Toxoplasmosis (Toxoplasma gondii)
Herpes simplex virus
Syphilis (Treponema pallidum)
Toxoplasmosis (Toxoplasma gondii)
Toxocariasis (Toxocara canis)
Varicella zoster virus
Lyme disease (Borrelia burgdorferi)
Tuberculosis (Mycobacterium tuberculosis)
Whipple’s disease (Tropheryma whippelii)
Leprosy (Mycobacterium leprae)
Cat scratch disease (Bartonella henselae)
Juvenile idiopathic arthritis (JIA)
Inflammatory bowel disease
Tubulointerstitial nephritis and uveitis syndrome (TINU)
Systemic lupus erythematosus (SLE)
Multiple sclerosis (MS)
Vogt-Koyanagi-Harada syndrome (VKH)
Chronic infantile neurologic cutaneous and articular/neonatal onset
Multisystem inflammatory disease syndrome (CINCA/NOMID)
Fuchs heterochromic uveitis (rubella virus associated)
Diffuse unilateral sclerosing neuroretinitis (DUSN)
Neuromyelitis optica/Devic’s syndrome
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
Drug induced (rifabutin)
Posttransplantation lymphoproliferative disease (PTLD)
Intraocular foreign body
Although uveitis is less common in children than in adults, accounting for only 5–10(16) % of all uveitis cases [8, 11], the visual outcome seems to be less favorable with up to 20 % of all affected children developing at least one blind eye and 3 % becoming legally bilateral blind [3–5, 7, 9–11]. In posterior uveitis, however, this percentage increases to more than 50 %. The unfavorable outcome of uveitis in children is due to the asymptomatic onset and therefore late detection with visual-threatening complications, persistent chronic inflammation, and difficulties in diagnosing in an uncooperative child. Additionally, ophthalmologist and parents hesitate to treat children with systemic medication because of the side effects. Especially treatment with systemic corticosteroids can negatively influence the growth and skeletal development in children. Therefore, systemic treatment should be installed in collaboration with a pediatrician, and it is very important to exclude an infectious cause before starting immunosuppressive treatment for uveitis. Also, ocular surgery for complication as cataract and glaucoma in inflamed eyes is more challenging in children . Finally, there is a risk of developing of amblyopia caused by uveitis or its complications in children under the age of 8 years.
Juvenile Idiopathic Arthritis-Associated Uveitis
Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and the most prevalent systemic disorder in children with uveitis [16, 17]. The common opinion is that JIA is a multifactorial autoimmune disorder, with a genetic predisposition that could be influenced by environmental factors and infections . So far it is unknown which individual patient with JIA is at risk of developing uveitis except from antinuclear antibody (ANA) positivity and JIA subtype [19, 20]. JIAU is a serious visual-threatening disorder resulting in 15 % of blindness of affected eyes despite intensive treatment. It develops in approximately 20 % of all JIA subtypes, but in patients with oligoarthritis (less than 4 joints involved), the risk incidence increases to 41 % (Table 16.2) . The peak incidence of JIAU is at the preschool age and girls are 3 times more often affected than boys . It is characterized by a chronic anterior uveitis with insidious silent onset, and if the patients notice visual deterioration, there are already serious ocular complications. In the majority of the cases, uveitis is bilateral and the major site of inflammation is the anterior chamber, with or without keratic precipitates. Cells in the anterior chamber are a sign of active ocular inflammation, and in severe cases, anterior vitreous cells might be seen caused by spillover. Flare in the anterior chamber results from vascular leakage caused by damage to the blood aqueous barrier and ciliary body that can be measured with laser flare photometry . Although clinically flare might persist, even in an inactive phase of uveitis, laser photometry flare reduces with aggressive treatment.
Cumulative uveitis incidence in the different juvenile idiopathic arthritis (JIA) subgroups after median duration of 4.3 years
No. of patients with uveitis
Cumulative uveitis incidence,% (95 % CI)
Median disease duration, years (IQR)
Polyarthritis (RF negative)
Polyarthritis (RF positive)
All JIA patients
In most cases the uveitis is nongranulomatous but granulomatous characteristics have also been reported occasionally . Severity of uveitis at presentation is by far and away the most important factor predicting a severe course and worse visual prognosis. In 1987 Wolf and later on Kanski identified that the eyes, which had posterior synechiae at presentation, had a worse visual outcome. Fifty-eight percent of these eyes had a final vision of 20/200 or worse compared with 3 % in the group with just flare and cells and keratic precipitates [24, 25]. Other clinical features, which define a severe course and a worse prognosis, are persistent inflammation despite intensive treatment, development of glaucoma, cataract requiring surgery, presence of cystoid macular edema, and recurrent episodes of ocular hypotony culminating eventually in blindness due to phthisis . Hypotony is more common in JIAU than any other form of uveitis due to chronic inflammation and damage to the secretory ciliary epithelium .
Several baseline risk factors for a worse prognosis that have been identified for JIAU are male gender, young age at onset of disease, short interval between arthritis and uveitis, severity of uveitis at onset, and ANA positivity [22, 26–31]. In one study male gender was an independent risk factor for the development of blindness .
