PROPHYLACTIC TREATMENT OF LATTICE DEGENERATION IN FELLOW EYES AFTER REPAIR OF UNCOMPLICATED PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To evaluate prophylactic treatment (PTx) of lattice degeneration (LD) on retinal tear (RT) and rhegmatogenous retinal detachment (RRD) risk in fellow eyes of patients after primary RRD repair in the first eye. METHODS: This was a consecutive case series with cohort control involving patients with RRD repair from January 1, 2013, through December 31, 2017. Patients received PTx (PTx cohort) or no PTx (No-PTx cohort) in fellow eye with 5-year follow-up. Primary outcome measure was proportion with new fellow eye RT/RRD. Secondary outcomes included logarithm of minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) and status of myopia, posterior vitreous detachment, and pseudophakia. RESULTS: Four hundred ninety-eight patients were divided into 146 and 352 in PTx and No-PTx cohorts, respectively. PTx cohort developed significantly ( P < 0.05) fewer RT/RRD (17%) than No-PTx cohort (41%). PTx significantly ( P < 0.05) lowered RT/RRD irrespective of posterior vitreous detachment and myopia status. PTx patients undergoing phacoemulsification demonstrated significantly ( P < 0.05) less RT/RRD (22%) than No-PTx cohort (31%). There was no significant ( P = 0.96) final BCVA difference between PTx (median = 0 logMAR) and No-PTx (median = 0 logMAR) cohorts. CONCLUSION: PTx of asymptomatic fellow eye LD reduced RT/RRD risk.

27-GAUGE PARS PLANA/PLICATA VITRECTOMY FOR PEDIATRIC VITREORETINAL SURGERY.

PURPOSE: To report on the feasibility of 27-gauge (G) vitrectomy for pediatric patients. METHODS: This study is an international, multicenter, retrospective, interventional case series. Participants were patients 17 years or younger who underwent 27-G vitrectomy for various indications. RESULTS: The records of 56 eyes from 47 patients were reviewed. Mean age was 5.7 ± 5.2 years. Diagnoses included retinopathy of prematurity (Stages 3 with vitreous hemorrhage, 4A, 4B, and 5), Terson's syndrome, traumatic macular hole, posterior capsular opacification, endophthalmitis, and others. Instruments used were the 27-G infusion, 27-G vitreous cutter, 27-G light pipe, and 27-G internal limiting membrane forceps. Instrument bending was noted in one (1.8%) case. There were no cases with intraoperative complications, infusion issues, or postoperative endophthalmitis. There were 67/145 (46%) sclerotomies that required suturing, of which most (51/145) were sutured out of precaution. There were four cases (7.1%) that required conversion to a larger gauge and three cases (5.3%) that developed postoperative hypotony. Mean visual acuity improved from logarithm of the minimum angle of resolution 1.32 (20/420) to 0.72 (20/105), after a mean follow-up of 125.1 days (P = 0.01). Anatomic success was achieved in 96.4% of eyes after a single surgery. CONCLUSION: Twenty-seven-gauge vitrectomy was safe and feasible in selected pediatric vitreoretinopathies. Further studies are warranted to examine indications and outcomes.

PORES OF THE INTERNAL LIMITING MEMBRANE: A Common Finding in Vitreomaculopathies.

PURPOSE: To describe presence and distribution of pores of the inner limiting membrane (ILM) in eyes with vitreomaculopathies. METHODS: Inner limiting membrane specimens were harvested from 117 eyes of 117 patients during vitrectomy with membrane peeling from eyes with vitreomacular traction syndrome, idiopathic and secondary epiretinal gliosis, and idiopathic full-thickness macular hole. All specimens were processed as flat-mounts for immunocytochemistry and examined by phase-contrast, interference, and fluorescence microscopy. Demographic and clinical data were correlated. RESULTS: Inner limiting membrane pores were found in all vitreomaculopathies. They were identified in 47 (40.2%) of 117 eyes being most evident with antilaminin. In eyes with full-thickness macular hole >400 µ m, pores were seen in more than half of all eyes. They occur as numerous and uniformly distributed defects of the flat-mounted ILM with a mean diameter of 9.5 ± 2.4 µ m. Edges of ILM pores are round with an irregular contour and no specific cellular pattern. Pores were distinguished from retinal vessel thinning and iatrogenic artefacts. CONCLUSION: Contrary to previous reports, ILM pores are a common finding in vitreomaculopathies easily visible with antilaminin staining. Further studies are needed to clarify whether their presence correlates with differences in disease progression or imaging before and after vitrectomy with ILM peeling.

