Uveitis is a relatively common feature of several localized autoinflammatory diseases that have both unique and shared genetic associations (Table 39.1). There is often a family history of a wide range of autoimmune and autoinflammatory conditions in children with idiopathic uveitis unaccompanied by systemic disease. However, despite the wide variety of identified genetic associations, uveitis patients only rarely cluster in families, other than those with a high prevalence of HLA-B27, and there must be many environmental triggers and other genetic causes that remain unidentified.

Table 39.1 Inflammatory disease associated with childhood uveitis

Experimental models of uveitis have concentrated upon antigen-specific autoimmune mechanisms of inflammation. Sympathetic ophthalmia and phacoanaphylaxis may be examples of ocular organ-specific autoimmunity but the majority of childhood uveitis syndromes are secondary to localized or generalized disorders of the control of inflammation. The phenotypes of human uveitis are more varied than the range of available animal models of autoimmunity; there is increasing interest in the variety of mechanisms, other than antigen-specific autoimmunity, that may underlie ocular inflammation. Advances in genetics and study of the differential response to treatment with non-specific and lymphocyte-specific or cytokine-specific immunosuppressants has led to a continuing reappraisal of disease classifications and the therapeutic implications of newly discovered genetic associations.

General considerations

When considering ocular inflammation in childhood one needs to ask:

1. Why has the inflammation started in childhood rather than adulthood?

2. Will the age of onset influence the disease phenotype?

3. Is there a genetic disorder of the control of inflammation?

4. Is there a disorder of immunity predisposing to autoimmunity?

5. Is the inflammation secondary to a genetic degenerative process?

Familial clustering of unusual disease patterns suggests rare or novel mutations. The immune system develops through childhood and adolescence when most infections are first encountered. An unusual ocular inflammatory response to infection may be the first expression of a congenital systemic immune disorder (Box 39.2).

Box 39.2

Immunodeficiency diseases associated with uveitis

Cyclic neutropenia

Chronic granulomatous disease of childhood

X-linked lymphoproliferative disease with Epstein-Barr virus and hypogammaglobulinemia

Common variable immunodeficiency

IgG₂ deficiency

Hyper IgM disease with hypogammaglobulinemia

Hypocomplementemic vasculitis

Organization of service

Childhood uveitis requires an organizational approach:

1. Early therapeutic decisions have to be made.

2. Effective management depends on primary care, pediatricians, and long-term social and educational planning.

3. Multiple surgical and medical specialties may be required.

4. Outcomes depend on public health measures as well as drugs and surgery.

5. General ophthalmologists need information about the threshold for tertiary referral. Late presentation and chronicity are common leading to high complication rates compared to similar conditions in adulthood.

6. In children, amblyopia, postsurgical glaucoma and fibrosis, the growth effects of parenteral steroids, and immunosuppressants pose special problems.

7. Compliance with treatment may be problematic for children and families.

Evaluation for systemic disease

Ocular inflammation may herald systemic disease (see Table 39.1). Physicians and ophthalmologists best work as teams. Symptoms of systemic disease may occur later than the ocular disease in oligoarticular juvenile idiopathic arthritis (JIA), sarcoidosis, Behcet’s disease, and Vogt-Koyanagi-Harada (VKH) syndrome.

Associated central nervous system (CNS) inflammation is difficult to diagnose if it presents with behavioral changes, deafness, retrobulbar optic neuritis, headaches, or movement disorders in preverbal toddlers. Optic disk edema is frequent in childhood uveitis and scleritis and should not invariably require the exclusion of raised intracranial pressure (ICP) by lumbar puncture and neuroimaging. However, the diagnosis of optic disk changes (Figs 39. 1 and 39. 2) may be challenging and raised ICP can occur in pediatric sarcoidosis, systemic lupus erythematosus (SLE),¹ chronic infantile neurologic cutaneous and arthritis (CINCA) syndrome, venous sinus thrombosis, and steroid use. Other causes of optic disk swelling include hypotony and optic neuritis.

Fig. 39.1 Persistent optic disk edema with anterior inferonasal vitreous band to disk, 1 year after remission of intermediate uveitis.

Fig. 39.2 Optical coherence tomography of persistent optic disk edema 15 years after onset of JIA-uveitis.

