|Year : 2013 | Volume
| Issue : 3 | Page : 140-150
Pediatric uveitis: An update
Parthopratim Dutta Majumder1, Jyotirmay Biswas2
1 Department of Uvea and Intraocular Inflammations, Sankara Nethralaya, Chennai, India
2 Director of Uveitis and Ocular Pathology Departments, Sankara Nethralaya, Chennai, India
|Date of Web Publication||30-Nov-2013|
Director of Uveitis and Ocular Pathology Departments Sankara Nethralaya No. 41, College Road, Nungambakkam, Chennai
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Because of their varied spectrum of clinical presentation and difficulty in management, pediatric uveitis remains a challenge to the ophthalmologist. Variations in clinical presentation, difficulties in eye examination, extended burden of the inflammation over quality of life, limited treatment modalities, risk of amblyopia are the main challenges in the management of pediatric uveitis. Pediatric uveitis is a cause of significant ocular morbidity and severe vision loss is found in 25-33% of such cases. This article summarizes the common causes of uveitis in children with special approach to the evaluation and diagnosis of each clinical entity.
Keywords: Pediatric Uveitis, Juvenile idiopathic arthritis, Pars planitis, Behηet′s disease, Sarcoidosis, Tubulointestinal nephritis and uveitis, Parasitic Uveitis
|How to cite this article:|
Majumder PD, Biswas J. Pediatric uveitis: An update. Oman J Ophthalmol 2013;6:140-50
| Introduction|| |
Pediatric uveitis remains a challenge to the ophthalmologist because of their varied spectrum of clinical presentation and difficulty in diagnosis as well as treatment. Pediatric uveitis accounts for 5-10% of all uveitis population.  Variations in clinical presentation, difficulties in comprehensive eye examination, delayed diagnosis, extended burden of the inflammation over quality of life, limited management options, risk of amblyopia are the main challenges in the management of pediatric uveitis. Because of the prolonged duration and increased risks of complications, pediatric uveitis can lead to significant ocular morbidity and severe vision loss is found in 25-33% of pediatric uveitis cases. 
Because of the varied and protean manifestations of the numerous uveitic entities in children, a detailed and complete discussion on them is beyond the scope of this article. In this review article, we have tried to summarize the common causes of uveitis in children with special approach to the evaluation and diagnosis of each clinical entity.
Juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) can be defined as a group of idiopathic arthritides, which occurs before the age of 16 years and persists for at least 6 weeks. It is the most common cause of uveitis in children and also major cause of visual impairment in children. The prevalence of uveitis in JIA patients varies from 4% to 38%. ,,,, JIA shows female preponderance with male:Female ratio of 2:3 and girls are five times more prone to have a longer course of the disease than boys. Chances of developing ocular manifestations are relatively more common in girls. ,,,, The major risk factors for developing uveitis in patients with JIA are female sex, antinuclear antibody (ANA) seropositivity, oligoarticular arthritis, rheumatoid factor seronegativity and early (less than 6 years) age of onset of arthritis [Figure 1].
The most common extraarticular manifestation of JIA is intraocular inflammation. The intraocular inflammation seen in JIA patients is typically bilateral nongranulomatous uveitis with chronic course. However granulomatous uveitis with mutton-fat keratic precipitates (KPs) has also been reported.  Variable anterior chamber reaction with inflammatory cells in anterior vitreous can be seen in slit lamp examination. Posterior synechiae are common. Posterior segment involvement in JIA is usually rare though CME can occur. The common causes of visual impairment in JIA are complicated cataract and band shaped keratopathy (BSK) [Figure 2]. Secondary glaucoma is another vision robbing complication of JIA. Other complications associated with JIA are epiretinal membrane, macular hole, hypotony with ciliary body shutdown or atrophy.
Diagnosis of JIA is always clinical; rather it is the diagnosis of exclusion. The key to the diagnosis includes elaborate history taking and careful general examination of patients often with a rheumatologist. Before initiation of treatment it is of paramount importance to rule out the infectious causes of uveitis. There is no specific laboratory investigation for JIA. The patients with JIA can have raised erythrocyte sedimentation rate, C-reactive protein leukocyte, and platelet count. Rheumatoid factor is not an important marker for the diagnosis of JIA. There is a strong association between ANAs and JIA associated with uveitis. However, it is also often present in other causes of uveitis.
Early diagnosis and prompt initiation of treatment to achieve complete quiescence of inflammation is the mainstay of management of JIA patients for prevention of sight-threatening complications. Topical corticosteroids along with short acting mydriatics and cycloplegics are the first line of treatment. The frequency and duration of the topical therapy largely depends on the severity of the inflammation. Care should be taken to reduce the excessive use of topical steroids because of their potential sight threatening complications like cataract formation, steroid induced ocular-hypertension, etc., Prolonged use of mydriatics and cycloplegics can lead to amblyopia  and frequent application of these medications can form synechiae in dilated position of the pupils, especially if the pupils remain nonmobile in dilated position for a long time in presence of significant inflammation in the anterior chamber.
