Anthony H. Chignell

Cytokines in proliferative vitreoretinopathy

This study determined the presence of interleukin 1 (IL-1), interleukin 6 (IL-6), tumour necrosis factor α (TNFa), tumour necrosis factor β (TNFβ), interferon γ (IFNγ), transforming growth factor β2 (TGFβ2) and fibroblast proliferation activity (FPA) in vitreous aspirates from eyes undergoing vitrectomy for the treatment of retinal detachment complicated by proliferative vitreoretinopathy (PVR) or uncomplicated retinal detachment (RD). Cadaveric vitreous from normal subjects were used as controls. The results showed that IL-1 and IL-6 predominated in vitreous from eyes with PVR or RD, and that concentrations of IL-6 >20 pg/ml were more frequently found in PVR than in RD (p = 0.031) or control specimens (p = 0.006). Low levels of TNFa were observed in 4/18 eyes with PVR, 1/15 eyes with RD and 1/15 control vitreous, and small concentrations of TNFα were seen in 3/18 eyes with PVR, 1/15 eyes with RD and 2/15 control vitreous. IFNγ was detected in 12/18 eyes with PVR, but only in 5/15 eyes with RD (p = 0.048) and 6/15 control specimens. TGFβ2 was present in all vitreous samples at concentrations ranging from 100 to 4,500 pg/ml with no significant differences among the three groups. Control vitreous possessed the greatest FPA when compared with vitreous from eyes with PVR (p = 0.031) or RD (p = 0.048). These observations provide further evidence that cytokine-mediated pathways of inflammation are involved in the pathogenesis of PVR and point to the possible involvement of IL-1, IL-6 and IFNγ in cellular interactions leading to chronicity.

Distribution of TNF alpha and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy.

AIMS: This study investigated the presence of the cytokine tumour necrosis factor alpha (TNF alpha) and the vascular adhesion glycoproteins ICAM-1, VCAM-1, E-selectin, P-selectin, and PECAM within fibrovascular membranes of eyes with proliferative diabetic retinopathy (PDR). METHODS: The presence of these molecules was determined by immunohistochemical staining using monoclonal antibodies and the APAAP technique. RESULTS: Staining for TNF alpha was observed on the retinal vascular endothelium of five of 12 specimens, on infiltrating cells within all membranes, and on the extracellular matrix of nine specimens. This staining wa abolished by absorption of the monoclonal antibody with human recombinant TNF alpha. Likewise, ICAM-1 staining was given by infiltrating cells and extracellular matrix of nine membranes and by the endothelium of three of the specimens. VCAM-1, E-selectin, and P-selectin staining was observed on the vascular endothelium of 5/12, 4/12, and 3/12 epiretinal membranes respectively. PECAM was expressed by the endothelium of 4/12 specimens, by infiltrating cells of 8/12 membranes, and also by the extracellular matrix of two of the specimens. CONCLUSION: The widespread distribution of TNF alpha and the nature of the adhesion molecules expressed by vascular endothelial cells in PDR membranes suggest that local activation of TNF alpha and enhanced expression of vascular cell adhesion molecules may play an important role in the development of the proliferative phase of diabetic retinopathy.

Pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment uncomplicated by advanced proliferative vitreoretinopathy.

A consecutive series of 114 eyes (112 patients) undergoing pars plana vitrectomy for rhegmatogenous retinal detachment not complicated by severe proliferative vitreoretinopathy is presented (follow up 1 to 4 years; mean 19 months). The indications for vitrectomy fell into two main groups: (1) where the retinal view was poor and vitrectomy was required to clear media opacities to allow identification of retinal breaks (n = 62); and (2) where technically difficult breaks existed and vitrectomy with internal tamponade was used to relieve vitreoretinal traction and facilitate retinal break closure (n = 44). In some of these cases the need for scleral buckling was eliminated. A smaller third group (n = 8) existed where the position of the break(s) was uncertain in the presence of an adequate view. The success rate with one procedure was 74% and with further surgery retinal reattachment was achieved in 92%. At 6 months after further surgery, beyond which interval no new failures were encountered, best corrected visual acuity was improved in 92 eyes (81%), unchanged in 14(12%), and worse in eight (7%). We conclude that pars plana vitrectomy is an effective method for treatment of selected cases of rhegmatogenous retinal detachment not complicated by proliferative vitreoretinopathy.

Distribution of cytokine proteins within epiretinal membranes in proliferative vitreoretinopathy.

