Müller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy.

Retinal gliosis is characterized by biochemical and physiological changes that often lead to Müller glia proliferation and hypertrophy and is a feature of many neuro-degenerative and inflammatory diseases such as proliferative vitreoretinopathy (PVR). Although Müller glia are known to release inflammatory factors and cytokines, it is not clear whether cytokine production by these cells mirrors the pattern of factors present in the gliotic retina. Lysates from normal cadaveric retina and gliotic retinal specimens from patients undergoing retinectomy for treatment of PVR, the Müller cell line MIO-M1 and four human Müller glial cell preparations isolated from normal retina were examined for their expression of cytokines and inflammatory factors using semi-quantitative dot blot antibody arrays and quantitative arrays. Comparative analysis of the expression of inflammatory factors showed that in comparison with normal retina, gliotic retina exhibited greater than twofold increase in 24/102 factors examined by semiquantitative arrays, and a significant increase in 19 out of 27 factors assessed by quantitative methods (P < 0.05 to P < 0.001). It was observed that with the exception of some chemotactic factors, the majority of cytokines and inflammatory factors were produced by Müller glia in vitro and included G-CSF, MCP-1, PDGF-bb, RANTES, VEGF, and TGFß2. These results showed that a large number of inflammatory factors expressed by Müller glia in vitro are upregulated in the gliotic retina, suggesting that targeting the production of inflammatory factors by Müller glia may constitute a valid approach to prevent neural damage during retinal gliosis and this merits further investigations.

SNP mistyping in genotyping arrays--an important cause of spurious association in case-control studies.

Using genome-wide association studies to identify genetic variants contributing to disease has been highly successful with many novel genetic predispositions identified and biological pathways revealed. Several pitfalls for spurious association or non-replication have been highlighted: from population structure, automated genotype scoring for cases and controls, to age-varying association. We describe an important yet unreported source of bias in case-control studies due to variations in chip technology between different commercial array releases. As cases are commonly genotyped with newer arrays and freely available control resources are frequently used for comparison, there exists an important potential for false associations which are robust to standard quality control and replication design.

Scleral-fixated intraocular lens implants-evolution of surgical techniques and future developments.

Varied options are available for the implantation of secondary intraocular lens implants in the absence of zonular or capsular support. Loss of the capsule can occur in the context of complicated cataract surgery, trauma or inherited conditions such as Marfan syndrome or pseudoexfoliation. Approaches to overcome this include optical measures such as the use of spectacles or contact lenses, and surgical therapy incorporating the use of anterior chamber, iris-fixated or scleral-fixated lenses. Surgical techniques to implant scleral-fixated lenses have undergone various modifications, since the first publication of sutured intrascleral fixation described in the 1980s. However, despite the advances in surgical techniques, studies are limited either by their retrospective nature, small sample size and most importantly small duration of follow-up. This comprehensive review aims to amalgamate the evolution of various surgical techniques with regards to intrascleral lens fixation and suggests areas for future development.

Randomized controlled trial of combined 5-Fluorouracil and low-molecular-weight heparin in the management of unselected rhegmatogenous retinal detachments undergoing primary vitrectomy.

