J. Carlos Pastor

Proliferative Vitreoretinopathy: An Overview

Proliferative vitreoretinopathy (PVR) is still the most common cause of failure of surgery for rhegmatogenous retinal detachment, despite the substantial effort that has been devoted to better understanding and managing this condition during the past 25 years. Basic research has indicated that PVR represents scarring, the end stage of the wound-healing process that occurs after retinal detachment surgery. Medical treatment has been directed toward preventing inflammation, the first phase of the wound healing process, and inhibiting cell proliferation, the second phase. The 1983 Retina Society classification was modified in 1989 by the Silicone Study Group, whose classification differentiates between posterior and anterior forms of PVR and recognizes three patterns of proliferation: diffuse, focal, and subretinal. The anterior form has a worse prognosis than the posterior form, and its treatment requires more complex surgical procedures. In this review, risk factors and pathobiology of PVR are discussed, and management of PVR of various degrees of severity are considered.

Proliferative vitreoretinopathy: risk factors and pathobiology

Proliferative vitreoretinopathy (PVR) is still a major cause of failure of retinal detachment surgery. Despite a dramatic increase in our pathobiologic knowledge of PVR during the last 10 years, little of this information has been used to modify the surgical management of the disease, and, thus, the anatomic and functional results are still unsatisfactory. Collaborative research involving clinicians and basic researchers must be encouraged. PVR must be considered a multifactorial disease caused by interaction of several cells and intra- and extraocular factors. Therefore, therapeutic options based on the inhibition of one factor or phenomenon may be regarded with scepticism. To prevent PVR, it is necessary to determine the factors involved in its development, and because of its relatively small prevalence, large, prospective, multicenter studies seem necessary. In addition, clinical research must not be underestimated. PVR affects both sides of the retina and the retina itself, a point to which little attention has been paid and that is critical for surgical results. Therefore, a new classification that provides information about clinical relevance, such as the evolutionary stages of the disease (biologic activity) and the degree of surgical difficulty (location of the fibrotic process), seems necessary.

Ocular Surface Alteration after Long-term Treatment with an Antiglaucomatous Drug

BACKGROUND This study was undertaken to see whether long-term locally applied ocular medications produced any alterations in the ocular surface, and, in particular, whether it caused damage to the mucus layer of the tear film. METHODS The authors studied the ocular surface of 40 control subjects (group 1), 21 patients (group 2) chronically treated with a commercial preparation of 0.5% timolol maleate, and 20 previously untreated glaucomatous patients (group 3) in need of treatment with the same drug. Parameters studied were Schirmers test, lacrimal meniscus height, break-up time, fluorescein and rose Bengal stains, conjunctival impression cytology, mucus staining, and the ferning test. RESULTS Patients in groups 2 and 3 showed a significant decrease (P less than 0.001) in the number of normal Schirmers and break-up time tests. All had positive vital stains. Results showed a significant decrease (P less than 0.001) in goblet-cell density, mucus granules, and reticular sheets, and an increase (P less than 0.001) in pathologic crystallization patterns. CONCLUSION These results demonstrate that chronic application of a commercial preparation of timolol maleate damaged the ocular surface, especially the mucus layer of the tear film.

Epidermal growth factor and corneal wound healing. A multicenter study.

A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in five centers to assess safety, ocular tolerance, and efficacy of an ophthalmic solution of epidermal growth factor (EGF) for the treatment of traumatic corneal epithelial defects. One hundred four patients completed the study: 47 received EGF and 57 placebo (the drug vehicle). Mean epithelial healing time was significantly enhanced in the EGFtreated group (44.17 h) compared with the placebotreated group (61.05 h) (p<0.01). The number of epithelial defects completely healed at 24, 48, and 72 h after the onset of treatment was significantly greater in the EGFtreated group. Local tolerance was adequate in both groups. These results indicated that topical EGF is well tolerated and may be a significant addition to the ophthalmologists armamentarium for treating corneal epithelial defects.

Characterization of epithelial primary cultures from human conjunctiva

Primary cultures of human epithelial cells from normal conjunctiva were developed and characterized to determine whether they retained epithelial characteristics. Conjunctival explants were obtained from the upper fornix of healthy donors and cultured in supplemented DMEM/F-12 medium for 5 days. The epithelial outgrowth was maintained for an additional 10 days. Primary cultures were then processed for light microscopy, transmission and scanning electron microscopy (TEM, SEM), and immunocytochemistry. They exhibited typical features of conjunctival epithelium on light microscopy (polygonal morphology, intimate cohesion, production of mucins), TEM (abundant desmosomes, keratin bundles, granules, microvilli), SEM (polygonal shape, microvilli, intimate cohesion), and immunocytochemistry (positivity for the receptor of epidermal growth factor, desmosomal proteins, and cytokeratins). In conclusion, primary cultures developed from normal human conjunctiva maintained the epithelial characteristics in vitro. Because the conjunctiva is a major component of the anterior ocular surface, we propose this in vitro system as suitable for physiopathologic and toxicologic studies.

Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical consequences

During the last four decades, proliferative vitreoretinopathy (PVR) has defied the efforts of many researchers to prevent its occurrence or development. Thus, PVR is still the major complication following retinal detachment (RD) surgery and a bottle-neck for advances in cell therapy that require intraocular surgery. In this review we tried to combine basic and clinical knowledge, as an example of translational research, providing new and practical information for clinicians. PVR was defined as the proliferation of cells after RD. This idea was used for classifying PVR and also for designing experimental models used for testing many drugs, none of which were successful in humans. We summarize current information regarding the pathogenic events that follow any RD because this information may be the key for understanding and treating the earliest stages of PVR. A major focus is made on the intraretinal changes derived mainly from retinal glial cell reactivity. These responses can lead to intraretinal PVR, an entity that has not been clearly recognized. Inflammation is one of the major components of PVR, and we describe new genetic biomarkers that have the potential to predict its development. New treatment approaches are analyzed, especially those directed towards neuroprotection, which can also be useful for preventing visual loss after any RD. We also summarize the results of different surgical techniques and clinical information that is oriented toward the identification of high risk patients. Finally, we provide some recommendations for future classification of PVR and for designing comparable protocols for testing new drugs or techniques.

Intraretinal immunohistochemistry findings in proliferative vitreoretinopathy with retinal shortening.

To report the major intraretinal pathological changes in retinas with proliferative vitreoretinopathy (PVR) and retinal shortening, 13 human retinal samples from postoperative PVR after primary surgery for retinal detachment were immunostained for vimentin, glial fibrillary acidic protein (GFAP), cytokeratins, and CD68. One more sample was studied with electron microscopy. Retinal disorganization, neuronal loss, and gliosis were observed in 12 out of 13 samples, but all 13 were positive for GFAP. Müller cell processes showed different degrees of intermediate filament hyperplasia. CD68-positive cells were present in 11 of 13 retinal samples. Conclusion: A gliotic response plays a major role in retinal shortening in PVR. In addition, the presence of macrophage-like cells in retinal tissues suggests a possible role of these cells in the pathogenesis of this variety of PVR.

Efficacy of Nedocromil Sodium and Cromolyn in an Experimental Model of Ocular Allergy

Background Because ocular allergic disorders are important in terms of frequency and severity, there is a constant search for new topical antiallergic drugs. Nedocromil sodium has recently been introduced as a potential substitute for the mast cell stabilizer cromolyn sodium. Objective We compared the efficacy of topical 2% nedocromil sodium to that of 2% cromolyn sodium in treatment of the early-phase reaction of an experimental model of allergic conjunctivitis. Methods Guinea pigs were challenged topically with egg albumin 14 days after systemic immunization. Fifteen minutes before, immediately prior to, and 15 minutes after topical challenge, the animals received either 2% nedocromil sodium or 2% cromolyn sodium topically in one eye and phosphate buffered saline (PBS) in the other eye. Antigen-induced increase in vascular permeability was measured by the extravasation of intravenously injected Evans blue dye. Animals that were immunized and topically challenged but did not receive Evans blue were used for histologic studies. Results Evans blue extravasation from ocular tissues significantly decreased in drug-treated eyes compared with PBS-treated eyes (P Conclusions Topical 2% nedocromil sodium reduces the early-phase reaction of the allergic response as effectively as 2% sodium cromoglycate in a guinea pig model of ocular anaphylaxis.

Development of predictive models of proliferative vitreoretinopathy based on genetic variables: the retina 4 project.

PURPOSE Machine learning techniques were used to identify which of 14 algorithms best predicts the genetic risk for development of proliferative vitreoretinopathy (PVR) in patients who are experiencing primary rhegmatogenous retinal detachment (RD). METHOD Data from a total of 196 single nucleotide polymorphisms in 30 candidate genes were used. The genotypic profile of 138 patients with PVR following primary rhegmatogenous RD and 312 patients without PVR RD were analyzed. Machine learning techniques were used to develop statistical predictive models. Fourteen models were assessed. Their reproducibility was evaluated by an internal cross-validation method. RESULTS The three best predictive models were the lineal kernel based on the Support Vector Machine (SMV), the radial kernel based on the SVM, and the Random Forest. Accuracy values were 78.4%, 70.3%, and 69.3%, respectively. The more accurate, although complex, algorithm uses 42 SNPs, whereas the simpler one uses only two SNPs, which makes them more suitable for routine diagnostic work. The radial kernel based on SVM uses 10 SNPs. The best individually predictor marker was rs2229094 in the tumor necrosis factor locus. CONCLUSION Genetic variables may be useful to predict the likelihood of the development of PVR. The predictive capabilities of these models are as good as those observed with clinical approaches. These results need external validation to estimate the true predictive capability and select the most appropriate ones for clinical use.

Intravitreal silicone and fluorosilicone oils: pathologic findings in rabbit eyes

Abstract The effects of medical‐grade intraocular silicone and commercial‐grade fluorosilicone oils were studied in rabbit eyes. The experimental model consisted of lensectomized and vitrectomized eyes that did not undergo further treatment (Group 1), and three groups of lensectomized and vitrectomized eyes that were injected intravitreously 3 months earlier with medical‐grade silicone oil of 1000 cs (Group 3), and 10 000 cs (Group 4). The silicone oil‐injected eyes developed proliferative membranes. The fluorosilicone oil caused an intravitreous inflammatory reaction with vacuolated macrophages present around the oil that may have been due to the higher concentration of low‐molecular‐weight components found in the oil.