Pharmacological therapy for proliferative vitreoretinopathy

We developed an animal model in the rabbit eye with intravitreally injected heterotransplanted bovine retinal pigment epithelial cells to test a pharmacological agent which would reduce extracellular matrix formation. Results with 20 and 60 g ofcis-hydroxyproline showed a 48% decrease in the rate of traction retinal detachments.Supported in part by National Institute of Health Grant no. 5 R01EY03874-03 and Research to Prevent Blindness, Kentucky Lions Eye FoundationPresented at the 1984 meeting of the Club Jules Gonin in Lausanne, Switzerland     

增生性玻璃体视网膜病变的药物治疗进展

孔源性视网膜脱离并发的增生性玻璃体视网膜病变(proliferative vineoretinopathy，PVR)为一系列的细胞活动，即去分化细胞的形成、迁移、粘附及增殖，形成视网膜表面膜并收缩，导致视网膜脱离手术失败。临床上对于PVR的手术治疗效果尚不理想。药物治疗包括柔红霉素、5-氟尿嘧啶和维甲酸等的应用。文章就PVR药物治疗的种类和不同给药途径作一简要回顾。     

Mechanisms in proliferative vitreoretinopathy

The wound-healing paradigm for proliferative vitreoretinopathy has provided numerous avenues for investigation into the pathobiology of the process. The emerging picture is a complex interaction of cytokines, matrix proteins, and metalloproteinases influencing cell behavior and resulting in the formation of undesirable periretinal membranes. It seems unlikely that focusing therapy on one particular target will be sufficient to stop the entire cascade of cellular events leading to proliferative vitreoretinopathy. Rather, multiple adjunctive agents targeted at different stages of the process and given at the appropriate time might be more successful in achieving improved visual outcomes for patients.     

Patomechanisms in proliferative vitreoretinopathy

Proliferative vitreoretinopathy (PVR) remains the most common cause of recurrent retinal detachment following retinal detachment surgery. The development of PVR is a complex process involving humoral and cellular factors. Surgical treatment of PVR, which consists of removal of the fibrous membranes and restoration of physiological anatomic ocular conditions is often unsuccessful. Therefore the surgery should by backed up by local medication to inhibit new formation of proliferative lesions. Unfortunately, there is no satisfactory antiproliferative treatment available so far. Proliferative vitreoretinopathy remains a therapeutic challenge.     

Apoptosis in proliferative vitreoretinopathy

PURPOSE: To study the involvement of apoptosis using different apoptosis markers in PVR pathogenesis. METHODS: The presence of mRNA coding for Fas, Fas ligand (FasL), and TNF-related apoptosis inducing ligand (TRAIL) was investigated in vitreous samples from 46 consecutive patients-25 with PVR, 11 with retinal detachment (RD) not complicated by PVR, and 10 with macular hole (MH)-using RT-PCR. From previously examined vitreous samples, 21 PVR, 9 RD, and 10 MH were examined for their levels of TGF-beta2 protein with sandwich ELISA kits. Five epiretinal membranes excised from five patients with PVR were also examined for apoptotic cell death using the terminal deoxytransferase (TdT) mediated dUTP-biotin nick end labeling (TUNEL) technique. RESULTS: FAS mRNA was detected in 72% of patients with PVR, 55% of patients with RD and 20% of patients with MH. TRAIL mRNA was detected in 67% of patients with PVR, 89% of patients with RD, and 20% of patients with MH. FasL mRNA was detected in 20% of patients with PVR, 9% of patients with RD, and 10% of patients with MH. The median levels of Fas and TRAIL mRNA were significantly higher (P < 0.05) in patients with PVR than in those with MH hole but between patients with PVR and those with RD the difference was not significant (P > 0.05). A significant difference was detected between RD and MH for TRAIL mRNA levels (P = 0.008). For FasL, no significant difference between groups was found. TGF-beta2 was detected in all investigated vitreous samples. A significant difference was found between the PVR and MH groups (P = 0.001) and between the RD and MH groups (P = 0.004), but not between the PVR and RD groups (P < 0.05). The level of TGF-beta2 was significantly correlated to the level of TRAIL mRNA (r = 0.86), but no correlation was found between TGF-beta2 and Fas mRNA levels (r = 0.21). Four of five examined PVR epiretinal membranes showed positive staining for apoptotic cells using the TUNEL technique. CONCLUSIONS: Apoptosis is one of the mechanisms that is involved in PVR pathogenesis. Different apoptosis markers suggest different pathways occur in PVR, including Fas/FasL, TRAIL, and TGF-beta2 mediated processes.     

