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Currently, there exists a lack of recent epidemiological data concerning ocular injuries due to welding related activities. Our study analyzes trends in ocular injuries related to usage of welding equipment in the U.S. from 2010 to 2019.Using the Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) Database, we queried data from January 1st 2010 to December 31st 2019 using the corresponding product code for welding equipment (896). Results were stratified by year, and standard descriptive statistical methods were applied to components including gender, age, diagnoses, and ED disposition. Circumstances leading up to the injuries were reviewed as well.Between 2010 and 2019 a total of 109,127 welding-associated ocular injuries occurred in the United States (95% CI, 86937-131,316). Estimates show a decreasing trend in cases from 13,415 (95% CI, 9979-16,851) in 2010 to 6944 (95% CI, 4868-9020) in 2019. A majority of cases occurred in men (98.2%) and in the 10-49 year age range (83.8%). 3.3% of cases involved spectators and 44% were bilateral. The top three ocular injury diagnoses were flash burns (62.1%), foreign body implantation (19.6%), and contusions/abrasions (11.1%). The number of radiation injuries trended down from 9286 in 2010 to 4023. With respect to a documented location, 38.9% occurred at home and 4.5% occurred in a school setting. Most patients (99.9%) were discharged from the ED; 0.1% were admitted to the hospital.The data suggests that number of ocular injuries related to welding has decreased significantly over the past 10 years. The most common injuries were radiation burns, foreign body disruption, and contusions/abrasions of the eye. Patients were predominantly men and between the ages of 10 and 49. Of note, almost half of all ocular injuries due to welding were bilateral, and 3% of ocular injuries were seen in spectators. more...

Population-based reports regarding bacterial endogenous endophthalmitis (BEE) are scarce in the literature. Our study sought to investigate the incidence of BEE, relative risk of comorbid conditions, and treatment patterns using a nationally representative database, the National Inpatient Sample (NIS).Retrospective cross-sectional study.Inpatients with bacteremia with and without BEE in the NIS database between 2002 and 2013.Demographic and comorbid medical conditions were evaluated in bacteremic patients who demonstrated BEE and in those who did not; furthermore, logistic regression was performed to predict the relative risk of comorbid conditions in BEE developing. Chi-square analysis was used to determine if certain organisms were more likely to cause BEE and their role in treatment method. Statistical analysis was performed using SPSS software version 22 (IBM, Armonk, NY).Comorbidities, associated microorganisms, and surgical management.Among 3 907 204 bacteremic inpatients, 1793 (0.05%) were found to have BEE. Patients were more likely to demonstrate BEE in the presence of endocarditis (P 0.001), bacterial meningitis (P0.001), pyogenic arthritis (P0.001), internal organ abscess (P0.001), osteomyelitis (P0.001), prostatitis (P0.001), diabetic retinopathy (P0.001), and vascular catheter placement or infection (P0.001). Diabetes mellitus without complications was not associated with an increased risk of BEE. Methicillin-resistant Staphylococcus aureus (MRSA), streptococcal, and pneumococcal bacteremia were found to significantly increase the risk of BEE (P0.001 for all), and the incidences of BEE associated with these organisms were 0.19%, 0.09%, and 0.07%, respectively. Fewer than 10% of patients with BEE underwent vitrectomy, and 1.6% of BEE patients underwent enucleation.Bacterial endogenous endophthalmitis was observed in approximately 1 in 2000 inpatients with bacteremia in this large cohort of NIS inpatients. It was seen more commonly with MRSA, streptococcal, and pneumococcal species. Endocarditis, meningitis, prostatitis, osteomyelitis, infected vascular catheter, internal organ abscess, and diabetic retinopathy showed a significant risk (P0.001) of being associated with BEE. more...

