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Granulomatous uveitis is an inflammation of the uveal tract characterized by the formation of granulomas due to infectious or non-infectious causes. It can involve any part of the uveal tract and may be associated with a systemic disease, including debilitating and life-threatening conditions for which ocular manifestations may be the first presentation. This activity outlines the evaluation and treatment of granulomatous uveitis and highlights the role of the healthcare team in managing patients with this condition. Objectives: Identify the etiology of granulomatous uveitis. Outline the typical presentation of a patient with granulomatous uveitis. Describe the imaging findings associated with granulomatous uveitis. Summarize the interprofessional evaluation and treatment considerations for patients with granulomatous uveitis to provide the best outcomes. Access free multiple choice questions on this topic.

The middle layer of the eye, also known as the uvea (uva or "grape" in Greek), is made up of the iris, the ciliary body, and the choroid. Uveitis is an inflammation of the middle layer of the eye which can involve one, two, or all three parts of the uveal tract. It can be classified in several ways; anatomically into anterior, intermediate, posterior, or panuveitis according to the site of inflammation, etiologically into infectious or non-infectious uveitis according to the underlying cause, and histopathologically into granulomatous or non-granulomatous uveitis according to the immunological response of the body to the cause of uveitis.[1] Because many conditions, both ocular and systemic, may result in uveitis, these classifications are important as they may help in narrowing down the differential diagnosis in a case of uveitis since each condition usually presents a characteristic clinical picture. In this article, we will review the multidisciplinary approach to the diagnosis and management of granulomatous uveitis.

Many conditions can result in granulomatous inflammation of the uveal tract including infectious and non-infectious conditions. Infectious Causes Tuberculosis Syphilis Herpes viruses[2] Cytomegalovirus[3] Lyme disease[4] Toxoplasmosis[5] Toxocariasis[6] Trematodes[7] Propionibacterium acnes[8] Post-streptococcal infections[9] Some fungal infections including following coronavirus disease-2019: candida, histoplasmosis, and cryptococcosis[10][11][12][11][13][11] Non-infectious Causes Sarcoidosis[14][15] Multiple sclerosis[16] Vogt-Koyanagi-Harada disease[17] Sympathetic ophthalmia[18] Lymphoma[19] Blau syndrome[20] Histiocytosis[21] Granuloma annulare[22] Lens-induced[23] Drug-induced: brimonidine and pembrolizumab, [24][25] Idiopathic (as multifocal choroiditis),[26] Common variable immune deficiency[27] Juvenile idiopathic arthritis[28] High-density silicone oil tamponade[29] Intraocular foreign bodies including caterpillar hair[30][31] Tattoo-associated granulomatous uveitis[32][32]

The epidemiology of granulomatous uveitis depends on several factors, including etiologic, geographic, and ethnic factors. For example, in areas that are endemic to tuberculosis, such as some developing countries as India and Egypt, tuberculosis is a common cause of granulomatous uveitis. At the same time, it is rare in developed countries such as the United States. However, cases of tuberculous uveitis have resurged in the United States following the HIV epidemic.[33][34][35][36] Sarcoidosis may be more common in Blacks than in Whites but less common in Asians than in Whites. At the same time, Vogt-Koyanagi-Harada disease is a common cause of non-infectious uveitis among Asians.[37][38] Toxoplasmosis is also a common cause of uveitis in Asia, South America, Central America, and parts of Africa.[38][39][40] Trematode-induced granulomatous uveitis is particularly common in Egypt and India, while Lyme disease is common in North America and Europe.[41][42] Blau syndrome occurs primarily in Whites.[43]