Is gas/air tamponade essential for eyes with small peripheral retinal breaks without detachment during vitrectomy?

BACKGROUND: To investigate the safety of vitrectomy with laser photocoagulation in eyes with small peripheral retinal breaks without air or gas tamponade. METHODS: Among patients who underwent vitrectomy for various retinal disorders, those with small peripheral retinal breaks treated by laser photocoagulation without air or gas tamponade were included in this study. Their medical records were assessed retrospectively, and we investigated the characteristics of small peripheral retinal breaks and the incidence of postoperative retinal detachment (RD). RESULTS: Thirty-one eyes of 31 patients who presented with small peripheral retinal breaks requiring endolaser photocoagulation during vitrectomy were included in this analysis. There were two cases of iatrogenic retinal breaks that occurred during vitrectomy, while others were preexisting lesions, including retinal tears, atrophic retinal holes, and retinal holes with lattice degeneration. There were no cases of RD during the follow-up period of at least 6 months. CONCLUSIONS: Adequate laser treatment without gas or air tamponade may be sufficient during vitrectomy in cases with small peripheral retinal breaks without concurrent RD, along with complete removal of vitreoretinal traction.

[Experimental stem cell replacement transplantation in retinal pigment epithelium atrophy]. / Zamestitel'naya transplantatsiya stvolovymi kletkami pri atrofii retinal'nogo pigmentnogo epiteliya v eksperimente.

PURPOSE: To develop and evaluate the results of the modified surgical technique for transplantation of retinal pigment epithelium (RPE) differentiated from human induced pluripotent stem cells (iPSC-RPE) in the form of a cell suspension into the subretinal space of rabbits with previously induced RPE atrophy. MATERIAL AND METHODS: The study was conducted on 10 New Zealand albino rabbits (20 eyes). One month after modeling RPE atrophy and retinal degeneration, rabbits were subjected to subretinal transplantation of iPSC-RPE cells in the form of a cell suspension. To prevent reflux of iPSC-RPE into the vitreal cavity, the injection site was sealed with 2-3 drops of autologous platelet-rich plasma (PRP). All rabbits underwent spectral optical coherence tomography (SOCT) and autofluorescence studies on the Heidelberg Spectralis system («Heidelberg Engineering¼, Germany). Enucleated animal eyes were studied with morphological and immunohistochemical methods. RESULTS: In this study we developed and evaluated a modified surgical technique of transplantation of iPSC-RPE in the form of a cell suspension into the subretinal space of rabbits with induced RPE atrophy. It was found that the use of PRP helps seal the defect and prevents cell suspension reflux into the vitreous cavity, effectively minimizing intra- and postoperative complications. Morphological in vivo study and examination of histological sections showed that implantable iPSC-RPEs were correctly integrated and adhered to the choroid in the surgery site. Immunohistochemical analysis involving fluorescence-marked antibodies confirmed the survival of iPSC-RPE integrated into the retina of model animals. CONCLUSION: This method improves the technology of iPSC-RPE transplantation on preclinical stages of the study, revealing new prospects in the treatment of degenerative diseases of the retina and the possibility of a personalized approach.

The effect of retinal scaffold modulus on performance during surgical handling.

Emerging treatment strategies for retinal degeneration involve replacing lost photoreceptors using supportive scaffolds to ensure cells survive the implantation process. While many design aspects of these scaffolds, including material chemistry and microstructural cues, have been studied in depth, a full set of design constraints has yet to be established. For example, while known to be important in other tissues and systems, the influence of mechanical properties on surgical handling has not been quantified. In this study, photocrosslinked poly(ethylene glycol) dimethacrylate (PEGDMA) was used as a model polymer to study the effects of scaffold modulus (stiffness) on surgical handling, independent of material chemistry. This was achieved by modulating the molecular weight and concentrations of the PEGDMA in various prepolymer solutions. Scaffold modulus of each formulation was measured using photo-rheology, which enabled the collection of real-time polymerization data. In addition to measuring scaffold mechanical properties, this approach gave insight on polymerization kinetics, which were used to determine the polymerization time required for each sample. Scaffold handling characteristics were qualitatively evaluated using both in vitro and ex vivo trials that mimicked the surgical procedure. In these trials, scaffolds with shear moduli above 35 kPa performed satisfactorily, while those below this limit performed poorly. In other words, scaffolds below this modulus were too fragile for reliable transplantation. To better compare these results with literature values, the compressive modulus was measured for select samples, with the lower shear modulus limit corresponding to roughly 115 kPa compressive modulus. While an upper mechanical property limit was not readily apparent from these results, there was increased variability in surgical handling performance in samples with shear moduli above 800 kPa. Overall, the knowledge presented here provides important groundwork for future studies designed to examine additional retinal scaffold considerations, including the effect of scaffold mechanical properties on retinal progenitor cell fate.

