Ocular inflammatory disorders can present at any age with varying frequency in pediatric patients. The prevalence of uveitis in children has been estimated at 31 per 100,000 patients, compared to a prevalence of 133 per 100,000 in adults.¹ The following provides an overview of the uveitides that present as noninfectious, infectious, or as masquerade syndromes, and how their presentations may vary in children compared to adults.

NONINFECTIOUS

Anterior Uveitis

Anterior uveitis is by far the most common uveitis in the pediatric population, accounting for about 57% of cases.² Although topical steroid drops are often the first step in management in both adult and pediatric patients, pediatric patients unlike adult patients are particularly sensitive to intraocular pressure elevation, and cataract formation is a more significant concern with long-term use. Dosing of prednisolone as low as 2 drops per day shows a 2-fold to 4-fold increased risk in elevated intraocular pressure at 2 years, and the risk progressively increases with increasing frequency of drop usage.³ Therefore, early initiation of systemic immunosuppression is favored in pediatric patients.

Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common diagnosis associated with pediatric noninfectious uveitis, accounting for 26.2% of total cases.¹ Uveitis occurs in up to 50% of pauciarticular JIA patients, being more common in female patients and those with positive antinuclear antibodies (ANA) and negative rheumatoid factor (RF).⁴ The strong relationship between ANA positivity and the development of disease have some authors posit that that it may be a more powerful criteria for defining JIA disease categories than the number of joints affected or RF status, and may be associated with worse visual outcomes.⁵ Examination typically shows a white, quiet eye, even with significant anterior chamber cell, highlighting the importance of screening examinations. The inflammation is often a bilateral, nongranulomatous iridocyclitis, with complications including band keratopathy, posterior synechiae, cataract, glaucoma, cystoid macular edema, hypotony, and phthisis if not optimally treated or with late presentation.⁴

HLA-B27

Seronegative spondyloarthropathies can manifest in children, including juvenile ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory-bowel-disease–related arthritis, and a subset of JIA that is HLA-B27 positive seen most often in older male pediatric patients. HLA-B27 iritis made up 2% of pediatric cases at a uveitis referral center, with the average age of uveitis onset of 10 years.² Presentation is similar to that of adults with HLA-B27 positivity, as patients present with more typical pain, redness, and light sensitivity compared to the white and quiet eye of a typical ANA-positive, RF-negative JIA of a younger female patient.

Tubulointerstitial Nephritis and Uveitis Syndrome

Tubulointerstitial nephritis and uveitis syndrome (TINU) is relatively rare and is characterized by systemic manifestations of fever, weight loss, and fatigue generally within a few months of uveitis onset, but patients may be systemically asymptomatic as well. Cases in the literature show a 3:1 female-to-male predominance; however, more recent trends show increasing proportions of males diagnosed, with a median age of onset of 15 years.⁶ Uveitis was limited to the anterior segment in 80% of cases and was bilateral at presentation in 77% of cases.⁶ Screening for TINU includes assessment of urinary β2 microglobulin, which can be abnormal for months. Systemic treatment is usually required and more than half of patients had recurrence or a chronic course of uveitis, with ocular complications occurring in 21% of patients with TINU.⁶

Postinfectious

Poststreptococcal uveitis syndrome predominantly affects children, with more than 50% of cases reported under the age of 15 years, presenting in the weeks after a streptococcus pharyngitis infection.⁷ Most frequently a bilateral nongranulomatous anterior uveitis, up to one-third of cases may have posterior manifestations. Elevated antistreptococcal lysin O titers are characteristic of the disease. Recurrence is possible though not characteristic.

Intermediate Uveitis

Intermediate uveitis makes up approximately one-fifth of pediatric uveitis cases and is most often bilateral.² Pain is uncommon, which may delay presentation in the pediatric population as young children may not voice visual symptoms. Complications are more common in pediatric populations and can include macular edema, optic nerve edema, secondary glaucoma, cataract, retinal vasculitis, neovascularization of the disc or peripheral retina, vitreous hemorrhage, and exudative or tractional retinal detachment.² Because of possible posterior involvement, fluorescein angiography is an important diagnostic tool to determine the extent of disease. Etiology of intermediate uveitis can be idiopathic (pars planitis), however infectious causes and masquerades should also be considered.

