Current approach in the diagnosis and management of panuveitis

Panuveitis is a generalized inflammation of not only the whole of the uveal tract but also involves the retina and vitreous humor. It differs from other anatomical sites of inflammation in terms of causes as well as distribution. The common causes of panuveitis in our population are tuberculosis, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, Behcet's disease and sarcoidosis. A large number of cases still remain idiopathic. A stepwise approach is essential while evaluating these patients to be able to identify and treat the disease timely and correctly. Ancillary tests can be appropriately applied once the anatomic site of inflammation is identified. An exhaustive approach comprising a full battery of tests is obsolete. Only specific tailored investigations are ordered as suggested by the preliminary clinical and ocular examination. The mainstay of the treatment of uveitis is corticosteroids. Immunosuppressive agents are administered if the inflammation is not adequately controlled with corticosteroids. One of the recent breakthroughs in the treatment of refractory uveitis includes the introduction of immunomodulating drugs: Tumor necrosis factor-alpha antagonist and Interferon-alpha. Vitrectomy has been used in uveitis for over a few decades for diagnostic and therapeutic purposes. When compared to other anatomical sites of inflammation, panuveitis has poor visual outcome due to more widespread inflammation. The side-effects of the chronic treatment that these patients receive cannot be overlooked and should be specifically monitored under the supervision of an internist with special interest in inflammatory diseases.


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Uveitis is one of the major causes of blindness in the world. [1] According to anatomical location, the International Uveitis Study Group (IUSG) defi nes panuveitis as generalized infl ammation of all three parts of the uvea, i.e., iris, ciliary body and the choroid. [2] It covers a large group of diverse diseases, which aff ect not only the uvea but also the retina and vitreous humor. Diagnosis of panuveitis is established in the presence of the following clinical signs: • Evidence of choroidal or retinal inflammation such as choroiditis (focal, multifocal or serpiginous), choroidal granuloma, retinochoroiditis, retinal vasculitis, subretinal abscess, necrotizing retinitis or neuroretinitis; with • evidence of vitreous infl ammation (vitreous cells or vitritis); and • presence of signs of anterior uveitis (cells and flare in the anterior chamber, keratic precipitates or posterior synechiae). The distribution of uveitis according to the anatomical site of inflammation and its causes are influenced by diverse geographic, racial, nutritional and socioeconomic diff erences. [3] Knowledge of the epidemiology of uveitis helps the clinician to bett er predict the likelihood of a systemic association and to order appropriate diagnostic testing. [4] Panuveitis is relatively more common in Asia, Africa and South America as compared to North America, Europe and Australia. [5] Tuberculosis (TB) and Vogt-Koyanagi-Harada (VKH) syndrome are the most common causes of panuveitis in India. [3,6] This article highlights the current clinical approach to the diagnosis and management of panuveitis, with special emphasis on the most common causes of panuveitis in our sett ing.

Clinical approach
Classifi cation and standardization of uveitis is important, as it enhances the precision and comparability of clinical examination. This helps in developing a complete picture of the course of the disorders and their response to treatment. The most widely used classifi cation of uveitis is the one devised by the IUSG in 1987, based on anatomical location of infl ammation. The standardization of uveitis nomenclature working group in 2005 standardized the approach to reporting clinical data (diagnostic terminology, grading of infl ammation and outcome measures) in uveitis research. [7] More recently, the IUSG in 2008 designed a simplifi ed classifi cation of uveitis into infectious, non-infectious and masquerade, based on etiological criteria. [8] To recognize a specifi c entity, we use the following stepladder approach when evaluating a patient with uveitis: 1. A detailed ocular history is elicited regarding the symptoms, duration (acute or chronic), number of episodes (recurrent), and laterality of the symptoms. 2. Thorough ocular examination is done to assess the anatomic location of the uveitis, type of infl ammation (granulomatous or non-granulomatous), to recognize any typical entity (such as Fuchs' heterochromic cyclitis). 3. Once the naming and meshing of the disease is done, systemic history (targeted questions) is asked to know any associated conditions or syndromes causing uveitis. 4. Only selective investigations are ordered.

Investigations
Nearly all cases of uveitis require investigations for correct diagnosis (or label) and guidance for treatable conditions (infections), to know the natural history and prognosis of the disease, to provide reassurance to the patient as well as doctor, to identify groups at particular risk [antinuclear antibody (ANA) status in juvenile idiopathic uveitis] and to avoid unnecessary treatments. Clinically, uveitis can be classifi ed into granulomatous and non-granulomatous uveitis. Anatomic approach is essential in the diagnosis of uveitis for proper application of ancillary tests.

