Sivakumar R. Rathinam

Interobserver Agreement in Grading Activity and Site of Inflammation in Eyes of Patients with Uveitis

PURPOSE To evaluate the reproducibility of new criteria for grading the site and activity of intraocular inflammation. DESIGN Cross-sectional agreement study. METHODS Grading of 202 eyes of 101 patients with uveitis was conducted by pairs of uveitis subspecialists at three uveitis subspecialty clinics. Agreement in grading location of inflammation, anterior chamber (AC) cells, AC flare, vitreous cells (present or absent), and vitreous haze was calculated. RESULTS Proposed criteria for grading the location of intraocular inflammation had moderate reproducibility (kappa range, 0.49 to 0.61). Reproducibility improved (kappa range, 0.61 to 0.73) when the newly proposed category of anterior and intermediate uveitis was excluded. The ranges of kappa statistics for exact agreement on gradings of AC cells (range, 0.34 to 0.43) demonstrated low to moderate levels of agreement, and gradings of AC flare (range, 0.50 to 0.64), vitreous cells (range, 0.48 to 0.51), and vitreous haze (0.53) were in the moderate agreement range. However, agreement within 1 grade was outstanding for AC cells (kappa range, 0.81 to 1.00) and vitreous haze (kappa, 0.75). For AC flare, a distribution skewed toward low grades within 1 grade made kappa statistics unstable. CONCLUSIONS Proposed methods for grading inflammatory activity have moderate reproducibility for exact agreement in most instances. However, agreement within 1 grade is excellent for grading of AC cells and vitreous haze. The method for grading the site of intraocular inflammation also produces moderate levels of agreement, and in our hands was improved by excluding both anterior and intermediate uveitis. Improved methods for grading AC flare and vitreous cells are needed.

Novel infectious agents causing uveitis.

In any patient with uveitis, an infectious cause should be ruled out first. The differential diagnosis includes multiple well-known diseases including herpes, syphilis, toxoplasmosis, tuberculosis, bartonellosis, Lyme disease, and others. However, clinician should be aware of emerging infectious agents as potential causes of systemic illness and also intraocular inflammation. Air travel, immigration, and globalization of business have overturned traditional pattern of geographic distribution of infectious diseases, and therefore one should work locally but think globally. This review recapitulates the systemic and ocular manifestations of several emergent infectious diseases relevant to the ophthalmologist including Rickettsioses, West Nile virus infection, Rift valley fever, Dengue fever, and Chikungunya. Retinitis, chorioretinitis, retinal vasculitis, and optic nerve involvement have been associated with these emergent infectious diseases. The diagnosis of any of these infections is usually based on pattern of uveitis, systemic symptoms and signs, and specific epidemiological data and confirmed by detection of specific antibody in serum. A systematic ocular examination, showing fairly typical fundus findings, may help establish an early clinical diagnosis, which allows prompt, appropriate management.

A Randomized Clinical Trial Comparing Methotrexate and Mycophenolate Mofetil for Noninfectious Uveitis

OBJECTIVE To compare the relative effectiveness of methotrexate and mycophenolate mofetil for noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN Multicenter, block-randomized, observer-masked clinical trial. PARTICIPANTS Eighty patients with noninfectious intermediate, posterior, or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. INTERVENTION Patients were randomized to receive 25 mg weekly oral methotrexate or 1 g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. MAIN OUTCOME MEASURES Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤10 mg of prednisone and ≤2 drops of prednisolone acetate 1% a day, and (3) no declaration of treatment failure because of intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. RESULTS Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (P = 0.09). Treatment failure from adverse events or tolerability was not different by treatment arm (P = 0.99). There were no differences between treatment groups in time to corticosteroid-sparing control of inflammation (P = 0.44), change in best spectacle-corrected visual acuity (P = 0.68), or resolution of macular edema (P = 0.31). CONCLUSIONS There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate.

The epidemiology of uveitis in developing countries.