Purpose A simulated switching study assessed the effects of continuing the same anti–vascular endothelial growth factor (VEGF) treatment among patients who typically are considered for a therapy switch. Post hoc analysis of data from HARBOR was undertaken. Patients with neovascular age-related macular degeneration who demonstrated a suboptimal response after 3 or 6 months of ranibizumab treatment were identified as switching candidates. Rather than switching, however, patients continued on ranibizumab treatment, and visual and anatomic outcomes from the point of the hypothetical switch were examined. Design Post hoc analysis of the phase 3 HARBOR clinical trial. Participants Patients were included in 3- and 6-month switcher analyses if they received 3 of 3 initial monthly ranibizumab doses and 5 of 6 initial monthly ranibizumab doses, respectively, and met all the following: 5-letter or fewer gain from baseline, best-corrected visual acuity (BCVA) 20/40 or worse, and intraretinal or subretinal fluid with central foveal thickness (CFT) equal to or greater than central subfield thickness. Methods Patient data were examined at months 3 and 6 to identify those who met predetermined switching criteria. Best-corrected visual acuity and CFT were examined from the point at which switching criteria were met through months 6, 12, 18, and 24 of HARBOR and compared with those who did not meet the criteria. Main Outcome Measures Outcome measures included mean BCVA and CFT change over time from the point (month 3 or 6) at which switching criteria were met. Results By months 3 and 6, only 44 of 1059 patients (4.2%) and 37 of 769 patients (4.8%), respectively, met the inclusion criteria for hypothetical switching. Patients who met switching criteria at month 3 gained, on average, 5.3 letters from months 3 to 12 and 2.7 letters from months 3 to 24. Month 6 switchers gained, on average, 1.6 letters from months 6 to 12 and 1.8 letters from months 6 to 24. Both groups experienced significant CFT reductions over 24 months. Conclusions Month 3 hypothetical switchers achieved vision and anatomic improvement while continuing their original ranibizumab treatment. Month 6 switcher outcomes replicated those commonly reported in published anti-VEGF switching studies: stable vision or nominal improvements in vision with continued substantial anatomic improvement. more...

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists’ Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses. more...

Purpose To describe the characteristics of open-globe injuries with posterior segment intraocular foreign bodies (IOFBs). Design Retrospective chart review study. Participants Patients treated for posterior segment IOFB injuries. Methods Retrospective analysis of all patients with posterior segment IOFBs from 2003 to 2014 was conducted. Data including demographics, mechanism of injury, type of IOFB, method of diagnosis, presenting examination, medical and surgical treatment, visual outcomes, and complications were recorded. Main Outcome Measures Visual acuity (VA); anatomically successful retinal reattachment; need for additional surgery; frequency of post-traumatic complications, such as sympathetic ophthalmia (SO), endophthalmitis, and enucleations; and accuracy of Ocular Trauma Score (OTS). Results Thirty-one patients (28 male; mean age, 36.6 years; 42% Hispanic) had posterior segment IOFB injuries, 23 (74%) of which were construction work related. Twenty-five IOFBs (81%) were metallic. Twenty-four IOFBs (77%) had Zone I entry. Computed tomography (CT) scan detected an IOFB in 21 of 22 eyes in which it was performed, with 1 scan highly suspicious for an IOFB. Average size of the IOFB was 10 mm3; size or initial VA did not have any correlation with final VA. The OTS had 60% accuracy in predicting final VA (n = 20). The majority of patients had traumatic cataract and vitreous hemorrhage (VH) on presentation (77% and 61%, respectively); 65% had a retinal tear or retinal detachment (RD), and these patients had worse final VA than those with no retinal pathology. Average time from injury to IOFB removal was 3 days because of the delay in presentation to our facility; 27 of 31 patients (87%) had IOFBs removed within 24 hours of presentation with pars plana vitrectomy (PPV) and either gas or silicone oil tamponade. Patients were admitted for an average of 4 days of intravenous antibiotics. The most common complication was recurrent RD in 11 patients (35%), which portended worse final VA. One patient (3%) developed SO. There were no cases of postoperative endophthalmitis or enucleation. Conclusions Open-globe injuries with posterior segment IOFBs have a guarded visual prognosis, particularly when associated with RD. Increased awareness of the importance of eye protection can help minimize the occurrence of these injuries. more...

Intraocular foreign body injuries may result in a wide range of intraocular pathology and visual outcomes based on the mechanism of injury, type of foreign body, and subsequent complications. We have reviewed the literature to describe the epidemiology and mechanisms of such injuries; types of foreign bodies; imaging tools for diagnosis; current trends in management, presurgical, and surgical interventions; as well as visual prognosis and potential complications. The purpose of this review is to familiarize clinicians with the recent advances in diagnosis and management of such injuries. more...