Methotrexate is the most common first line systemic medication used in JIA. , Oral corticosteroids because of their potential side effects on growth and bone metabolism in children are not indicated for long-term use. Methotrexate is usually well tolerated in children; very few develop gastrointestinal side effects, where the drug can be administered intramuscularly or subcutaneously. However, the drug needs 1-2 months to achieve the desired plasma level and thus cannot be used in the treatment of acute cases of intraocular inflammation. Folic acid supplementation is recommended to minimize the risk of bone-marrow toxicity. Liver enzymes and complete blood counts are monitored every 4-6 weeks in patients on methotrexate therapy. If parameters of the liver function tests are elevated to twice the normal, dosage of the drug should be adjusted or stopped. Other immunosuppressives available for the treatment of JIA are azathioprine, cyclosporine,  and chlorambucil.  All these drugs should be used with careful monitoring of the efficacy and potential side effects. Recently, tumor necrosis factor alpha (TNF-α) inhibitors have been used in the management of intraocular inflammations associated with JIA with promising results. Adalimumab has been found to be very effective against intraocular inflammation related to JIA and usually tolerated well by children.  Rituximab, a chimeric monoclonal antibody against CD20, has been found to be useful in the treatment of uveitis related to JIA, which remains refractory to treatment with TNF-α antagonists. 
According to Standardization of Uveitis Nomenclature (SUN) classification, pars planitis is the intermediate uveitis without any systemic disorders. Careful slit lamp examination of these patients reveals mild-to-moderate anterior chamber inflammation with small KPs. Posterior synechiae and peripheral anterior synechiae are also commonly seen in patient with pars planitis. BSK is also a common finding in such patients.
The primary site of the inflammation in pars planitis is vitritis, which is sine qua non of this disease. Clinically inflammatory cells in anterior vitreous can be seen during slit lamp examination. In case of long standing or chronic infections, degenerative changes in the vitreous in the form of coarse vitreous strands with both old and fresh inflammatory cells can be seen. It is interesting to note that though posterior vitreous detachment is uncommon before 40 years of age, it is often seen in patients with pars planitis. Most of the time vitritis is of moderate grade but it can be severe in approximately 10% cases. Snowballs are the round yellowish white aggregates of inflammatory cells in vitreous that lie in close approximately to the retina but never in contact with it. Snow banking of pars plana though most commonly seen inferiorly, can occur superiority too and in case of long standing inflammation, fibrotic condensation of the inflammatory exudates in the form of cyclitic membrane can be seen. This can often lead to tractional retinal detachment. Often inflammation of the peripheral retinal vessels in the form of sheathing, sclerosis (healed), etc., retinal vasculitis is seen and neovascularization can occur too. In a study conducted in Mexican population, retinal vascularization was observed in 90% of the involved eye of the pars planitis cases.  Optic nerve head swelling is not uncommon.
The most common complications of pars planitis is cystoid macular edema and is the most common cause of diminution of vision in such patients. Other common complications are complicated cataract, secondary glaucoma, vitreous hemorrhage and peripheral tractional disorders.
A stepladder approach is usually used to treat the inflammation in pars planitis.  The modified Kaplan approach is most commonly used and consists of periocular corticosteroids, oral nonsteroidal antiinflammatory drugs (NSAIDs), systemic corticosteroids, systemic immunosuppressants, cryotherapy, and vitrectomy. Topical corticosteroids are indicated in cases of severe anterior segment inflammations and should be judiciously used because of their potential side effects like cataract or glaucoma. Periocular corticosteroids have the advantage of delivery of the required drugs at desired anatomical locations and side effects related to oral corticosteroid can be avoided. However, sometimes it may be difficult to administer the medications in small children. Rise of intraocular pressure (IOP) is a dreaded complication associated with this procedure and frequent IOP monitoring is required. Oral corticosteroid is usually administered as 1 mg/kg of body weight and depending on the response, tapered in 2-3 weeks and discontinued as early as possible. However, because of its potential side effects, it should not be used for prolonged period. Immunosuppressives like methotrexate, azathioprine, cyclosporine, mycophenolate mofetil are used as mono therapy to those who are not responding to systemic corticosteroid or as combination therapy along with corticosteroid to reduce corticosteroid dosage. If systemic parameters are closely monitored, immunosuppressives can be used to effectively manage the intraocular inflammations and the authors advocate their early use, where indicated, to prevent the permanent damage.