Posterior Uveitis

Posterior uveitis involves the retina and choroid and accounts for about 6% of pediatric uveitis cases, often presenting with decreased vision, photopsias, or floaters.²

Collagen Vascular Disease

While the majority of pediatric uveitis is idiopathic, posterior uveitis may also be observed in association with pediatric chronic inflammatory diseases, systemic connective tissue disease, and systemic vasculitis (Behçet disease, Kawasaki disease).⁸

White Dot Syndromes

White dot syndromes are uncommon in children, but they can occur. Care needs to be taken to rule out systemic autoimmune disease and infectious etiology, especially in the pediatric population. Spital et al estimated the relative frequency of white dot syndromes in pediatric uveitis patients to be 1% to 5%. The authors noted acute posterior multifocal placoid pigment epitheliopathy (4 cases), multiple evanescent white dot syndrome (4 cases), multifocal choroiditis and panuveitis (3 cases), and 1 case of serpiginous chorioretinitis in a cohort of 407 pediatric uveitis patients.⁹

Panuveitis or Variable Presentation

Panuveitis comprised about 16% of presenting pediatric patients at a tertiary referral uveitis center.² Presentation is variable, and primary complaint can vary depending on the degree of inflammation and involved ocular structures.

Sarcoidosis

Early-onset sarcoidosis and Blau syndrome are considered the sporadic and inherited forms of the same disease, respectively, and they present in early childhood. In typical cases, a scaly erythematous rash appears on the trunk and extremities in the first year of life, polyarthritis develops between the age of 2 and 4 years, and uveitis can develop in 60% to 80% of patients by 4 years of age. Similar to ocular sarcoidosis in adults, it often presents with bilateral granulomatous uveitis than can present as anterior, intermediate, posterior, or panuveitis. Older children may present with sarcoidosis that is more similar in systemic presentation to adults, with pulmonary involvement found more commonly than in younger children.¹⁰

Behçet Disease

Pediatric Behçet disease is defined as onset before age 16 years, and is most common in people of Middle Eastern, Mediterranean, and Japanese descent. Genital ulcers are less common than in adult-onset Behçet disease. Aphthous ulcers are present in nearly all cases, and skin findings are common.¹¹ Ocular presentation may be unilateral or bilateral. Panuveitis occurs in 52.9% of patients, and anterior uveitis and panuveitis may also be observed.¹¹ Retinal vasculitis of both arterioles and venules is the most common ocular finding, present in 83.3% of cases.¹²

Vogt-Koyanagi-Harada Disease

Vogt-Koyanagi-Harada disease (VKH) is a systemic disease involving bilateral granulomatous panuveitis with exudative retinal detachments, vitiligo, auditory symptoms, and signs of meningeal irritation. Most commonly presenting in early adulthood, onset prior to age 14 was seen in 13 of 97 consecutive cases in one study. Children with VKH had higher rates of ocular complications and vision loss compared to adults which the authors attributed to more severe inflammation.¹³

INFECTIOUS UVEITIS

The most prevalent causes of pediatric uveitis vary greatly depending on the geographic region being studied, with infectious etiologies more prevalent in southeast Asia, the Middle East, and developing nations.¹³ Posterior uveitis is the most common presentation in pediatric infectious uveitis, followed by anterior uveitis, panuveitis, and intermediate uveitis.¹⁴ Infectious uveitis is treated with antimicrobial therapies and can be exacerbated by corticosteroids and other immunomodulators, emphasizing the importance of correct diagnosis.^14,15