Ancillary tests
Whereas anterior segment infl ammations involving the iris are routinely picked up by slit-lamp examination, ciliary body involvement can best be confirmed by ultrasound biomicroscopy (UBM). Baseline color fundus photography serves as an extremely good clinical reference when monitoring the fundus changes during follow-up periods. Digital color fundus photography allows easy storage and retrieval of fundus images. A composite montage of the retina can be made to document bett er the lesions in the peripheral fundus. [9] Fundus fl uorescein angiography (FA) is mandatory for retinal and choroidal lesions. The FA allows identifi cation of active infl ammation of the retinal vessels as seen in vasculitis due to sarcoidosis, tuberculosis, Behcet's disease and syphilis. The patt ern of staining and leakage provides diagnostic clues. Vascular occlusions can also be detected. Clinically absent macular edema or optic disc edema can be revealed on FA. Besides the active lesions, complications of uveitis that are best studied on FA include cystoid macular edema (CME), neovascularization of retina, capillary dropout, subretinal neovascularization and retinal pigment epithelium (RPE) changes. Exudative retinal detachment in the early stage of VKH begins as bilateral, multifocal points in the posterior pole. Multifocal leaks at the level of RPE with pooling of the dye in the areas of exudative detachment are typically seen on the FA in VKH patients. Similar lesions on FA may also be seen in sympathetic ophthalmia. Staining of a hypofl uorescent lesion starting at the border and then progressing to the center is typical of toxoplasmic retinochoroiditis. Indocyanine green angiography (ICGA) is the technique of choice for imaging the choroid. The alteration of the normal choroidal ICGA background fluorescence is the main parameter studied, and information is obtained mostly from late angiographic phases when choroidal infl ammatory lesions may appear as areas of decreased or absent fl uorescence. Using ICGA, choroidal vasculitis in posterior uveitis can be characterized and subdivided into two main patt erns: (1) primary infl ammatory choriocapillaropathy and (2) stromal infl ammatory vasculopathy. [10] The fi rst patt ern consists of hypofl uorescent areas up to the late phase of angiography characteristic of choriocapillaris non-perfusion and includes entities such as multiple evanescent white dot syndrome, acute posterior multifocal placoid pigment epitheliopathy, multifocal choroiditis, ampiginous choroiditis and serpiginous choroiditis. The second patt ern consists of fuzzy indistinct appearance of vessels in the intermediate angiographic phase and diff use choroidal hyperfluorescence in the late phase indicating infl ammatory vasculopathy of larger choroidal vessels. This patt ern has been described in active VKH disease, ocular sarcoidosis and tuberculosis and birdshot chorioretinopathy. In Behçet's uveitis of recent onset, choriocapillaris perfusion delay and fuzzy choroidal vessels without diffuse late choroidal hyperfl uorescence has been described. Ultrasound is a safe, noninvasive, dynamic tool for the evaluation of the posterior segment when direct visualization of the fundus is obscured due to severe infl ammation or its complications. It is useful also for the evaluation of infl ammatory infi ltration of the choroids in VKH syndrome or sympathetic ophthalmia (SO). [11] It is especially helpful in diff erentiating choroidal thickening associated with choroiditis from posterior scleritis which may mimic posterior or even panuveitis. It is also useful when evaluating patients prior to the use of intraocular drugs or surgery. UBM allows an objective, quantitative evaluation of the ciliary body. [12] It can be of great help in deciding the course of treatment by detecting the underlying structural abnormalities in ocular hypotony associated with uveitis. [13] Optical coherence tomography (OCT) is a noncontact and noninvasive imaging tool. Although certain complications of uveitis such as CME, neovascularization of retina, epiretinal membrane, or vitreomacular traction syndrome can be demonstrated extremely well on the OCT, its use in panuveitis may be restricted by hazy media. Recently, our experience with the use of OCT in uveitic eyes has revealed that highdefi nition (HD) spectral-domain OCT [SD-OCT] (Cirrus HD-OCT; Carl Zeiss, Dublin, California, USA) has an advantage over time-domain OCT [TDOCT] (Stratus version 4; Carl Zeiss) for imaging macula in patients of uveitis by providing bett er identifi cation of normal and pathologic structure in patients with poor media clarity. [14] Laboratory tests Recent advances in the understanding of the pathogenetic mechanisms of uveitis have changed the diagnostic and therapeutic approach to these patients. In most textbooks, the exhaustive approach is presented. Such lists are not very useful. Random screening with a full batt ery of tests is needless. One should concentrate on a limited number suggested by namingmeshing. We routinely order the following laboratory tests:  [15] ) • ANA for juvenile rheumatoid arthritis and antineutrophil cytoplasmic antibody for vasculitis associated with Wegener granulomatosis • X-ray of sacro-iliac joint for ankylosing spondylitis • Antibodies against Toxoplasma gondii A repeat evaluation and follow-up is required in cases where laboratory test results do not yield any positive information. Cases that remain undiagnosed by the routinely available laboratory tests are labeled as idiopathic. [3] In some of the etiologies (infectious endophthalmitis, acute retinal necrosis), a clinical diagnosis can be made and therapy can be immediately started, while the specifi c confi rmation tests are being ordered or carried out. Whereas culture still remains the gold standard for diagnosing microbial infections, defi nitive diagnosis of intraocular infl ammation due to infectious agents is diffi cult to obtain from ocular fl uids or tissue specimens in routine clinical practice. Our ability to detect infectious agents has been strengthened by the use of polymerase chain reaction (PCR). It has been used to diagnose uveitis, including viral uveitis, mycobacterial intraocular infections, infectious endophthalmitis, and protozoal eye diseases. [16] PCR is a powerful molecular technique for evaluation of very small amounts of Deoxyribonucleic acid and Ribonucleic acid. It can be a simple, rapid, sensitive, and specifi c tool for the diagnosis of infection, autoimmunity, and masquerade syndromes in the eye.
Certain tests such as liver function and renal function tests are ordered only during the course of treatment while evaluating a patient before considering immunosuppressive therapy or while evaluating the adverse eff ects of these drugs or certain antimicrobial drugs.