Behçet's disease is a multisystem inflammatory disease of unknown etiology. The principal pathological process in Behçet's disease is a vasculitis predominantly involving the veins and is characterized by oral ulceration, genital ulcers, skin lesions, ocular lesions, gastrointestinal involvement, vascular lesions, and neurologic manifestations. The incidence and the severity of Behçet's disease varies according to the geographic location and the population studied. High prevalence is reported in Mediterranean and Far and Middle Eastern countries along the ancient silk route and in Japan.  The mean age of onset of Behçet's disease is usually 25-30 years and early onset in children is relatively uncommon. Epidemiological analysis has shown that even in countries with high prevalence of the disease, Behçet's disease is not common cause of pediatric uveitis.  When affected, the age of onset in children is relatively late - 10-15 years of age. ,,,
Various different diagnostic criteria are available for the diagnosis of Behçet's disease. However, there is no separate criteria that has been devised for the diagnosis of pediatric Behçet's disease. The most widely accepted one is the International Study Group for Behçet's disease criteria  [Table 1].
Eye is the most commonly involved organ in Behçet's disease,  fortunately incidence of ocular manifestations in children is less common compared with adults.  Ocular manifestation usually starts within 2-3 months of onset of the disease; though ocular manifestation can be the presenting manifestation of the Behçet's disease in one-fifth cases.  Ocular involvement in Behçet's disease is characterized by recurrent, but spontaneously resolving attacks of hypopyon iridocyclitis with or without panuveitis. Ocular involvement is bilateral in 80% of the cases. Females are less prone to have ocular manifestation and severity of the involvement is less in them compared with males.  Because of the minimal fibrinoid exudates in it, hypopyon in Behçet's disease is mobile in nature. Posterior segment involvement occurs most commonly as vasculitis and is devastating in nature. It is characterized by severe and persisting vitritis with periphlebitis. Retinitis, retinal hemorrhages, optic nerve edema can also be seen. Cystoid macular edema is a common complication in Behçet's disease and can lead to macular hole formation in long standing cases.
Unfortunately there is no specific laboratory test for the diagnosis of Behmmo's disease and mainstay of the diagnosis relies on detailed history and meticulous systemic examination. Routine blood investigation may show anemia, raised erythrocyte sedimentation rate and leukocytosis. HLA-B51 (HLA B-5101) can be considered in suspected patients; however, presence or absence of the HLA-B51 does not confirm or exclude the possibility of the disease.
Intraocular inflammation associated with Behçet's disease is the most challenging and difficult to treat. In spite of all available treatment modalities, visual prognosis in ocular involvement of Behçet's disease is very poor.  Mild-to-moderate anterior segment inflammation is usually treated with topical corticosteroids, topical mydriatics, and periocular corticosteroids. Acute and severe forms of inflammation require treatment with oral corticosteroid or intravenous pulse therapy with methylprednisolone. Considering their potential side-effects and requirement of long-term therapy in patients, corticosteroid is not a popular choice for the treatment of Behçet's disease. Also many a times the inflammation remains nonresponsive to corticosteroid therapy. Prior to the development of biologicals, immunosuppressives had been the keystone therapy to control and the recurrences of the sight-threatening intraocular inflammation of Behçet's disease and still in use in various situations. Various immunosuppressives used for the treatment of Behçet's disease are cyclosporine, azathioprine, chlorambucil, cyclophosphamide, and methotrexate. Recently, anti-TNF-α agents, especially infliximab, has been reported to be very effective in the treatment of intraocular inflammation associated with Behçet's disease. ,, These agents are found to be very useful in controlling symptoms, minimizing recurrences, and significantly decreasing the daily dose of corticosteroids or other immunomodulators and are considered as preferred first line agent for treatment of Behçet's disease.
Sarcoidosis is a chronic systemic granulomatous disease of unknown etiology with varied clinical manifestations. The disease is relatively rare in children. Most common age group involved is 8-15 years. The sarcoidosis in children aged below 5 years presents with predominantly ocular involvement, joint pain, skin manifestations, and lung involvement in this age group is relatively less common. Also ocular involvement in sarcoidosis to this age group is limited most commonly to anterior segment inflammation.  The involvement in older children is similar to adults and involve both anterior and posterior segment of the eye.
Granulomatous chronic anterior uveitis with mutton-fat KPs, iris nodules are the most common ocular manifestations in pediatric sarcoidosis [Figure 3]. Intermediate uveitis with moderate-to-severe vitreous inflammation, snowball and snow banking of pars plana region with inflammatory exudates can be seen. Multiple choroidal granuloma or sarcoid tubercles, periphlebitis with candle wax drippings are common findings in sarcoid associated with posterior uveitis.