Trophic factors are endogenously secreted proteins that act in an autocrine and/or paracrine fashion to affect vital cellular processes such as proliferation, differentiation, and regeneration, thereby maintaining overall cell homeostasis. In the eye, the major contributors of these molecules are the retinal pigment epithelial (RPE) and Müller cells. The primary paracrine targets of these secreted proteins include the photoreceptors and choriocapillaris. Retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa are characterized by aberrant function and/or eventual death of RPE cells, photoreceptors, choriocapillaris, and other retinal cells. We discuss results of in vitro and in vivo animal studies in which candidate trophic factors, either singly or in combination, were used in an attempt to ameliorate photoreceptor and/or retinal degeneration. We also examine current trophic factor therapies as they relate to the treatment of retinal degenerative diseases in clinical studies. more...

Herein, we discuss recent applications of nanotechnology to ophthalmology, including nanoparticles for drug, gene, and trophic factor delivery; regenerative medicine (in the areas of optogenetics and optic nerve regeneration); and diagnostics (eg, minimally invasive biometric monitoring). Specific applications for the management of choroidal neovascularization, retinal neovascularization, oxidative damage, optic nerve damage, and retinal degenerative disease are considered. Nanotechnology will play an important role in early- and late-stage interventions in the management of blinding diseases. more...

The earliest impact of nanomedicine in ophthalmology is likely to involve the areas of biopharmaceuticals, implantable materials (e.g. tissue regeneration scaffolds, bioresorbable materials), implantable devices (e.g. glaucoma drainage valves), and diagnostic tools (e.g. intraocular pressure (IOP) monitors). Nanotechnology will bring about the development of regenerative medicine (i.e. replacement and improvement of cells, tissues, and organs) and artificial vision. In this chapter, we review ophthalmic applications of nanotechnology in the following areas: drug and trophic factor therapy for glaucoma, retinal degenerative, and retinal vascular disease; gene therapy for retinal degenerative disease; regenerative medicine, including optogenetics and optic nerve regeneration; and diagnostics (minimally invasive IOP monitoring). Nanotechnology will play an important role in both early-stage and late-stage intervention in the management of blinding diseases. more...

Transplanted cells can secrete numerous molecules that may exert a beneficial effect on the host retina and/or choroid even if they do not cure the underlying disease. Ideally, with a single transplant operation, many different pathways can be modified, which may reduce the chance of ‘escape’ associated with typical pharmacotherapy as well as the need for repeated drug administration. In addition, transplanted cells can replace dead cells (e.g. photoreceptors). Because of their pluripotency and unlimited proliferative capacity, stem cells seem to be a logical choice for starting material because they can be produced en masse safely and they can be induced to differentiate into ocular cells with potential for replacement and rescue therapy. Although preclinical studies demonstrate the feasibility of using embryonic stem cells and induced pluripotent stem cells for treating degenerative retinal diseases associated with abnormalities in the retinal pigment epithelium and/or photoreceptors, some issues may limit the use of stem cells in clinical practice. These issues include: immunogenicity of the cells, stability of cell phenotype (both inherent and environment-induced), the propensity to form tumors in situ, the abnormal microenvironment that can accompany degenerative disease and the synaptic rewiring that accompanies retinal degeneration. In the case of non-exudative age-related macular degeneration, cell transplants might prevent progression of geographic atrophy (through replacement of dysfunctional or dead RPE) and might even bring about some visual improvement in selected cases (through rescue of photoreceptors that are dying but not dead). Cell-based therapy may one day be sight-restoring for patients who are blind due to retinal degeneration of various etiologies. RPE transplantation is an attractive starting point for this sort of therapy as these cells can integrate with the host retina easily. more...

Nanotechnology involves the creation and use of materials and devices at the size scale of intracellular structures and molecules, and involves systems and constructs in the order of

Diabetic macular edema is a major cause of visual impairment. The pathogenesis of macular edema appears to be multifactorial. Laser photocoagulation is the standard of care for macular edema. However, there are cases that are not responsive to laser therapy. Several therapeutic options have been proposed for the treatment of this condition. In this review we discuss several factors and mechanisms implicated in the etiology of macular edema (vasoactive factors, biochemical pathways, anatomical abnormalities). It seems that combined pharmacologic and surgical therapy may be the best approach for the management of macular edema in diabetic patients. more...