Toxoplasmosis

Toxoplasma gondii, an intracellular parasite, is the most common cause of posterior infectious uveitis in children. It is contracted orally or congenitally with greatest risk in the third trimester of pregnancy. Congenital toxoplasmosis occurs 1 in 10,000 births. Bilateral posterior uveitis is the most common presenting feature in children, and may present with decreased vision, strabismus, leukocoria, nongranulomatous anterior uveitis, vitritis, vasculitis, neuroretinitis, and chorioretinal lesions with the classic “headlight in fog” presentation. Diagnosis is clinical; laboratory testing including serologic ELISA testing for IgM and IgG may be corroboratory. Intraocular fluid testing by PCR is available but may be difficult to obtain in children. Patients with congenital disease or active disease-threatening vision should receive antiparasitic drug therapy. Classic therapy includes sulfadiazine, pyrimethamine, and folinic acid with prednisone. Other treatments include trimethoprim-sulfamethoxazole, clindamycin, and atovaquone.¹⁶

Herpes Virus

Herpes simplex virus 1 and 2, varicella zoster virus (VZV), cytomegalovirus, and Epstein-Barr virus have been found to cause pediatric uveitis.¹⁵ In one study, viral uveitis represented 30% of cases of pediatric uveitis, with VZV identified as the most common pathogen, affecting 7 of the 18 viral cases. Five VZV-associated cases were limited to anterior uveitis, however 2 had acute retinal necrosis.¹⁷ Cytomegalovirus can present as typical Fuchs heterochromic iridocyclitis, or as a retinitis that can occur in immunocompetent patients with congenital cytomegalovirus or in immunosuppressed children.¹⁴

Tuberculosis

Tuberculosis has been reported in 3.9% of pediatric uveitis cases in India where the disease is endemic, but cases are observed worldwide.^18,19 Posterior uveitis is the most common presentation and choroidal tubercules, retinal vasculitis, neuroretinitis, and serpiginous-like choroiditis may be observed. Treatment includes the 4-drug regime therapy at pediatric dosing including isoniazid, rifampicin, ethambutol, and pyrazinamide, and should be guided by an infectious-disease specialist.

Toxocariasis

Toxocara canis and Toxocara cati are contracted through fecal–oral route from infected animals, often puppies or kittens. Ocular toxocariasis presents unilaterally with a peripheral white granuloma of varying size, complicated by vitritis with tractional bands, retinal detachment, and macular heterotopia. Diagnosis is made clinically with confirmatory ELISA antibodies; eosinophilia may be present in serum. B-scan ultrasonography demonstrates a solid, highly reflective mass; however, calcification is uncommon and would suggest retinoblastoma. Treatment with antihelminthic agents has been tried with varying success, and vitrectomy is required for traction threatening the macula or retinal detachment.²⁰

Lyme Disease

Lyme disease, transmitted by bite from an Ixodes tick infected with Borrelia burgdorferi, is an uncommon uveitis that may present with iridocyclitis, vitritis, multifocal choroiditis, exudative retinal detachment, or panophthalmitis.²¹ Routine screening for Lyme disease in uveitis patients is not recommended due to its very low prevalence. Review for risk factors including history of tick bite, residence in an endemic area, or systemic symptoms should raise clinical suspicion.²² Uveitis is classically a late finding of Lyme disease, but early antibiotic treatment is highly effective at preventing late manifestations of Lyme disease.

Cat-scratch Disease

Cat-scratch disease, caused by the gram-negative bacterium Bartonella henselae, presents in patients with recent history of cat scratches or bites.¹⁴ Ocular presentation includes neuroretinitis or Parinaud oculoglandular syndrome with palpebral swelling, conjunctival granulomatous nodules, and lymphadenopathy. Neuroretinitis may be unilateral or bilateral, presenting with optic-nerve swelling, peripapillary hemorrhages, and classic stellate macular hard exudates. Most cases are self-limited and benign; however, severe inflammation or visual decline may warrant treatment with trimethoprim-sulfamethoxazole because doxycycline can cause permanent yellowing of the teeth in children younger than 8 years old.²³ In patients with severe inflammation, steroid therapy after institution of antibiotic therapy may be useful.