Anterior proliferative vitreoretinopathy

During a four-year period, 53 of 92 eyes (58%) undergoing vitreoretinal surgery for a retinal detachment with proliferative vitreoretinopathy demonstrated anterior proliferative vitreoretinopathy. We classified anterior proliferative vitreoretinopathy according to tractional direction, location, extent, and severity. Initially, the eyes were treated with a high scleral buckle and laser endophotocoagulation as an adjunct to vitrectomy. Treatment then evolved into a direct approach in which the anterior proliferative tissue was surgically cut or excised. Of the 42 eyes followed up for at least six months, 25 (59%) were totally reattached and 18 (43%) had a visual acuity of 5/200 or better.     

Evaluation of radiation therapy for experimental proliferative vitreoretinopathy in rabbits

We evaluated effects of radiation therapy on experimental proliferative vitreoretinopathy (PVR) induced in rabbits by double gas compression of the vitreous followed by homologous dermal-skin fibroblast injection. Electrons were irradiated in two rabbit groups. Group A animals (20 eyes) received 1000 cGy of irradiation immediately after cell injection; group B rabbits (9 eyes), which showed pucker formation 7 days after cell injection, were irradiated on that day at the same dose as was given to group A rabbits. Control animals (14 eyes) were not irradiated. The incidences of traction retinal detachment on day 28 were: control, 86%; group A, 10%; and group B, 22%. There were statistically significant differences between control and group A values and between control and group B values. No significant difference was found between group A and group B. Irradiation of 1000 cGy did not alter the histological picture of experimental PVR. The results showed that radiation suppressed the development of PVR when applied not only immediately after cell injection but also during pucker stages.This study was partly supported by Grant-in-Aids for Scientific Research A-61440075 and 01010042 from the Ministry of Education, Science and Culture of the Japanese government     

增生性玻璃体视网膜病变中组织型转谷氨酰胺酶的表达

目的:检测增生性玻璃体视网膜病变(PVR)视网膜前膜和视网膜色素上皮(RPE)细胞中组织型转谷氨酰胺酶(tTG)的表达情况,探讨tTG是否参与PVR的发病过程.方法:PVR患者21例,收集视网膜前膜,C级8例,D级13例,行tTG免疫组织化学染色.另对培养3-5代的人RPE细胞分别用含有1 00mL/L PVR玻璃体液、正常玻璃体液和PBS的DMEM培养液进行孵育24h后行tTG免疫细胞化学染色.光镜下观察,比较C级和D级膜的表达阳性率,显微图像分析测量3组RPE细胞染色的平均灰度值.结果:在PVR视网膜前膜中tTG呈阳性表达(81%),C级和D级膜表达阳性率无差异 (C级88%,D级77%,P＞0.05).培养的人RPE细胞表达tTG,在PVR患者的玻璃体液作用下,tTG表达的平均灰度值为137.0±2.6,与正常玻璃体液组(143.5±2.9)及PBS对照组(143.6±3.0)相比,表达水平升高(P＜0.05).结论:PVR视网膜前膜和培养的人RPE细胞tTG表达阳性,在PVR患者的玻璃体液作用下,RPE细胞的tTG表达水平升高,这表明tTG参与了PVR的发病过程,在PVR视网膜前膜的形成过程中可能有重要作用.     