The purpose of this study was to examine the change in integrin expression in adult human retinal pigment epithelium (RPE) after culturing and to characterize the role of integrins in RPE adhesion to aged submacular human Bruch's membrane. Expression of alpha integrin subunits 1 through 6 in adult RPE cells, cultured or uncultured, was examined by reverse transcription/real-time polymerase chain reaction (PCR) and Western blotting. RPE was cultured on bovine corneal endothelial cell-secreted extracellular matrix (BCE-ECM). The role of alpha integrin subunits in RPE attachment was examined by immunofluorescent localization of these subunits at sites of focal adhesions in cultured adult RPE attached to laminin or collagen-I-coated culture dishes. Additionally, the effect of function-blocking antibodies to alpha integrin subunits on RPE attachment to laminin, collagen I, and aged submacular human Bruch's membrane was determined. Cultured adult RPE had increased expression of alpha1-5 integrin subunits by PCR compared to uncultured RPE. Western blots showed that alpha2, 3, and 5 subunit levels were low or absent in uncultured adult RPE. Cultured adult RPE had a substantially higher expression of these integrins. Alpha 1-3 subunits co-localized with phosphorylated focal adhesion kinase (FAK) at focal adhesions in RPE cells spread on laminin. Only alpha2 and alpha3 co-localized with phosphorylated FAK in focal adhesions of RPE on collagen I. Using function blocking antibodies, blocking alpha1 subunit singly or in combination with alpha2 and/or alpha3 significantly decreased RPE adhesion to laminin. Blocking alpha1 and alpha2 or blocking alpha1, alpha2, and alpha3 subunits significantly decreased RPE adhesion to collagen I. Compared to controls, significantly fewer RPE cells were able to spread on aged submacular human Bruch's membrane when alpha1-6 integrin subunits were blocked. These results indicate that alpha 1-5 subunits that are upregulated by culturing on BCE-ECM are necessary for RPE attachment to aged submacular human Bruch's membrane. Relative lack of these integrin subunits in uncultured adult RPE may be responsible for poor resurfacing of aged submacular human Bruch's membrane by these cells. more...

Resurfacing of diseased or iatrogenically damaged Bruch's membrane with healthy retinal pigment epithelium (RPE) has been proposed as adjunctive treatment for age-related macular degeneration (AMD). The purpose of this study was to determine whether cultured fetal human RPE cells can attach and differentiate on aged submacular human Bruch's membrane. Bruch's membrane was debrided to expose native RPE basement membrane, the superficial inner collagenous layer directly below the RPE basement membrane, or the deep inner collagenous layer. These are three surfaces that transplanted RPE cells will encounter in situ. Approximately 3146 cultured fetal RPE cells mm(-2) were seeded onto these three surfaces and grown in organ culture for 1, 7, or 14 days. Explants were bisected and examined histologically or analyzed with a scanning electron microscope. RPE nuclear density was measured on stained sections. Morphology and cell density were compared to cells seeded onto bovine corneal endothelial cell-extracellular matrix (BCE-ECM). In situ submacular RPE nuclear density was also measured in tissue sections of donor eyes ranging from 18 weeks gestation to 88 years of age to determine the effect of age on RPE density. Compared to cells seeded onto BCE-ECM at similar density, RPE cell coverage and cellular morphology on aged submacular human Bruch's membrane was poor at all time points. In contrast to cells on BCE-ECM, RPE cell density on Bruch's membrane decreased with time. In general, cell morphology on all three Bruch's membrane surfaces worsened by day-7 compared to day-1. Although some cells were more pigmented on RPE basement membrane and the deep inner collagenous layer at day-7, poor cellular morphology indicated the remaining cells were not well differentiated. At day-14, the cells were uniform and cuboidal on BCE-ECM, with cell density similar to that at day-7 and similar to in situ density of young donors ( more...