PEDIATRIC MASQUERADE SYNDROMES

Several pathologies can mimic uveitis in children. A complete history with review of systems as well as a thorough ophthalmic exam, including a dilated fundus exam and examination under anesthesia when indicated, should be performed for all pediatric patients presenting with suspected uveitis to best determine the underlying pathology.

Retinoblastoma

Retinoblastoma is the most common malignant intraocular primary cancer of childhood. The tumor presents with equal gender distribution, typically under age 3 years, and rarely after 5 years. Mutation in the RB1 tumor suppressor gene is pivotal for the development of retinoblastoma and most cases are unilateral and nonhereditary.²⁴ Leukocoria and strabismus are the most common presenting signs. Observed intraocular inflammation can represent either true inflammation secondary to tumor necrosis or tumor cells in the anterior chamber mistaken for inflammatory cells. An anterior uveitis masking underlying tumor in the posterior segment can be seen. Pseudohypopyon with chalky-white flocculent material within the anterior chamber and white iris nodules have been described. An aqueous tap cytology can reveal tumor cells.^25,26 Treatment modalities include intra-arterial, intravitreous and systemic chemotherapy. Cryopexy, laser photocoagulation, and plaque irradiation can be considered for small tumors, with enucleation considered for advanced cases.²⁷

Juvenile Xanthogranuloma

Juvenile xanthogranuloma is predominantly a skin disorder of young children characterized by a solitary papule or nodule that develops into tumor tissue. Diffuse or nodular iris infiltration is the most common ocular presentation, typically present within the first year of life, however other involvement of the uveal tract or ocular adnexa are possible.²⁸ Patients can develop a spontaneous hyphema, heterochromia iridis, or redness and pain along with anterior-chamber flare and cells mimicking iridocyclitis. Secondary glaucoma can occur due to infiltration of the angle structures or blockage of the trabecular meshwork by blood in the anterior chamber.^29,30 Aqueous paracentesis with or without an iris biopsy can aid in making this diagnosis.^29,30 Close observation for development of ocular lesions is necessary.²⁸ Juvenile xanthogranuloma uveal lesions are treated with topical or subconjunctival steroids. For recalcitrant disease, systemic steroids or low-dose irradiation are considered.^31,32

Leukemia

The leukemias are the most common malignant neoplasms in childhood.³³ Anterior-segment involvement most often occurs in patients with acute lymphoblastic leukemia but can also occur in acute and chronic myelogenous leukemias. Patients can present with unilateral or bilateral symptoms with or without conjunctival injection. An apparent iridocyclitis composed of a pseudohypopyon or a spontaneous hyphema may develop. The pseudohypopyon is creamy white, composed of shaggy, free-floating material that fails to completely settle, giving rise to a “lumpy bumpy” appearance. Iris discoloration, iris masses and nodules or heterochromia iridis may develop due to iris infiltration by leukemic cells. Infiltration of the trabecular meshwork or choroidal infiltration can result in glaucoma.^34-36 Diagnosis is made by anterior-chamber paracentesis and cytologic examination of the aqueous humor for malignant cells. Prompt referral to an oncologist can be lifesaving.

Retinitis Pigmentosa

Retinitis pigmentosa is a group of progressive inherited retinal diseases characterized by the primary degeneration of rod photoreceptors, followed by the loss of cone photoreceptors.³⁷ Age at onset varies widely, and some patients develop symptomatic vision loss in early childhood, whereas others can remain asymptomatic until mid-adulthood.³⁸ In addition to the characteristic retinal findings, patients may develop cystoid macular edema and posterior subcapsular cataracts.³⁷ When the pigment changes in the fundus are subtle and not fully apparent, the presentation of anterior vitreous cells, cystoid macular edema, and posterior subcapsular cataracts can be mistaken for chronic uveitis. Fluorescein angiography can help distinguish this disease from inflammatory etiologies. An electroretinogram can be diagnostic and reveals the characteristic loss of photoreceptor function, primarily among rod photoreceptors rather than cones in early stages of the disease. RP

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