Zdenek J. Gregor

Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study.

Objectives To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration. Design Prospective, double masked, multicentre, randomised controlled trial. Setting Three ophthalmology centres in the United Kingdom. Participants 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control. Interventions Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration). Main outcome measures Primary outcome: proportion of patients gaining ≥15 letters of visual acuity at one year (54 weeks). Secondary outcomes: proportion of patients with stable vision and mean change in visual acuity. Results Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care. Conclusions Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075

Intravitreal growth factors in proliferative diabetic retinopathy: correlation with neovascular activity and glycaemic management

AIM Many growth factors are implicated in proliferative diabetic retinopathy (PDR). It was decided to test the hypothesis that no one factor is predominant but that a regular profile of levels of different growth factors might be operating, and that the profile might differ according to whether or not insulin therapy was part of the patient’s glycaemic management. The levels of several growth factors in vitrectomy samples were therefore determined from diabetic patients with tractional, non-haemorrhagic sequelae of PDR and these levels were correlated with (a) each other (growth factor profile), (b) neovascular activity, and (c) the method of glycaemic management (insulin treated (IT) or non-insulin treated (NIT)). METHODS 72 samples of vitreous were obtained from either diabetic patients with PDR (n = 51) or non-diabetic (control) patients (n = 21). Levels of bFGF, IGF-I, EGF, and insulin were determined by radioimmunoassay; levels of TGF-β2 by ELISA; and levels of IGF-I binding protein by western ligand blotting. The data were analysed using appropriate statistics. RESULTS There was no regular growth factor profile. bFGF levels were significantly greater in vitreous from NIT patients compared with IT patients and controls. The highest levels of bFGF were found in NIT patients with actively vascularised membranes. TGF-β2 levels were significantly greater in vitreous from IT patients compared with NIT patients and controls The highest levels of TGF-β2 were found in IT patients with actively vascularised membranes. IGF-I levels were significantly greater in diabetics (irrespective of insulin treatment) than non-diabetics and the highest levels of IGF-I were found in IT patients with actively vascularised membranes. A 34 kDa IGFBP was the predominant IGFBP identified in vitreous and was found to be elevated in diabetics patients. CONCLUSION In PDR there is a correlation between intravitreal growth factor levels and both disease state (whether active or fibrotic) and method of glycaemic management.

Matrix metalloproteinases and their natural inhibitors in fibrovascular membranes of proliferative diabetic retinopathy

AIM To examine epiretinal membranes of proliferative diabetic retinopathy (PDR) for the presence of selective matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), in order to determine whether neovascularisation and fibrosis, characteristic of this complication of diabetes mellitus, are associated with specific anomalies of MMP or TIMP expression. METHODS The presence of selected MMPs and TIMPs was investigated in 24 fibrovascular epiretinal membranes of PDR, and the findings compared with that observed in 21 avascular epiretinal membranes of proliferative vitreoretinopathy (PVR) and five normal retinas. Specimens were examined for deposition of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase A (MMP-2), gelatinase B (MMP-9), and three tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, and TIMP-3). RESULTS The results showed that unlike normal retina, which constitutively expresses MMP-1 and TIMP-2, a large proportion of PDR membranes (> 62%) stained for MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, and TIMP-3. There were no differences in the expression of these molecules when compared with PVR membranes. A characteristic staining for MMP-9 was observed within the perivascular matrix of PDR membranes, and there was a significant increase in TIMP-2 expression by PDR membranes (p= 0.036) when compared with PVR membranes. CONCLUSIONS The findings that MMPs involved in degradation of fibrovascular tissue matrix, as well as TIMP-1 and TIMP-2, are found in a large proportion of PDR membranes, and that their expression does not differ from that of PVR membranes, suggest the existence of common pathways of extracellular matrix degradation in pathological processes leading to retinal neovascularisation and fibrosis.

Pars plana vitrectomy with and without peeling of the inner limiting membrane for diabetic macular edema

Purpose: A prospective, comparative, nonrandomized study to evaluate the efficacy of pars plana vitrectomy (PPV) with and without inner limiting membrane (ILM) peeling for persistent diffuse clinically significant macular edema. Methods: Eighteen patients with persistent diffuse clinically significant macular edema despite laser photocoagulation were recruited for the study. Clinical assessment included determination of best-corrected visual acuity, fundus fluorescein angiography, optical coherence tomography, and perifoveal cone function testing. Eight patients underwent PPV with elevation and removal of the posterior hyaloid alone, and 10 patients underwent vitrectomy and ILM peeling. The follow-up was 12 months. Results: Patients with ILM peeling had improvement in foveal thickness (P = 0.07) and significant improvement in the macular volume (P = 0.039) 12 months after surgery but did not have significant improvement in Early Treatment Diabetic Retinopathy Study vision or perifoveal cone function. There was no significant difference in outcome parameters between the no peeling group and the ILM peeling group. Conclusions: In this prospective, comparative study of PPV with and without ILM peeling for diffuse clinically significant macular edema, structural improvement was seen but with limited visual improvement after ILM peeling.