Anterior segment ischemia is a rare complication of posterior segment surgery with a broad spectrum of presentations. Most frequently, it follows a mild self-limited course. Cases that are more prominent usually result from a co-incidence of precipitating factors. Recognition of precipitating factors and appropriate action can avoid anterior segment ischemia. Management includes nonspecific steps, such as topical medications (ie, corticosteroids and cycloplegics) and face-mask and eye-mask oxygen delivery, as well as specific steps related to the underlying cause (eg, removal of an encircling scleral buckle). more...

Spontaneous closure of macular holes occurs in 3% to 9% of patients over 6 years [3,58]. Visual acuity can recover dramatically once the hole closes. The risk for hole development in the fellow eye in the absence of PVD is approximately 29%. The presence of vitreomacular separation reduces the risk to less than 5%. Most of the fellow eyes that develop macular holes do so within 2 years [59]. Macular hole surgery has been evolving. ILM peeling is a recent, widely accepted innovation. Meta-analysis of 12 published case series indicates anatomic success in 77% and functional success in 55% of patients with the traditional technique of epiretinal peeling and no adjuvant use. Meta-analysis of 22 series with techniques using adjuvants indicates an anatomic success rate of 81% and a functional success rate of 60%. Meta-analysis of 4 studies involving 221 cases indicates an anatomic success rate of 96% and a functional success rate of 81% [5]. True superiority of one approach versus another cannot be determined without a randomized, prospective clinical trial, which is unlikely to be conducted. In the meantime, surgeons must choose an approach based on individual features of a given patient and their own surgical experience. more...

Retinal pigment epithelium (RPE) transplantation might replace cells lost as a consequence of choroidal neovascular membrane excision in patients with age-related macular degeneration (AMD). Autologous transplantation of RPE cells harvested from a peripheral biopsy may overcome problems of immune rejection. To study the feasibility of autologous RPE cell transplantation, the authors examined the attachment of freshly harvested RPE cells from aged donors onto Bruch's membrane explants, debrided to (1) remove or (2) preserve the RPE basement membrane. Human retinal pigment epithelial sheets were harvested from adult donor eyes (N = 12, mean age 79.00 +/- 9.40 years) and, following incubation in collagenase, were mechanically fragmented into microaggregates. Microaggregates (approximately 120 000 cells) were seeded onto the paired explants (7 mm diameter) and incubated for 20 min, 1, 4, or 24 hr at 37 degrees C. The percent coverage of the debrided surface by microaggregates was determined by sampling the center of the explants with scanning electron microscopy. RPE microaggregate attachment to Bruch's membrane was significantly greater at all time points analysed in samples with intact basement membrane versus those with an exposed inner collagenous layer. Coverage of debridements retaining intact RPE basement membrane was 1.83 +/- 1.10% at 20 min, 3.54 +/- 2.14% at 1 hr, and 8.68 +/- 2.63% at 4 hr. Coverage of debridements lacking basement membrane was 0.10 +/- 0.04% at 20 min, 0.39 +/- 0.25% at 1 hr, and 0.63 +/- 0.42% at 4 hr. Based on their morphologic appearance, many cells were dying as early as 1 hr following seeding. To increase surface coverage, the authors seeded four times the above number of cells and incubated the specimens for 1 hr. Coverage on explants lacking RPE basement membrane showed no increase in the number of cells attached to the inner collagenous layer. There was a significant approximately three-fold increase in the number of cells attached in the presence of basement membrane. These results indicate that if RPE cells from aged human donors are used for transplantation, some modification of the Bruch's membrane surface or the cells must be considered for cell attachment and eventual cell survival. more...

