initial therapy. The prostaglandin analogues may be used when maximizing topical therapy, despite reservation about their use in the past because of the propensity to perpetuate inflammation in adults (41). If topical treatment fails, and there are no systemic contraindications, oral acetazolamide may be tried.
Goniotomy has become the first choice in surgical management of uveitic glaucoma, offering a success rate of approximately 70% (42,43). Goniotomy-induced hyphema rates in uveitic children approach 100%, but in our experience, these clear rapidly. Immediate pre- and postoperative topical alpha-2 agonist instillation may be useful in reducing this complication. When goniotomy fails, other standard surgical choices for glaucoma apply. If tube implantation is selected, remember that some “valved” tubes may get clogged by fibrin and other cellular debris from iritis. One study found a higher rate of scleral patch graft erosion over tubes placed in children with uveitis (44). Cyclodestructive procedures can disproportionately induce intraocular inflammation.
Other Complications
Hypotony is usually a late complication of chronic uveitis secondary to ciliary body shutdown after chronic inflammation, or it can be due to cyclitic membrane formation. Topical steroids may improve hypotony secondary to inflammation. Surgery may relieve hypotony due to cyclitic membranes. If hypotony is left untreated, macular and optic nerve edema, and eventually phthisis bulbi, may result. CME is less common in pediatric uveitis but can be associated with pediatric intermediate uveitis (pars-planitis). A retrospective review conducted in Iran reported CME as the second most frequent complication (19.7%) with pars planitis (45).
PEDIATRIC ANTERIOR UVEITIS
Juvenile Idiopathic Arthritis
Table 13.3 provides a differential diagnosis for pediatric anterior uveitis.
This term encompasses all idiopathic childhood arthritis in children younger than 16 years old, persisting for more than 6 weeks, as defined by the International League of Associations of Rheumatology (ILAR) (46). This classification defines seven categories of JIA.
Systemic Juvenile Idiopathic Arthritis
Systemic-onset JIA (sJIA, Still’s disease) constitutes 10% to 20% of JIA, yet accounts for approximately two-thirds of mortality associated with JIA (47,48). Morbidity and mortality is often secondary to destructive arthritis, secondary amyloidosis, and other treatment complications, including infection and osteoporosis. sJIA is characterized by arthritis, daily spiking fever, evanescent rash, serositis, and a variety of other extraarticular features (Still GF). Males and females are affected equally. Patients are both antinuclear antibody (ANA) and rheumatoid factor (RF) negative. Because of the infrequency of uveitis,
screening by ophthalmologists is advised only yearly (49,50). Acquired tenosynovitis of the superior oblique tendon (Brown syndrome) has been described (51).
screening by ophthalmologists is advised only yearly (49,50). Acquired tenosynovitis of the superior oblique tendon (Brown syndrome) has been described (51).
TABLE 13.3 DIFFERENTIAL DIAGNOSIS OF ANTERIOR UVEITIS IN CHILDREN | |||||||||||||||
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Oligoarthritis
Oligoarthritis, also known as pauciarticular arthritis, involves no more than 1 to 4 joints in the first 6 months of disease onset. It is characterized by asymmetric arthritis, early onset (before age 6), female predilection, positive ANA, and high risk of iridocyclitis (52). Oligoarthritis is further subdivided into persistent, affecting four joints or less throughout the disease course and extended, affecting more than 4 joints after the first 6 months (46). Boys are affected more commonly in the late-onset pauciarticular JIA. These patients are both ANA and RF negative, and approximately 75% of boys with this subtype are HLA-B27 positive.
Polyarthritis
Polyarticular JIA affects five or more joints during the first 6 months of disease. It may be characterized by low-grade fever, anemia, and malaise within the first 3 months. Girls are more affected than boys. There are two subtypes: RF positive and RF negative. The former seldom develop uveitis and tend to develop arthritis in late childhood and adolescence. Definitive diagnosis of RF-positive polyarthritis must be confirmed on two separate occasions at least 3 months apart (46). Between 7% and 15% of patients with JIA with uveitis have polyarticular onset (54). Screening is recommended every 6 months (50).
Enthesis-Related Arthritis
Enthesis-related JIA is characterized by chronic arthritis associated with inflammation of muscle and tendon attachment to bone as well as arthritis of one or more joints. Patients are more often HLA-B27-positive boys, usually in the preadolescent to adolescent age group. Uveitis often presents suddenly, and is symptomatic and unilateral. Extraarticular manifestations can occur, such as gastrointestinal, mucosal, and cutaneous manifestations (55,56,57).
Psoriatic Arthritis
In addition to the presence of psoriasis and arthritis, this diagnosis requires at least two of the following: dactylitis, nail pitting or onycholysis, psoriasis in a first-degree relative. Positive RF is an exclusion criterion (46). Uveitis is usually insidious and chronic anterior, and is seen in 10% of affected children (58).
Undifferentiated Arthritis
This is the last subtype of JIA, which is essentially a diagnosis of exclusion of the other subtypes.
JUVENILE SPONDYLOARTHROPATHIES
The juvenile spondyloarthropathies (JSpA) are an interrelated group of uveitic entities, in children under 16 years old, associated with systemic disease, that are strongly HLA-B27 positive and usually RF negative. They represent the third most common etiology of anterior uveitis in children (59,60,61).
Juvenile Ankylosing Spondylitis
Over 90% of patients are HLA-B27 positive (62,63). Ocular symptoms are characterized by a recurrent nongranulomatous anterior uveitis. Bilateral uveitis occurs in 80% but usually not simultaneously (64). Severe uveitis can present with hypopyon.
Boys are affected more than girls, and lower extremities are affected, as opposed to lower back involvement in adults. Peripheral arthropathy may present prior to the radiographic finding of sacroiliac joint involvement. Early detection of sacroiliitis may require contrast-enhanced magnetic resonance imaging (65). Stamato et al. reported the occurrence of aortic regurgitation in children with JSpA (66).
Juvenile Psoriatic Arthritis
Girls are affected more frequently. Ocular manifestations include chronic nongranulomatous anterior uveitis. Juvenile psoriatic arthritis (JPsA) is the cause of approximately 3% to 4% of HLA-B27-positive uveitis and accounts for approximately 5% of JIA. Joint disease may be pauciarticular or polyarticular. Systemic features include psoriatic skin changes and nail pitting (46).
Juvenile Reactive Arthritis (Previously Known as Reiter Syndrome)
Reactive arthritis is described as the classic triad of conjunctivitis, arthritis, and urethritis, though more recently, it has been recognized that all three need not necessarily occur simultaneously (67). Conjunctivitis is the most frequent presenting sign in children. Boys are more commonly affected than girls. Ocular involvement includes nongranulomatous anterior uveitis in approximately 3% to 12% of patients (54). Possible etiologies include prior infection with Salmonella or Shigella enterocolitis.
SARCOIDOSIS
Most reported cases of pediatric sarcoidosis are in the age group 13 to 15 years, but it can present even in infancy (68,69,70,71
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