Keratinocyte transglutaminase in proliferative vitreoretinopathy

PURPOSE: Proliferative vitreoretinopathy (PVR) is an excessive wound-healing process and the major complication in rhegmatogenous retinal detachment. The present study was designed to investigate the expression of keratinocyte transglutaminase (kTgase) in PVR membranes and retinal pigment epithelial (RPE) cells and to evaluate its expression in response to growth factors known to be increased in PVR disease. METHODS: Distribution of kTgase and its relation to fibronectin have been investigated immunohistochemically. PVR membranes and native and cultured RPE cells were analyzed by RT-PCR for the presence of kTgase mRNA. In vitro, RPE cells were treated with transforming growth factor (TGF)-beta2, basic fibroblast growth factor, interleukin-6, and interleukin-1beta. Expression of kTgase was studied by Northern and Western blot analysis. The effect of connective tissue growth factor (CTGF) silencing on the TGF-beta2-modulated expression of kTgase was investigated by transfection with CTGF small interfering (si)RNA before TGF-beta2 treatment. RESULTS: mRNA expression of kTgase was present in all PVR membranes. Immunohistochemical staining for kTgase showed an inhomogeneous pattern with localized accumulation and little colocalization with fibronectin. Although native RPE cells contained only a basal level of kTgase mRNA, the expression of kTgase was increased under culture conditions and was further enhanced by TGF-beta2 treatment. Silencing of CTGF expression did not attenuate the TGF-beta2-mediated induction of kTgase. CONCLUSIONS: The findings demonstrate that kTgase is present in PVR membranes. Its amount is related to the differentiation state of RPE cells and stimulation by TGF-beta2. TGF-beta2-mediated increase seems to be independent of CTGF.     

Subretinal membranes in proliferative vitreoretinopathy

Subretinal membranes (SRMs) are an important but rarely identified component of proliferative vitreoretinopathy (PRV). In 153 consecutive cases that had vitreoretinal surgery for this condition and were followed for at least 6 months, SRMs were encountered in 72 eyes (47%). In 20 (28%) of the 72 eyes, the SRMs prevented complete retinal reattachment and needed to be removed or excised through one or multiple retinotomies. Intraoperative complications related to the SRMs or their removal included choroidal or retinal hemorrhage in three eyes (15%), subretinal air in three eyes (15%), and unplanned extension of the retinotomies in two eyes (10%). The 20 eyes requiring SRMs removal were followed for a median of 11 months. Retinas were reattached in 13 eyes (65%), although only 4 eyes (20%) had a visual acuity of 5/200 or better. Recognizing SRMs as a component of PVR is important in helping to maximize the anatomic success rate although the effects on visual function are not fully known.     

增殖性玻璃体视网膜病变的玻璃体手术治疗

目的 评估玻璃体手术治疗增殖性玻璃体视网膜病变的疗效。方法 Ｃ２级以上ＰＶＲ合并视网膜脱离２１眼,特发性ＰＶＲ１４眼,外伤性ＰＶＲ７组,Ｃ级９眼,Ｄ级１２眼,均作常规玻璃体切除术联合环扎、膜剥离、视网膜切开、气体或硅油填充等附加术式。结果随访２～９个月,视网膜复位１５眼（７８．９％）,视力提高２０眼（９５．２％）。４眼手术失败,均系ＰＶＲ再次复发所致。结论 现代玻璃体手术是治疗严重ＰＶＲ的理想术     

增殖性玻璃体视网膜病变的玻璃体手术治疗

目的 评估玻璃体手术治疗增殖性玻璃体视网膜病变（ＰＶＲ）的疗效。方法 Ｃ２级以上ＰＶＲ合并视网膜脱离２１眼,其中特发性ＰＶＲ１４眼,外伤性ＰＶＲ７眼;Ｃ级９眼,Ｄ级１２眼,均作常规玻璃体切除术联合巩膜环扎、膜剥离、松解性视网膜切开、气体或硅油填充等附加术式。结果 出院时２１眼视网膜全部复位（１００％）,１９眼随访２～９个月,视网膜复位成功率为７８．９％（１５／１９）、术后视力提高９５．２％（２０／     