Uveitis represents a major cause of ocular morbidity worldwide. In the western world, uveitis affects approximately 200 per 100,000 in the population, resulting in an estimated annual incidence of 20 per 100,000 person-years. More than half of all patients with uveitis develop complications related to their disease, and up to 35% of patients suffer severe visual impairment. Uveitis is believed to account for 5% to 10% of all causes of legal blindness in the United States and Europe. Uveitis and its complications are even more common in the developing world, in which the condition occurs in up to 714 per 100,000 in the population, and accounts for up to 25% of all blindness. The causes of uveitis are numerous, and include infection, trauma, noninfectious systemic or ocular disease, and masquerade syndromes. To generate a differential, clinicians must consider all available information, including the anatomic location, character (granulomatous vs. nongranulomatous), laterality, and chronicity of inflammation. Moreover, the frequency and pattern of uveitis in a given population must be considered. This is particularly important in resource-poor settings, in which avoiding costly and unnecessary diagnostic tests is a priority. Numerous studies have examined the pattern of uveitis around the world. Many are from western countries, including the United States and countries in Europe, whereas data from developing countries are less common. In general, developing countries see a larger proportion of infectious causes of uveitis, including tuberculosis,

LruA and LruB Antibodies in Sera of Humans with Leptospiral Uveitis

ABSTRACT Uveitis can be a serious complication of leptospirosis. Previous studies indicated that the leptospiral lipoproteins LruA and LruB are expressed in the eyes of uveitic horses and that antibodies directed against those proteins show in vitro cross-reactivity with components of equine lens, ciliary body, and/or retina. We now demonstrate that sera from a significant proportion of humans who have leptospiral uveitis also contain antibodies against LruA and LruB. Different categories of nonleptospiral uveitis and autoimmune uveitis were also screened; patients diagnosed with Fuchs uveitis or Behçets syndrome produced antibodies that cross-reacted with LruA and LruB, suggesting similarities of the autoimmune responses in those diseases with those of leptospiral uveitis.

Molecular detection and characterization of West Nile virus associated with multifocal retinitis in patients from southern India

BACKGROUND In late 2009/early 2010, approximately 2000 people were affected by a mysterious viral outbreak in a southern district of Tamil Nadu; this particularly affected those living in coastal areas. Blood samples from affected patients were sent for clinical analysis to determine the actual cause of the illness, but reports were inconclusive. METHODS The present study describes the clinical observations and laboratory investigations involving molecular methods performed on 170 of the 2000 clinically suspected cases. These were patients who were admitted to Aravind Eye Hospital, Madurai, Tamil Nadu with ocular complications. Conventional reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and reverse transcription loop-mediated isothermal gene amplification (RT-LAMP) assays were used to detect West Nile virus (WNV) infection. Further investigation of the genetic diversity of the WNV implicated in ocular complications was undertaken by sequence phylogeny. RESULTS Out of 170 samples, 25 (15%) were positive for chikungunya IgM antibody, 10 (6%) for chikungunya antigen, and 30 (18%) were positive for dengue IgM antibody. The remaining 105 seronegative samples were further processed for WNV detection by IgM capture ELISA and molecular methods. Out of the 105 samples, 35 (33%) were positive for WNV IgM antibody, 15 (14%) were positive for WNV by RT-PCR, and 27 (26%) were found to be positive for WNV by both real-time RT-PCR and RT-LAMP assays. Comparative evaluation with acute-phase patient serum samples revealed 100% concordance between the real-time RT-PCR and RT-LAMP assays. These assays had an overall higher sensitivity than the conventional RT-PCR as they picked up 12 additional samples with a low copy number of template. Further genotyping through sequence phylogeny revealed that all the WNV isolates were grouped in lineage I. CONCLUSIONS The association of West Nile virus with ocular infection in South India during an epidemic of mysterious fever in the first half of 2010 was clearly established through molecular approaches employing envelope gene-specific real-time RT-PCR and RT-LAMP assays followed by nucleotide sequencing.

Presumed trematode-induced granulomatous anterior uveitis: a newly recognized cause of intraocular inflammation in children from south India

PURPOSE To describe the epidemiologic, clinical, and histopathologic features of a presumed trematode granulomatous anterior uveitis, primarily in children from south India. DESIGN Prospective, noncomparative, case series. METHODS Children with clinical evidence of granulomatous anterior uveitis were selected for the study. Those who presented with distinct anterior chamber nodules were evaluated. Demographic details, such as clinical findings and course of illness, were noted. Patients underwent either medical treatment or surgical aspiration of the lesion based on the size of the lesion. Aspirated materials were subjected to histopathologic analysis and cultures for bacteria and fungi. Response to treatment and final visual status were evaluated. RESULTS One hundred thirteen patients with anterior chamber nodules were seen between 1998 and 2000. Ninety-three (82.4%) were males and 20 (17.7%) were females. The median age was 11.0 years. All patients were from south India and all gave a history of bathing or swimming in the local pond or river. All had normal systemic work ups. Of the 113 patients, 110 had anterior chamber nodules and three had both anterior chamber and subconjunctival nodules. Aspirates of the anterior chamber lesions revealed lymphocytes, intact and necrotic neutrophils, and eosinophils admixed with histiocytes. One subconjunctival nodule showed necrotizing granuloma, displaying the tegument of a trematode. Those patients who were followed had good visual recovery after medical or surgical intervention or both. CONCLUSION The present study shows a newly recognized granulomatous anterior uveitis caused by a presumed water-borne trematode infection. This infection appears to be a common cause of pediatric granulomatous anterior uveitis in south India.

