Vitreous composition modification after transpalpebral electrical stimulation of the eye: Biochemical analysis.

Electrical stimulation (ES) of the eye represents a therapeutic approach in various clinical applications ranging from retinal dystrophies, age-related macular degeneration, retinal artery occlusion and nonarteritic ischemic optic neuropathy. In clinical practice, ES of the eye is mainly performed with a transcorneal or transpalpebral approach. These procedures are non-invasive and well-tolerated by the patients, reporting only minimal and transient adverse events, while serious adverse effects were not observed. Despite the growing literature on animal models, only clinical parameters have been investigated in humans and few data are available about biochemical changes induced by ES of the eye. The purpose of this study is to investigate the possible mechanism that regulates the beneficial effects of ES on retinal cells function and survival in humans. 28 patients undergoing pars plana vitrectomy (PPV) for idiopathic epiretinal membrane (iERM) were randomly divided in two groups: 13 patients were treated with transpalpebral ES before surgery and 15 underwent surgery with no prior treatment. Vitreous samples were collected for biochemical analysis during PPV. ES treatment leads to a reduction in the vitreous expression of both proinflammatory cytokines, namely IL-6 and IL-8, and proinflammatory lipid mediators, such as lysophosphatidylcholine. Indeed, we observed a 70% decrease of lysophosphatidylcholine 18:0, which has been proven to exert the greatest proinflammatory activities among the lysophosphatidylcholine class. The content of triglycerides is also affected and significantly decreased following ES application. The vitreous composition of patients undergoing PPV for iERM displays significant changes following ES treatment. Proinflammatory cytokines and bioactive lipid mediators expression decreases, suggesting an overall anti-inflammatory potential of ES. The investigation of the mechanism by which this treatment alters the retinal neurons leading to good outcomes is essential for supporting ES therapeutic application in various types of retinal diseases.

Two cases of diabetic macular edema complicated by an atypical macular hole.

BACKGROUND: Here we report two patients who developed an atypical macular hole (MH) during the treatment course for diabetic macular edema (DME). CASE PRESENTATIONS: Patient 1 was a 73-year-old male. Optical coherence tomography (OCT) revealed perifoveal retinoschisis (RS) in addition to cystoid macular edema and serous retinal detachment (SRD) in his left eye, and that an MH had developed during the clinical course. A convex surface was formed at the MH margin toward the vitreous cavity, and granular shadows were observed in the fluid cuff. Intraoperative findings revealed a thin epiretinal macular membrane (ERM) around the MH. Patient 2 was a 79-year-old male. Although the patient underwent pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) in both eyes, RS and a thin ERM in addition to SRD was observed in his left eye after surgery, and an MH developed during the clinical course. As in Patient 1, a convex surface was formed at the fluid cuff margin toward the vitreous cavity. CONCLUSIONS: Both patients had persistent DME, SRD, RS, and a thin ERM before the development of the MH. OCT revealed the formation of a convex surface at the MH margin toward the vitreous cavity, suggesting that the fragility of the layered structure of the retina combined with tangential retinal traction may have been involved in the atypical MH form.

Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern(®) Guidelines.

UNLABELLED: IDIOPATHIC EPIRETINAL MEMBRANE AND VITREOMACULAR TRACTION PREFERRED PRACTICE PATTERN® GUIDELINES: New evidence-based Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern® (PPP) guidelines, describing recommendations for the diagnosis, treatment, and management of patients.

Biomechanical Properties of the Internal Limiting Membrane after Intravitreal Ocriplasmin Treatment.