Management of Panuveitis
The treatment of uveitis has three main goals: to prevent visionthreatening complications, to relieve the patient's complaints and, when feasible, to treat the underlying disease. [17] It can be  . Diagnosed as probable Vogt-Koyanagi-Harada's syndrome, she was treated with intensive topical betamethasone and mydriatics drops. She also received intravenous methyl prednisolone 1 g for fi ve days followed by oral steroids  Uveitis due to infectious agents is treated by specific antimicrobial therapy (antibiotic, antiparasitic or an antiviral) for appropriate duration, with or without corticosteroids. The mainstay of treatment of noninfectious uveitis is antiinfl ammatory therapy. Severe or refractory panuveitis needs immuno suppressive agents.

Corticosteroids
Corticosteroids are the drugs of choice in most types of uveitis. They inhibit the inflammatory process by suppressing the arachidonic acid metabolism and activation of complement. [17] In panuveitis, both topical and systemic corticosteroids are needed. Depending upon the severity of the disease, oral prednisolone is started in a loading dose of 1 mg/kg/day. As the infl ammation subsides, tapering of corticosteroids by 5-10 mg per week is begun within two to four weeks of initiating therapy. Once the eye is completely quiescent, the patient is followed on a maintenance dose ranging from 2.5-10 mg daily of prednisolone. A reasonably long period of low-dose corticosteroids is required as maintenance therapy in VKH syndrome and SO.
The normal response to the corticosteroid therapy may be interrupted by recurrence of uveitis in which case the frequency of instillation of topical drops is increased besides raising the oral corticosteroid to the initial high-dose levels. Unilateral cases may be given a trial with periocular injection of depot corticosteroids into the posterior subtenon space. The sideeff ects and complications of topical or systemic corticosteroids must be looked for at every follow-up visit of the patient. These include secondary glaucoma, posterior subcapsular cataract, increased susceptibility to infection (ocular or systemic), hypertension, gastric ulcer, diabetes, obesity, growth retardation, osteoporosis and psychosis.

Supportive therapy
Cycloplegics are administered to relieve pain due to ciliary spasm. Posterior synechiae formation is prevented by instilling a mydriatic agent. Atropine is used in acute att acks while intermediate acting agents (homatropine) are used to maintain pupillary dilatation.

Immunosuppressive agents
The three main classes of immunosuppressives that are widely used today in addition to glucocorticosteroids are antimetabolites, T cell inhibitors and alkylating agents. Antimetabolites include azathioprine, methotrexate and mycophenolate mofetil (MMF). T cell inhibitors include cyclosporine and tacrolimus. Alkylating agents include cyclophosphamide and chlorambucil. When corticosteroid therapy is insuffi cient to control ocular infl ammatory disease, immunosuppressive agents are given. They exert their benefi cial eff ects by actually killing the rapidly dividing clones of lymphocytes that cause the inflammation. Indications of immunosuppressive therapy in panuveitis are: severe infl ammation that is sight-threatening; chronic infl ammation that is not responding to the primary conventional corticosteroid therapy; multiple relapses of uveitis; or intolerance or contraindications to systemic corticosteroids. The clinician should discuss extensively with the patient regarding the sideeff ects of such therapy.
These drugs have to be used only aft er ruling out a possible infectious agent as the cause of uveitis. VKH syndrome and SO are the uveitis conditions that are usually resistant to corticosteroids or require long-term treatment with corticosteroids. In such conditions, immunosuppressive agents are initiated as immediate second line therapy or as steroidsparing agents as fi rst-line therapy. All patients are evaluated for hemoglobin, blood cell counts (leucocytes and platelets), liver and renal function tests to rule out contraindications to treatment before starting any immunosuppressive drug, and every four weeks while receiving these medications. Low-dose immunosuppressive drugs such as azathioprine or methotrexate (MTX) are also initiated before any intraocular surgery to control the infl ammation for a prolonged time and sustain it aft er surgery for a favorable outcome. [18,19] Cyclosporine [20] and azathioprine [21] have been found to be eff ective in the treatment of Behcet's disease in randomized controlled trials, whereas the effi cacy of other agents is shown by uncontrolled case series.