The exact pathophysiology of granulomatous uveitis depends on the underlying cause. However, a similar general mechanism is responsible for forming granulomas in most granulomatous inflammations regardless of the causative antigen. Tissue-resident antigen-presenting cells, such as dendritic cells and monocytes circulating in the blood, are responsible for first detecting an antigen, which is then presented to T helper cells, which in turn results in recruitment and activation of more circulating monocytes and lymphocytes into the affected tissue, with the production of various cytokines and chemokines including tumor necrosis factor-alpha and interferon-gamma that are responsible for regulating granulomatous immune responses, and the formation of epithelioid and multinucleated giant cells by the activated macrophages. These cells assemble around the culprit antigen, leading to granuloma formation.[44][45][46] This antigen may be of bacterial origin as in tuberculosis or of unknown origin as in sarcoidosis.[47] In lymphoma cases, inflammation may be due to a host immune response to lymphomatous cells or a paraneoplastic granulomatous inflammation. In contrast, in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia, the altered immune response may be directed towards melanocytes.[19][48] Impairment in the immunosuppressive role of regulatory T cells may also contribute to the exaggerated immune response in granulomatous uveitis. Simultaneously, specific HLA class II antigens may play a role in the development of granulomatous inflammation.[47] Blau syndrome is a monogenic familial autoinflammatory systemic granulomatous disease associated with a mutation in the NOD2 gene. This gene encodes a protein that is a member of the pattern-recognition intracellular receptor family, expressed in macrophages, monocytes, and dendritic cells, and plays an important role in the innate immune defense system against pathogens.[43] The mutation leads to the unfolding of the NOD2 protein from its autoinhibited state, leading to the hyperactivation of nuclear factor kappa B and the excessive production of inflammatory cytokines and chemokines, which results in systemic granulomatous inflammation, including skin rash, arthritis, and granulomatous uveitis.[49]

Microscopically, granulomas consist of macrophages, epithelioid cells, multinucleated giant cells, and lymphocytes that may involve any part of the uveal tract. Granulomatous inflammation of the uvea is typically divided into three distinct morphologic categories: zonal, sarcoidal, and diffuse. In tuberculous uveitis, histopathology of microbiologically proven cases reveals zonal granulomatous inflammation of the uvea with central caseous necrosis that occasionally contains acid-fast bacilli.[50] At the same time, in sarcoidal granulomas, they are typically non-caseating.[51] There may also be perivascular granulomas surrounding the retinal vessels in cases of retinal vasculitis with T-cell infiltration.[50] Fungal infections, foreign bodies, lymphomas, and tattoo-associated uveitis may also result in granulomatous inflammation of the sarcoidal type.[48][52][53] In diffuse granulomatous inflammation, there is diffuse lymphocytic infiltration throughout the uvea with focal collections of epithelioid cells and occasionally multinucleated giant cells. Examples of diffuse granulomatous inflammation include Vogt-Koyanagi-Harada disease and sympathetic ophthalmia, which may also show focal clusters of lymphocytes and epithelioid cells with pigment located between the retina pigment epithelium and Bruch's membrane known as Dalen-Fuchs nodules.[48]

General Examination Detailed history taking is an integral part of evaluating a patient with uveitis since it will help in directing further examinations and investigations. The history will differ according to the underlying etiology of uveitis. Attention to certain details in a quick review of systems, such as a history of coughing or dyspnea, may provide clues to the diagnosis of tuberculosis or sarcoidosis. In contrast, details in sexual history may point to a diagnosis of syphilis or herpes. A tick bite history with the subsequent development of a bulls-eye rash may indicate Lyme disease, especially when occurring in an endemic area. In contrast, a history of cat exposure may suggest toxoplasmosis. Traveling to an area that is endemic in tuberculosis or having a history of a contralateral eye injury may sometimes be the only clue to the diagnosis. This should be followed by a focused examination performed by a specialist tailored to the main complaints and symptoms of the patient. For example, chest examination of a patient with a history of dyspnea or skin examination of a patient with a history of a rash may help in ordering further imaging or laboratory investigations more efficiently.[54][55] Ocular Examination Patients with uveitis usually present with the blurring of vision, ocular pain, redness, and photophobia. These may vary according to the anatomical location of the inflammation. Anterior segment examination of a patient with granulomatous uveitis may reveal ciliary injection, elevated or decreased intraocular pressure, mutton fat keratic precipitates (large deposits on the back of the cornea), anterior chamber flare and cells, iris, and angle granulomas, anterior and posterior synechia, cataract especially posterior subcapsular, cataract surgery in phakoanaphylactic uveitis and anterior vitreous cells. Some signs may also be present that indicate specific etiologies such as corneal scars and iris atrophy in herpetic uveitis, vascularized iris nodules known as roseola in syphilis, and an anterior chamber granuloma in trematode uveitis.[56][7]