PURPOSE: To assess the stiffness of the human internal limiting membrane (ILM) and evaluate potential changes of mechanical properties following intravitreal ocriplasmin injection for vitreomacular traction. METHODS: This is an interventional comparative case series of 12 surgically excised ILM specimens consecutively obtained from 9 eyes of 9 patients after unsuccessful pharmacologic vitreolysis with ocriplasmin. During the same time period, 16 specimens from 13 other eyes without ocriplasmin treatment were harvested during vitrectomy and served as controls. All patients presented with macular holes or vitreomacular traction and underwent vitrectomy with ILM peeling either with or without brilliant blue (BB) staining. All specimens were analyzed using atomic force microscopy with scan regions of 25 × 25 µm. In all specimens, both the retinal side and vitreal side of the ILM were analyzed. RESULTS: Atomic force microscopy revealed no significant differences in elasticity of ILM specimens removed from eyes with or without ocriplasmin treatment. Undulated areas of the retinal side presented stiffer than the vitreal side of the ILM. Topographical mapping of both the vitreal and retinal side of the ILM showed no apparent alteration of the morphology in ocriplasmin-treated eyes compared to untreated eyes. Staining with BB resulted in an increase of tissue stiffness. CONCLUSIONS: Intravitreal injection of ocriplasmin does not change biomechanical properties of the human ILM. There is no evidence of a potential enzymatic effect of ocriplasmin interfering with the stiffness of this basement membrane.

Management of Vision-Threatening Complications of Vasoproliferative Tumors of the Retina.

AIMS: To report the management of vision-threatening complications of vasoproliferative tumors of the retina. METHODS: Clinical records of 31 eyes of 30 patients treated at our centers from 1998 through 2013 were reviewed. The main outcome measures included: type of treatment, tumor regression, tumor relapse and final visual acuity. RESULTS: Seventeen patients (57%) underwent vitrectomy for epimacular membranes (n = 10), rhegmatogenous retinal detachment (n = 2), vitreous hemorrhage (n = 2), tractional retinal detachment (n = 1), serous retinal detachment (n = 1) and subhyaloid hemorrhage (n = 1). After the initial treatment, 10 additional surgeries were performed for vitreoretinal complications. Tumor activity was treated in all eyes either with photocoagulation or cryotherapy. Control of tumor activity was achieved in all cases, after treatment of recurrences. There were no statistically significant differences between initial and final visual acuity (p = 0.437). Recurrence showed a statistically significant association with the presence of proliferative vitreoretinopathy (p = 0.024), tumor thickness (p = 0.026), basal diameter (p = 0.031), and use of photocoagulation alone as initial treatment (p = 0.006, logistic regression). CONCLUSION: In our series, more than half of vasoproliferative tumors of the retina required surgery as the initial treatment. Recurrence was associated with tumor size, presence of proliferative vitreoretinopathy, and use of photocoagulation alone as the initial treatment.

Cryotherapy-induced release of epiretinal membrane associated with retinal vasoproliferative tumor: analysis of 16 cases.

PURPOSE: To evaluate epiretinal membrane (ERM) response after cryotherapy for retinal vasoproliferative tumors (VPTs). METHOD: Retrospective interventional case series. RESULTS: Of 16 eyes with VPT and ERM, the tumor was classified as primary in 12 (75%) eyes or secondary in 4 (25%) eyes. The median patient age was 44 years (mean, 43 years; range, 9-70 years). The tumor was located in extramacular zone (n = 16, 100%) and inferotemporal quadrant (n = 12, 75%). The mean tumor base was 6 mm, and thickness was 3 mm. The ERM involved the macula in 12 (75%) eyes and extramacular zone in 4 (25%) eyes, with best-corrected visual acuity of 20/40 or better in 6 (38%) eyes. Associated features included cystoid macular edema (n = 8, 50%), subretinal fluid (n = 10, 63%), vitreous cells (n = 9, 56%), and vitreous hemorrhage (n = 7, 44%). Single-session cryotherapy (double freeze-thaw) to the VPT was performed in each case. Over mean follow-up of 68 months (median, 54 months; range, 8-252 months), tumor regression was documented in 16 (100%) cases, with ERM release in 10 (63%) cases. After ERM release, the foveal anatomy was normal in 12 (75%) eyes. Final visual acuity improved (n = 5, 31%), remained stable (n = 9, 56%), or worsened (n = 2, 13%). Posttreatment best-corrected visual acuity was 20/40 or better in 10 (63%) eyes. CONCLUSION: Cryotherapy is remarkably effective for VPT of 6 mm or less in basal dimension. After cryotherapy, VPT-related ERM spontaneously released in 63% of the cases, without the need for surgical intervention.

Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications.

