CAUSES AND CLINICAL MANIFESTATIONS OF MASQUERADE SYNDROMES IN INTRAOCULAR INFLAMMATORY DISEASES.

OBJECTIVE: To identify the clinical characteristics and prevalence of neoplastic and nonneoplastic inflammatory masquerade syndromes (IMSs) in a tertiary center and determine the useful diagnostic tests. METHODS: A retrospective cohort study of consecutive 1906 patients diagnosed with intraocular inflammatory disease. RESULTS: Of all patients initially diagnosed with intraocular inflammatory disease, we identified 116 (6%) patients with noninflammatory causes (neoplastic IMSs in 36/116; 31% and nonneoplastic IMSs in 52/116; 45%). In addition, 26 patients (22%, 1.4% of all) had drug-induced uveitis and 2 (2%, 0.1% of all) had paraneoplastic uveitis. The large B-cell lymphoma was the most common neoplastic IMS (78%), and the major clinical features were presence of cells and floaters in the vitreous (69%) and chorioretinal lesions (33%). The causes of nonneoplastic IMSs included retinal vascular disorders (38%), hereditary retinal diseases (31%), and degenerative ocular disorders (19%). The common clinical manifestations consisted of chorioretinal scars (27%), small white-yellow retinal lesions (17%), and leaking vessels on fluorescein angiography (14%). CONCLUSION: Noninflammatory causes were determined in 6% of a large population with initial diagnosis of intraocular inflammatory disease. Although neoplastic IMS was commonly characterized by vitreous cells and opacities, most common definitive diagnoses in nonneoplastic IMS encompassed diverse retinal disorders.

Are a Double Duct Sign or Endoscopic Biopsies Reliable Predictors of Malignancy in Periampullary Lesions.

AIM: To determine the predictive value of a double duct sign (DDS) and endoscopic biopsies to differentiate invasive carcinoma from premalignant lesions. METHODS: Two hundred and forty one patients (mean age 65.8; male 55.6%) diagnosed with a periampullary lesion from January 1987 through March 2013 were reviewed retrospectively with regard to background characteristics, histology of endoscopic biopsy, diameter of both common bile duct (CBD) and main pancreatic duct (PD), bilirubin levels and final diagnosis. RESULTS: DDS predicted malignancy with 73% specificity and 72% sensitivity. Endoscopic biopsies predicted malignancy with 96% specificity, 71% sensitivity and a negative predictive value (NPV) of 51%. Multivariable logistic regression analysis showed that DDS is a significant predictor for the presence of malignancy with an odds ratio of 6.37 adjusted to age, gender and endoscopic biopsy. CONCLUSION: Although DDS is indicative of malignancy in periampullary lesions, its clinical use is limited, given the low sensitivity and specificity. The diagnostic value of endoscopic biopsies is also poor due to a low sensitivity and NPV. If a double duct sign is present, physicians must be aware of an increased possibility of a malignant underlying cause, even if the histopathological examination of the biopsies did not show invasive malignancy.

Relapse in ocular tuberculosis: relapse rate, risk factors and clinical management in a non-endemic country.

AIMS: To assess the risk of uveitis relapse in ocular tuberculosis (OTB) following clinical inactivity, to analyse clinical factors associated with relapses and to describe the management strategies for relapses. METHODS: A retrospective study was conducted on a 10-year patient registry of patients with OTB diagnosed at Erasmus MC in Rotterdam, The Netherlands. Time-to-relapse of uveitis was evaluated with Kaplan-Meier curve and risk factors for relapses were analysed. RESULTS: 93 OTB cases were identified, of which 75 patients achieved clinical inactivity following treatment. The median time to achieve uveitis inactivity was 3.97 months. During a median follow-up of 20.7 months (Q1-Q3: 5.2-81.2) after clinical inactivity, uveitis relapse occurred in 25 of these 75 patients (33.3%). Patients who were considered poor treatment responders for their initial uveitis episode had a significantly higher risk of relapse after achieving clinical inactivity than good responders (adjusted HR=3.84, 95% CI: 1.28 to 11.51). 13 of the 25 relapsed patients experienced multiple uveitis relapse episodes, accounting for 78 eye-relapse episodes during the entire observation period. Over half (46 out of 78, 59.0%) of these episodes were anterior uveitis. A significant number of uveitis relapse episodes (31 episodes, 39.7%) were effectively managed with topical corticosteroids. CONCLUSIONS: Our results suggest that approximately one-third of patients with OTB will experience relapse after achieving clinical inactivity. The initial disease course and poor response to treatment predict the likelihood of relapse in the long-term follow-up. Topical corticosteroids were particularly effective in relapse presenting as anterior uveitis.