Patients with uveitis usually present with the blurring of vision, ocular pain, redness, and photophobia. These may vary according to the anatomical location of the inflammation. Anterior segment examination of a patient with granulomatous uveitis may reveal ciliary injection, elevated or decreased intraocular pressure, mutton fat keratic precipitates (large deposits on the back of the cornea), anterior chamber flare and cells, iris, and angle granulomas, anterior and posterior synechia, cataract especially posterior subcapsular, cataract surgery in phakoanaphylactic uveitis and anterior vitreous cells. Some signs may also be present that indicate specific etiologies such as corneal scars and iris atrophy in herpetic uveitis, vascularized iris nodules known as roseola in syphilis, and an anterior chamber granuloma in trematode uveitis.[56][7] Posterior segment examination may show vitritis, vitreous opacities, snowballs, snow banking in intermediate uveitis, perivascular exudates, retinal hemorrhages in retinal vasculitis, cystoid macular edema, and optic disc edema, as well as posterior segment complications such as choroidal neovascularization, retinal neovascularization, and epiretinal membrane.[57] Certain posterior segment signs may be associated with specific conditions such as sunset glow fundus in Vogt-Koyanagi-Harada disease, focal chorioretinitis adjacent to an area of old chorioretinal scarring in toxoplasmosis, optic disc granulomas in sarcoidosis, and a choroidal granuloma in tuberculosis (tuberculoma).[15][17][58] Diagnostic Criteria When available, the use of diagnostic criteria may assist in the diagnosis of specific causes of granulomatous uveitis[59]. These criteria usually include a combination of clinical and investigative findings.[60]

Systemic Investigations Laboratory Investigations Laboratory investigations should be directed towards the most probable cause of uveitis according to the patient's history and clinical picture. Knowledge of each test's positive and negative predictive value is particularly important to help reach the correct diagnosis and avoid false-positive and false-negative test results that may lead to an incorrect diagnosis and improper treatment. General investigations to be performed include complete blood picture, erythrocyte sedimentation rate, and C reactive protein level. Investigations for infectious causes include tuberculin skin testing and Quantiferon-TB Gold for tuberculosis, venereal disease research laboratory test, rapid plasma reagin test, fluorescent treponemal antibody absorption test, and the microhemagglutination assay for treponema pallidum for syphilis, serum IgM and IgG antibodies against herpes and cytomegaloviruses, serum IgM and IgG antibodies against Borrelia and Toxoplasma using enzyme-linked immunosorbent assays, detection of antibodies against Histoplasma and Cryptococcus, and blood cultures for systemic bacterial and fungal infections.[61][62][63] Investigations for non-infectious causes include serum angiotensin-converting enzyme and calcium levels for sarcoidosis and cerebrospinal fluid analysis for oligoclonal bands in multiple sclerosis. Some investigations may be required before starting specific medications, such as tuberculin skin testing before initiating anti-tumor necrosis factor treatment or testing for thiopurine S-methyltransferase polymorphisms in patients starting azathioprine therapy.[64][65][66][67] Imaging