Epidemiology of pediatric uveitis

Childhood uveitis is uncommon; rising with age. In 0- to 4-year-olds, the incidence is 3/100 000, in 10- to 14-year-olds 6/100 000, and in adults aged 17–25/100 000. It comprises 5% of most series of uveitis patients.²

The most common type of pediatric uveitis at a population level is idiopathic. The most common pattern in young children is chronic anterior uveitis; in those aged 8–16 it is intermediate uveitis. After age 16, the pattern of uveitis types is similar to that in adulthood (Box 39.3). Idiopathic chronic painful bilateral anterior uveitis, idiopathic anterior and intermediate uveitis, and idiopathic panuveitis are also not uncommon in children. Specific uveitis syndromes, such as birdshot retinochoroidopathy, are exceptionally rare in children.³

Box 39.3

Commonest types of uveitis by age

0–6 years	JIA-CAU
7–12 years	Idiopathic CAU, IU
13–16 years	IU, B27-associated AAU
Adult	B27-associated AAU

For abbreviations, see text.

Juvenile idiopathic arthritis (JIA) is the most common extraocular disease reported in tertiary referral series followed by those with no systemic disease (idiopathic uveitis), enthesitis related arthritis (ERA), sarcoidosis,⁴ inflammatory bowel disease (IBD), and Behçet’s disease. Even in countries with high rates of Behcet’s disease, Behcet’s uveitis is uncommon in childhood.⁵ VKH⁶ and tubulointerstitial nephritis and uveitis syndrome (TINU)⁷ can begin in childhood. Behçet’s disease and VKH syndrome are 10–100 times more common in some Oriental, Asian, and Mediterranean groups than in Caucasians.

Epidemiology of vasculitis

The commonest type of childhood systemic vasculitis is Henoch-Schonlein purpura which does not have ocular involvement;⁸ giant cell arteritis does not occur in childhood. The incidence of SLE is 0.8/10 000 and juvenile dermatomyositis 0.4/100 000. Childhood polyarteritis nodosa (PAN) is the fourth most common and ocular involvement is not uncommon. Wegener’s granulomatosis, Behçet’s disease, and microscopic polyangiitis are very rare – each less than 0.1/100 000.

Takayasu’s disease and Kawasaki’s disease are more common in Asians and Orientals. In Japan, the incidence of Kawasaki’s disease in under 5s is 110/100 000: in the UK it is about a hundred times less frequent.

Clinical types of uveitis

Idiopathic uveitis

Classification is best made on the basis of the site of visible inflammation: unilateral or bilateral, acute or chronic, painful or painless and redness present or not (Fig. 39.3). The anatomic classification and terms for clinical activity of uveitis have been revised.⁹ Patients with significant cell counts in both the anterior chamber and vitreous should be classified as “anterior and intermediate uveitis.” This describes some cases of JIA-uveitis and some previously classified as intermediate uveitis. Chronic unilateral uveitis suggests an infective cause but should not preclude a search for systemic disease. Twenty percent of JIA-uveitis remains unilateral.

Fig. 39.3 Idiopathic chronic anterior uveitis with granulomatous KPs and limbal inflammation.

Although acute and chronic are classifying terms, they rely on a history and are less helpful in children. It is more practical to introduce a distinction between red and painful eyes, at presentation, as distinct from inflammation associated with white and painless eyes at presentation.

Painful anterior uveitis

Unilateral, painful, acute anterior uveitis (AU) is most frequently associated with HLA-B27-related diseases. They present in later childhood, rarely under 6 years; an infective or posterior segment cause is likely in this age group. Bilateral painful AU is the most frequent uveitis type following infection or severe systemic inflammation and is a common pattern of uveitis in otherwise healthy 7- to 14-year-olds where it can persist for a couple of years. Complications, other than ocular hypertension, are uncommon in chronic painful AU despite the length of disease when compared to the chronic painless AU of JIA.

Painless anterior uveitis

Chronic painless AU, without systemic disease, is common in young children. The arthritis of JIA may develop up to 7 years after the onset of chronic painless AU (Fig. 39.4). Investigation of renal function, for TINU syndrome, sarcoidosis, and possible immunodeficiency is also indicated. Skin rashes are a common manifestation of sarcoid, Blau’s early onset sarcoidosis syndrome and CINCA: they are easier to biopsy. Fuchs’ heterochromic cyclitis is very rare in early childhood

Fig. 39.4 Idiopathic chronic anterior uveitis in white eyes presenting with left cataract in a 4-year-old. JIA developed 7 years later.