OBJECTIVE: To determine the efficacy of a combination of 5-fluorouracil (5FU) and low-molecular-weight heparin (LMWH) in the treatment of unselected rhegmatogenous retinal detachment (RRD) undergoing primary vitrectomy. DESIGN: Double-masked, prospective, randomized, placebo-controlled clinical trial. PARTICIPANTS: Six hundred forty-one patients presenting with primary RRD were recruited from 2 specialized vitreoretinal units-Moorfields Eye Hospital, London (n = 553) and St. Pauls Eye Unit, Liverpool (n = 88). INTERVENTION: All patients underwent primary vitrectomy and gas endotamponade. Adjuvant therapy in the treatment group consisted of 5 IU/ml LMWH and 200 mug/ml 5FU added to the perioperative infusion fluid. MAIN OUTCOME MEASURES: The primary outcome measure was retinal reattachment after primary vitrectomy without any reoperations at 6 months. Secondary outcome measures recorded at 6 months were the occurrence and grade of proliferative vitreoretinopathy (PVR), best-corrected visual acuity in logarithm of the minimum angle of resolution, intraocular pressure (mmHg), corneal clarity, and complications. RESULTS: The overall primary success rate was 84.4%; in the treatment group, the primary success rate was 82.3% compared with 86.8% in the placebo group (P = 0.12). At 6 months, the final complete anatomical reattachment rate was 97.9% in both treatment and placebo groups. The number of patients who failed due to the development of PVR was not statistically significant, 23 in the treatment group (7.0%) and 14 in the placebo group (4.9%) (P = 0.309). There was no significant difference in the mean visual acuity at 6 months in the placebo group (0.48) versus the treatment group (0.53; P = 0.072). The visual acuity at 6 months of patients presenting with a macula-sparing retinal detachment was significantly worse in the treatment group (P = 0.0091). There was no significant difference between the 2 groups in patients who presented with a macula involving retinal detachment (P = 0.896). CONCLUSIONS: Primary vitrectomy has a high anatomic and visual success rate for RRD. Adjuvant therapy with 5FU and LMWH does not improve the anatomic or visual success rate of unselected primary retinal detachments undergoing vitrectomy. After adjuvant therapy, a worse visual outcome was observed in patients presenting with macula-sparing retinal detachments. A combination of 5FU and LMWH should not be used routinely for primary RRD surgery.

Silicone oil versus gas tamponade for giant retinal tear-associated fovea-sparing retinal detachment: a comparison of outcome.

PurposeSilicone oil is the most common choice of tamponade agent used when managing a giant retinal tear (GRT). Concern exists regarding its potential detrimental effect on vision. We herein report on visual and surgical outcomes of all patients treated at Moorfields Eye Hospital for a GRT over a five year period. We further analysed a subgroup of fovea-sparing retinal detachments (RD) treated by pars plana vitrectomy (PPV) with either silicone oil or gas tamponade.MethodsRetrospective comparative, non-randomised, cross-sectional review of patients with a new diagnosis of GRT from 1 September 2005 to 31 August 2010ResultsOne hundred twenty four eyes of 118 patients were identified with mean age of 45.5 years and median follow-up of 24 months. Subgroup analysis of fovea-sparing RDs (Silicone Oil n=49, Gas n=15) revealed visual loss (≥2 Snellen Lines of vision) in 49.0% (n=24) of patients managed with oil compared to 13.3% (n=2) of gas patients (P=0.019). In all, 73.3% (n=11) in the gas group achieved a final vision of 6/12 or better, compared to 36.7% (n=18) in the oil group (P=0.031). No difference was observed in eventual or primary anatomical success rate (100 vs 93.9%, and 66.7 vs 79.6%, gas vs oil, respectively, (P>0.1)). Postoperative complications were absent in 66.7% (n=10) of gas patients compared with 14.3% (n=7) of oil patients (P=0.002). Multiple variable linear regression determined tamponade choice as the only variable predictive of final visual acuity (P=0.046).ConclusionEyes with fovea-sparing GRT-related RDs managed with gas achieved a better visual outcome with fewer postoperative complications and no significant difference in anatomical success. A multicentre approach to investigate this further is advised.

Ranibizumab pretreatment in diabetic vitrectomy: a pilot randomised controlled trial (the RaDiVit study).

PurposeOur aim was to evaluate the impact of intravitreal ranibizumab pretreatment on the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy. The objective was to determine the feasibility of a subsequent definitive trial and estimate the effect size and variability of the outcome measure.Patients and methodsWe performed a pilot randomised double-masked single-centre clinical trial in 30 participants with tractional retinal detachment associated with proliferative diabetic retinopathy. Seven days prior to vitrectomy surgery, participants were randomly allocated to receive either intravitreal ranibizumab (Lucentis, Novartis Pharmaceuticals UK Ltd, Frimley, UK) or subconjunctival saline (control). The primary outcome was best-corrected visual acuity 12 weeks following surgery.ResultsAt 12 weeks, the mean (SD) visual acuity was 46.7 (25) ETDRS letters in the control group and 52.6 (21) letters in the ranibizumab group. Mean visual acuity improved by 14 (31) letters in the control group and by 24 (27) letters in the ranibizumab group. We found no difference in the progression of tractional retinal detachment prior to surgery, the duration of surgery, or its technical difficulty. Vitreous cavity haemorrhage persisted at 12 weeks in two of the control group but none of the ranibizumab group.ConclusionRanibizumab pretreatment may improve the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy by reducing the extent of post-operative vitreous cavity haemorrhage. However, the effect size appears to be modest; we calculate that a definitive study to establish a minimally important difference of 5.9 letters at a significance level of P<0.05 would require 348 subjects in each arm.