Characterization and allogeneic transplantation of a novel transgenic cone-rich donor mouse line.

OBJECTIVES: Cone photoreceptor transplantation is a potential treatment for macular diseases. The optimal conditions for cone transplantation are poorly understood, partly because of the scarcity of cones in donor mice. To facilitate allogeneic cone photoreceptor transplantation studies in mice, we aimed to create and characterize a donor mouse model containing a cone-rich retina with a cone-specific enhanced green fluorescent protein (EGFP) reporter. METHODS: We generated OPN1LW-EGFP/NRL-/- mice by crossing NRL-/- and OPN1LW-EGFP mice. We characterized the anatomical phenotype of OPN1LW-EGFP/NRL-/- mice using multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, immunohistology, and transmission electron microscopy. We evaluated retinal function using electroretinography (ERG), including 465 and 525 nm chromatic stimuli. Retinal sheets and cell suspensions from OPN1LW-EGFP/NRL-/- mice were transplanted subretinally into immunodeficient Rd1 mice. RESULTS: OPN1LW-EGFP/NRL-/- retinas were enriched with OPN1LW-EGFP+ and S-opsin+ cone photoreceptors in a dorsal-ventral distribution gradient. Cone photoreceptors co-expressing OPNL1W-EGFP and S-opsin significantly increased in OPN1LW-EGFP/NRL-/- compared to OPN1LW-EGFP mice. Temporal dynamics of rosette formation in the OPN1LW-EGFP/NRL-/- were similar as the NRL-/- with peak formation at P15. Rosettes formed preferentially in the ventral retina. The outer retina in P35 OPN1LW-EGFP/NRL-/- was thinner than NRL-/- controls. The OPN1LW-EGFP/NRL-/- ERG response amplitudes to 465 nm stimulation were similar to, but to 535 nm stimulation were lower than, NRL-/- controls. Three months after transplantation, the suspension grafts showed greater macroscopic degradation than sheet grafts. Retinal sheet grafts from OPN1LW-EGFP/NRL-/- mice showed greater S-opsin + cone survival than suspension grafts from the same strain. CONCLUSIONS: OPN1LW-EGFP/NRL-/- retinae were enriched with S-opsin+ photoreceptors. Sustained expression of EGFP facilitated the longitudinal tracking of transplanted donor cells. Transplantation of cone-rich retinal grafts harvested prior to peak rosette formation survived and differentiated into cone photoreceptor subtypes. Photoreceptor sheet transplantation may promote greater macroscopic graft integrity and S-opsin+ cone survival than cell suspension transplantation, although the mechanism underlying this observation is unclear at present. This novel cone-rich reporter mouse strain may be useful to study the influence of graft structure on cone survival.

Interleukin-13 Gene Modification Enhances Grafted Mesenchymal Stem Cells Survival After Subretinal Transplantation.

Mesenchymal stem cells (MSCs) hold great potential for cell- and gene-based therapies for retinal degeneration. Limited survival is the main obstacle in achieving successful subretinal transplantation of MSCs. The present study sought to evaluate the effect of interleukin-13 (IL-13) gene modification on the phenotypic alteration of retinal microglia (RMG) and the survival of MSCs following subretinal grafting. In this study, LPS-activated RMG were cocultured with MSCs or IL-13-expressing MSCs (IL-13-MSCs) for 24 h, and activated phenotypes were detected in vitro. Western blotting was performed to quantify cytokine secretion by light-injured retinas following subretinal transplantation. The numbers of activated RMG and surviving grafted cells were analysed, and the integrity of the blood-retinal barrier (BRB) was examined in vivo. We found that, compared with normal MSCs, cocultured IL-13-MSCs suppressed the expression of pro-inflammatory factors and major histocompatibility complex II, promoted the expression of anti-inflammatory cytokines by activated RMG and simultaneously inhibited the proliferation of and phagocytosis by RMG. The subretinal transplantation of IL-13-MSCs increased the expression of neurotrophic factors, IL-13 and tight junction proteins in the host retina, decreased the number of phagocytic RMG and improved the survival of grafted cells. Furthermore, IL-13-MSCs alleviated BRB breakdown induced by subretinal injection. Our results demonstrate that IL-13-MSCs can polarize activated RMG to the neuroprotective M2 phenotype and enhance the survival of grafted MSCs against the damage stress induced by subretinal transplantation.