Investigations for non-infectious causes include serum angiotensin-converting enzyme and calcium levels for sarcoidosis and cerebrospinal fluid analysis for oligoclonal bands in multiple sclerosis. Some investigations may be required before starting specific medications, such as tuberculin skin testing before initiating anti-tumor necrosis factor treatment or testing for thiopurine S-methyltransferase polymorphisms in patients starting azathioprine therapy.[64][65][66][67] Imaging Imaging is required in the diagnosis or exclusion of several infectious and non-infectious causes of granulomatous uveitis such as chest x-ray or computed tomography scan of the chest for the diagnosis of pulmonary tuberculosis or sarcoidosis, magnetic resonance imaging (MRI) of the brain and spine for the diagnosis of multiple sclerosis or central nervous system lymphoma, and computed tomography scan of the abdomen for abdominal sarcoidosis or lymphoma.[68][69] Fluorine-18 fluorodeoxyglucose positron emission tomography scanning may help in the diagnosis of tuberculosis and sarcoidosis.[70][71] Specific investigations may be needed to exclude systemic complications associated with certain multisystemic conditions such as electrocardiography and echocardiography in cardiac sarcoidosis and MRI of the spine in Pott disease.[72][73] Tissue Biopsy A tissue biopsy, when available, is the gold standard for the diagnosis of several conditions associated with granulomatous uveitis by either allowing the detection of the causative organism by using special stains such as the Ziehl-Neelsen stain for Mycobacterium tuberculosis and fungal stains or by allowing the detection of characteristic histopathologic features associated with the condition such as non-caseating granulomas in sarcoidosis.[74] Tissue biopsy may also allow polymerase chain reaction (PCR) testing or the culture of the causative organism to facilitate its detection.[75] Other uveitis-causing conditions mainly diagnosed using tissue biopsy include lymphoma and histiocytosis.[19][21] Ocular Investigations Laboratory Investigations

A tissue biopsy, when available, is the gold standard for the diagnosis of several conditions associated with granulomatous uveitis by either allowing the detection of the causative organism by using special stains such as the Ziehl-Neelsen stain for Mycobacterium tuberculosis and fungal stains or by allowing the detection of characteristic histopathologic features associated with the condition such as non-caseating granulomas in sarcoidosis.[74] Tissue biopsy may also allow polymerase chain reaction (PCR) testing or the culture of the causative organism to facilitate its detection.[75] Other uveitis-causing conditions mainly diagnosed using tissue biopsy include lymphoma and histiocytosis.[19][21] Ocular Investigations Laboratory Investigations Aqueous humor sampling through anterior chamber paracentesis or vitreous humor sampling through a vitreous tap may allow the diagnosis of infectious and non-infectious causes of uveitis. The sample can be tested using western blotting to detect local antibody production to a specific organism, or it can be used to determine the Goldmann-Witmer coefficient.[76] PCR testing can also be used to amplify and identify the DNA or RNA of various viruses, bacteria, parasites, and fungi.[77] Both real-time PCR and multiplex PCR are useful and have their own set of advantages.[78] Cytopathological examination and microbiological testing of the sample can also be performed. Interleukin 10-to-interleukin 6 ratio obtained from aqueous or vitreous samples can be used to diagnose primary intraocular lymphoma.[79] Imaging Ocular B-scan ultrasonography may be used in cases with media opacities obscuring fundus examination such as cataracts or severe anterior chamber reaction to evaluate posterior segment involvement. Laser flare meter and ocular fluorometry may be used to allow an objective measure of aqueous flare in uveitis.[80][81] Confocal microscopy can be used to differentiate between granulomatous and non-granulomatous keratic precipitates.[82]