The use of corticosteroids for choroidal neovascularisation in young patients.

Purpose To investigate the role of systemic corticosteroids in the treatment of sight-threatening choroidal neovascularisation (CNV) in patients with punctate inner choroidopathy (PIC) and multifocal inner choroiditis (MIC).Methods Twelve eyes of 10 patients with evidence of PIC or MIC with recent visual symptoms were identified. All eyes had CNV within the foveal avascular zone on fundus fluorescein angiography (FFA). Systemic oral prednisolone at an initial dose of 1 mg/kg (60-80 mg) was given for 3-5 days and the dose was subsequently tapered. Changes in best corrected visual acuity and leakage on FFA were recorded during follow-up. Systemic side-effects of the corticosteroids were monitored.Results In 10 of 12 eyes vision improved or stabilised. Leakage on FFA resolved in 9 eyes and was reduced in 3. Four patients required more than one course of oral corticosteroids. One patient was maintained on low-dose oral corticosteroids for recurrent CNV activity. No systemic complications from the treatment were observed.Conclusion A course of oral corticosteroids in healthy young patients with subfoveal CNV in PIC or MIC may reduce subretinal vascular leakage and stabilise vision when no other proven treatment option is available.

Visual field loss following vitrectomy for stage 2 and 3 macular holes.

AIM--To describe the phenomenon of peripheral field loss following routine pars plana vitrectomy for stage 2 and 3 full thickness macular hole and to investigate the underlying mechanism. METHODS--Five patients, who reported peripheral field defects after apparently uncomplicated vitrectomy, posterior cortical vitreous peeling, and perfluoropropane (C3F8) gas tamponade, were studied retrospectively with slit-lamp biomicroscopy, automated and kinetic perimetry, fundal fluorescein angiography, focal electroretinography (ERG), and colour contrast sensitivity (CCS) testing. RESULTS--All five patients, who were between 50 and 73 years of age, reported an inferotemporal field defect following resolution of the intraocular gas bubble. In all eyes, the scotomata encroached to within 20 degrees to 30 degrees of fixation and to within 5 degrees to 15 degrees of the blind spot. In one eye, a partial altitudinal component was evident. All scotomata subsequently remained stable and three eyes developed subtle segmental nasal disc pallor and nerve fibre loss corresponding to the field defect. CCS testing revealed absent colour contrast in the scotomatous area, in the presence of a preserved focal quadrantic flash ERG, compared with normal CCS protan thresholds and focal ERGs in unaffected quadrants, indicating preserved outer retinal function in the area of the scotoma. CONCLUSIONS--These observations support the hypothesis that field defects occur as a result of retinal nerve fibre layer damage. It is proposed, on the basis of intraoperative observations and other evidence, that the most likely site of nerve fibre damage is at the nasal portion of the optic nerve rim or peripapillary retina, probably due to traction during cortical vitreous peeling.

Macular holes: vitreoretinal relationships and surgical approaches

Idiopathic full-thickness macular holes develop as a result of anteroposterior and tangential traction exerted by the posterior vitreous cortex at the fovea. Vitreoretinal relationships during the development of macular holes can be demonstrated in detail by ocular coherence tomography, facilitating an improved understanding of their pathogenesis and guiding clinical management. Surgical strategies for the repair of macular holes are designed to relieve vitreofoveal traction and to promote flattening and reapposition of the macular hole edges by intraocular gas tamponade. A period of face-down positioning postoperatively is conventionally advised. However, the evidence to support this recommendation is weak and practice varies considerably. Surgical removal of the inner limiting membrane (ILM) is advocated to ensure thorough removal of any tangential tractional components including any residual cortical vitreous. Current evidence suggests that ILM peeling can improve anatomical outcomes but the effect on visual function is less predictable; unsuccessful attempts to peel the ILM can be associated with poor visual outcome. The use of vital dyes can facilitate visualisation of the ILM and help achieve complete, atraumatic peeling. Indocyanine green dye can enable high rates of macular hole closure but has been associated with poorer visual outcomes suggesting a dose-dependent toxicity. Trypan blue dye offers an alternative that may have a more favourable risk profile. An improved understanding of vitreoretinal relationships may facilitate a tailored approach to surgery in individuals with macular holes. Vitrectomy to relieve anteroposterior traction is central in the management of all full-thickness holes. The use of long-acting gases, prolonged face-down positioning, and ILM peeling may be more valuable for larger holes, longstanding holes, and those that have failed to close following conventional surgery.