Ocular Tuberculosis Diagnosis Through Biomarkers: Clinical Relevance of Serum C1q and Whole Blood Interferon Gene Signature Score.

PURPOSE: To assess the clinical relevance of pathophysiology-based biomarkers, specifically serum C1q and whole blood interferon gene signature score (IGSS), in ocular tuberculosis (OTB) diagnosis by conducting an integrative analysis of clinical presentations and treatment response. METHODS: This retrospective cohort study analysed data from 70 patients with suspected OTB at a tertiary care uveitis practice in Indonesia. Serum C1q levels and whole blood IGSS were quantified. Patients were categorized into four quadrants based on their biomarker profiles: quadrant 1 (high C1q & low IGSS), quadrant 2 (high C1q & high IGSS), quadrant 3 (low C1q & high IGSS), and quadrant 4 (low C1q & low IGSS). Characteristics of clinical presentations, work-up results, and treatment outcomes were explored according to the predefined quadrants. RESULTS: We identified that the majority of OTB patients diagnosed with concurrent active pulmonary TB were in quadrant 1, 2, or 3 (20/23, 87.0%). Twenty-seven patients (27/47, 57.4%) with clinically undifferentiated uveitis were in quadrant 4 (p < 0.001). Among patients in quadrants 1, 2, and 3, completion of a full course of antitubercular treatment (ATT) was associated with a lower number of patients showing persistence or recurrence of ocular inflammation compared to those who were not fully treated with ATT (14.3% vs 85.7%, p = 0.001). CONCLUSIONS: Based on the analysis of clinical features and treatment outcomes, patients with elevated levels of either or both serum C1q and whole blood IGSS may reflect active TB disease in the eye, necessitating full ATT management.

Clinical Features and Predictors of Treatment Outcome in Patients with Ocular Tuberculosis from the Netherlands and Indonesia: The OculaR TB in Low versus High Endemic Countries (ORTEC) Study.

PURPOSE: To describe and compare clinical features, treatment approaches, and treatment outcomes of ocular tuberculosis (OTB) patients in the Netherlands, a low tuberculosis (TB)-endemic country, and Indonesia, a high TB-endemic country. We also aimed to identify predictors of treatment outcomes. METHODS: A medical chart review of 339 OTB patients (n = 93 from the Netherlands and n = 246 from Indonesia) was performed. The primary outcome was response to treatment, whether with or without anti-tubercular treatment, after six months of treatment initiation (good versus poor responders). RESULTS: Indonesian OTB patients displayed a higher prevalence of chest radiograph findings indicative of TB infection (p < 0.001) and concurrent active systemic TB (p = 0.011). Indonesian cohort exhibited a more acute and severe disease profile, including uveitis duration ≤ 3 months (p < 0.001), blindness (p < 0.001), anterior chamber (AC) cells ≥ 2+ (p < 0.001), and posterior synechiae (p < 0.001). Overall proportions of good responders to treatment were 67.6% in the Netherlands and 71.5% in Indonesia. Presence of AC cell ≥ 2+ (adjusted odds ratio (aOR): 2.12, 95% CI: 1.09-4.14), choroidal lesions other than serpiginous-like choroiditis (SLC) or tuberculoma (aOR: 4.47, 95% CI: 1.18-16.90), and retinal vasculitis (aOR: 2.32, 95% CI: 1.10-4.90) at baseline were predictors for poor response to treatment. CONCLUSIONS: Despite a more severe initial clinical presentation in the Indonesian cohort, the overall treatment outcomes of OTB was comparable in both cohorts. Three baseline clinical features were identified as predictors of treatment outcomes.

The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies.

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary.

Long-term follow-up after treatment of tubercular uveitis: case series and review of the literature.

