Omar M. Durrani

Degree, duration, and causes of visual loss in uveitis

Background/aims: Uveitis is a major cause of visual morbidity in the working age group. The authors investigated the duration, degree, and causes of visual loss in uveitis patients with the aim of better defining the visual morbidity and identifying potential risk factors. Methods: A retrospective, non-interventional, observational survey of 315 consecutive patients attending a tertiary referral uveitis service. Results: The mean duration of follow up was 36.7 months. Reduced vision (⩽6/18) was found in 220/315 (69.95%) of the patients with a subset of 120 patients having vision ⩽6/60. Unilateral visual loss occurred in 109 (49.54%), while 111 (50.45%) had bilateral loss. The mean duration of visual loss was 21 months. Of the 148 patients with pan-uveitis, 125 (84.45%) had reduced vision, with 66 (53%) having vision ⩽6/60. Main causes of visual loss were cystoid macular oedema (CMO) (59/220, 26.8%), cataract (39/220, 17.7%), and combination of CMO and cataract (44/220, 20%). The following were predictive of a poorer visual prognosis: pan-uveitis (p = 0.0005), bilateral inflammation (p = 0.0005), increasing duration of reduced vision (p = 0.0005), an Indian or Pakistani ethnic background (p = 0.004), and increasing patient age (p = 0.02). Conclusion: Prolonged visual loss occurred in two thirds of uveitis patients, with 70 (22%) patients meeting the criteria for legal blindness at some point in their follow up. Older patients with bilateral inflammation and an increasing duration of reduced vision are at the greatest risk of severe visual loss (⩽6/60). CMO and cataract were responsible for visual loss in 64.5% of patients.

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

Primary anti-phospholipid antibody syndrome (APS): Current concepts

Primary anti-phospholipid syndrome (APS) is a thrombophilic state characterized by recurrent arterial and venous thrombosis, recurrent pregnancy loss, and the presence of circulating anti-phospholipid antibodies that may be responsible for thrombophilia and pregnancy morbidity. Ophthalmologic features are present in 15-88% of the patients with primary APS, thus ophthalmologists are one of the first physicians to whom the patient will present. An accurate diagnosis may save the patient from recurrent, potentially life-threatening thrombosis. In the U.S.A., an estimated 35,000 new cases of APS-related venous thrombosis occur each year in a population that is several decades younger than the patient population typically affected by thrombosis. Clinical features, such as chorea, transverse myelitis, cardiac valvular lesions, and accelerated atherosclerosis, are hypothesized to be due to a direct tissue-antibody interaction and cannot be explained purely by thrombosis. The use of recently proposed, well-defined diagnostic criteria, and better standardization of laboratory assays for the anti-phospholipid antibodies should help enable epidemiological surveys to establish the prevalence of these antibodies in patients with thrombosis and in the general population. Diagnosis of APS should be considered in all patients with recurrent systemic or ocular thrombosis in the absence of known risk factors. Several well-designed prospective studies show an increased risk of thrombosis in the presence of medium to high antibody level. With ocular involvement in as many as 88% of APS patients, an ophthalmic assessment should be an integral part of the clinical work-up of any patient with suspected or confirmed APS. The presence of isolated ocular thrombophilia with persistently elevated anti-phospholipid antibodies or lupus coagulant should confirm the diagnosis of APS. Management of these patients must be a multi-disciplinary effort with either a rheumatologist or a hematologist having the overall responsibility for coordinating treatment and monitoring the patients immune status and anticoagulation. Treatment of isolated ocular thrombophilia in the presence of moderate to high titers of antiphospholipid antibodies should be on the same principles as patients with APS to prevent recurrent ocular or cerebral thrombosis.

Postcataract endophthalmitis: Incidence and microbial isolates in a United Kingdom region from 1996 through 2004

PURPOSE: To investigate the incidence of endophthalmitis after cataract surgery, analyze the microbiologic spectrum of infecting organisms, and assess the diagnostic utility of an anterior chamber paracentesis and vitreous biopsy. SETTING: United Kingdom tertiary referral center used by 13 operating suites. METHODS: A retrospective noncomparative consecutive series comprised 105 postcataract endophthalmitis cases. RESULTS: The annual mean incidence of endophthalmitis over the study period was 0.099% (10/101 920), and there was no significant increase in the incidence during the study. The culture‐positive rate was 58.1% (61/105). Gram‐positive microbes were isolated in 93.4% of cases (57/61), with coagulase‐negative staphylococci accounting for 62.3% (38/61). Anterior chamber taps yielded positive cultures in 25.7% of cases, and vitreous biopsy was positive in 53.4%. CONCLUSIONS: The incidence of endophthalmitis in this region of the United Kingdom remained stable, with gram‐positive microbes accounting for 93.4% of the isolates. A combination of anterior chamber tap and vitreous biopsy should be performed in suspected cases of endophthalmitis.