Mainly knee and wrist joints are involved in childhood sarcoidosis, often with boggy, nontender effusions and synovial thickening. There is usually no movement restriction. As in adults, the skin lesions seen in pediatric sarcoidosis are nonspecific. The clinical picture of arthritis and uveitis in pediatric age group often give rise the confusion of the diagnosis with JIA. The salient distinguishing features of differentiating JIA from sarcoidosis in pediatric age group are highlighted in [Table 2].
|Table 2: Differentiation of JIA from sarcoidosis in paediatric age group|
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Serum angiotensin converting enzyme (ACE) and serum lysozyme are often used routinely in laboratory diagnosis of sarcoidosis and both tests measure macrophage products produced by the sarcoid granulomas. The level of serum ACE reflects the total body mass of active sarcoid granulomas. However, serum ACE is not pathognomonic of sarcoidosis and levels may also be raised in various other conditions. Raised serum ACE levels are commonly seen in children, the reason for which it cannot be used for the diagnosis of sarcoidosis in children. The combined sensitivity, specificity, and positive and negative predictive values of raised serum lysozyme in diagnosis of sarcoidosis are better than raised serum ACE levels.  Liver, being one of the occult sites of sarcoid granuloma, increased liver enzymes are of diagnostic value in such cases. Also hypercalcemia and hypercalciuria occur in some patients with sarcoidosis. Skin, conjunctiva, and lacrimal glands are the common sites of sarcoid nodules lesions in sarcoid and the diagnosis of definite ocular sarcoidosis can be made by solid-tissue biopsy showing classic noncaseating granulomas, and preferably at more than one site.
Corticosteroids in the form of topical, periocular or systemic steroids, depending on the site and severity of the intraocular inflammation are the primary mode of management. Immunosuppressives like methotrexate; azathioprine can be used in the management of recalcitrant cases or in patients with chronic, long standing inflammations.
Vogt-Koyanagi-Harada (VKH) syndrome is a bilateral granulomatous panuveitis associated with various systemic manifestations involving central nervous, auditory, and integumentary systems. The condition has slight female preponderance and involves most commonly 20 and 50 years of age. Pediatric VKH is relatively uncommon.
VKH syndrome consists of four phases. The prodromal phase, initiation of the inflammatory processes, is characterized by neurologic and auditory manifestations in the form of malaise, nausea, fever, headache, and signs and symptoms of meningeal irritation. The common findings of acute uveitic phase include bilateral granulomatous anterior uveitis with mild-to-moderate vitritis, exudative retinal detachment or pockets of sub-retinal fluids, optic nerve edema. The convalescent stage is characterized by depigmentation of the choroid and skin and common findings observed in this stages are depigmented (sunset glow) fundus due to the loss of retinal pigment epithelial cells, Dalen-Fuchs like depigmented nodules in fundus and perilimbal vitiligo (Sugiura's sign).
Recurrences of inflammation in VKH are not uncommon. Chronic recurrent phase carries the risk of most vision-threatening complications, which occurs in this disease process. Recurrent and prolonged inflammation is common in children and can trigger potentially blinding complications like subretinal fibrosis, choroidal neovascularization, posterior synechiae, cataract, and glaucoma. Intravenous methyleprednisolone is advocated in the treatment of acute attack of visually threatening intraocular inflammation in children followed by oral steroid in tapering schedule. In cases of chronic, longstanding inflammation, where long-term immunosuppression is required or in refractory cases, immunomodulatory therapy is required.
Sympathetic ophthalmia is a rare cause of bilateral granulomatous uveitis in children. Reported incidence of this clinical entity ranges from 0.2% to 0.5% following injury and 0.01% following intraocular surgery.  Ocular surgical intervention has been found to be the most common cause of sympathetic ophthalmia in recent studies, whereas earlier studies reported ocular trauma as the most common cause. Though majority of the cases occur within 1 year of insult or injury, the onset of sympathetic ophthalmia varies with a range of 10 days to 66 years. The cause of this clinical entity is not completely understood. Though rare, sympathetic ophthalmia is a dreaded cause of visual morbidity. Proper and rapid treatment, if not started early can lead to irreversible loss of vision. Sympathetic ophthalmia classically presents as bilateral panuveitis. Common findings are bilateral anterior granulomatous uveitis associated with mutton-fat KPs, moderate-to-severe vitritis, exudative retinal detachment, papilitis, and choroiditis. Sub-RPE yellowish white nodules mainly seen in peripheral retina are known as Dalen-Fuchs nodules and found in one-third patients of sympathetic ophthalmia. Corticosteroids remain the mainstay of treatment in such cases. Immunosuppressants like azathioprine and chlorambucil have been used in fulminant and recalcitrant cases.
The role of enucleation, within 2 weeks of injury, is controversial, and with advent of newer immunosuppressives and better understanding of the disease process, it is rarely used as a management option.