Introduction: There is a scarcity of long-term follow-up data and management strategies for recurrent uveitis in tubercular uveitis (TBU), especially in cases extending beyond 10 years after the completion of initial antitubercular treatment (ATT). Methods: This retrospective study involved five TBU patients who were initially treated with a combination of four-drug ATT for 6 months, and the five of them had more than 10 years of follow-up after uveitis resolution upon ATT completion. We describe the occurrence of recurrent uveitis and present our approach to managing these recurrent episodes. Results: Recurrent uveitis and cystoid macular edema (CME) developed in three out of five included TBU patients with a median of 18 years (range 13-20 years) of follow-up. The anatomical sites of the recurrences were anterior, intermediate, and pan-uveitis. The recurrent episodes varied from 6 years to 15 years after ATT completion. Systemic or local corticosteroids/immunosuppressants successfully resolved all recurrent episodes, but one was also treated with the combination of isoniazid monotherapy again. Two patients needed anti-tumor necrosis factor-α therapy. Conclusion: Long-term monitoring of TBU patients after ATT completion is warranted. Further well-designed studies with larger sample sizes are required to better estimate the risk of recurrences, investigate the underlying mechanism of recurrences, and identify biomarkers that predict who is at risk for recurrences.

Destructive inflammatory reaction after an autologous retinal pigment epithelium and choroid transplantation: no detection of an auto-immune response.

PURPOSE: Five patients who underwent uncomplicated retinal pigment epithelium (RPE)-choroid transplantation for neovascular age-related macular degeneration developed a destructive inflammatory reaction causing subretinal fluid accumulation and extensive RPE atrophy in the graft. We hypothesized that this inflammation could be caused by an auto-immune response against the graft, resulting in circulating auto-antibodies. The aim of our study was to examine a potential autoimmune origin, which would allow a more targeted therapy approach. METHODS: Five above-mentioned patients and four control groups of five patients each were included: 1) after uncomplicated RPE-choroid transplantation, 2) after full macular translocation, 3) treated with anti-vascular endothelial growth factor, and 4) healthy controls. Histopathology of rejected graft tissue was performed using standard procedures. Presence of RPE-choroid autoantibodies in serum was examined by indirect immunofluorescence and Western blot, and human leukocyte antigen (HLA) typing was performed. RESULTS: Histopathological examination of an explanted graft showed infiltration of T-lymphocytes and macrophages in the choroid and RPE, and an increased number of B-cell lymphocytes were found in the choroid. Indirect immunofluorescence showed weak RPE-choroid autoantibody immunoreactivity in three patients of different groups. Western blot did not show specific RPE-choroid autoantibody immunoreactivity and no difference of HLA genotypes between the groups was found. CONCLUSIONS: Although local mononuclear inflammatory cell infiltration and a high number of B-lymphocytes were observed in an explanted graft, we did not detect serological evidence of an autoimmune origin of the postoperative inflammation using direct immunofluorescence and Western Blot. Alternatively, the graft failure may have been caused by local innate inflammation, triggered by breakdown of tolerance. Based on our current findings of this small study group, we have no rationale to pursue therapies targeted towards autoreactive graft failure. More research is needed to confirm our findings.

Vitreous proteomics, a gateway to improved understanding and stratification of diverse uveitis aetiologies.

PURPOSE: The vitreous proteome might provide an attractive gateway to discriminate between various uveitis aetiologies and gain novel insights into the underlying pathophysiological processes. Here, we investigated 180 vitreous proteins to discover novel biomarkers and broaden disease insights by comparing (1). primary vitreoretinal lymphoma ((P)VRL) versus other aetiologies, (2). sarcoid uveitis versus tuberculosis (TB)-associated uveitis and (3). granulomatous (sarcoid and TB) uveitis versus other aetiologies. METHODS: Vitreous protein levels were determined by proximity extension assay in 47 patients with intraocular inflammation and a prestudy diagnosis (cohort 1; training) and 22 patients with a blinded diagnosis (cohort 2; validation). Differentially expressed proteins identified by t-tests on cohort 1 were used to calculate Youden's indices. Pathway and network analysis was performed by ingenuity pathway analysis. A random forest classifier was trained to predict the diagnosis of blinded patients. RESULTS: For (P)VRL stratification, the previously reported combined diagnostic value of IL-10 and IL-6 was confirmed. Additionally, CD70 was identified as potential novel marker for (P)VRL. However, the classifier trained on the entire cohort (cohort 1 and 2) relied primarily on the interleukin score for intraocular lymphoma diagnosis (ISOLD) or IL-10/IL-6 ratio and only showed a supportive role for CD70. Furthermore, sarcoid uveitis displayed increased levels of vitreous CCL17 as compared to TB-associated uveitis. CONCLUSION: We underline the previously reported value of the ISOLD and the IL-10/IL-6 ratio for (P)VRL identification and present CD70 as a potentially valuable target for (P)VRL stratification. Finally, we also show that increased CCL17 levels might help to distinguish sarcoid uveitis from TB-associated uveitis.