Newer strategies
Biologic drugs were introduced as an alternative mode of therapy for recalcitrant uveitis about 15 years ago, with encouraging outcomes. These are therapeutic agents with biologic properties, including monoclonal antibodies and soluble cytokine receptors. The main biologics in current use include anti-tumor necrosis factor-α (TNF-α), cytokine receptor antibodies and interferon-α (IFN-α). These are believed to have a superior anti-infl ammatory potential than the conventional immunosuppressives and have been proposed as a second-line strategy aft er failure with conventional immunosuppressants for the treatment of refractory uveitis, especially with ocular BD. [22] Anti-tumor necrosis factor-α TNF-α is an infl ammatory cytokine found in animal models of uveitis as well as the aqueous of eyes with uveitis. The three currently commercially available anti-TNF-α agents are infl iximab, adalimumab and etanercept. Infl iximab and adalimumab are monoclonal immunoglobulin G1 (IgG1) antibodies against TNF-α. They both form stable bonds with the soluble and transmembrane forms of TNF-α. Etanercept is a dimeric soluble form of the p75 TNF-α receptor linked to IgG1 and forms less stable bonds mainly with the transmembrane form. Anti-TNF-α agents are increasingly proving to be eff ective in the control of uveitis. Infliximab in particular has been found to be effective in reducing infl ammation in about 80% of refractory uveitis with relatively few serious adverse reactions. [23][24][25] However, repeated infusions every four to eight weeks are oft en required to prevent recurrences. In BD, the response to infl iximab is especially rapid, occurring as early as 24 h aft er the infusion, even in patients who have recurrences despite being heavily immunosuppressed. [26,27] Adalimumab is given as a subcutaneous injection of 40 mg at weekly to two-weekly intervals; hence it can be self-administered, and because it is fully humanized, there is less likelihood of formation of antibodies. There has been only one report on its use in three adult patients with BD and three small studies in childhood uveitis. All three Behcet's patients had achieved remission with infl iximab but were switched to adalimumab as it could be self-administered. [28] Etanercept is given twice weekly also as a subcutaneous injection of 25 mg and is consistently found to be less eff ective than the other two agents in uveitis. This is att ributed to its relatively weak binding, mainly to the transmembrane form of TNF-α. [23,24] One potentially fatal complication of anti-TNF-α therapy is disseminated tuberculosis. Screening for latent tuberculosis may be compromised by the fact that these patients are usually already on other immunosuppressants, which may result in a false-negative purifi ed protein derivative test, and the primary focus may be extrapulmonary.

Cytokine receptor antibodies
Daclizumab is a humanized monoclonal antibody that targets the CD25 subunit of the human interleukin-2 receptor of T lymphocytes. It is given as an intravenous infusion of 1 mg/kg at two to four-week intervals. A subcutaneous form is currently still undergoing trials but shows promise as a more accessible route of administration. [29] Daclizumab has been found to be clinically benefi cial in controlling the infl ammation and, hence, preserving vision in birdshot chorioretinopathy, but is yet to be proved to be effi cacious in the treatment of BD.

Interferon-α2a
IFN-α2a is a cytokine released in viral infections and has been used mainly for the treatment of BD as it is thought to have a possible viral origin. It is given as a subcutaneous injection at a dose of 3-9 million units/day daily or thrice a week. [22,30] Biologic agents are effective and comparatively welltolerated options in the treatment of refractory uveitis in both adults and children in the short term, except for etanercept. The predominant side-eff ects of antimetabolites are bone marrow suppression and hepatotoxicity; that of T cell inhibitors is renal toxicity and that of alkylating agents are bone marrow suppression and the development of malignancies. The uncertainty of their long-term results, their high costs as well as the necessity for repeated intravenous infusions in the case of infl iximab limit their widespread use. [31] Mycophenolate mofetil is another effi cacious, fairly well-tolerated and less costly immunosuppressant. It has the additional advantage of an oral formulation.