Intermediate uveitis

This refers to vitritis with a variable retinal inflammation and a minimal anterior segment inflammation (Table 39.2). The average age of onset is 9–13 years. Young children present late, and there may be extensive retinal complications rarely seen in adults. Children are less likely to develop macular edema but it is more difficult to resolve. Optic disk edema with chronic vitritis is more common than in adults. Peripheral vascular abnormalities are difficult to detect and may only be suspected when they cause hemorrhage. Neovascularization of the optic disk and retina may be caused solely by inflammation and subside with immunosuppression.¹⁰

Table 39.2 Structural complications of JIA-uveitis and IU

JIA-uveitis	Intermediate uveitis
Anterior segment changes
AC cells and flare	AC signs only in “anterior and intemediate uveitis,” and usually confined to cells only
Band keratopathy
Extensive posterior synechiae
Progressive anterior synechiae
Iris hyperemia and rarely vascularization
Unexplained hyphema
Iris vascularized membrane
Pupillary membrane
Early irreversible ciliary body damage with chronic hypotony and phthisis	Hypotony rare
high risk glaucoma	Low risk glaucoma
Early cataract formation	Late developing despite persistent inflammation
Persistent diffuse vitreous flare and opacities with minimal vitritis	Vitritis necessary for diagnosis
	Opacities tend to be dependent and aggregate – snowballs, snowbanks
Diffuse macular and disk edema and subretinal fluid with minimal vitritis	Disk edema can be marked in absence of macular edema
Disk neovascularization	Disk and peripheral retinal neovascularization
Vitreous hemorrhage	Vitreous hemorrhage
Retinal detachment rare without
Coexisting hypotony	Retinal detachment, pars plana cysts, localized peripheral detachments
Coexisting hypotony	Retinoschisis
Postoperative complications
IOL membrane formation	Usually tolerates IOL
Universal posterior capsular opacification
Membrane formation following capsulotomy

Changing signs in the inferior fundus are useful to monitor disease progression as the level of vitritis is difficult to monitor in children and visual acuity may be maintained despite progressive extramacular damage. Sarcoidosis produces aggregates of white cells in the inferior vitreous (“snowballs”) rather than pars planitis (“snow bank”) and multifocal choroiditis is characteristic. IU associated with MS rarely produces vitreous opacities. Focal retinal pigment epithelial scars can develop inferiorly at sites of previous retinal inflammation and do not necessarily indicate the development of choroiditis. Retinal vascular leakage and periphlebitis may be marked in acute IU but are not diagnostic of any specific cause.

Panuveitis and multifocal choroiditis

Unifocal, unilateral choroiditis suggests infection such as toxoplasmosis. Multifocal, bilateral disease suggests systemic disease or a white spot syndrome, both rare in childhood. Many children with multifocal choroiditis and vitritis resemble sarcoidosis, with no evidence of extraocular disease. Some infections such as brucellosis, borreliosis, and varicella may also mimic sarcoid choroiditis. Multifocal choroiditis and panuveitis rarely occurs in childhood. It can be complicated by severe visual loss from secondary choroidal neovascularization and warrants aggressive control of inflammation (Fig. 39.5). If the fundus cannot be seen in children with AU it must be assumed they have panuveitis. Ultrasound may disclose scleritis or focal infection or tumor.

Fig. 39.5 Idiopathic panuveitis and multifocal choroiditis complicated by cataract, glaucoma, and choroidal neovascular membranes.

Retinitis

Focal infiltrates of the inner retina with little overlying vitritis are typical of acute viral infections (Fig. 39.6). They are more discrete and persistent and yellower than cotton-wool spots. Retinal infiltrates in Behçet’s disease always have signs of retinal vasculitis.

Fig. 39.6 Postviral retinitis with multiple retinal infiltrates and normal acuity.

Neuroretinitis

In neuroretinitis, swelling of the neuroretina, maximal at the optic disk, is out of proportion to signs of posterior segment inflammation (see Chapter 53). Exudates around the fovea form a macular star. Children are more likely to develop edema in response to infections that trigger optic neuritis and neuroretinitis. Cat-scratch disease typically involves the posterior segment in this manner.

Post-traumatic uveitis

Trauma may provoke an autoimmune response to ocular antigens. Children are as prone as adults to these rare conditions.