Tubulointestinal nephritis and uveitis
Tubulointestinal nephritis and uveitis (TINU) is a rare, mostly idiopathic, and under-diagnosed cause of childhood uveitis. Median age of onset of this clinical entity is 15 years with female preponderance. The cause of the immune-mediated disease process remains largely unclear. The common presenting symptoms are malaise, fever, flank tenderness, anorexia, and weight loss. Most common ocular symptoms are redness, pain, photophobia, and diminution of vision. Anterior segment examination reveals varying degree of anterior chamber reaction and most case reports described the anterior uveitis of nongranulomatous variety. Posterior segment involvement is in the form of vitritis, papilitis, cystoid macular edema, choroioretinitis, and multifocal choroiditis.  Most of the time, eye involvement is bilateral and recurrence of ocular inflammation is common. Suspected cases of TINU should thoroughly be investigated and referred to a nephrologist. Urinalysis may show presence of glycosuria, proteinuria, aminoaciduria, and microscopic hematuria. Necrosis of renal tubule epithelium, interstitial edema, and lymphocytic infiltrates can be seen in renal biopsy. The tubulointestinal nephritis usually resolves spontaneously, though oral steroids are often indicated to prevent structural damage to the renal tissue. Chronic nephropathy occurs in 11% of cases. Depending on the severity and site of the inflammation, topical, periocular, and oral steroids are used and inflammation usually responds well to steroids. Rarely immunosuppressives like mycophenolate moefetil are required to treat chronic uveitic cases.
Toxocara canis or toxocara cati are parasitic nematodes that reside in the small intestine of dogs, cats, and wild carnivores. Humans acquire this infection presumably due to ingestion of larvae from soil or food contaminated with eggs. Ocular infection due to toxocara though rare, can be seen in children. Seroprevalence of toxocara infection in pediatric population has been estimated to be 4-31% in developed countries; however, it may increase up to 86% in developing countries. 
Two syndromes related to toxocariasis have been described. Visceral larva migrans is the systemic form of toxocara infection and can be attributed to the migration capabilities of the second stage larvae of Toxocara canis. Though it is usually self-limited and often subclinical; fever, malaise, cough, hepatomegaly, eosinophilia, pallor, irritability, and anorexia can occur. Visceral larva migrans is usually seen in children aged 6 months to 5 years. , In contrast, ocular toxocariasis has been reported to occur in relative older children. ,
Ocular toxocariasis is unilateral in 90% of cases. , Clinical presentation of ocular toxocariasis can be classified into three types: Peripheral inflammatory granuloma, posterior pole granuloma, and endophthalmitis like picture.  The most common presentation is the presence of a granuloma in the retinal periphery. The granuloma is white in color, elevated and usually measures two-third to three disc diameters in size [Figure 4]. Surrounding inflammatory process in the peripheral retina and ciliary body can mimic the picture of pars planitis or retinitis. Retinal folds may be seen radiating or extending from the peripheral mass to other areas of the fundus. Severe loss of vision may occur if heterotrophia of macula occurs because of the inflammatory processes. Often posterior pole is involved. Clinical examination show white choroioretinitis patch with ill-defined margins with severe overlying vitritis. With subsiding inflammation, granuloma is seen as well-defined mass of three to four disc diameters, occupying the posterior pole. Chronic endophthalmitis like picture can be seen in some cases of toxocariasis and is characterized by low-to-moderate grade anterior chamber reactions, moderate-to-severe vitritis with vitreous membranes. The inflammation is largely localized in the periphery and can be seen as a yellowish white mass, which can be often confused with endophytic retinoblastoma. Severe vitritis can result into leucocoria causing a difficult diagnostic dilemma for the clinicians. ,,
In a study by Shields et al., 16% of the pseudoretinoblastoma patients had ocular toxocariasis.  Toxocara endophthalmitis is painless and not associated with redness and photophobia. However, hypopyon may occur in severe cases.  Sometimes tractional band resulted because inflammation can pull the retina causing retinal detachment.
Because of diverse presentations, it is often difficult to establish the diagnosis of ocular toxocariasis based on clinical manifestations alone. Leukocytosis and eosinophilia are seen in patients with systemic toxocariasis or visceral larva migrans; however, eosinophilia is usually uncommon in patients with ocular toxocariasis. Enzyme-linked immunosorbent assay (ELISA) with toxocara excretory-secretory antigen has been shown to be highly specific for toxocara infection.  Presence of specific antibodies in aqueous humor and calculation of Goldmann-Witmer coefficient demonstrate their intraocular production and can aid in confirmation of the diagnosis. 
Patients with concomitant ocular and systemic toxocariasis are usually treated with systemic benzimidazole derivative like albendazole, thiabendazole, and mebendazole. Albendazole is the most commonly available, well tolerated of these drugs and administered as oral doses of 400 mg bid for children and 800 mg bid for adults for 5 days. Many authors do not advocate treatment with antihelminthic drugs because of the possibility of intense inflammatory reactions following death of larvae. Primary aim of treatment in ocular toxocariasis is to minimize inflammation and prevention of the formation of membranes or tractional bands that can consequently affect intraocular integrity. This is primarily achieved with the help of steroid. Anterior uveitis can be treated with topical corticosteroids and cycloplegics. Vitritis is treated with periocular or systemic steroid (1 mg/kg of body weight). Surgery is usually indicated for complications of intraocular inflammations such as persistent vitreous opacification, retinal detachment, and epiretinal membrane formation with vitreomacular traction. Prevention of the toxocariasis in the form of regular deworming of pets with benzimidazoles is the most important. Deworming of pets reduces the worm loads and reduces the number of eggs deposited in the environment and prevents the spread of toxocariasis.