Incidence of idiopathic full-thickness macular holes in fellow eyes: A 5-year prospective natural history study

PURPOSE This study aimed to determine the incidence of idiopathic full-thickness macular hole (FTMH) in normal fellow eyes and to evaluate the role of electrodiagnostic and psychophysical tests in identifying eyes at risk. PATIENTS AND METHODS A prospective longitudinal natural history study of a cohort of patients with unilateral holes and normal, asymptomatic fellow eyes without posterior vitreous detachment was conducted. Subjects underwent baseline examination, pattern reversal electroretinography, electro-oculography (EOG), and color contrast sensitivity (CCS) testing for protan, deutan, and tritan thresholds and were recalled for clinical examination at 18 months and 5 years. RESULTS At baseline, 114 patients were examined. Eighty were available for review at 18 months, of whom 6 had full-thickness macular holes develop in the fellow eye. At 5 years, 67 of the remaining 74 patients who had not developed holes at 18 months were re-examined and a further 5 were found to have holes develop in the fellow eye. A posterior vitreous detachment without hole formation had developed in 20 fellow eyes at 5 years. Although mean pattern reversal electroretinography and EOG responses were within normal limits in affected and fellow eyes at baseline, mean CCS protan, deutan, and tritan thresholds were elevated significantly in affected eyes at baseline (P = 0.0001). Unaffected fellow eyes showed normal mean protan and deutan thresholds, but significantly elevated mean tritan thresholds (P = 0.01) at baseline. Mean tritan CCS loss was, however, similar in fellow eyes in which holes later developed and in fellow eyes in which holes did not. CONCLUSIONS The Kaplan-Meier estimated risk of fellow eye involvement is 15.6% (range, 8.4%-22.3%; P = 0.05) at 5 years. Although electrodiagnostic and psychophysical testing was not predictive of fellow eye involvement, tritan CCS loss at baseline, in apparently normal fellow eyes, may indicate subclinical foveal dysfunction, the nature of which is unclear.

Is prophylactic 360° laser retinopexy protective?: Risk factors for retinal redetachment after removal of silicone oil

OBJECTIVES To identify risk factors for retinal redetachment after removal of silicone oil. To determine the effectiveness of prophylactic laser in preventing retinal redetachment after removal of silicone oil. DESIGN A nonrandomized retrospective comparative interventional trial. PARTICIPANTS Three hundred seventy-six patients undergoing vitrectomy with silicone oil tamponade for rhegmatogenous retinal detachment at one institution over a 4-year period. Two hundred eighty-seven patients with fully attached retinas subsequently underwent removal of silicone oil. One hundred thirty-eight cases had undergone prophylactic 360 degrees laser retinopexy before removal of silicone oil, either at the time of their final retinal reattachment procedure (n = 36) or as a separate supplementary procedure (n = 102). METHODS A retrospective case note review was performed to identify clinical and demographic factors associated with increased or reduced odds of retinal redetachment after removal of silicone oil. Both univariate and multiple variable analysis were used to identify significant risk factors. MAIN OUTCOME MEASURES Incidence of retinal redetachment after removal of silicone oil. RESULTS Median follow-up after removal of silicone oil was 272 days. Three hundred sixty-degree prophylactic laser retinopexy was associated with a reduction from 26% to 14% in the incidence of redetachment after removal of silicone oil (adjusted odds ratio, 0.42; 95% confidence interval, 0.22-0.78; P = 0.006). Patients requiring further retinal reattachment surgery after their first oil procedure were at twice the odds of re-detachment after oil removal (adjusted odds ratio, 2.10; 95% confidence interval, 1.03-4.26; P = 0.04). CONCLUSIONS The need for retinal reattachment surgery subsequent to a first silicone oil procedure was associated with twice the odds of retinal redetachment after removal of silicone oil. Prophylactic laser retinopexy may halve the incidence of retinal redetachment after removal of silicone oil.

Angiopoietin concentrations in diabetic retinopathy

Background/aim: Angiopoietin 1 and 2 interact with vascular endothelial growth factor (VEGF) to promote angiogenesis in animal and in vitro models. Although VEGF concentrations are elevated, there is little information regarding angiopoietin concentration in the vitreous of patients with diabetic retinopathy. Methods: Angiopoietin concentrations were measured by luminescence immunoassay in vitreous samples from 17 patients with non-proliferative diabetic retinopathy (NPDR) and clinically significant diabetic macular oedema (CSMO), 10 patients with proliferative diabetic retinopathy (PDR), and five patients with macular hole (controls) obtained at pars plana vitrectomy. Results: Angiopoietin 1 concentrations were low in patients with macular hole (median 17 pg/ml) while in NPDR with CSMO they were 2002 pg/ml (range 289–5820 pg/ml) and in PDR 186 pg/ml (range 26–2292 pg/ml). Angiopoietin 2 concentrations in NPDR with CSMO were a median of 4000 pg/ml (range 1341–14 329 pg/ml). For both macular hole and PDR patients angiopoietin 2 was below the limit of detection. Conclusions: Angiopoietin 2 concentration was twice that of angiopoietin 1 in NPDR with CSMO. Angiopoietin 2 is the natural antagonist of angiopoietin 1 which is thought to act as an anti-permeability agent. The predominance of angiopoietin 2 may allow VEGF induced retinal vascular permeability in patients with CSMO. The relatively low concentration of both angiopoietin 1 and 2 in patients with proliferative diabetic retinopathy may reflect the established nature of the neovascularisation in cases proceeding to vitrectomy.