Ocular B-scan ultrasonography may be used in cases with media opacities obscuring fundus examination such as cataracts or severe anterior chamber reaction to evaluate posterior segment involvement. Laser flare meter and ocular fluorometry may be used to allow an objective measure of aqueous flare in uveitis.[80][81] Confocal microscopy can be used to differentiate between granulomatous and non-granulomatous keratic precipitates.[82] Fluorescein angiography, including wide-field imaging, may assist in the evaluation of papillitis, optic disc granulomas, cystoid macular edema, choroiditis, choroidal neovascularization, and retinal vasculitis, while optical coherence tomography may be useful in the evaluation and follow up of cystoid macular edema, epiretinal membranes, and choroidal neovascularization, and in the evaluation of the choroid using enhanced depth imaging.[15][83] Optical coherence tomography angiography allows the non-invasive evaluation of the foveal avascular zone, areas of retinal ischemia, and choroidal neovascular membranes without obscuration by dye leakage or macular xanthophyll pigments.[84][85] Indocyanine green angiography may allow enhanced imaging of choroidal lesions in cases of posterior uveitis.[86] Tissue Biopsy Biopsy of ocular tissues may also help diagnose the cause of granulomatous uveitis, but its use varies depending on the suspected underlying etiology. For example, a biopsy of the conjunctiva, whether directed or non-directed, is a simple and inexpensive method that may assist in the diagnosis of sarcoidosis, while a chorioretinal biopsy is a complex procedure that may help provide useful information in patients with progressive chorioretinal lesions with an unknown etiology despite extensive testing.[87][88][89][90]

Treatment of granulomatous uveitis includes local (ocular) and systemic treatment and treatment of complications: Ocular Treatment Ocular treatment involves non-specific topical treatment for inflammation, such as topical steroids and cycloplegics. Periocular and intravitreal steroid injections, including steroid implants, may be given to rapidly and consistently control inflammation in non-infectious conditions or infectious conditions under appropriate anti-microbial cover.[91][92][93] Intravitreal antimicrobial injections may be used, such as clindamycin for toxoplasma, and antifungals such as voriconazole for candida to achieve higher intraocular concentrations a better therapeutic response.[94] Intravitreal immunosuppressants such as sirolimus may also be used in the treatment of non-infectious uveitis.[95][96] Surgical aspiration may be useful in lens-induced (phakoanaphylactic) cases or cases associated with large trematodal anterior chamber granulomas.[97] Systemic Treatment Systemic treatment is needed to control the systemic condition associated with uveitis and is directed towards the causative etiology. This is also associated with the improvement of ocular disease. Systemic steroids and immunomodulatory agents such as azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil are used in non-infectious conditions such as Vogt-Koyanagi-Harada and sarcoidosis.[15][98] In contrast, systemic antimicrobials are used to treat infectious conditions such as anti-tuberculous agents for tuberculosis, penicillin for syphilis, and acyclovir for herpetic uveitis.[99][100][101] Biological agents such as tumor necrosis factor inhibitors may also be useful in some non-infectious conditions.[102][103] In case of drug-induced uveitis, the offending drug should be discontinued. Treatment of Complications Treatment of complications includes cataract extraction with or without intraocular lens implantation.[104][105][106] Glaucoma can be treated medically using various topical and systematic medications or surgically if necessary. Some clinicians recommend avoiding prostaglandin analogs in cases of uveitis associated with active inflammation or cystoid macular edema, while other studies showed it to be a safe option.[107][108][109]

Treatment of complications includes cataract extraction with or without intraocular lens implantation.[104][105][106] Glaucoma can be treated medically using various topical and systematic medications or surgically if necessary. Some clinicians recommend avoiding prostaglandin analogs in cases of uveitis associated with active inflammation or cystoid macular edema, while other studies showed it to be a safe option.[107][108][109] Surgical treatment of glaucoma includes iridectomy, trabeculectomy, and glaucoma drainage devices. Some studies suggest that glaucoma drainage devices could be more effective than trabeculectomy for uveitic glaucoma over the long term, while other studies showed equal efficacy.[110][111] The use of glaucoma shunts may also possibly improve the outcome of trabeculectomy in uveitic glaucoma cases.[112] Intravitreal injections of anti-vascular endothelial growth factor agents such as bevacizumab or ranibizumab may be used to treat cystoid macular edema and choroidal neovascularization associated with granulomatous uveitis.[113][114][115] Laser photocoagulation can be used to treat retinal ischemia associated with retinal neovascularization to prevent vitreous hemorrhage and fibrovascular proliferation [116]. At the same time, pars plana vitrectomy can be performed in cases complicated by non-resolving vitreous hemorrhage, vitreous opacities, epiretinal membranes, and macular holes.[117][118]