Sympathetic ophthalmia

There is a bilateral chronic panuveitis with peripheral multifocal choroiditis with many clinical and histologic similarities to VKH and sarcoidosis. Vitritis may be severe. It follows unilateral penetrating trauma, cycloablation, or intraocular surgery. It may coexist with lens-induced uveitis.

Lens-induced uveitis

This is a granulomatous panuveitis that may occur hours to months after the release of lens material and can complicate severe uveitis from other causes.

Parainfectious uveitis

Childhood is a time when airborne pathogens are first encountered and transient ocular inflammation may result. Varicella and streptococcal infections are frequent causes of reactive uveitis. Reported associations may be coincidental and identification of intraocular viruses in specific uveitis types remains rare. Clusters of severe acute panuveitis in children have been reported from Tanzania and Nepal; in the former the incidence was 540/100 000 in the under 9s.⁵^–⁸

Acute anterior uveitis (AAU) is the most common ocular inflammation following varicella but mild retinal vasculitis, a self-limiting retinitis, and multifocal choroiditis can occur, usually within 4 weeks (Fig. 39.6). Chronic inflammation and progressive retinitis is an absolute indication for antiviral treatment, not usually necessary for AAU.

Enteric infections triggering reactive arthritis may cause a reactive uveitis: HLA-B27 positivity is a risk factor. Reactive arthritis with urethritis and uveitis is very rare in children.

Localized autoinflammatory diseases

Juvenile idiopathic arthritis

JIA describes chronic joint inflammation starting before 16 years and lasting more than 6 weeks. Early onset rheumatoid arthritis, vasculitides, and ERA are extremely rare causes of arthritis under the age of 7.

Epidemiology

The incidence of juvenile arthritis is 10/100 000. Only half are patients with oligoarticular or polyarticular JIA, and the incidence of JIA-uveitis is 1/100 000 (Table 39.2).

JIA types associated with CAU

The ILAR classification of arthritis starting before the age of 16 years uses a personal or family history of psoriasis, a family history of HLA-B27-related disease and rheumatoid factor to aid classification. The classification was designed primarily to aid the epidemiologic study of arthritis. Antinuclear antibody (ANA) and age at onset are not used in the classification but are major independent risk factors for uveitis.

Genetic studies suggest similarities between oligoarticular and polyarticular JIA in the youngest groups.¹¹ Older children with ANA-negative polyarticular JIA may have a distinct pattern of disease and appear to be at a much lower risk of CAU. JIA is found in all races; JIA-uveitis may be more common in Caucasians.

Several genes, including HLA, are associated with different clinical types of JIA.^13,¹⁴ Oligoarticular onset JIA is associated with HLA genes common to polyarticular JIA (DRB1*08), psoriatic arthropathy (DRB1*1301), and systemic onset JIA (DRB1*11), as well as unique associations such as DPB1*02. Uveitis appears to be associated primarily with the DRB1*13 haplotype, which is most frequent in oligoarticular JIA, and DPB1*02. ERA and early onset rheumatoid arthritis are clinically and genetically distinct from the types of JIA associated with CAU.

Oligoarticular JIA is defined by the involvement of less than five joints at the onset of disease. If more joints are later involved it is classified as extended oligoarticular JIA. If more than five joints are involved at onset it is classified as polyarticular. The cut-off is artificial and age at onset of arthritis and ANA status are as important as the number of joints in defining JIA phenotypes.

All children with chronic painless AU are screened for joint abnormalities and to exclude other systemic diseases. Uveitis is associated with oligoarticular, ANA-positive JIA of early onset: the highest risk groups may have a frequency of uveitis of over 50%. The risk of uveitis diminishes to zero in those whose arthritis starts after age 13, and the cut-off may be much younger in those with polyarticular ANA-negative JIA. ANA status does not change the risk sufficiently to alter screening policy.

In those developing uveitis, arthritis typically starts at 28 months and uveitis 13 months later: 86% have oligoarticular onset JIA, 75% are female, and 80% are ANA-positive.^10,¹²

Investigation of CAU

Routine laboratory testing in CAU can be limited to white count, serum angiotensin converting enzyme (sACE), ANA, immunoglobulins, antistreptolysin titers, electrolytes, and C-reactive protein. Other autoantibodies, such as double-stranded DNA, anticardiolipin and perinuclear antineutrophil cytoplasmic, as well as raised ASO titers, may occur in JIA. Raised sACE, immunoglobulins, and a lymphopenia suggest sarcoid which may present with arthritis indistinguishable from JIA.

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Uveitis

Introduction