Ocular toxoplasmosis is a major cause of infectious uveitis in children and young patients owing to the widespread distribution of the causative organism Toxoplasma Gondi throughout the world. It has been estimated that Toxoplasma gondii infects up to a third of the world's population. The organism is an obligate intracellular parasite, ubiquitous in nature and its definitive host is the cat. Oocysts, the cyst form of the organism, are excreted in cat feces and may remain infective for more than 1 year in soil. Other animals including human beings are infected from the contamination of the soil, fruit, and vegetables, etc., and become intermediate hosts.
The hallmark of ocular toxoplasmosis is focal necrotizing retinochoroiditis. The choroid is usually secondarily involved and very rarely choroidal lesions can be seen without retinal involvement. The active lesion is typically yellowish white in color, varies in size and usually circular or oval in shape located mainly in the posterior pole. Necrotizing retinochoroiditis is usually accompanied by severe vitritis, producing the classic 'headlight in the fog' appearance [Figure 5]. Often reactivation of the infection is characterized by appearance of new active lesions, adjacent to an old atrophic scar with hyper-pigmentation along the borders and are called satellite lesions. , Sometimes a cluster of lesions with usually one focus of activity can be seen and this clinical picture is often called punctate outer retinal toxoplasmosis. , Granulomatous anterior uveitis is seen commonly, with mutton-fat KPs, cells and flare, and posterior synechiae. Raised IOP is often encountered in ocular toxoplasmosis. Optic nerve head involvement in the form of neuroretinitis, papillitis can be seen. Complication like choroidal neovascularization is relatively more common in ocular toxoplasmosis in pediatric populations. ,,
|Figure 5: Left: Fundus photograph of active toxoplasma choroioretinitis (note the classic "headlight in fog" appearance) Right: Fundus photograph of healed toxoplasma choroiretinitis|
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Diagnosis of ocular toxoplasmosis is always clinical. The role of serological tests in the diagnosis of ocular toxoplasmosis is limited and primarily used in the diagnosis of atypical presentation of the clinical entity.
Laboratory diagnosis of ocular toxoplasmosis is primarily based on the measurement of intraocular parasite-specific antibody production, an indirect proof of the presence of the parasite within the eye. The serological tests used in the diagnosis of ocular toxoplasmosis include Sabin-Feldman test, the complement fixation test, the agglutination tests, the indirect immunofluorescence assay (IFA), and the ELISA. The Sabin-Feldman dye test, once considered as the gold standard for the diagnosis of toxoplasmosis, is no longer performed routinely as it requires the constant maintenance of virulent organisms in the laboratory with the associated risk of cross-infection to the laboratory personnel. IgG antibody directed against Toxoplasma Gondii appears within 1-2 weeks of the infection and remains detectable for rest of the life.  Because of the prevalence of seropositivity of the organism, the positive predictive value of IgG is low and thus cannot be used for laboratory diagnosis of the toxoplasma infection. It is important to understand that though the presence of anti-T. gondii IgG antibodies does not confirm the diagnosis, a negative IgG usually discards the possibility. Anti-T. gondii IgM usually appears in the first week after the infection, reaches its peak concentration at 1 month, and disappears after 9 months.  Anti-T. gondii IgA antibodies are usually used for the diagnosis of congenital toxoplasmosis, because of slower and weaker IgM production in new-borns and maternal origin of most of the IgG antibodies.  Anti-T. gondii IgA antibodies rise early after an acquired T. gondii infection but disappear earlier than IgM antibodies. Ongkosuwito et al.  observed that IgA is a more sensitive measure of acquired infection than standard techniques, although it may be less specific. Ronday et al.  also reported the increased sensitivity of diagnosis of T. gondii infection with antitoxoplasma IgA titers.
Over the past decade, polymerase chain reaction (PCR) has become an important tool for detection of infectious uveitis. PCR combined with the determination of the Goldmann-Witmer coefficient increases the probability of diagnosing ocular toxoplasmosis with a sensitivity up to 72%.  Real-time polymerase chain reaction (RT-PCR) has been utilized as a rapid and sensitive technique for quantitatively evaluating ocular samples for the presence of T. gondii. 
The primary aim of treatment for ocular toxoplasmosis is prevention of the multiplication of protozoa thereby minimizing the duration and intensity of intraocular inflammation and irreversible tissue damage. The combination of pyrimethamine and sulfadiazine is the most commonly used treatment regimen for ocular toxoplasmosis. The other commonly used drugs are trimethoprim/sulfamethoxazole, clindamycin, and azithromycin. Like pyrimethamine and sulfadiazine, trimethoprim and sulfamethoxazole acts by inhibiting DNA synthesis, but does not necessitate the need for folinic acid supplementation. The combination of trimethoprim and sulfamethoxazole is found to be effective in prevention of the recurrence of ocular toxoplasmosis.  Azithromycin, a macrolide antibiotic, has been found to be effective on both tachyzoites and tissue dormant cysts of the organism.  Clindamycin, another semisynthetic antibiotic, is frequently used in the treatment of ocular toxoplasmosis. It inhibits protozoal activity by blocking protein synthesis and has found to be effective against the cyst form of the organism.  However, there are no reports that clindamycin can reduce recurrence of the toxoplasma infections. Clindamycin can cause pseudomembranous colitis. Atovaquone selectively inhibit the mitochondria electron transport chain in toxoplasma and has very few side effects. However, the drug is considerably more expensive than the other available agents against toxoplasma.