Experimental gene therapy for an in vitro model of proliferative vitreoretinopathy

BACKGROUND: Proliferative vitreoretinopathy (PVR) is the leading cause of failure of retinal reattachment surgery. Since a key component of PVR is cell proliferation, we performed a study to examine whether the ribonucleotide-reductase-deficient herpes simplex virus type I (HSV-I) mutant hrR3 can be effective at destroying proliferating retinal pigment epithelial (RPE) cells and thus prevent epiretinal membrane formation and PVR, while sparing nondividing cells, such as neurons. METHODS: Primary cultures of rat RPE cells and rat cortical neurons were infected with 300 microL of hrR3 HSV-I to achieve a multiplicity of infection of 1.0. After 1 hour at 37 degrees C, 700 microL of growth medium was added to raise the total volume of medium to 1 mL. At 0, 12, 24 and 36 hours the cultures were observed, and the ratio of dead cells to live cells was determined. HSV infection and protein expression were confirmed by a beta-galactosidase histochemical assay or an antihuman HSV-I immunoassay, or both. RESULTS: At 24 hours more than 95% of the RPE cells and neurons stained positively for HSV infection, although beta-galactosidase was expressed predominantly in RPE cells. At 36 hours 72% (standard deviation 2.1%) of the RPE cells were dead. There was no noticeable cell death in the neuronal or mock-infected control cultures. INTERPRETATION: The results suggest that the hrR3 mutant strain of HSV-I can be used to infect and selectively kill actively proliferating rat RPE cells while sparing normal, nonreplicating cells. This model may be used to explore potential therapies for PVR in humans.     

增生性玻璃体视网膜病变增生膜再塑型机制的研究

目的 观察不同病程增生性玻璃体视网膜病变（PVR）增生膜中不同细胞成分、细胞外基质（ECM）、基质金属蛋白酶（MMPs）及其抑制剂（TIMPs）随病程变化的规律，探讨PVR增生膜的再塑型机制。 方法 病程2个月至8年的孔源性视网膜脱离伴PVR患者的增生膜手术标本16例，用免疫组织化学方法标记增生膜中视网膜色素上皮（RPE）细胞、胶质细胞等不同的细胞成分，纤维连接蛋白（FN）、层粘连蛋白（l aminin）、Ⅰ～Ⅳ型胶原等不同ECM成分，以及MMPs（MMP2、MMP9）和TIMP1，分析不同病程PVR增生膜中各标记成分的变化以及与病程的相关性。 结果 随PVR病程延长，增生膜中RPE细胞、MMP2、FN表达逐渐减少(P=0.014，P=0.001，P=0.008)， 胶质细胞、Ⅰ、Ⅲ型胶原逐渐增多（P=0.022，P=0.001，P=0.008)，层粘连蛋白和Ⅱ、Ⅳ型胶原均有表达，但不随病程变化。RPE细胞、MMP2、纤维连接蛋白的表达与病程呈负相关，胶质细胞、Ⅰ、Ⅲ型胶原的表达与病程呈正相关；MMP2与FN变化呈正相关。MMP9、TIMP1始终都有表达，但不随病程变化。 结论 在PVR增生膜形成和发展的过程中，增生膜中的RPE细胞、胶质细胞、FN、Ⅰ、Ⅲ型胶原、MMP2参与了PVR的再塑型过程。 (中华眼底病杂志， 2006， 22： 308-312）     