Vitrectomy in panuveitis
Vitrectomy for uveitis began in the late 1970s for diagnostic purposes and for treating infections. Diagnostic vitrectomy combined with PCR can significantly improve diagnostic yield in otherwise idiopathic uveitis, and can frequently make a diagnosis in cases complicated by media opacity or other features that make traditional exam-based diagnosis diffi cult or impossible. Vitrectomy may be considered as a therapeutic option when uveitis persists despite maximum tolerable medical treatment with corticosteroids and/or other immunosuppressants. It may also be indicated when visual loss occurs due to complications of longstanding inflammations, such as a densely opacified vitreous, scar tissue pulling on the ciliary body causing hypotony, cystoid macular edema, an epiretinal membrane, a dense posterior lens capsule opacifi cation or a tractional retinal detachment. [32] Vitrectomy removes the lodged lymphocytes in the vitreous, infl ammatory debris, immune complexes and autoantigens. It also increases the uveal penetration of anti-infl ammatory cells. [33] Besides providing a better access for complete removal of the cataractous lens material along with posterior capsule, the combined approach of pars plana lensectomy and vitrectomy allows easy performance of intraocular maneuvers and prevents formation of cyclitic membrane. [34] Complications of vitrectomy may be mild or severe and include bleeding, cataract, glaucoma, infection, retinal detachment or blindness.
Some of the common uveitis entities seen in our population causing panuveitis are discussed.

Tuberculosis
Tuberculosis (TB)-related uveitis is being increasingly reported from Southeast Asian, Western Pacifi c, and Eastern Mediterranean regions. [3,35,36] The true prevalence of tubercular uveitis remains a major concern, especially in TB-endemic areas and because of lack of defi nite diagnostic criteria. TB can aff ect any part of the eye and patients present with a spectrum of clinical signs. Although it may mimic other clinical entities, a positive tuberculin skin test, healed lesions on chest X-ray or associated systemic TB corroborates the diagnosis of presumed intraocular TB. Administration of anti-tubercular therapy (isoniazid 5 mg/kg/day, rifampicin 450 mg/day if body weight is < 50 kg and 600 mg/day if body weight is > 50 kg, ethambutol 15 mg/kg/day, and pyrazinamide 25 to 30 mg/kg/day initially for three to four months; thereaft er, rifampicin and isoniazid are used for another nine to 14 months) in addition to the standard corticosteroids signifi cantly reduces recurrences of uveitis in these patients. [37] In our experience, the most common presentation of tubercular uveitis is posterior uveitis, followed by anterior uveitis. Panuveitis and intermediate uveitis are less common. The recently introduced immune-based rapid blood tests [QuantiFERON-TB Gold test (QFT-G) and TSPOT (TB test)] seem to be a signifi cant upgrade of the century-old tuberculin skin test for diagnosing latent TB infection. QFT-G assay measures the amount of interferon-gamma (IFN-γ) released by the patient's sensitized T-cells when his whole blood is incubated with two synthetic peptide antigens ESAT-6 and CFP-10. These antigens are present in Mycobacterium tuberculosis but not in the Bacilli-Calmett e-Guerin (BCG) or atypical mycobacteria. The advantages of these tests over the routine tuberculin skin test are that these are not aff ected by the previous BCG vaccination or atypical mycobacteria, the results are available within 24 h without any need for a second visit to the hospital and they are free from any booster eff ect. [38,39] The major limitation of these tests is that they are expensive.