Currently, there is no vaccine available against human toxoplasmosis. Live attenuated tachyzoites have been reported to induce a protective cell-mediated immune response in animals, however, it has not been found safe in human beings.  Thus one of the best way in prevention of toxoplasmosis is to vaccinate the domestic pets. 
Acute retinal necrosis and other viral infections
Though rare, acute retinal necrosis is a vasoocclusive necrotising retinitis. Usually it affects healthy, immune-competent individuals. Though it commonly involves 20-50 years of age, involvement in children has been reported. There is no sex predilection and in one-third of the cases it is bilateral. Viruses implicated are herpes simplex virus (HSV) type 1 and type 2, varicella zoster virus (VZV), and, rarely, cytomegalovirus.
American uveitis society has published the criteria for the diagnosis of acute retinal necrosis.  Slit lamp examination of the eye shows mild-to-moderate anterior chamber reaction, which is commonly granulomatous. Usually there is severe vitritis, which progresses significantly with increasing retinal necrosis, sloughing of the dead tissue and inflammatory products. Retinal necrosis, which starts at the periphery of the retina, must show one or more foci with discrete borders and which progresses rapidly in absence of any treatment. The necrosis spreads in a circumferential pattern toward the posterior pole [Figure 6]. Active vasculitis is characterized by vascular sheathing and characteristically arteries are more affected than veins. Optic nerve may show optic disc edema. Macular involvement in acute retinal necrosis, though not a characteristic feature, does not preclude the diagnosis.
Necrosis-induced retinal thinning and atrophy starts peripherally and often contributes to the development of retinal holes or tears, which typically appear at the junction of normal and affected retina. Retinal holes, combined with subsequent vitreous organization and resultant traction, lead to retinal detachment in up to 75% of cases.  Thus retinal detachments in acute retinal necrosis patients have both a rhegmatogenous and a tractional component.
The primary aim of medical therapy in acute retinal necrosis is rapid recovery of the disease and prevention of fellow eye involvement. Acyclovir is the current medical treatment of choice for acute retinal necrosis and recommended therapeutic regimen consists of induction with 15 mg/kg/day intravenous acyclovir in three divided doses for 7-10 days and oral antiviral medication is then with either acyclovir (800 mg, 5 times a day), valacyclovir (1 g, 3 times a day), or famcyclovir (500 mg, 3 times a day) is continued up to 6 weeks or more. CMV does not respond to treatment with acyclovir. In such cases or in cases with acyclovir resistant strains of HSV and VZV, gancicilovir can be used. Though gancicilovir is highly effective against HSV and VZV, but for its greater risks of systemic toxicity, it should be used cautiously. Corticosteroid has been used to minimize the inflammatory component of acute retinal necrosis because vitritis and vitreous organization progress in spite of effective antiviral treatment. Corticosteroid helps in reducing intraocular inflammation and clearing vitreous haze in acute retinal necrosis. A significant reduction in occurrence of retinal detachment can be achieved by applying prophylactic confluent laser photocoagulation posterior to the areas of active retinitis to create a "new artificial ora serrata" posterior to the affected zones in which retinal holes are likely to develop. ,
Surgical management of retinal detachment in acute retinal necrosis patients is often frustrating. However, with the advent modern equipments and techniques like parsplana vitrectomy, air-ften exchange, endolaser, and gas or silicone oil tamponade varying reports of success rate, even up to 100% has been published.
Various other viruses have been implicated in pediatric uveitis. Retinal involvement in an acute viral infections typically shows focal infiltrates of the inner retina with overlying mild-to-moderate vitreitis, Iridocyclitis due to HSV or VZV infection can be seen in children and often accompanied with raised IOP.
It has been estimated that approximately one-third of the world's population is infected with Mycobacterium tuberculosis.  However, major part of this global burden is contributed by the developing countries and tuberculosis (TB) remains a leading cause of mortality and morbidity in these countries.