Bone Marrow-Derived Mononuclear Cell Transplants Decrease Retinal Gliosis in Two Animal Models of Inherited Photoreceptor Degeneration.

Inherited photoreceptor degenerations are not treatable diseases and a frequent cause of blindness in working ages. In this study we investigate the safety, integration and possible rescue effects of intravitreal and subretinal transplantation of adult human bone-marrow-derived mononuclear stem cells (hBM-MSCs) in two animal models of inherited photoreceptor degeneration, the P23H-1 and the Royal College of Surgeons (RCS) rat. Immunosuppression was started one day before the injection and continued through the study. The hBM-MSCs were injected in the left eyes and the animals were processed 7, 15, 30 or 60 days later. The retinas were cross-sectioned, and L- and S- cones, microglia, astrocytes and Müller cells were immunodetected. Transplantations had no local adverse effects and the CD45+ cells remained for up to 15 days forming clusters in the vitreous and/or a 2-3-cells-thick layer in the subretinal space after intravitreal or subretinal injections, respectively. We did not observe increased photoreceptor survival nor decreased microglial cell numbers in the injected left eyes. However, the injected eyes showed decreased GFAP immunoreactivity. We conclude that intravitreal or subretinal injection of hBM-MSCs in dystrophic P23H-1 and RCS rats causes a decrease in retinal gliosis but does not have photoreceptor neuroprotective effects, at least in the short term. However, this treatment may have a potential therapeutic effect that merits further investigation.

Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration.

Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host-graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications.

Visual outcome following phacoemulsification in English Cocker Spaniels with suspected progressive retinal atrophy: A retrospective multicenter study of 54 cases (2002-2017).

OBJECTIVE: To describe the visual outcome following phacoemulsification in English Cocker Spaniels (ECS) affected by cataracts and suspected progressive retinal atrophy (PRA). ANIMALS STUDIED: Fifty-four client-owned dogs. PROCEDURES: A multicenter, retrospective study was performed including ECS with suspected PRA which underwent phacoemulsification. PRA was suspected on ophthalmic examination before and after surgery, and/or after electroretinography (ERG) was performed. Visual outcome was assessed by menace response per eye at seven time periods post-surgery (P1= 25-90 days, P2 = 91-180 days, P3 = 181-364 days, P4 = 365-549 days, P5 = 550-729 days, P6 = 730-1094 days, and P7 ≥ 1095 days). Descriptive statistics were performed. Generalized estimating equations were used to identify predictors associated with vision after surgery. Odds ratio and confidence intervals were reported. Significance was set at P < 0.05. Owners were invited to participate in a questionnaire. RESULTS: Phacoemulsification was performed in 85 eyes. Median age at surgery was 9.09 years (min. 2.17 years, max. 13.49 years). At all re-examinations, up to and including P5, significantly more eyes were visual than before surgery (P ≤ 0.003). Odds for vision were significantly increased for eyes that underwent surgery. Electroretinograms were performed in 75/85 eyes that underwent surgery, demonstrating low b-wave amplitudes. There was no significant effect of the age, gender, vision before surgery, presence of dazzle reflex, cataract stage or abnormality on gonioscopy on visual outcome. The questionnaire response rate was 48.2%. Most participants (92.5%) felt that cataract surgery led to improvement of the dog's quality of life. CONCLUSIONS: English Cocker Spaniels with suspected PRA may benefit from phacoemulsification with vision up to 2 years following surgery.

Sheets of human retinal progenitor transplants improve vision in rats with severe retinal degeneration.