VKH syndrome
VKH is a severe bilateral granulomatous panuveitis associated with various extraocular manifestations involving the central nervous, auditory, and integumentary system. [40] This syndrome usually aff ects adults between 20-50 years Vol. 58 No. 1 of age. Evidence suggests that it involves a T-lymphocytemediated autoimmune process directed against an as yet unidentified antigen (or antigens) associated with melanocytes. [41][42][43] The mechanism that triggers this autoimmune att ack is unknown, but sensitization to melanocytic antigens by means of cutaneous injury, or viral infection have been proposed as possible factors in some cases. Although the exact target antigen has not been identifi ed, candidates have been proposed. They include tyrosinase or tyrosinase-related proteins, an unidentifi ed 75 kDa protein obtained from cultured human melanoma cells (G-361), and the S-100 protein. VKH disease is typically characterized as aff ecting primarily those of more pigmented groups, such as Hispanics (Mestizos), Asians, Native Americans, Middle Easterners, and Asian Indians, but not blacks of sub-Saharan African descent. This fi nding, in combination with the evidence of an increased risk among those with certain HLA genotypes, points to a genetically determined susceptibility to the triggering event for VKH disease. [44][45][46][47][48][49] Once diagnosed, multiple therapeutic regimens have been used in the treatment of VKH disease, including regional, oral, and intravenous corticosteroids, cyclosporine, antimetabolites, and alkylating agents. The diagnosis of VKH is clinical and several criteria have been proposed in the past, such as the American Uveitis Society (AUS) criteria [50] and Sugiura's criteria. [51] The revised diagnostic criteria subdivide patients into complete, incomplete, or probable categories according to the presence of extraocular manifestations. [52] VKH disease is a single entity with very diff erent clinical manifestations depending on the stage at which the patient is examined. Thus, patients presenting soon aft er the onset of the disease may complain of auditory and neurological manifestations (severe headache and meningismus) followed by the onset of decreased vision, with the fi nding of exudative retinal detachments and optic disc hyperemia. Conversely, a patient presenting months to years aft er the initial episode will more typically have the signs and symptoms of an anterior uveitis with photophobia and cell and fl are in the aqueous humor [ Figure 1], along with the possible additional manifestations of cutaneous and ocular hypopigmentation. The ocular manifestations are divided into those occurring early and those occurring late in the course of the disease. In its early stages, there is the occurrence of a diff use choroiditis manifested by a number of fi ndings, including diff use choroidal infl ammatory signs and exudative detachment of the retina, the latt er of which may appear as focal areas of subretinal fl uid accumulation, development of larger bullous detachments, or both. When the patient presents months to years aft er the initial episode, he must demonstrate any of the late fi ndings such as sunset glow fundus or Sugiura sign (perilimbal vitiligo) with nummular chorioretinal depigmentation scars (also sometimes erroneously referred to as Dalen-Fuchs nodules), generalized RPE clumping or migration, and recurrent or chronic anterior uveitis. The disease is typically characterized by exacerbations and remissions. The clinical course is variable: some patients may have limited infl ammatory activity; while others have recurrent episodes of severe intraocular infl ammation causing rapid visual loss. [53] VKH disease is a multisystem disorder. Unequivocal diagnosis therefore requires evidence of the involvement of more than the ocular system. When the patient presents at disease onset, evidence of meningeal infl ammation in the form of malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these features (commonly referred to as meningismus), or auditory involvement in the form of tinnitus is required. If neither meningismus nor tinnitus is present, pleocytosis on cerebrospinal fl uid examination is required. Cutaneous fi ndings such as vitiligo, poliosis or alopecia are late manifestations of this disease.
Apart from routine fundus photography and FA, ICGA has an immense role in diagnosing and following VKH patients. The major ICGA signs described in an acute initial uveitis episode include (1) early choroidal stromal vessel hyperfl uorescence and leakage, (2) hypofl uorescent dark dots, (3) fuzzy vascular patt ern of large stromal vessels and (4) disc hyperfl uorescence. [54] In the absence of an ICGA follow-up, undetected smoldering subclinical disease may persist. So VKH disease should be followed by ICG angiography and, in the case of choroidal subclinical reactivation, a reversal of therapy tapering and an extension of therapy duration should be considered.
Traditionally, VKH disease has been treated with highdose corticosteroids, oft en with immunosuppressive drug therapy reserved for patients with disease that is refractory to corticosteroid therapy. Treatment for VKH disease often is aimed at treating individual exacerbations of infl ammation.. The typical treatment for VKH disease is highdose corticosteroid therapy followed by a slow tapering of the drug over three to six months. The course of treatment of uveitis in such patients is usually aggressive, increasing the chances of sight-threatening complications like cataract, glaucoma and choroidal neovascular membrane. Our initial approach to the treatment of VKH-associated panuveitis includes frequent topical and systemic corticosteroids (1 mg/kg/day) along with cycloplegics [ Figure 2]. Acute exacerbations require admission of the patient in the hospital and are controlled by intravenous methyl prednisolone injection (1 g/day) for three consecutive days followed by oral prednisolone (1.0-1.5 mg/kg/day). Immunosuppressive agents (azathioprine 2.0-2.5 mg/kg/day) are added as and when indicated. They are also started when a prolonged period of quiescence of infl ammation is desired in the eye before undergoing an intraocular surgery (cataract, glaucoma, vitrectomy).