No Evidence for Circulating Retina Specific Autoreactive T-cells in Latent Tuberculosis-associated Uveitis and Sarcoid Uveitis.

Purpose: To detect circulating retina-specific autoreactive CD4+ T-cells and antiretinal antibodies (ARA) in latent tuberculosis (TB)-associated uveitis or sarcoid uveitis patients.Methods: The presence of crude retinal extract (RE) autoreactive CD4+ T-cells was determined by a highly sensitive flowcytometric-based technique examining co-expression of CD25 and CD134 (OX40) on RE stimulated PBMC. The presence of ARA in available matched serum samples was assessed by indirect immunofluorescence.Results: No autoreactive CD4+ T-cells against RE could be detected in either latent TB-associated uveitis or sarcoid uveitis patients, while ARA were detected in the serum of the majority (5/6) of latent TB-associated uveitis and all (3/3) sarcoid uveitis patients.Conclusion: Even with the use of this highly sensitive flowcytometric technique circulating retina-specific autoreactive CD4+ T-cells could not be detected. In contrast, ARA were detected in the majority of patients indicating an adaptive humoral immune response toward retinal antigens had occurred.

The role of antibody indexes in clinical virology.

BACKGROUND: Serological techniques are an essential part of the diagnostic tools used in clinical virology. Among these techniques, antibody indexes are not novel, but do require specific expertise. Their niche has expanded substantially in recent years due to increasing evidence of their performance to diagnose viral infections. OBJECTIVES: This narrative review describes the background and clinical applications of antibody indexes. The first objective is to provide an overview of the theoretical background, insights for implementation, limitations and pitfalls. The second objective is to review the available evidence for the diagnostic performance, with a specific focus on viral encephalitis and uveitis. SOURCES: A comprehensive literature search was performed in PubMed, including original studies and reviews, with no time limit on the studies included. The following search terms were used: antibody index, Goldmann-Witmer coefficient, Reibergram, viral encephalitis, viral uveitis, herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, rubella virus, measles virus, enterovirus, influenza virus, flaviviruses. CONTENT: Antibody indexes can support the diagnosis of a spectrum of viral infections in immune privileged sites such as the central nervous system and the eye, through the demonstration of virus-specific intrathecal or intraocular antibody production. This is especially useful in situations where PCR has a lower positivity rate: infections with rapid viral clearance due to natural immunity or treatment and chronic stages of viral infections. IMPLICATIONS: Antibody indexes expand the clinical microbiologist's diagnostic toolbox. Careful interpretation of the results of these assays is crucial and further standardization of methods is required to improve interchangeability of results between laboratories.

Antiretinal antibodies in central serous chorioretinopathy: prevalence and clinical implications.

PURPOSE: To investigate the possible role of autoimmune reactions directed against retinal tissue in central serous chorioretinopathy (CSC), by analysing the presence of serum antiretinal antibodies (ARAs) and establishing their clinical relevance. METHODS: Sixty-three patients with CSC were included, and clinical characteristics were collected. Serum samples of all patients with CSC, 101 uveitis patients and 60 healthy donors were analysed for the presence of ARAs by indirect immunofluorescence. Furthermore, all CSC serum samples were analysed on Western blot. Correlations between laboratory findings and clinical features of CSC were determined by logistic regression. RESULTS: Antiretinal antibodies (ARAs) were present in 54% of the patients with CSC, in 46% of uveitis patients (p = 0.153) and in 17% of healthy controls (p < 0.001). The majority of ARAs in CSC were directed against photoreceptors (27%), which occurred significantly more often compared to uveitis patients (15%, p = 0.039) and to healthy controls (5%, p = 0.003). No associations between clinical CSC characteristics and the presence of ARAs were found. CONCLUSION: Serum ARAs are present in more than half of the patients with CSC, and especially, ARAs directed against photoreceptors were detected more frequently compared to both healthy controls and uveitis patients. Further research is warranted to unravel the role of ARAs in the pathogenesis of CSC.

Rubella Virus-associated Anterior Uveitis in a Vaccinated Patient: A Case Report.