Drusen are subretinal pigment epithelial deposits that are characteristic of but not uniquely associated with age-related macular degeneration (AMD). Age-related macular degeneration is associated with two types of drusen that have different clinical appearances and different prognoses. Hard drusen appear as small, punctate, yellow nodules and can precede the development of atrophic AMD. Areolar atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and outer retina develop as the drusen disappear, but drusen can regress without evidence of atrophy. Soft drusen appear as large (usually larger than 63 microm in diameter), pale yellow or grayish-white, dome-shaped elevations that can resemble localized serous RPE detachments. They tend to precede the development of clinically evident RPE detachments and choroidal neovascularization. Drusen characteristics correlated with progression to exudative maculopathy include drusen number (five or more), drusen size (larger than 63 microm in diameter), and confluence of drusen. Focal hyperpigmentation in the macula and systemic hypertension also are associated with an increased risk of developing choroidal new vessels (CNVs). Large drusen are usually a sign of diffuse thickening of Bruch's membrane with basal linear deposit, a vesicular material that probably arises from the RPE, constitutes a diffusion barrier to water-soluble constituents in the plasma, results in lipidization of Bruch's membrane, and creates a potential cleavage plane between the RPE basement membrane and the inner collagenous layer of Bruch's membrane through which CNVs can grow. Disappearance of drusen spontaneously and in areas adjacent to laser photocoagulation scars was first noted by Gass (Gass JD: Arch Ophthalmol 90:206-217, 1973; Trans Am Acad Ophthalmol Otolaryngol 75:580-608, 1971). Subsequent reports have confirmed these observations. Photocoagulation-induced drusen regression might prevent patients with drusen from developing exudative maculopathy. The mechanism for spontaneous drusen regression probably involves RPE atrophy. The mechanism for photocoagulation-induced drusen regression is unknown. If photocoagulation-induced drusen regression is anatomically similar to atrophy-associated drusen regression, then the former will be associated with dissolution of basal linear deposit and a residuum of basal laminar deposit. Sarks and coworkers (Sarks JP, Sarks SH, Killingsworth MC: Eye 11:515-522, 1997) proposed that this in turn will eliminate the potential cleavage plane between the RPE basement membrane and inner collagenous layer of Bruch's membrane through which CNVs grow, thus retarding the growth of CNVs. more...