Once the inflammation is adequately controlled, the corticosteroids are tapered very gradually over months and years [ Figures 3 and 4]. The patients are followed on lowdose topical and systemic corticosteroid with or without immunosuppressive agent as the maintenance therapy. Lowdose azathioprine therapy has been found to be eff ective as corticosteroid-sparing agent in VKH disease. [55] Although relatively a rare cause of uveitis in children, VKH has been reported in children below 16 years of age during the last 50 years. [54,[56][57][58][59][60][61][62][63] The course of VKH-associated uveitis is more aggressive in children than adults. Early use of corticosteroid-sparing agents has been recommended in pediatric patients because of hazards of cataract, glaucoma and growth retardation with long-term and high-dose corticosteroids. [64] Sympathetic Ophthalmia SO is an autoimmune condition in which injury to one eye (exciting eye) causes sight-threatening infl ammation in the otherwise normal contralateral eye (sympathizing eye). [65] It typically presents as bilateral granulomatous panuveitis. It is a rare disease with an incidence of 0.03/1,00,000. [66] The classical description of signs include granulomatous mutt on fat keratic precipitates, anterior chamber, and vitreous infl ammation with or without yellow -white lesions in the retinal periphery. Other fundus lesions like retinal detachment, papillitis, optic atrophy, and vasculitis are reported uncommonly and are generally seen in conjunction with anterior segment infl ammation. [67,68] There are no defi nite tests for confi rming the diagnosis of SO. A history of an intraocular surgery or an ocular trauma combined with the clinical signs of infl ammation support the diagnosis of SO. However, routine laboratory and ancillary tests are performed in the clinical practice to rule out the possibility of other granulomatous panuveitis conditions that mimic SO such as VKH syndrome or sarcoidosis. The mainstay of treatment is aggressive use of corticosteroids. All patients seen in the acute phase of disease in our clinic receive systemic corticosteroids with a starting dose of 1.5-2 mg/kg body weight that is tapered slowly to a maintenance dose between 5 and 10 mg/day over the next four to six months, which is then continued for a period of two to fi ve years. [69] In case of recurrences, the dose of oral corticosteroids is increased to 1.5-2 mg/kg body weight if the patient has new fundus lesions or severe anterior segment infl ammation. The maintenance dose, this time, is not reduced below the level at which the recurrence has occurred. Topical corticosteroids and cycloplegics are given as per requirement. Severe or recurrent cases require additional therapy, including more than one immunosuppressive agent. Patients seen in the chronic recurrent form receive oral azathioprine in a dosage of 100-150 mg/day to begin with, which is gradually reduced over the next 6-12 months. Patients who initially respond to but are unable to continue corticosteroids due to either sideeff ects (fi ve patients) or recurrence (three patients) also receive immunosuppressive therapy. Intravenous cyclophosphamide (750 mg/ week every three to four weeks with a maximum of seven doses) is given for managing acute recurrences while oral azathioprine (100-150 mg/day) or methotrexate (7.5-10.0 mg/day) is used as steroid sparer.
Behcet's disease BD is a multisystem disorder characterized by recurrent eye infl ammation, oral ulcers and genital ulcers. Eye involvement, which affects 60-80% of BD patients, is characterized by unilateral or bilateral acute episodes of iridocyclitis with or without hypopyon, and/or panuveitis. [70][71][72] The majority of patients with ocular BD present with recurrent panuveitis. [73] There is evidence that the disease is more severe with the risk of losing useful vision higher in men than in women. [74] Eye disease in BD patients is mostly a recurrent nongranulomatous uveitis with necrotizing obliterative retinal vasculitis, which may be found either in the anterior or the posterior segment, or both. [75][76][77][78] It aff ects the posterior eye segment more oft en and more severely than the anterior one. Diagnosis of BD is mostly based on several sets of diagnostic criteria. Today the most widely used are the criteria of the international study group for BD. [79] However, these were developed as classifi cation and not as diagnostic criteria, so, especially in early stages of the disease, the diagnosis of BD is oft en very diffi cult. [80] Older sets of criteria, most commonly those by Mason and Barnes, [81] O'Duff y [82] and Dilsen et al., [83] and in Asia the Japanese, [84] are therefore still in use.
Systemic corticosteroids are widely used in the therapy of ocular BD. They are usually administered as oral prednisolone at an initial dose of 1-2 mg/kg/day, followed by a gradual tapering by 5-10 mg/week. However, they are not always suitable as a monotherapy for maintaining remission of uveitis due to adverse side-eff ects. In such cases, it becomes necessary to add an immunosuppressive drug as a steroid-sparing agent.
Cyclosporine A is the only immunosuppressant approved for uveitis therapy in several countries and is known to be the most commonly used immunosuppressive drug for ocular BD. Along with low-dose corticosteroids, it has been proved to be eff ective and safe for treating acute uveitis episodes as well as for reducing recurrence rates of uveitis in ocular BD at a dose of 3-5 mg/kg/day. [85][86][87] Azathioprine, in a dose of 2.5 mg/ kg/day has also been shown to eff ectively control intraocular infl ammation, to maintain visual acuity, and to prevent onset or progression of eye disease in ocular BD. [88] Despite aggressive immunosuppressive treatment, the visual prognosis of ocular BD remains generally poor. Openlabel clinical trials in Japan and Turkey have shown infl iximab to be eff ective in improving the prognosis of the disease in ocular BD. [89,90] IFN-α has antiviral, antiproliferative and various immunomodulatory eff ects. [91] Unfortunately, these new drugs are very expensive and therefore they may be not universally available in countries with a low economic status.
The treatment of BD has to follow a multidisciplinary approach because of possible involvement of multiple organs, which necessitates early referral of patients to specialized internists with experience in diagnosis and treatment of this disorder. The fact that no standardized treatment regimens exist complicates the treatment of ocular BD.