Diagnosis of ocular tuberculosis: a role for new testing modalities?

Tuberculosis (TB) is a disease caused by the acid-fast bacillus (AFB) Mycobacterium tuberculosis. TB usually affects the lungs [pulmonary TB (PTB)], but it can also affect any other part of the body [extrapulmonary TB (EPTB)]. EPTB with no evidence of pulmonary involvement accounted for 21.1% of those with TB in 2005, which represents an increase from 16% in 1992. The increase in the proportion of TB cases that are HIV coinfected has contributed to this increase in EPTB. The general symptoms of TB include weakness, weight loss, fever, and night sweats. Symptoms of PTB may also include coughing, chest pain, and hemoptysis. Symptoms of EPTB depend on the area affected. TB is spread from person to person through the air when a person with PTB coughs, sneezes, or speaks. Persons who breathe in the air containing M. tuberculosis can become infected asymptomatically; this is called latent TB infection (LTBI). It is estimated that one-third of the world’s population has LTBI. LTBI is not contagious, but about 5% of persons with LTBI (about 100 million people) will develop TB disease in the future. Progression of LTBI to TB is more common among those with compromised immune systems, those who were recently infected with M. tuberculosis, and people with certain medical conditions. Progression of LTBI to TB can be prevented with treatment such as 9 months of isoniazid.

An outbreak of trematode-induced granulomas of the conjunctiva

PURPOSE To describe the epidemiologic, clinical, and histopathologic features of trematode granulomas of the conjunctiva, eyelid, and anterior chamber in pediatric patients. DESIGN Prospective noncomparative case series. PARTICIPANTS Forty-one children from a southern Indian village with conjunctival granulomas. METHODS The village of Sellananthal was selected for a field visit after analysis of earlier hospital-based allergic conjunctival granuloma cases. Children with ocular diseases were examined, and histories of exposure to assumed risk factors and clinical findings were evaluated. Selected patients were brought to the base hospital for excisional biopsy. Serial sections obtained from the excised nodules were examined for the presence of a parasite. MAIN OUTCOME MEASURES Histopathologic examination of excised conjunctival lesions or response of lesions to local medical therapy. RESULTS In this year-long prospective study, 41 children (16 years or younger; 38 boys and 3 girls) with clinical features of allergic conjunctival granulomas were examined. Thirty-four patients were from a single village located in the southern Indian state of Tamil Nadu; the remaining 7 were from various parts of the same state. All children swam in their villages freshwater pond. Twenty patients with nodules less than 5 mm in diameter received medical treatment; 13 with larger nodules underwent surgical excision of the lesions. Nine of these 13 cases revealed a zonal granulomatous inflammation admixed with eosinophilic leukocytes; 4 of these 9 displayed fragments of the tegument and internal structures of a trematode and Splendore-Hoeppli phenomenon. The remaining 4 of the 13 cases revealed nongranulomatous inflammation made up of lymphocytes, histiocytes, and eosinophils. Eight patients refused surgical treatment. CONCLUSIONS In southern India, one cause of allergic conjunctival granulomas in children seems to be trematode infection. The clustering of cases in a single village and exposure to a village freshwater pond indicate the need for an epidemiologic investigation and study of the parasites life cycle. Sporadic cases from other parts of the state with similar histories of exposure to their local pond or river water suggest a widespread distribution of the etiologic agent.

TB or not TB? The perennial question.

Tuberculosis is the leading infectious cause of morbidity and mortality worldwide.12 The World Health Organization (WHO) currently estimates that nearly two billion people, or one third of the worlds population, are infected by tuberculosis, and that roughly 10% of these infected people will develop clinical disease at some point during their lifetime. This enormous pool of infected individuals results in 8–10 million new cases of tuberculosis and nearly three million deaths due to infection each year. Countries in the developing world, particularly in Africa and South East Asia, bear the brunt of the burden, with more than 95% of new infections and 98% of infection related deaths occurring in these regions. The situation is made even more difficult by the growing human immunodeficiency virus (HIV) epidemic, since simultaneous infection by HIV greatly increases the risk of developing …