Intraocular TB in children is not uncommon and has been reported in 1 year old also.  Mycobacterium tuberculosis can involve any part of the eye or adnexae. Anterior uveitis usually presents as acute or chronic granulomatous anterior uveitis associated with iris nodules, mutton-fat KPs and broad-based posterior synchiae. Intermediate uveitis is often associated with intraocular TB and can present as low grade chronic spill over anterior uveitis with mild-to-moderate vitritis with snowball, snow banking of the pars plana region with inflammatory exudates and peripheral vasculitis.  Involvement of the choroid with nodules or tubercles is the most common presentation of tuberculous posterior uveitis. The nodules are multiple in numbers, situated most commonly in the posterior pole and whitish yellow in color. Often a large tuberculoma or subretinal access [Figure 7] may occur and may be associated with exudative or serous detachment of the retina. These mass like lesions respond well to anti-TB treatment (ATT).  Laboratory diagnosis of intraocular TB is challenging. Tuberculosis skin test (TST) or Mantoux test limited value in children, because of the chances of cross reactivity with antigens used in the test with previously administered BCG vaccines and should be judiciously used. Also uveitis has been reported in children after TST.  Interferon gamma release assay (IGRA) measure in vitro T-cell responses to mycobacterial antigens by quantification of interferon gamma using an ELISA or an enzyme-linked immunospot assay and is claimed to be more specific than the TST because of less cross-reactivity to BCG vaccine and nontuberculous mycobacteria. High-resolution computerized tomography (HRCT) is an useful tool in diagnosis of intraocular TB. According to a study by Ganesh et al., findings of HRCT chest in 80.9% of the patients with granulomatous uveitis were suggestive of healed or active TB. HRCT chest, due to its ability to image the mediastinum, and may be useful in cases where a systemic focus of TB is strongly suspected and can be superior to conventional X-rays.
Endogenous endophthalmitis, sometimes also termed meta-static endophthalmitis, is a dreaded cause of vision-threatening uveitis. Premature babies, children with prolonged hospitalization or history of intravenous medications, malnutrition, septicaemia, and immunocompromized children are at increased risk of developing endogenous endophthalmitis. Fungal endogenous endophthalmitis is more common than bacterial endogenous endophthalmitis. Candida albicans is the most common pathogen responsible for fungal endogenous endophthalmitis followed by Aspergillus. Most common cause of bacterial endogenous endophthalmitis is Staphylococcus aureus.
Most common presentations in such patients are pain, redness, floaters, discharge, and decreased vision. A meticulous history remains the mainstay of diagnosis in endogenous endophthalmitis. Confirmation diagnosis rests on isolation and culture of the organism from the ocular fluid. Rapid intervention is required to restore the vision and includes appropriate use of local and systemic antimicrobial agents.
Masquerade syndromes should always be considered in children with uveitis, especially in conditions nonresponsiveness to standard antiinflammatory therapies. Masquerade syndromes, though rare, require aggressive approach to diagnosis and management because of the potentially life-threatening nature of these underlying entities. The most common cause of masquerade syndromes in children include malignancies like retinoblastoma, leukemia, medulloepithelioma, and juvenile xanthogranuloma; inherited retinal degenerations like retinitis pigmentosa; congenital eye disorders like Coat's disease, etc., Leukemia, the most common malignancy of childhood, can often present with the signs of posterior uveitis. Common signs of posterior segment involvement in leukemia include vascular sheathing, perivascular exudates, retinal hemorrhages, cotton-wool spots, and hard exudates. Retinal infarction, though rare, can occur. Anterior chamber inflammation is relatively uncommon and rarely children can present with hyphema or pseudohypopyon. Retinoblastoma, the most common cause of intraocular malignancy in children, can present as a red, watery eye with a "pseudo-hypopyon". Vitreous may show tumor cells or seeding and examination under general anesthesia reveals the intraocular mass or tumor. Juvenile xanthogranuloma is a disorder of unknown etiology, characterized by abnormal proliferation of nonLangerhans histiocytes. Very rarely, juvenile xanthogranuloma can masquerade as uveitis in childhood in the absence of skin lesions. Slit lamp examination may reveal localized or diffuse yellow or creamy-white iris lesion, hyphema and anterior chamber reactions. Medulloepithelioma or diktyoma is rare tumor of ciliary epithelium, and presents as visible iris tumor with distorted pupil, hyphema, decreased vision with or without strabismus.
| Conclusion|| |
Pediatric uveitis differs in various aspects from uveitis in adults. The association with systemic diseases in uveitis is different in children and presentation of a single systemic disease differs significantly between these two age groups. Uveitis in children is often asymptomatic despite the severity of the inflammation and diminution of vision. Thus, most of the time pediatric uveitis presents late in uveitis clinic and often discovered incidentally during comprehensive eye checkup. Systemic medications such as corticosteroids, most commonly used in the treatment of intraocular inflammation, have deleterious side effects on the developing bone and growth of children and should be used judiciously. Similarly steroid sparing immunosuppressives should be used with close monitoring of the patients. Outcome of the surgical procedures in management of various complications of pediatric uveitis, such as cataract, retinal detachment, glaucoma, are often frustrating and disappointing. Thus prevention and early identification and treatment of any vision threatening complications plays most important role in the management of pediatric uveitis.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]