Sarcoidosis
The organs aff ected more oft en are the lungs, skin, and eyes. The frequency of ocular involvement ranges from 26-50%. [92] Anterior segment involvement has been reported to be the most common. Panuveitis occurs in 6-33% of patients with sarcoidosis. [93][94][95][96] Presence of panuveitis is considered as a poor prognostic factor in patients with sarcoidosis. [93,97,98] The gold standard in the diagnosis of sarcoidosis is histopathological evidence of noncaseating granuloma. [99] The routine clinical tests for diagnosing sarcoid uveitis include Mantoux test, chest X-ray, serum angiotensin converting enzyme levels, erythrocyte sedimentation rate. When suspecting extraocular sarcoidosis, biopsy of the involved organ is performed to confi rm the diagnosis. Otherwise, in all suspected cases of sarcoid uveitis, the diagnosis remains presumptive. A negative Mantoux test that corroborates the clinical diagnosis of sarcoidosis can be explained by a preponderance of suppressor cells in the peripheral blood leading to depletion of T-helper cells and monocytes that actually cause the delayed hypersensitivity response.
Sarcoid uveitis is uncommon in the Asian Indian population and its diagnosis oft en remains clinical. [3,5,6] In a series of histologically confirmed systemic sarcoidosis with ocular involvement in India, anterior and intermediate uveitis have been found to be the commonest sites. [92,100] Besides topical corticosteroid and cycloplegic eye drops for anterior uveitis, systemic corticosteroids (prednisolone 1 mg/kg/day) are the mainstay of treatment for intermediate, posterior or panuveitis. Unilateral cases may benefi t from posterior subtenon injection of triamcinolone acetonide (20 mg). The oral corticosteroids are tapered over 8-10 weeks by 5-10 mg per week depending upon the clinical response, in consultation with the pulmonologist. Although immunosuppressive agents in general have had very limited use in the treatment of ocular sarcoidosis, a state of controlled infl ammation has been achieved and reported by a few authors using low-dose Methotrexate in the otherwise diffi cult-to-treat patients of panuveitis. [19,101] Benefi cial eff ect of Methotrexate in patients undergoing cataract surgery has also been observed by a few authors in controlling the preoperative infl ammation (that was otherwise persistent on corticosteroids alone) and sustaining improved visual acuity aft er surgery. [19] Because sarcoidosis is a multisystem disorder, the immunosuppressive drugs also help in managing the non-ocular manifestations of the disease. Certain side-eff ects may be seen with low-dose Methotrexate but they are better tolerated than those with long-term corticosteroids. [102] Conclusion A systematic tailored approach in making accurate diagnosis is central to employment of specifi c, more eff ective treatment for all types of uveitis, irrespective of the anatomical site of infl ammation. [1] What we prefer not to do is the exhaustive approach.
Uveitis will continue to be increasingly more important as a group of potentially sight-threatening infl ammatory eye diseases that have a signifi cant impact on both the visual and systemic health of the generally young adult population that is aff ected. [5] The use of a prospective analysis in a collaborative, multi-center approach would facilitate therapeutic trials and provide valuable breakthrough in managing some of the most refractory sight-threatening types of panuveitis. Therapeutic decisions are dictated by disease location and severity.
As uveitis oft en affl icts the young adult population in their most productive years of life, the personal and population burden of this sight-threatening disease is significant. [5] Irrespective of the cause, visual morbidity is poor in panuveitis. There is an increased risk of development of cataract, secondary glaucoma and cystoid macular edema as a result of more widespread infl ammation and more aggressive treatment with corticosteroids. While identifying the causes of blindness in patients with intraocular infl ammation, Rothova et al. found that panuveitis had the worst visual outcome as far as the anatomical site of involvement was concerned. [98] The aim to treat a patient of panuveitis is to achieve a successful outcome in terms of quiescence of infl ammation in both anterior as well as posterior segments, prevent recurrences of infl ammation, minimal or no side-eff ects of chronic treatment which these patients receive, and favorable visual recovery in the long term. Although uveitis workup is teamwork requiring an accurate description of uveitis type and etiology, a selective approach to general investigations and an internist to monitor systemic treatment, an ophthalmologist plays a crucial role in the diagnosis and management of these patients.