PURPOSE: To evaluate the effects of intervals between preoperative intravitreal injection of bevacizumab (IVB) and surgery on the components of removed diabetic fibrovascular proliferative membranes. DESIGN: Interventional, consecutive, prospective, comparative case series. PARTICIPANTS: A total of 52 eyes of 49 patients with active diabetic fibrovascular proliferation with complications necessitating vitrectomy. METHODS: Participant eyes that had IVB were divided into 8 groups in which vitreoretinal surgery was performed at days 1, 3, 5, 7, 10, 15, 20, and 30 postinjection. A group of eyes with the same diagnosis and surgical intervention without IVB injection was used for comparison. In all eyes, proliferative membrane specimens obtained during vitrectomy were sent for histopathologic examination using hematoxylin-eosin stain, immunohistochemistry (CD34 and smooth muscle actin), and Masson's trichrome stain. MAIN OUTCOME MEASURES: Comparative analysis of different components of the fibrovascular proliferation (CD34, smooth muscle actin, and collagen) among the study groups. RESULTS: Pan-endothelial marker CD34 expression levels starting from day 5 postinjection were significantly less than in the control group (P < 0.001), with minimum expression (1+) in all specimens removed at or after day 30 postinjection. Positive staining for smooth muscle actin was barely detected in the control eyes at day 1, and consistently intense at day 15 and beyond (P < 0.001). The expression level of trichrome staining was significantly high at day 10, compared with control eyes (P < 0.001), and continued to increase at subsequent surgical time points. CONCLUSIONS: A profibrotic switch was observed in diabetic fibrovascular proliferation after IVB, and our results suggest that at approximately 10 days post-IVB the vascular component of proliferation is markedly reduced, whereas the contractile components (smooth muscle actin and collagen) are not yet abundant.

Treatment for Central-Peripheral Rivalry-Type Diplopia ("Dragged-Fovea Diplopia Syndrome").

PURPOSE: To report the effectiveness of treatments for central-peripheral rivalry (CPR)-type diplopia due to retinal misregistration. DESIGN: Retrospective, interventional case series. METHODS: Fifty adults with retinal misregistration and CPR-type diplopia (minimum frequency of "sometimes" at distance and/or for reading) caused by epiretinal membrane (n = 44) or other retinal disorders (n = 6) were enrolled in this study, conducted at adult strabismus clinics, Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, a tertiary medical center. Treatments included Bangerter filter, adhesive tape, Fresnel prism, clear prism (incorporated into glasses or loose prism in the office), iseikonic manipulation (using iseikonic lenses or contact lenses), a MIN lens, or epiretinal membrane (ERM) peeling (alone or in any combination). Not all patients underwent all of these treatments. RESULTS: Main outcome measurements were diplopia frequency, evaluated using the Diplopia Questionnaire. Success was defined as "never" or "rarely" diplopic for distance and reading, using the Diplopia Questionnaire, at an outcome examination as close as possible to 6 months. Overall, 17 of 50 patients (34%; 95% confidence interval [CI], 21%-49%) were classified as successful. Fresnel prism was successful in 4 of 7 patients (57%; 95% CI, 18%-90%); Bangerter filter in 4 of 28 patients (14%; 95% CI, 4%-33%); ERM peeling in 8 of 18 patients (44%; 95% CI, 22%-69%); and iseikonic manipulation in 1 of 23 patients (using a contact lens; 4%; 95% CI, 0%-22%). CONCLUSIONS: CPR-type diplopia may be relieved in some patients using nonsurgical treatment options consisting of Fresnel prism or Bangerter filter. ERM peeling was surprisingly successful and should be considered.

Laser photocoagulation, intravitreal anti-VEGF, and vitreous surgery for the treatment of juxtapapillary retinal capillary hemangioma.

Juxtapapillary retinal capillary hemangiomas (JRCHs) are benign vascular tumors located on or adjacent to the optic nerve head. A 19-year-old girl presented with epiretinal membrane (ERM) associated with an elevated and round vascular tumoral mass located in the juxtapapillary region of her left eye. She was subsequently diagnosed with isolated JRCH. A combined approach with laser photocoagulation and intravitreal bevacizumab injection was used to facilitate shrinkage of the tumor preoperatively and pars plana vitrectomy was used to remove the tumor and ERM. A small remnant of tumoral mass remained intact and did not show any growth for 7 years.