Rubella virus is involved in the pathogenesis of Fuchs heterochromic uveitis and almost all cases in Europe show an active antibody production in the aqueous humor against rubella virus. Herein we report a case of a fully vaccinated patient with common variable immunodeficiency who developed unilateral Fuchs heterochromic uveitis secondary to rubella virus which was proven by intraocular fluid examination. Awareness of rubella associated anterior uveitis should remain also in vaccinated patients, especially those without a fully competent immune system.

The accuracy of MRI, endorectal ultrasonography, and computed tomography in predicting the response of locally advanced rectal cancer after preoperative therapy: A metaanalysis.

BACKGROUND: To perform a metaanalysis to determine and compare the diagnostic performance of MRI, endorectal ultrasonography (ERUS), and computed tomography (CT) in predicting the response of locally advanced rectal cancer after preoperative therapy. METHODS: All previously published articles on the role of MRI, CT, and/or ERUS in predicting the response of rectal cancer to preoperative therapy were collected. We divided the objective in 3 parts: the accuracy to assess (i) complete response, (ii) to detect T4 tumors with invasion to the circumferential resection margin (CRM), and (iii) to predict the presence of lymph node metastasis. The pooled estimates of, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated using a bivariate mixed effect analysis. RESULTS: Forty-six studies comprising 2,224 patients were included. (i) The pooled accuracy to assess complete tumor response were (a) 75% for MRI, (b) 82% for ERUS, (c) and 83% for CT. (ii) Pooled accuracy to detect T4 tumors with invasion to the CRM were (a) 88% and (b) 94% for ERUS. (iii) Pooled accuracy to predict the presence of lymph node metastasis was (a) 72% for MRI, (b) 72% for ERUS, (c) and 65% for CT. CONCLUSION: MRI, CT, and ERUS cannot be used to predict complete response of locally advanced rectal cancer after CRT. In addition, the positive predictive value for these imaging techniques is low for the assessment of tumor invasion in the CRM. The accuracy of the modalities to predict the presence of metastatic lymph node disease is also low.

Prevalence and clinical impact of antiretinal antibodies in uveitis.

PURPOSE: To determine the prevalence of serum antiretinal antibodies (ARAs) among patients with uveitis and establish their clinical relevance. METHODS: This prospective study assessed the presence of ARAs by indirect immunofluorescence (IIF) using primate retina in 126 patients with uveitis and 60 healthy controls. Clinical data of uveitis patients were collected from medical charts and included the classification of uveitis, cause of uveitis or its association with systemic disease, stage and activity of uveitis and specific retinal features. Correlations between the presence of specific ARAs and various clinical characteristics were analysed. RESULTS: The presence of ARAs was observed in 49 of 104 (47%) of patients with uveitis and in 10 of 59 (17%) of healthy controls (p < 0.001). Staining of the nuclear layers or the photoreceptors were both more often observed in patients with uveitis compared to healthy controls (p = 0.002 and p = 0.018, respectively). No specific associations were found between the presence of serum ARAs and various clinical characteristics. CONCLUSION: Serum ARAs were more frequent in patients with uveitis compared to healthy controls, but their clinical role remains elusive. The assessment of intraocular production of specific ARAs may provide further insight into the role of ocular autoantibodies in diverse uveitis entities.

[Severe visual loss caused by autoimmune retinopathy]. / Ernstige visusdaling door auto-immuunretinopathie.

BACKGROUND: Autoimmune retinopathy (AIR) is a rare disorder which may present as a paraneoplastic syndrome. AIR is associated with the presence of anti-retinal antibodies. These antibodies are assumed to cause damage to the retina, resulting in progressive vision loss. CASE DESCRIPTION: A 74-year-old man visited the ophthalmologist with a serious, progressive loss of vision, without any noteworthy abnormalities at routine ophthalmological examination. The electroretinogram was characteristic of loss of photoreceptor function. Anti-retinal antibodies against recoverin were detected in serum. After referral to an internist on account of a suspected diagnosis of paraneoplastic AIR, the patient was diagnosed with a lung carcinoma, confirming the diagnosis of cancer-associated paraneoplastic AIR. CONCLUSION: An unexplained loss of vision is highly suggestive of paraneoplastic AIR, even in patients without a known malignancy. Laboratory techniques for the detection of the anti-retinal antibody against recoverin have recently been implemented in the Netherlands, facilitating the diagnosis of AIR.