Infliximab: A Novel Treatment for Sight-Threatening Thyroid Associated Ophthalmopathy

We describe a patient with sight threatening thyroid associated ophthalmopathy (TAO) who was successfully treated with infliximab, an anti-tumour necrosis factor (TNF)-α antibody.

The safety of anterior chamber paracentesis in patients with uveitis

Anterior chamber (AC) paracentesis is a valuable procedure in the management of uveitis, particularly in diagnosing infective causes.1,2 It may also be used therapeutically to lower intraocular pressure,3 and it provides samples for clinical research. Nevertheless, there have been isolated reports of AC paracentesis related serious complications, including endophthalmitis and corneal abscess.4,5 As the risk of trauma to the iris and lens are also major concerns, AC paracentesis is often used with reluctance. Although there are many studies on the analysis of aqueous humour obtained from AC paracentesis, our literature search showed only one publication on the safety of AC paracentesis.6 The purpose of this study was to describe a method of AC paracentesis that can be easily performed as an outpatient procedure with the patient sitting at the slit lamp. A total of 70 patients (41 male, 29 female) aged 18–83 years (median 39 years) with various types of active uveitis attending the Birmingham and Midland Eye …

Characterisation of 11β-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat

Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0·001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0·05; protein, P<0·001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0·05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease.

TIRAP Ser180Leu polymorphism is associated with Behçet's disease

OBJECTIVES The initiating cause of Behçets disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD. METHODS TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain-containing adaptor protein) in patients with BD from different geographical regions. RESULTS TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients. CONCLUSION TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions.

Use of a novel topical hemostatic sealant in lacrimal surgery: a prospective, comparative study.

Purpose: FloSeal Matrix is a new, two-component (collagen granules and thrombin), topical hemostatic sealant. We prospectively evaluated the role of FloSeal Matrix in achieving hemostasis in dacryocystorhinostomy (DCR) surgery and its intraoperative characteristics (ease of use). We hypothesize that FloSeal will efficiently control bleeding in patients and eliminate the need for postoperative intranasal dressing. Methods: FloSeal was used during surgery in 10 consecutive patients undergoing DCR. A further 10 consecutive patients (comparative group) had DCR without FloSeal; nasal packing was performed to control postoperative bleeding. The severity of postoperative bleeding and patient comfort were compared between the two groups at three time points (immediately after surgery, 12 hours after surgery, and 24 hours after surgery). Results: All patients in the comparative group had some degree of postoperative bleeding (minimal to severe), whereas the nine patients in the FloSeal group had none or minimal bleeding. The difference was statistically significant at all three measured time points (p = 0.047, 0.006, 0.05). The FloSeal group also had less postoperative discomfort (p = 0.0001). Conclusions: FloSeal Matrix is an effective hemostasis adjunct in patients undergoing lacrimal surgery. It has the added benefits of high patient satisfaction and ease of use.

The Role of 11ß-Hydroxysteroid Dehydrogenase 1 in Adipogenesis in Thyroid-Associated Ophthalmopathy

CONTEXT Thyroid-associated ophthalmopathy (TAO) is a sight-threatening autoimmune disease in which de novo adipogenesis has been identified as a fundamental pathogenic mechanism. 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) increases cortisol bioavailability and is pivotal in mediating glucocorticoid responses in adipose tissue and inflammation. OBJECTIVE In this study we characterize 11beta-HSD1 as a determinant of the adipogenic and inflammatory pathways in TAO orbital fat (OF) compared with normal OF. PATIENTS AND METHODS OF was harvested from 46 TAO and 44 control patients undergoing orbital surgery. Samples were examined by a combination of immunohistochemistry, real-time RT-PCR, primary cell culture, specific enzyme assays, colorimetric proliferation assays, and bead-based ELISA. RESULTS Glucocorticoid (glucocorticoid receptor-alpha,11beta-HSD1, hexose-6-phosphate dehydrogenase) and inflammatory cytokines (IL-1beta, IL-1 receptor, IL-6, TNF-alpha, TNF-alpha inductible protein, TGF-beta2) target genes together with markers of late adipocyte differentiation (fatty-acid-binding-protein-4, glycerol-6-phosphate-dehydrogenase) were highly expressed in TAO whole OF (P < 0.05) compared with controls. Primary cultures of TAO OF stromal cells demonstrated greater 11beta-HSD1 oxoreductase activity (P < 0.05), which was regulated by cytokines, most notably TNF-alpha (P < 0.01), compared with controls. Activity increased across differentiation, and this was most marked in TAO cells (P < 0.01). Similarly, stromal cell proliferation was limited by incubation with cortisol in TAO cells only. Furthermore, cortisone decreased IL-6 (P < 0.005), IL-8 (P < 0.05), and macrophage chemoattractant protein-1 (P < 0.05) production by cultured TAO cells only, an effect that was abrogated by inhibition of 11beta-HSD1. CONCLUSIONS Induction of 11beta-HSD1 activity and expression by inflammatory cytokines (TNF-alpha, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11beta-HSD1 may also have a role in regulating the local orbital inflammatory response.