Surgical Removal of Internal Limiting Membrane and Layering of AAV Vector on the Retina Under Air Enhances Gene Transfection in a Nonhuman Primate.

Purpose: To determine if the surgical removal of the internal limiting membrane (ILM) in nonhuman primates (NHPs) will result in safe and effective transfection of adeno-associated viral (AAV2) vectors using green fluorescent protein (GFP) as a reporter. Methods: Six Macaca fascicularis NHP eyes underwent vitrectomy, ILM peel with layering of 1.7 × 1013 genome copies per milliliter of AAV2-GFP under air. Four control eyes underwent only vitrectomy and pooling under air. The intensity and area transfected was quantified in vivo with fundus autofluorescence (FAF) imaging. NHPs were euthanized 16 weeks postsurgery and immunohistochemical analysis assessed GFP expression at the cellular level. Results: There was a larger area of fluorescence in ILM peeled eyes then in non-ILM peeled eyes (50.7 [33.1-58.4] pixel2 versus 5.1 [0.6-7.6] pixel2, P < 0.01). The intensity of fluorescence was also higher in ILM peeled eyes (10.3 [2.2-18.5] vs. 1.9 [0.6-4.4], P = 0.05). Non-ILM peeled eyes displayed fluorescence confined to the foveal center. Histological sections showed colocalization in the Müller cell layer, ganglion cell layer, and photoreceptor cell layer in the ILM peeled eyes. In non-ILM peeled eyes GFP expression was only in the ganglion cell layer in three eyes and was confined to the immediate vicinity of the fovea. Conclusions: ILM appears to be the predominate barrier to AAV transfection. An efficacious and safe method of AAV2 gene delivery, taking into account the potential need for repeat treatments, appears to be the surgical removal of ILM and layering of AAV under air.v.

Vision Preference Value Scale and Patient Preferences in Choosing Therapy for Symptomatic Vitreomacular Interface Abnormality.

Importance: While symptomatic vitreomacular interface abnormalities (VIAs) are common, assessment of vision preference values and treatment preferences of these may guide treatment recommendations by physicians and influence third-party payers. Objective: To determine preference values that individuals with VIA assign to their visual state and preferences of potential treatments. Design, Setting, and Participants: In this cross-sectional one-time questionnaire study conducted between December 2015 and January 2017, 213 patients from tertiary care referral centers in Thailand, the United Kingdom, and the United States were studied. Patients with symptomatic VIA diagnosed within 1 year of data collection, visual acuity less than 20/20 OU, and symptoms ascribed to VIAs were included. Data were analyzed from January 2017 to November 2017. Main Outcomes and Measures: The primary end points were overall mean preference value that individuals with VIA assigned to their visual state and patients' preferences for potential treatments. Preference values were graded on a scale from 0 to 1, with 0 indicating death and 1 indicating perfect health with perfect vision. Results: Of the 213 included patients, 139 (65.3%) were women, and the mean (SD) age was 65.6 (7.7) years. Diagnoses included epiretinal membrane (n = 100 [46.9%]), macular hole (n = 99 [46.5%]), and vitreomacular traction (n = 14 [6.6%]). The mean (SD) vision preference value was 0.76 (0.15), without differences identified among the 3 VIA types. More participants were enthusiastic about vitrectomy (150 [71.1%]) compared with intravitreal injection (120 [56.9%]) (difference, 14.2%; 95% CI, 5.16-23.3; P = .002). Adjusted analyses showed enthusiasm for vitrectomy was associated with fellow eye visual acuity (odds ratio, 10.99; 95% CI, 2.01-59.97; P = .006) and better-seeing eye visual acuity (odds ratio, 0.03; 95% CI, 0.001-0.66; P = .03). Overall enthusiasm for treatment was associated with fellow eye visual acuity (odds ratio, 7.22; 95% CI, 1.29-40.40; P = .02). Overall, most participants (171 [81.0%]) were enthusiastic about surgery, injection, or both. Conclusions and Relevance: Study participants reported similar preference values among 3 types of VIAs. The data suggest that most patients with these conditions would be enthusiastic about undergoing vitrectomy or an injection to treat it, likely because of the condition's effect on visual functioning, although there may be a slight preference for vitrectomy at this time.