Vitreopapillary traction in proliferative diabetic vitreoretinopathy

AIM: To present the clinical profile of a new entity in advanced proliferative diabetic vitreoretinopathy (PDVR). Mechanisms of vision loss due to vitreopapillary traction on the nasal optic disc are described, followed by an introduction of methods for prevention and treatment in such cases. METHODS: 17 patients with PDVR and traction on the nasal side of the optic disc, pallor of the optic nerve head, and reduced visual acuity were included in the study. Six patients were observed retrospectively and 11 patients prospectively before and after pars plana vitrectomy. Pre- and postoperative examinations included visual acuity, Goldmann's visual field, fluorescein angiography, and measurements of visual evoked potentials (VEP). RESULTS: During a postoperative follow up period of 3 to 24.5 months (mean 14.5 months) an improvement in optic disc appearance combined with an increased visual acuity (mean increase in VA = 0.171) was observed in 15/17 (88.3%) patients. In addition, 8/17 (47%) of these patients showed higher VEP amplitudes (mean 3.83 microV), and eight (6/8 of the same patients as VEP amplitudes) patients showed a reduction of latency (mean reduction 22.25 ms) during VEP assessment. CONCLUSION: These results suggest that vitreopapillary traction may damage the anterior optic nerve, via decreased axoplasmatic flow in the optic nerve fibres and/or mechanical reduction of perfusion in the posterior ciliary arteries. The effects of each mechanism appear to be reversible, but in the long term might lead to irreversible optic nerve atrophy. Therefore, in patients with vitreopapillary traction, early vitrectomy should be considered as a method to prevent optic neuropathy.     

Iris neovascularization in proliferative vitreoretinopathy.

PURPOSE: The purpose of this study is to report on the prevalence, incidence, and associated risk factors of iris neovascularization in nondiabetic patients undergoing vitrectomy for retinal detachment complicated by proliferative vitreoretinopathy (PVR). METHODS: The authors conducted a retrospective review of 141 consecutive non-diabetic patients undergoing vitrectomy for recurrent retinal detachment resulting from PVR. Univariate and multivariate analyses were performed on all patients to determine which preoperative, intraoperative, and postoperative factors were associated with the development of postoperative iris neovascularization. RESULTS: Twenty-seven of the 141 (19%) patients were noted with preoperative and/or postoperative iris neovascularization. Four of eight patients presenting with preoperative iris neovascularization had complete regression after successful reattachment of the retina. Results of analysis of the remaining 133 patients without iris neovascularization preoperatively showed residual retinal detachment as the most significant risk factor for postoperative iris neovascularization. In the absence of panretinal photocoagulation, none of the 27 patients developed neovascular glaucoma. CONCLUSIONS: The development of iris neovascularization preoperatively or post-operatively is not necessarily a predictor of a poor anatomic and/or visual result. Iris neovascularization in PVR rarely if ever progresses to neovascular glaucoma. Panretinal photocoagulation is not indicated in these patients. Retinal reattachment is the most important factor in the prevention and/or resolution of postoperative iris neovascularization. The development of iris neovascularization in PVR appears to be a multifactorial process requiring multiple variables acting in concert.     

Clinical diagnosis of proliferative vitreoretinopathy

The clinical features of a proliferative vitreoretinopathy (PVR) are systematically described. The patient's history reveals moderate lost of vision and metamorphopsia. Ophthalmoscopy, biomicroscopy of the fundus with the contact lens, and black-and-white photography usually lead to the correct diagnosis. Early stages of PVR are characterized by increased reflectance and a cellophane appearance of the inner retinal surface and tortuosity of both small and larger vessels. Advanced epiretinal tissue formation causes development of surface wrinkling and single or multifocal star-folds. In cases of retinal detachment with PVR, the retina is immobile, the detachment being concave due to traction or bullous if there are secondary breaks. In the final stages of posterior and/or anterior PVR the detached retina forms a narrow or closed funnel.     

Current management of proliferative vitreoretinopathy

The recognition of APVR and its dissection, along with the use of perfluorocarbon liquids, has greatly improved the success rate in surgery for severe PVR. In reviewing our first 71 cases using these techniques, 75% were attached with one operation and 90% were attached with one or more operations. These techniques have greatly improved our operative results and have obviated the use of retinal tacks and suturing, retinotomy (in most cases), and the need for very high scleral buckles. (We rarely alter an in-place scleral buckle.)