Loss of photoreceptors and other retinal cells is a common endpoint in retinal degenerate (RD) diseases that cause blindness. Retinal transplantation is a potential therapy to replace damaged retinal cells and improve vision. In this study, we examined the development of human fetal retinal sheets with or without their retinal pigment epithelium (RPE) transplanted to immunodeficient retinal degenerate rho S334ter-3 rats. Sheets were dissected from fetal human eyes (11-15.7 weeks gestation) and then transplanted to the subretinal space of 24-31 d old RD nude rats. Every month post surgery, eyes were imaged by high-resolution spectral-domain optical coherence tomography (SD-OCT). SD-OCT showed that transplants were placed into the subretinal space and developed laminated areas or rosettes, with clear development of plexiform layers first seen in OCT at 3 months post surgery. Several months later, as could be expected by the much slower development of human cells compared to rat cells, transplant photoreceptors developed inner and later outer segments. Retinal sections were analyzed by immunohistochemistry for human and retinal markers and confirmed the formation of several retinal subtypes within the retinal layers. Transplant cells extended processes and a lot of the cells could also be seen migrating into the host retina. At 5.8-8.6 months post surgery, selected rats were exposed to light flashes and recorded for visual responses in superior colliculus, (visual center in midbrain). Four of seven rats with transplants showed responses to flashes of light in a limited area of superior colliculus. No response with the same dim light intensity was found in age-matched RD controls (non-surgery or sham surgery). In summary, our data showed that human fetal retinal sheets transplanted to the severely disturbed subretinal space of RD nude rats develop mature photoreceptors and other retinal cells, integrate with the host and induce vision improvement.

Transplantation of rat embryonic stem cell-derived retinal cells restores visual function in the Royal College of Surgeons rats.

AIM OF STUDY: To evaluate the feasibility of transplantation of embryonic stem cell (ESC)-derived retinal cells in the treatment of retinal degeneration. MATERIALS AND METHODS: Rat ESCs were isolated and induced into retinal progenitor cells (RPCs) in vitro, which were subsequently induced into retinal pigment epithelium cells (RPEs) and photoreceptors (PRCs). All cells were identified by Western blot detection of their specific markers. RPEs and PRCs were, respectively, injected into the retina of Royal College of Surgeons (RCSs) rats. Control group was injected with PBS. Post-transplantation visual function was determined by electroretinography (ERG). The histology of the whole eye was compared by H&E staining. RESULTS: RPEs and PRCs were successfully derived from rat ESCs through the two-step differentiation as indicated by the presence of ESC- (Oct-3/4, Nanog, TRA-1-60 and TRA-1-81), RPC- (Rx, Mitf, Pax6 and Chx10), RPE- (RPE65 and keratin) and PRC-specific markers (blue opsin, red/green opsin, recoverin and rhodopsin) in Western blot. The amplitude of ERG a- and b-wave in RPE- and PRC-transplanted groups at week 2 and 10 after transplantation was markedly higher compared with PBS controls. Retinal injury and vascular stress response was not detected in any of the RCS rats after transplantation. CONCLUSION: The developed stepwise protocol can derive retinal cells from ESCs. Transplantation of these retinal cells can restore visual function of RCS rats. Our study provides evidence for potential clinical application of ESC-based cell therapy for retinal degeneration.

Cross-task perceptual learning of object recognition in simulated retinal implant perception.

The perception gained by retina implants (RI) is limited, which asks for a learning regime to improve patients' visual perception. Here we simulated RI vision and investigated if object recognition in RI patients can be improved and maintained through training. Importantly, we asked if the trained object recognition can be generalized to a new task context, and to new viewpoints of the trained objects. For this purpose, we adopted two training tasks, a labelling task where participants had to choose the correct label out of other distracting labels for the presented object, and a reverse labelling task where participants had to choose the correct object out of other distracting objects to match the presented label. Our results showed that, despite of the task order, recognition performance was improved in both tasks and lasted at least for a week. The improved object recognition, however, can be transferred only from the labelling task to the reverse labelling task but not vice versa. Additionally, the trained object recognition can be transferred to new viewpoints of the trained objects only in the labelling task but not in the reverse labelling task. Training with the labelling task is therefore recommended for RI patients to achieve persistent and flexible visual perception.

Human limbal neurospheres prevent photoreceptor cell death in a rat model of retinal degeneration.