Visual function and quality of life following vitrectomy and epiretinal membrane peel surgery.

AIM: To investigate the effect of epiretinal membrane (ERM) peel on patients' health related quality of life (HR-QOL) and to explore the association between self reported HR-QOL and conventional measures of visual function. METHODS: The National Eye Institute 25 Item Visual Function Questionnaire (VFQ-25) and the 36 Item Short-Form Health Survey (SF-36) were self administered by 20 patients before and 4 months following surgery. Preoperative and postoperative data collected included logMAR near and distant visual acuity (VA), contrast sensitivity, and metamorphopsia. Questionnaire scores were compared preoperatively and postoperatively and their correlation with traditional methods of visual function evaluation analysed. RESULTS: Postoperatively there was no significant improvement in mean logMAR VA. However, eight (40%) subjects improved by two or more ETDRS lines and nine eyes (45%) reached a final VA of 6/18 or better. Metamorphopsia decreased significantly (p = 0.019) and there was significant improvement in VFQ-25 mean scores for the general vision (p = 0.03), distance activities (p = 0.05), and composite score (p = 0.03). Baseline binocular VA was significantly correlated with baseline VFQ-25 composite score (r = 0.631, p = 0.004). CONCLUSIONS: ERM surgery appears to improve patients' subjective perception of visual function as indicated by higher composite scores in VFQ-25 and improved metamorphopsia in the absence of significant improvement in mean logMAR VA.

The effect of pars plana vitrectomy on cystoid macular oedema associated with chronic uveitis: a randomised, controlled pilot study.

AIM: To evaluate the efficacy of pars plana vitrectomy (PPV) in the management of chronic uveitic cystoid macular oedema (CMO). METHODS: A prospective, interventional, randomised, controlled, pilot study. 23 eyes of 23 patients with CMO secondary to chronic intermediate or posterior uveitis unresponsive to medical treatment were randomised into a surgical (group S) or medical group (group M). 12 patients in group S underwent PPV as opposed to 11 patients in group M who received systemic corticosteroid and/or immunosuppressive treatment during the study period. The primary outcome measures of the study were change in visual acuity and angiographic appearance of CMO at 6 months. RESULTS: Mean visual acuity in group S improved significantly from 1.0 (0.62) at baseline to 0.55 (0.29) at 6 months following vitrectomy (p = 0.011), with five (42%) eyes reaching vision of 20/40 or better. Conversely, mean visual acuity in group M improved only marginally by 0.03 (0.27) (p = 0.785). CMO after vitrectomy was angiographically improved in four (33%) eyes, remained unchanged in seven (58%) eyes, and deteriorated in one (8%) eye. In the medical group, fluorescein leakage decreased in one eye, did not alter in four eyes, and deteriorated in two eyes. CONCLUSION: PPV for macular oedema secondary to chronic uveitis despite angiographic improvement in only one third of the patients, seems to have a significant beneficial effect on visual function. This study provides enough evidence to justify a large scale trial which would define the role of vitrectomy in uveitic macular oedema.

Retinal detachment neuropathology and potential strategies for neuroprotection.

Understanding the neuropathology of retinal detachment from postmortem and animal models allows identification of cellular targets, receptors and mediators for pharmacological manipulation. In this review, concepts of retinal detachment and neuropathology are examined at cellular and structural anatomical levels using postmortem and animal model data. Possible neuroprotective strategies are reviewed in the setting of the new environment created by successful retinal reattachment surgery.

Variability in the content of Indian generic ciprofloxacin eye drops.