This study reports on the immunohistochemical staining for cytokine proteins of 26 epiretinal membranes obtained from eyes undergoing surgery for the treatment of proliferative vitreoretinopathy. All specimens were investigated for the distribution of staining for interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) and interleukin-2 (IL-2). The results showed that 22 of the membranes (85%) stained for TNF alpha not only intracellularly but also in the extracellular matrix. This contrasts with the findings that only 2 membranes stained for IL-1 alpha and that another 3 were positive for IL-1 beta. Staining for the cytokines IL-6 and IFN gamma was also observed in 9 and 7 membranes respectively. None of the specimens investigated stained with antibodies to IL-2 or control antibodies, and none of three normal retinas stained with any of the antibodies used. Pre-absorption of anti-cytokine antibodies with the corresponding human recombinant cytokines abolished staining of cells and extracellular matrix. The present findings support growing evidence that cytokine-mediated pathways of inflammation are involved in the pathogenesis of proliferative vitreoretinopathy, and draw attention to the possibility that interaction between extracellular matrix-bound cytokine and inflammatory leucocytes or resident cells of the retina may promote the development and perpetuation of this condition.

Pars plana vitrectomy for retinal detachment with unseen retinal holes

A study was made of a consecutive series of 47 cases of rhegmatogenous retinal detachment treated by pars plana vitrectomy in which no holes were identified preoperatively. The view of the fundus during preoperative examination varied from being totally clear to completely obscured by media opacities. The role of pars plana vitrectomy in finding retinal holes peroperatively is considered. The incidence of discovering holes and the locations of those found at the time of surgery are presented. The significance of these findings is discussed. Where the preoperative view was good and the extent of proliferative vitreoretinopathy (PVR) did not exceed grade C2, retinal reattachment was achieved in 75% of the cases. A review made of a similar group of patients treated with conventional retinal buckling before the introduction of pars plana vitrectomy revealed that successful retinal reattachment was achieved in 70% of cases. The study concludes that pars plana vitrectomy, while being necessary for cases of rhegmatogenous retinal detachment when the view of the retina is obscured, will not always reveal the presence of a retinal break. If the preoperative view of the retina was good and the extent of PVR did not exceed grade C2, pars plana vitrectomy did not seem to offer obvious advantages over conventional buckling procedures.

Expression of mRNA coding for TNFα, IL-1β and IL-6 by cells infiltrating retinal membranes

Abstract• Background: Cellular mechanisms of inflammation are thought to be involved in the pathogenesis of proliferative vitreoretinopathy, and cytokines, which are products of cell activation, are known to play an important role in the development and maintainance of inflammatory reactions. It was the aim of this work to investigate the presence of cells expressing cytokine mRNA within retinal membranes. • Methods The presence of mRNA coding for the cytokines interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor α (TNFα) was investigated in 19 epiretinal membranes obtained from eyes undergoing vitrectomy for the treatment of retinal detachment complicated by proliferative vitreoretinopathy. • Results Cells expressing mRNA for IL-1β were observed in 7 membranes, cells positive for IL-6 mRNA were seen in 12 membranes, and cells exhibiting mRNA for TNFα were present in 9 specimens. Only three membranes contained cells expressing mRNA for all the cytokines investigated. Four membranes possessed positive cells for IL-6 and TNFα, two contained cells expressing mRNA for IL-6 and IL-1β, and two others exhibited cells expressing mRNA for TNFα and IL-1β. Five membranes contained IL-6 mRNA-positive cells only, whilst two exhibited cells expressing mRNA for IL-1β, or TNFα only. • Conclusion The present findings indicate that cellular activation may occur during the development of PVR, and suggest that these cytokines may be locally produced by cells infiltrating epiretinal membranes. The presence of IL-1β, IL-6 and TNFα mRNA-positive cells within retinal membranes provides further evidence of a pathogenic role of these cytokines in proliferative vitreoretinopathy.

Pseudophakic retinal detachment.

The clinical findings, surgical techniques, anatomic results and visual recovery in 71 pseudophakic and 71 aphakic eyes with retinal detachment repaired concurrently were compared. Preoperative visibility of the peripheral retina was significantly reduced in the pseudophakic group. Intraoperative identification of retinal breaks was useful for the pseudophakic eyes. The surgical techniques used in the two groups were similar. Anatomic success was achieved in 65 pseudophakic eyes (92%) and 63 aphakic eyes (89%); however, the visual recovery after a mean follow-up period of 18 months was poorer in the pseudophakic group, only 35 (54%) of which, compared with 39 (62%) of the aphakic group, had a final best-corrected visual acuity of 6/15 or better.

Primary vitrectomy for rhegmatogenous retinal detachment: an analysis of failure.