Non-granulomatous uveitis [119] Pigment dispersion syndrome [120] Uveal melanoma [121] Uveal metastasis [122][123] Retinoblastoma [124] Intraocular lymphoma [125] Bilateral acute depigmentation of the iris [126]

The prognosis of granulomatous uveitis depends on the underlying condition and its severity. Early and appropriate diagnosis and treatment may lead to a marked improvement of the condition and avoidance of vision and life-threatening complications.

Cataract especially posterior subcapsular Posterior synechia and seclusio pupillae Peripheral anterior synechia Cyclitic membrane Ocular hypotony [132][133] Secondary open-angle glaucoma Secondary closed-angle glaucoma Steroid-induced glaucoma [134] Cystoid macular edema [115] Epiretinal membrane [118] Choroidal neovascularization [135] Retinal vasculitis Retinal neovascularization [135] Vitreous hemorrhage Retinal detachment [116] Macular hole [118] Band keratopathy Amblyopia Systemic complications associated with the underlying disease such as arrhythmias in cardiac sarcoidosis[136]

Patients with granulomatous uveitis should be educated on their conditions, including their ocular and systemic manifestations and complications, their treatment and prognosis, and the complication of their treatment. Compliance with follow-up and treatment in patients with granulomatous uveitis is of utmost importance to follow up and control the disease activity, allow early detection and management of ocular complications, and monitor for systemic complications well as complications of local and systemic treatment. Patients on systemic medications may need to undergo routine laboratory testing to monitor for drug-induced adverse events.

Granulomatous uveitis can be caused by many conditions, both infectious and non-infectious, which can be differentiated based on history, examination, and investigative findings. It is important to promptly exclude infectious causes of uveitis to allow the early institution of anti-inflammatory treatment using steroids and immunomodulatory agents, including in idiopathic cases, to allow the early and rapid control of inflammation and to improve prognosis. If an infectious etiology is identified or suspected, steroid and immunomodulatory treatment may be commenced only after appropriate anti-microbial agents are initiated to avoid exacerbation of the condition.[137] In fact, the use of steroids and immunomodulatory agents in these conditions, in addition to the appropriate anti-microbial therapy, may be necessary to avoid the paradoxical worsening of inflammation that is known to occur following the treatment of infectious uveitis.[138][139][140]

The management of granulomatous uveitis and the associated systemic disease is challenging. It frequently requires the collaboration of an interprofessional team of specialists consisting of ophthalmologists, infectious disease specialists, pulmonologists, internists, rheumatologists, and dermatologists. The nurses are also vital members of this interprofessional group as they will monitor the patient's vital signs and assist with the patient and family's education. Frequent and effective communication between the ophthalmologist and the systemic disease specialists is vital in managing granulomatous uveitis as frequently the ophthalmologist will be the one monitoring the ocular disease activity prescribing local ocular treatment. In contrast, a systemic disease specialist will prescribe the systemic treatment and monitor its systemic adverse events and systemic disease activity. Both uveitis and systemic disease specialists must be involved in the initial evaluation of a patient with uveitis to direct further testing and allow an accurate diagnosis of the underlying condition to formulate an effective management plan.[141] The use of standardized red flags for the interprofessional referral may also assist in timely referral during follow-ups.[142] This will improve the quality of patient care and optimize treatment outcomes while minimizing complications and side effects of treatment. The evidence level available for granulomatous uveitis management varies and ranges from large randomized controlled clinical trials (Level 1) to case series and expert opinion (Level 5).[143][144]