BACKGROUND/AIMS: Under-potent generic antibiotics sold in developing world countries may be contributing to positive selection of resistance organisms and to unpredictability in clinical outcome, leading to a loss of confidence among physicians locally. The objective of this study was to determine whether reports of unpredictable outcome for generic ciprofloxacin antibiotic eye drops in India could be the result of inadequate concentration of preparations sold by pharmacies. METHODS: 130 ciprofloxacin eye drop samples sold by pharmacies were collected from seven locations in north, central, and south India; 30 were randomly selected for testing. All samples were assayed using validated methods of reverse phase chromatography and fluorescence detection at a international antibiotic reference laboratory in the United Kingdom. Results were compared with advertised concentrations within the context of internationally accepted variability ranges. RESULTS: In total, six out of the 30 samples tested had ciprofloxacin concentrations lower than the standard advisory ranges of plus or minus 5% of stated content for 3 mg/ml pharmaceutical preparations. The ciprofloxacin content of these eye drops ranged from -36.4% to -16.1% of the stated content (median -21.73%). 24 out of 30 samples were found to be over the standard advisory ranges of plus or minus 5%, at a median of +19.42% (interquartile range (IQR) +14.28 to +25.13). Intra-batch variability of two selected samples was wide at -22.83% to +33.93% (n=11) and -17.07% to +31.20% (n=12). CONCLUSIONS: Approximately 20% of generic ciprofloxacin eye drops, purchased without prescription in India were under-potent. In a number of preparations the antibiotic content was sufficiently low as to have a potential impact on clinical outcome and possibly lead to the selection of resistant isolates in individual patients. More widespread studies are justified to identify the extent of under-potency of widely used generic antibiotic medications in developing countries.

The incidence of unexplained visual loss following removal of silicone oil.

PURPOSE: To assess the incidence and clinical features of unexpected visual loss after removal of silicone oil (ROSO). PATIENTS AND METHODS: A retrospective cross-sectional observational study of 421 consecutive eyes, which underwent silicone oil removal at one institution over a 2-year period. RESULTS: Fourteen (3.3%) patients, (12 male, mean age of 53.1 years) suffered unexplained visual loss. In these eyes, the mean duration of silicone oil fill was 141 days (range 76-218). The mean loss of visual acuity was 3.7 (range 2-6) Snellen lines (SL) at 1 month, 3.5 (2-6) SL at 3 months and 2.91 (0-6) SL at 6 months. The change from preoperative visual acuity was statistically significant at all visits (P=0.02). Subgroup analysis of 20 fovea-sparing giant retinal tear (GRT) detachments, observed 10 (50%) cases of visual loss after ROSO. Electrodiagnostic testing suggested predominantly macular dysfunction, with optic nerve involvement in one case. Five of the 14 cases had variable recovery of vision. CONCLUSION: There is a 3.3% overall incidence of visual loss following ROSO with a high rate (50%) observed in maculae on GRT detachments. Although recovery of visual acuity is seen in a minority of cases, visual loss after ROSO remains a serious and unexplained concern for vitreoretinal surgeons.

Soluble TNF receptors in vitreoretinal proliferative disease.

PURPOSE: To measure vitreous levels of soluble TNF-receptors (sTNF-Rs) types I and II in eyes with rhegmatogenous retinal detachment (RRD), uncomplicated or complicated with proliferative vitreoretinopathy (PVR), and in eyes with proliferative diabetic retinopathy (PDR). To examine whether there is any relationship between vitreous levels of sTNF-Rs and clinical features of these conditions and between vitreous sTNF-Rs and TNFalpha levels and serum levels of sTNF-RS: METHODS: Vitreous levels of sTNF-Rs and TNFalpha were measured by enzyme-linked immunosorbent assay in 30 eyes with PVR, 30 eyes with uncomplicated RRD, and 29 eyes with PDR. Vitreous from eyes of 10 deceased donors and 9 eyes with macular holes served as control specimens. Serum levels of sTNF-Rs were measured in 17 patients with PDR and 21 patients with PVR. RESULTS: Vitreous levels of sTNF-Rs I and II were increased in eyes with PVR, RRD, and PDR when compared with control eyes (P < 0.002). However, vitreous levels of sTNF-Rs I and II were higher in eyes with PVR than in eyes with RRD (P < 0.01) or PDR (P < 0.03). This contrasted with the findings that serum sTNF-Rs were higher in PDR than in PVR (P < 0.016) and that vitreous levels of TNFalpha were higher in eyes with PDR than in eyes with PVR (P < 0.0005). In PVR, vitreous sTNF-Rs levels were associated with the duration of retinal detachment, number of previous external operations, and grade of severity, whereas in PDR these levels were not related to the type or duration of diabetes or its complication with traction retinal detachment. CONCLUSIONS: These observations suggest the existence of TNF inhibitory mechanisms within the eye during retinal processes of inflammation and angiogenesis. That high vitreous levels of sTNF-Rs relate to severity of retinopathy suggests that these molecules may constitute reactive products of inflammation. Effective control of TNFalpha activity by sTNF-Rs within the retinal microenvironment may determine the outcome and severity of retinal proliferative conditions.