Purpose To find the cause of failure in primary vitrectomy for rhegmatogenous retinal detachment. Methods Retrospective review of 171 consecutive cases of RRD treated by primary pars plana vitrectomy (PPV) from a tertiary referral centre to identify the 25 cases in which surgery had failed. Detachments with giant or macula breaks at initial presentation, with proliferative diabetic retinopathy or with PVR greater than grade B were excluded. Results The failure rate after the first operation was 14.6% and the commonest cause of failure was missed retinal breaks, accounting for 64.3% of failures. Conclusion Missed retinal breaks are the commonest cause of failure of primary PPV for RRD although proliferative vitreoretinopathy may contribute to surgical failure. This re-emphasises the importance of assiduous peroperative retinal examination.

Vitreous levels of intercellular adhesion molecule 1 (ICAM-1) as a risk indicator of proliferative vitreoretinopathy

AIM To investigate whether high vitreous levels of the soluble intercellular adhesion molecule 1 (sICAM-1) may be related to clinical risk factors of proliferative vitreoretinopathy (PVR) and whether their measurement may serve as an additional risk indicator of this complication in eyes with rhegmatogenous retinal detachment (RRD). METHODS Levels of sICAM-1 were measured by enzyme linked immunosorbent assays (ELISA) in vitreous from 36 eyes with RRD clinically considered to be at high risk of developing PVR (large retinal breaks, vitreous haemorrhage, long standing RRD, and previous vitreoretinal surgery). Levels of sICAM-1 in this group were compared with those in vitreous from 31 eyes with RRD without clinical risk factors for PVR, 32 eyes with established PVR and 10 eyes with macular holes. RESULTS Vitreous from eyes with RRD at high risk of developing PVR contained significantly higher levels of sICAM-1 (range 6.1–97.7 ng/ml; Mann–Whitney test, p=0.0002) than those from eyes with RRD at low risk of developing this complication (range 4.8–17.7 ng/ml). Vitreous sICAM-1 levels in eyes with RRD at high risk of developing PVR were significantly lower than in eyes with established PVR (p=0.037), but higher than in eyes with macular holes (p <0.0001). Levels of sICAM-1 ⩾15 ng/ml (3 × median of the levels present in control eyes) provide a useful cut off point for a highly specific test (96.7%) with high positive (91.6%) and negative (96.7%) predictive values, despite a relatively low sensitivity (30.5%). CONCLUSIONS The present findings suggest that laboratory measurement of sICAM-1 levels in vitreous from eyes with RRD may constitute an additional factor for identifying patients at high risk of PVR. Hence, determination of sICAM-1 levels may aid in the monitoring of patients likely to develop this complication and in the identification of patients who may benefit from adjuvant anti-inflammatory therapy.

Proliferative vitreoretinopathy : An examination of the involvement of lymphocytes, adhesion molecules and HLA-DR antigens

This paper addresses the molecular basis of interactions between leucocytes, other cells in the vitreoretinal environment and extracellular matrix that may underlie the pathogenesis of proliferative vitreoretinopathy. In this study we report the expression of adhesion molecules (CD11a, CD11c, CD18 and ICAM-1), lymphocyte surface markers (CD3, CD4, CD8 and CD22) and HLA-DR molecules in 25 epiretinal membranes obtained from eyes undergoing vitrectomy for the treatment of retinal detachment complicated by epiretinal membrane formation. Retinas from normal cadaveric eyes were used as controls. The results showed that cells expressing the adhesion molecules CD11a, CD11c and CD18 were present in 5 of 25, 17 of 25 and 11 of 23 membranes, respectively. Cells stained with antibodies against intracellular adhesion molecule 1 (ICAM-1) were observed in 24 of 25 membranes, whilst HLA-DR positive cells were seen in all membranes investigated. Immunohistochemical staining revealed that the molecules ICAM-1 or HLA-DR were not only expressed on inflammatory cells but also distributed within the extracellular matrix in several specimens. Lymphocytes expressing CD3 markers were present in 12 of 25 membranes, whilst T lymphocytes expressing CD4 and CD8 markers were observed in 5 of 18 and 12 of 24 membranes, respectively. In contrast, B lymphocytes expressing CD22 molecules were not found in any of the membranes. Leucocyte surface molecules were not expressed in control cadaveric retinas, although occasional cells expressing ICAM-1 were identified in the inner plexiform layer. The present findings indicate that selective interaction between infiltrating leucocytes and adhesion molecules present in extracellular matrix may well be involved in epiretinal membrane formation, and that T lymphocytes may play an important role in the pathogenesis of proliferative vitreoretinopathy.