PECULIARITIES OF VITRECTOMY AND MORPHOLOGIC CHANGES IN THE EPIRETINAL MEMBRANE AFTER INTRAVITREAL AFLIBERCEPT IN PATIENTS WITH SEVERE PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To examine the peculiarities of vitrectomy and morphologic changes in the epiretinal membrane after intravitreal aflibercept in patients with proliferative diabetic retinopathy. METHODS: Prospective study of 21 consecutive cases with proliferative diabetic retinopathy complicated by vascularized epiretinal membrane forming tractional retinal detachment that underwent pars plana vitrectomy 4 days after intravitreal injection of aflibercept. After removal, the epiretinal membranes were taken for histologic examination using light microscopy. Obliteration of neovascularization of epiretinal membranes, the lack of bleeding in the intraoperative and early postoperative periods, retinal attachment, and improvement of visual acuity were taken for the criteria of treatment effectiveness. RESULTS: On the fourth day after intravitreal injection, newly formed vessels of epiretinal membranes were completely obliterated. There was no bleeding during segmentation and delamination of epiretinal membranes during vitrectomy. In the early postoperative period, bleeding complications were not noted. A microscopic examination of epiretinal membranes showed single-thin-walled capillary vessels lined with endothelial cells, the lumen of which does not contain blood cells. Capillaries are submerged in the connective tissue of different degrees of maturity. CONCLUSION: Intravitreal aflibercept resulted in the obliteration of neovascularization of epiretinal membranes, thus avoiding intraoperative and postoperative bleeding during vitrectomy. The improvement in visual acuity was noted in all cases. Histologic examination of epiretinal membranes determined single-thin-walled capillary vessels lined with endothelial cells without blood cells.

Immunohistochemical Evaluation of Idiopathic Epiretinal Membranes and In Vitro Studies on the Effect of TGF-ß on Müller Cells.

PURPOSE: The purpose of this study was to investigate the presence of type VI collagen and glial cells in idiopathic epiretinal membrane (iERM) and the role of TGF-ß in the expression of collagens and α-smooth muscle actin (α-SMA) in retinal Müller cells. METHODS: Idiopathic ERM samples from vitrectomy were analyzed for glial acidic fibrillary protein (GFAP), cellular retinaldehyde-binding protein (CRALBP), α-SMA, and type VI collagen using flat-mount immunohistochemistry. To study intracellular collagen expression in relation to cellular phenotype, spontaneously immortalized human Müller cells (MIO-M1) were treated with TGF-ß1 for 48 hours, and the expression of α-SMA and intracellular type I, II, IV, and VI collagens was studied by using immunocytology. Findings in Müller cells were compared with those in fetal lung fibroblasts and newborn skin fibroblasts. RESULTS: A colocalization of GFAP/CRALBP and GFAP/α-SMA was found in iERM, indicating a dynamic process of activation of retinal Müller cells in vivo. Transforming growth factor-ß1 induced up-regulation of α-SMA stress fibers in retinal Müller cells and both types of fibroblasts in vitro. The intracellular staining intensity of type I, II, and VI collagens was decreased in retinal Müller cells containing α-SMA stress fibers, whereas the intracellular staining intensity of type I and VI collagens in both types of fibroblasts was not affected. CONCLUSIONS: Type VI collagen and activated retinal Müller cells are present in iERM. Transforming growth factor-ß1 induces an up-regulation of α-SMA stress fibers in retinal Müller cells and fibroblasts and appears to have a cell-specific effect on intracellular collagen expression.

Histopathological findings in proliferative membrane from a patient with sarcoid uveitis.