Since early detection is crucial for the final visual prognosis, all patients with JIA are screened 1 to 4 times a year by an ophthalmologist for the presence of uveitis according to the recommendations of the American Academy of Pediatrics . This screening frequency has been modified depending on JIA subtype, age at onset, interval since onset of arthritis, and ANA positivity (Table 16.3) [21, 33]. Seventy-five and 90 % the JIAU patients will develop uveitis within 1 year and 4 years after the onset of arthritis, respectively . During the course of uveitis, many sight-threatening complications might develop including band keratopathy, posterior synechiae, cataract, secondary glaucoma, macular edema, hypotony, epiretinal membrane, and optic nerve edema [21, 30].
Suggested screening intervals in patients with juvenile idiopathic arthritis (JIA)
Age at JIA onset (in years)
JIA duration (in years)
Recommended screening intervals (in month)
Rheumatoid factor-negative polyarthritis
Rheumatoid factor-positive polyarthritis
Patients with uveitis
According to uveitis course
It has been suggested that JIAU might resolve during adolescence but recent studies showed progression during puberty and adulthood . In one such study, half of the adult patients with JIA still had active uveitis after 24 years with increased development of cataract and secondary glaucoma .
The main goal of treatment of JIAU is to achieve the absence of cells in the anterior chamber. The first treatment option is topical steroids with or without short-acting mydriatics. Topical corticosteroid are associated with an increased risk of cataract formation independent of active uveitis or the presence of posterior synechiae; however, chronic use of topical corticosteroids dosed at ≤3 drops per day was associated with an 87 % lower risk of cataract formation compared with eyes treated with >3 drops daily . Also, early treatment with methotrexate is associated with a significant delay in cataract development . If uveitis persists or more than three steroids drops are needed to maintain inactive inflammation, 97 % of the uveitis specialists are of the opinion that there is an indication for systemic immunosuppressive medication with methotrexate as first choice . In the Systemic Immunosuppressive Therapy for Eye Disease Study, a large study from the USA, treatment with systemic immunosuppressive medication was associated decreased risk of visual loss in JIAU . If active inflammation persists, the next step according to 73 % of the pediatric uveitis specialists is additional treatment with TNF-α inhibitor adalimumab (49 %) or infliximab (24 %). Till now, small case series of treatment of refractory JIAU with rituximab, abatacept, and tocilizumab have been reported.
Next to drug treatment, ocular surgery is frequently necessary to treat the complication in JIAU like cataract and glaucoma. In the recent past, the high complication rates for cataract surgery resulted in high percentages of poor visual outcome . The explanation for this dramatic outcome was thought to be multifactorial. The most important factors were the surgical insult to severely compromised and chronically inflamed eyes and the development of secondary membrane formation. It has become the generally accepted opinion that eyes should be free of inflammation for at least 3 months before surgery and that intensive anti-inflammatory treatment should be administered in the perioperative period. Most ocular surgeons use nowadays surgical approaches for cataract in JIAU, where lens aspiration is combined with or without (anterior) vitrectomy, and even IOL implantation has lead to favorable VA [41, 42]. Secondary glaucoma is one of the major causes of blind eyes in JIAU. One reason for the poor prognosis is the many risk factors for failure of trabeculectomy like young age, inflamed eyes, and previous ocular surgery . The glaucoma drainage devices are nowadays commonly used with favorable results. Postoperative hypotony is a problem in JIAU in which the ciliary body epithelium might be severely damaged. It seems that Ahmed valve implants have lower risk of postoperative hypotony compared to the non-valved devices. However glaucoma devices might compromise the cornea on the long term since progressive corneal endothelium cell loss was reported in secondary glaucoma JIAU treated with Ahmed implant .
In conclusion, JIA is the most common identifiable systemic association with chronic anterior uveitis in the USA and Europe. Risk factors for the development of uveitis among patients with JIA include oligoarticular onset of arthritis, younger age of onset, female sex, and presence of circulating antinuclear antibodies (ANA). Despite intensive screening programs, JIAU is still a serious blinding disease but there seems to be a trend toward reduction of visual loss compared to 25 years ago, which is partly due to the introduction of systemic immunomodulating treatment at an early stage of uveitis. Many of the well-known risk factors for a severe course and poor prognosis are unavoidable – such as young age at onset, male sex, ANA status, and having severe disease at onset when uveitis precedes the arthritis. Early introduction of methotrexate followed by regimes with biological agents results in many less children falling into the category of persistent disease despite treatment and hence a reduction in the number of blind eyes.
Sarcoidosis in children is a rare disease that clinically might be difficult to recognize and diagnose [45, 46]. In young children, sarcoidosis has mainly an extrapulmonary manifestation with a classic presentation of a triad with rash, arthritis, and uveitis, which might be indistinguishable from JIA [47–51]. Older children might have pulmonary and lymph node involvement comparable with the adult form. Renal involvement can occur at any age. Ocular inflammation might start as anterior uveitis, but during the course of the disease, posterior segment involvement might occur including multifocal choroiditis and choroidal granuloma, resulting in panuveitis . The diagnosis of sarcoidosis can be confirmed by tissue biopsy of inflamed organs such as the skin or kidneys. Keratitis with multiple subepithelial corneal nebulae might occur in the early stage of sarcoidosis in preschool children . In young children, granulomatous inflammation of several organs might be part of Blau syndrome which is characterized by familial granulomatous arthritis, uveitis, and skin granulomas. It is comprising an autosomal dominantly inherited syndrome that overlaps sarcoidosis. It is associated with mutations in the NOD2 (a.k.a. CARD15) gene on chromosome 16 .