CD4+ lymphocyte involvement in ocular Behçet's disease.

Despite extensive study, the pathogenic mechanisms of Behçet's disease remain uncertain. The ocular inflammation caused by this disease is severe, often causing significant visual loss and, although the nature of the cellular infiltrate has been examined in many of the involved organs, the infiltrating cells in inflamed eyes have not. To investigate the mechanisms involved in perpetuating the ocular inflammation, five enucleated eyes from patients with Behçet's disease were examined by immunohistochemical staining using a panel of monoclonal and polyclonal antibodies. Control eyes from patients with chronic intraocular inflammation from other causes were also examined. Cellular infiltrates were a consistent finding in choroid and periretinal scar tissue, formed almost entirely by mononuclear cells. T lymphocytes were found to predominate (largely the CD4+ subset). B lymphocytes and NK cells were infrequent findings but macrophages were present in significant numbers. No complement or immunoglobulin deposits were found. Infiltrating lymphocytes and macrophages were HLA DR positive. Retinal vascular and retinal pigment epithelium were only occasionally positive. Our findings suggest that cell mediated immunity, rather than immune complex deposition is responsible for the perpetuation of the ocular inflammation in Behçet's disease and that CD4+ T lymphocytes play a central role in this.

Combined pars plana vitrectomy and sutured posterior chamber implant.

OBJECTIVE: To describe the surgical technique, visual acuity results, and complications of sutured posterior chamber intraocular lenses with complete pars plana vitrectomy. METHOD: A retrospective review of 63 eyes was combined with a telephone survey of the patients and their ophthalmologists. RESULTS: The preoperative diagnoses were trauma, 25 eyes; ectopia lentis, 24 eyes; aphakia following retinal detachment surgery, 7 eyes; cataract surgery, 6 eyes; and endophthalmitis, 1 eye. Mean follow-up was 20 months. Preoperative best-corrected visual acuity was 20/40 or better in 36% (23 of 63 eyes), 20/60 to 20/120 in 33% (21 of 63 eyes), and 20/200 or worse in 31% (19 of 63 eyes) improving to 20/40 or better in 76% (48 of 63 eyes), 20/60 to 20/120 in 18% (11 of 63 eyes), and 20/200 or worse in 6% (4 of 63 eyes) at final follow-up. Preoperative complications included iatrogenic retinal breaks in 3 cases, difficulty with a fixation suture in 1 case, and mild vitreous hemorrhage in 1 case. Postoperative complications included retinal detachment in 2 cases, choroidal hemorrhage in 1 case, intermittent pupil capture in 9 cases, self-limiting vitreous hemorrhage in 3 cases, and late intraocular lenses dislocation in 1 case. CONCLUSIONS: Suturing a posterior chamber implant concurrently, or following, a complete pars plana vitrectomy is a safe procedure. Complete vitrectomy may reduce the rate of long-term complications. Optimal visual rehabilitation can be achieved without the need for contact lens wear with an acceptable additional risk of surgical complications. Arch Ophthalmol. 2000;118:905-910

Macular hole opercula. Ultrastructural features and clinicopathological correlation.