BACKGROUND: Sarcoid uveitis is occasionally accompanied by proliferative changes, such as retinal neovascularization and vitreous hemorrhage. Steroid administration, retinal photocoagulation, and vitrectomy may be indicated in such proliferative cases. CASE: A 19-year-old woman presented with proliferative sarcoid uveitis accompanied by recurrent vitreous hemorrhage. OBSERVATIONS: At the initial examination, bilateral vitreous opacity, retinal exudates, mild vitreous hemorrhage, retinal vasculitis, and neovascularization of the retina and optic disc were observed. Although prednisolone was administered and panretinal photocoagulation was performed several times, recurrent vitreous hemorrhage continued. Since the vitreous hemorrhage was not absorbed, pars plana vitrectomy and lensectomy were performed. After surgery, neovascularization and intraocular inflammation decreased, and the corrected visual acuity in the right eye improved to 20/50. Histopathologic analysis of the proliferative membrane removed during surgery revealed substantial neovascularization and numerous neutrophils in the vessels. CONCLUSIONS: Based on these findings, an inflammatory reaction as well as retinal ischemia were thought to be involved in the proliferative changes in this patient.

Management of macular epiretinal membrane by vitrectomy and intravitreal triamcinolone.

A patient underwent successful vitrectomy for macular epiretinal membrane with anatomical and functional improvement. 10 weeks later, there was a recurrence of macular edema with corresponding visual decline. An intravitreal injection of triamcinolone acetonide not only restored the macular anatomy but also improved the visual outcome beyond that achieved after surgery.

[Influence of postoperative oral steroid treatment on retinal sensitivity in patients after macular surgery. A randomized, controlled, clinical trial]. / Einfluss postoperativer oraler Steroidgabe auf die retinale Sensitivität bei Patienten nach Makulachirurgie. Eine randomisierte, kontrollierte, klinische Studie.

BACKGROUND: The aim of this study was to evaluate the effect of postoperative systemic steroid treatment on retinal sensitivity in patients with epiretinal membrane (ERM) after successful surgery. PATIENTS AND METHODS: A total of 28 patients with ERM, macular edema and visual loss were included in this study. All patients were treated with combined 23 gauge vitrectomy and peeling of the ERM and inner limiting membrane (ILM). After randomization the first group (n = 14) was treated with postoperative systemic steroids (100 mg prednisolone per day for 5 days) and the second group (n = 14) served as a control group. Follow-up examinations were performed up to 12 months. RESULTS: After 12 months a statistically significant increase in visual acuity with a gain of 17/10 letters in the steroid/control group as well as significant decrease of the central retinal thickness of 107/128 µm could be observed (p < 0.05). In the steroid/control group mean retinal sensitivity increased from 14.0/14.3 dB after 12 months in comparison to 11.7/11.9 dB at baseline examination (p < 0.05). CONCLUSIONS: Postoperative oral steroid treatment does not seem to be beneficial in patients with macular pucker surgery.

Idiopathic vitreomacular traction and macular hole: a comprehensive review of pathophysiology, diagnosis, and treatment.

Posterior vitreous detachment (PVD) is a common phenomenon in the aging eye. However, this may be complicated by persistent symptomatic vitreomacular adhesions that exert tractional forces on the macula (vitreomacular traction; VMT). VMT itself may be associated with epiretinal membrane formation and the development of idiopathic macular holes (IMH). Such pathologies may cause visual disturbances, including metamorphopsia, photopsia, blurred vision, and decreased visual acuity, which impact an individual's quality of life. Technologies such as optical coherence tomography allow an increasingly more accurate visualisation of the macular anatomy, including quantification of macular hole characteristics, and this facilitates treatment decision-making. Pars plana vitrectomy remains the primary treatment option for many patients with VMT or IMH; for the latter, peeling of the inner limiting membrane (ILM) of the retina has shown improved outcomes when compared with no ILM peeling. The development of narrow-gauge transconjunctival vitrectomy systems has improved the rate of visual recovery following surgery. Ocriplasmin, by degrading laminin and fibronectin at the vitreoretinal interface, may allow induction of PVD in a non-invasive manner. Indeed, clinical studies have supported its use as an alternative to surgery in certain patient populations. However, further research is still needed with respect to greater understanding of the pathophysiology underlying the development of VMT and IMH.