BACKGROUND: The culture of retinal progenitors from an accessible adult stem cell source such as the limbus could provide a useful autologous source of retinal cell therapies. The human corneoscleral limbus contains multipotent stem cells that can be cultured as floating neurospheres. Previous work in rodents has demonstrated neuronal and photoreceptor differentiation from limbal neurosphere cultures. Here, this study has examined undifferentiated cultured adult human limbal neurospheres as donor cells for retinal cell therapies by transplantation into a rat model of retinal degeneration. METHODS: Gene expression in limbal neurospheres was examined by immunostaining and western blot. Human limbal neurospheres were transplanted into the subretinal space of Royal College of Surgeon's rats. Rats were monitored by optical coherence tomography for 6 weeks then processed for retinal histology. RESULTS: Human limbal neurospheres expressed the neural lineage markers, Nestin, sex determining region box-2 and N-cadherin, and the retinal transcription factors microphthalmia-associated transcription factor, sex determining region box-2 and orthodentical homeobox-2. Human limbal neurospheres could be cultured to express NeuN, neurofilament and rhodopsin. Rats receiving saline or no injection underwent complete degeneration of the retinal outer nuclear layer after 3 weeks. In contrast, rats injected with human limbal neurospheres or retinal pigment epithelial cells maintained the outer nuclear layer for up to 6 weeks. Gene expression in transplanted limbal neurospheres was inconsistent with the production of mature retinal pigment epithelial or photoreceptor cells. CONCLUSIONS: Human limbal neurospheres represent an accessible source of autologous donor cells for the treatment of retinal diseases.

PERIPHERAL RETINAL DEGENERATIONS AND RHEGMATOGENOUS DETACHMENT IN PRIMARY CONGENITAL GLAUCOMA.

BACKGROUND: To determine the prevalence of peripheral retinal degenerations (PRD) and rhegmatogenous retinal detachment in patients with primary congenital glaucoma (PCG). METHODS: Records of all patients with PCG operated from year 2000 onwards were evaluated to look for the prevalence of rhegmatogenous retinal detachment. Of these, those children who were old enough to cooperate and had sufficient medial clarity were screened with an indirect ophthalmoscopy in a cross-sectional evaluation from 2010 to 2014. Peripheral retina was examined, and prevalence of PRD was estimated in this subset. For statistical purposes, only one eye of each patient was considered in this cross-sectional analysis. RESULTS: Of the 310 eyes (180 patients with PCG) operated from the year 2000 onwards, a rhegmatogenous retinal detachment was noted in 13 eyes (4%). Mean axial length of these eyes was 26.3 ± 3.2 mm (range, 19.8-34.7 mm). Among the eyes screened for PRD (n = 60), prevalence of pathologic PRD (lattices with/without atrophic holes and isolated holes/tears) was 15%. The average follow-up between glaucoma filtering surgery and the date of last examination was 8.55 ± 3.98 years (range, 5-20 years) in this subset. Mean axial length was significantly greater in eyes with pathologic PRD than in those without (28.1 ± 3.3 mm vs. 25.8 ± 2.6 mm; P = 0.01). For axial length ≥ 26 mm, the odds of having a pathologic PRD were 14.4 times more than those with axial length < 26 mm (P < 0.001; 95% confidence interval, 1.7-120.5). CONCLUSION: Prevalence of PRD among eyes with PCG is high. Peripheral retinal screening should be performed in eyes with PCG, especially those with axial lengths ≥ 26 mm.

Neonatal disease environment limits the efficacy of retinal transplantation in the LCA8 mouse model.

BACKGROUND: Mutations of Crb1 gene cause irreversible and incurable visual impairment in humans. This study aims to use an LCA8-like mouse model to identify host-mediated responses that might interfere with survival, retinal integration and differentiation of grafted cells during neonatal cell therapy. METHODS: Mixed retinal donor cells (1 ~ 2 × 104) isolated from neural retinas of neonatal eGFP transgenic mice were injected into the subretinal space of LCA8-like model neonatal mice. Markers of specific cell types were used to analyze microglial attraction, CSPG induction and retinal cell differentiation. The positions of host retinal cells were traced according to their laminar location during disease progression to look for host cell rearrangements that might inhibit retinal integration of the transplanted cells. RESULTS: Transplanted retinal cells showed poor survival and attracted microglial cells, but CSPG was not greatly induced. Retinas of the LCA8 model hosts underwent significant cellular rearrangement, including rosette formation and apical displacement of inner retinal cells. CONCLUSIONS: Local disease environment, particularly host immune responses to injected cells and formation of a physical barrier caused by apical migration of host retinal cells upon disruption of outer limiting membrane, may impose two major barriers in LCAs cell transplantation therapy.