OBJECTIVE: To investigate the ultrastructural features of idiopathic full-thickness macular hole (FTMH) opercula excised during vitrectomy and to correlate them with the outcome of surgery. METHODS: Opercula were collected from eyes undergoing vitrectomy for stage 3 FTMH using noncrushing, cupped foreign body forceps. Following immediate fixation, specimens were processed for transmission electron microscopy. The ultrastructural features were correlated with the clinical data recorded for each patient before and after surgery. RESULTS: Eighteen specimens were studied. Native vitreous collagen was identified on the surface of all 18, while fragments of internal limiting membrane were present in 11 (61%). Eleven (61%) were found to contain only glia, comprising fibrous astrocytes and Müller cells in variable proportions. The remaining 7 (39%) were found to contain, in addition to glia, neurites and synaptic complexes, of which some were typical of cone photoreceptors. The initial surgical closure rate was significantly better in eyes in which only glia were present (9/11 [82%]), compared with those with neurites (1/7 [14%]) (P = .01). Once closure had been achieved with reoperation, the median final visual acuity was 20/60 in both groups (P = .26), although the likelihood of achieving an acuity of 20/40 or better was greater in the former (50%) than the latter group (17%). CONCLUSIONS: Two distinct types of opercula occur in association with stage 3 FTMH--those containing only glia (pseudo-opercula), which are probably associated with a foveal dehiscence and little or no loss of foveal tissue, and those containing both glia and a significant number of avulsed foveal cones (true opercula), which arise from a full-thickness foveal tear. Although the loss of foveal tissue in true opercula would seem to explain the worse initial anatomical and more modest visual results in some eyes, significant visual improvement may still be achieved after successful closure. The presence of neurites in true opercula suggests that, in at least some cases, direct traction on the foveal retina leads to macular hole formation.

Progression of an iris melanoma over 41 years.

An iris melanoma first recorded in 1945 progressed over a period of 41 years to produce secondary glaucoma resulting in enucleation. The case illustrates the advancing nature of such lesions.

Posterior penetrating injury of the orbit with retained foreign body.

A case of a retained orbital foreign body following a penetrating injury in a 2-year-old boy is described. Diagnosis and management of such cases is discussed.

Comparison of the expression of interferon gamma, IL2, IL4, and lymphotoxin mRNA in experimental autoimmune uveoretinitis.

The aim of this study was to investigate the T lymphocyte subsets involved in experimental autoimmune uveoretinitis (EAU) by quantifying the numbers of cells expressing mRNA for each of the lymphokines interferon gamma, interleukin 2, interleukin 4, and lymphotoxin throughout the disease process. Lewis rats were immunised with retinal S-antigen to provide a model of inflammatory eye disease. In situ hybridisation using cDNA probes specific for interferon gamma, IL2, IL4, and lymphotoxin mRNA were utilised to localise lymphokine mRNA expression by infiltrating cells and the numbers of positive cells counted. Localisation of mRNA for all four probes was found on increasing cell numbers as the disease process progressed. Similar numbers of cells expressed mRNA for each lymphokine, generally a small percentage of the T lymphocyte total. Activated cells within the eye express mRNA for interferon gamma, IL2, IL4, and lymphotoxin in EAU suggesting a mixed population of T lymphocyte subsets.

Multifocal posterior uveitis: clinical and pathological findings.

A pathological study was performed on the necropsy eyes of a 59-year old-woman who had suffered for nine years from multifocal posterior uveitis. The disease had been controlled by steroid therapy with good preservation of visual function. Extensive investigation did not reveal the aetiology. On macroscopic examination numerous focal lesions with various degrees of pigmentation were observed scattered across the fundi. These lesions were studied by light and electron microscopy and immunohistochemistry. There was ongoing chorioretinal inflammation in the foci, producing destruction of Bruch's membrane, the retinal pigment epithelium (RPE), and the outer retina. The focal scars showed migration of RPE and glial cells and neovascularisation. Capillary and venule endothelial cells were swollen at the inflammatory sites. Attempts to establish a cause for this condition were unsuccessful.

Acute posterior multifocal placoid pigment epitheliopathy complicated by central retinal vein occlusion.

A case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) complicated by a central retinal vein occlusion five weeks after presentation is described. After eight months' follow-up there was mild residual visual impairment, macular scarring, and angiographic changes. The association of these two conditions is discussed.