Plasmin Enzyme-Assisted Vitrectomy in Pediatric Patients with Vitreoretinal Diseases.

PURPOSE: To evaluate the efficacy and safety of using plasmin-assisted vitrectomy in pediatric patients with vitreoretinal diseases. METHODS: We prospectively recruited children aged 16 years or younger who presented with vitreoretinopathies and underwent plasmin-assisted vitrectomy between 2012 and 2013. The main outcome measure was the induction of posterior vitreous detachment (PVD) using a suction power of 200 mm Hg or less during surgery. RESULTS: Eleven eyes of 11 patients (mean age: 3.7 years; average follow-up duration: 14.1 months) were included. Of these 11 patients, there were 3 (27%) cases of stage 5 retinopathy of prematurity, 2 (18%) cases of persistent fetal vasculature, 2 (18%) cases of rhegmatogenous retinal detachment, 2 (18%) cases of idiopathic epiretinal membrane, 1 (9%) case of traumatic macular pucker, and 1 (9%) case of traumatic vitreous hemorrhage (9%). PVD was achieved in all cases (100%) during surgery using low suction after plasmin treatment (mean: 150 ± 39 mm Hg; range: 100-200). Overall, anatomical success was achieved in 8 eyes (73%). Visual acuity improved in all 5 (100%) patients for whom vision could be measured at 6 months after the operation. Cataracts were found in 4 eyes (36%), and a rise in transient intraocular pressure was observed in 1 eye (9%). CONCLUSIONS: Plasmin-assisted vitrectomy offers an effective and less traumatic intervention for a variety of pediatric vitreoretinal diseases.

Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation.

One strategy to restore vision in retinitis pigmentosa and age-related macular degeneration is cell replacement. Typically, patients lose vision when the outer retinal photoreceptor layer is lost, and so the therapeutic goal would be to restore vision at this stage of disease. It is not currently known if a degenerate retina lacking the outer nuclear layer of photoreceptor cells would allow the survival, maturation, and reconnection of replacement photoreceptors, as prior studies used hosts with a preexisting outer nuclear layer at the time of treatment. Here, using a murine model of severe human retinitis pigmentosa at a stage when no host rod cells remain, we show that transplanted rod precursors can reform an anatomically distinct and appropriately polarized outer nuclear layer. A trilaminar organization was returned to rd1 hosts that had only two retinal layers before treatment. The newly introduced precursors were able to resume their developmental program in the degenerate host niche to become mature rods with light-sensitive outer segments, reconnecting with host neurons downstream. Visual function, assayed in the same animals before and after transplantation, was restored in animals with zero rod function at baseline. These observations suggest that a cell therapy approach may reconstitute a light-sensitive cell layer de novo and hence repair a structurally damaged visual circuit. Rather than placing discrete photoreceptors among preexisting host outer retinal cells, total photoreceptor layer reconstruction may provide a clinically relevant model to investigate cell-based strategies for retinal repair.

Human retinal progenitor cell transplantation preserves vision.

Cell transplantation is a potential therapeutic strategy for retinal degenerative diseases involving the loss of photoreceptors. However, it faces challenges to clinical translation due to safety concerns and a limited supply of cells. Human retinal progenitor cells (hRPCs) from fetal neural retina are expandable in vitro and maintain an undifferentiated state. This study aimed to investigate the therapeutic potential of hRPCs transplanted into a Royal College of Surgeons (RCS) rat model of retinal degeneration. At 12 weeks, optokinetic response showed that hRPC-grafted eyes had significantly superior visual acuity compared with vehicle-treated eyes. Histological evaluation of outer nuclear layer (ONL) characteristics such as ONL thickness, spread distance, and cell count demonstrated a significantly greater preservation of the ONL in hRPC-treated eyes compared with both vehicle-treated and control eyes. The transplanted hRPCs arrested visual decline over time in the RCS rat and rescued retinal morphology, demonstrating their potential as a therapy for retinal diseases. We suggest that the preservation of visual acuity was likely achieved through host photoreceptor rescue. We found that hRPC transplantation into the subretinal space of RCS rats was well tolerated, with no adverse effects such as tumor formation noted at 12 weeks after treatment.