In this issue of the American Journal of Ophthalmology, Dr. Radtke and his colleagues report on the results of a phase 2 clinical trial of fetal retinal pigment epithelium (RPE)-retina transplants in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD).1 Visual acuity improved in 7 of 10 study eyes and in 3 of 10 control fellow eyes. Some issues that merit consideration are: the study design, the basis of the visual improvement, the potential immunogenicity of the transplant, alternative approaches to retinal transplantation, and current challenges to further progress. Each of these issues is considered below. Regarding methodology, a strength of the trial is that visual acuity was studied carefully before and after surgery. All patients underwent cataract extraction with intraocular lens placement and posterior capsulotomy pre-operatively in the study eye. Because fellow eyes did not, as a matter of protocol, undergo this procedure, there is a potential source of bias in the study design. Among the fellow eyes, seven had undergone cataract surgery before the transplant; two had subsequent cataract surgery; and one did not have cataract surgery (Norman Radtke, personal communication). Thus, the visual loss in the fellow eyes probably was due largely to progressive retinal degeneration. The use of experimental visual stimulation videos might be a confounding variable. Patients were instructed to cover the non-transplanted eye, but compliance was a concern (Norman Radtke, personal communication). If these videos have an effect, it might be masked by the way in which the stimulation was applied. Some of the diagnostic testing (e.g., OCT, MP1, SLO, multifocal ERG) was not standardized. This limitation does not detract from the fundamental finding of the study. Some of these tests probably do not have the resolution needed to identify the portion of host retina re-vitalized by the graft. Evidence from Stargardt disease patients indicates that one can lose ~90% of the cones in the fovea and still retain 20/30–20/100 vision.2 Thus, the number of functioning photoreceptors mediating improved visual acuity in the study patients might be so small that they cannot be visualized currently, even with high-resolution techniques such as adaptive optics.3 SLO and MP1 testing, however, are valuable, as they permit identification of the preferred fixation locus(i) with respect to the graft. It is possible that visual improvement in the study eyes is not due entirely to the transplanted cells. In one animal model of RP, lensectomy and vitrectomy alone improves retinal survival.4 Retinal detachment seems to have a neuroprotective effect on cones and rods in another animal model of RP.5 Furthermore, as the authors note, inserting a needle into the subretinal space without injecting cells can result in improved vision in animal models of retinal degeneration. The authors posit that effect of surgery alone (vs. the transplant) is unlikely to account for the sustained improvement in vision, based on the duration of the sham surgery effect in preclinical models. Nonetheless, since there is evidence that lensectomy, vitrectomy, and retinal detachment can improve photoreceptor survival in preclinical models and since the existence (and duration) of this effect in humans with RP and/or AMD is unknown, there may be limitations in using “unoperated” fellow eyes as controls. Ideally, a fellow eye with a similar degree of disease severity at the start of the study that undergoes the same surgery as the study eye except for the receipt of the retinal graft is the best control for the sight-restoring effect of the transplanted cells. This approach poses ethical dilemmas, but they may not be insurmountable. If visual improvement was due to the transplant, it seems likely to have been largely via a “rescue” (vs. “replacement”) mechanism,6 which is consistent with the MP1 findings in patient 1 showing increased sensitivity in an area adjacent to but not overlying the graft. Whether visual recovery mediated by a retinal transplant is better/same/worse than that achieved by administration of a specific neurotrophic factor(s) is unknown. In principle, RPE-retina transplants can produce more than one neurotrophic substance, which might be an advantage of this approach. The degree of visual improvement in the eyes receiving transplants was quite modest. Perhaps visual recovery would have been better if patients had undergone surgery earlier in the course of their disease. At this time, it may not be wise to place fetal RPE-retina grafts under the fovea in patients with vision of 20/20–20/100 based on the results of this study. However, visual stabilization is highly desirable for patients with inexorably progressive disease. Assuming that the main benefit of the grafts is photoreceptor rescue, one might consider placing the tissue adjacent to the fovea in patients with relatively good visual acuity. Dr. Radtke and his colleagues assessed immune surveillance of the transplants carefully. As they note, the HLA antibody studies do not rule out the possibility that the donor tissue was recognized. The absence of inflammation on fluorescein angiography is encouraging in this regard, but recent results in AMD indicate that chronic inflammation can occur at the level of RPE-Bruch’s membrane with no signs of inflammation on angiography. The loss of RPE pigmentation in 8 of 10 patients may be innocuous. In some cases, it may signify RPE death, which would be consistent with the progressive choriocapillaris atrophy seen in patient 7.7 It seems unlikely that, if effective, fetal RPE-retina transplants can be provided on a large scale. Different approaches merit consideration, depending on whether one is attempting rescue vfeplacement. RPE cells and photoreceptors can produce substances that have a rescue effect on host photoreceptors.8, 9 Thus, one might be able to transplant adult RPE-photoreceptor sheets to stabilize vision. (It is possible that fetal tissue is less likely to undergo immune rejection.) In some cases, gene therapy probably will be more effective for photoreceptor rescue than cell-based therapy.10, 11 Different types of cells might be used to achieve photoreceptor replacement (Table). Multipotent retinal progenitor cells,12 immature post-mitotic rod precursors,13 and fetal RPE-retina sheets14 all have been transplanted in preclinical retinal degeneration models and have shown evidence of synapse formation with host retina and some improvement in visual behavior. At this time, however, the process is extremely inefficient. In one study, less than 0.5% of transplanted cells integrated with the host retina.13 Table Some potential sources of cells for photoreceptor replacement.* Significant challenges for foveal reconstruction by replacement therapy include: efficient tissue delivery,16 integration of the transplant with the host and re-establishment of functional synaptic circuitry,17 maintenance of an appropriate state of differentiation by the transplanted tissue,15 and immune surveillance.18 Solutions to these challenges may depend on the specific retinal degenerative disease in question, the duration of the disease, and the type of cell one is transplanting. Restoration of precision vision for patients with advanced disease seems more likely to be achieved by a replacement strategy than by rescue, so these obstacles are worth addressing. The work of Dr. Radtke, his colleagues, and many other investigators is bringing us closer to the resolution of these issues and the establishment of sight-restoring therapy for retinal degenerative disease. more...

Retinal pigment epithelium transplantation has been proposed as adjunctive treatment for age-related macular degeneration following surgical excision of choroidal neovascular membranes. The goal of this study was to develop a model to evaluate retinal pigment epithelium transplantation onto human Bruch's membrane in vitro. We investigated the ability of cultured fetal human retinal pigment epithelium to colonize human cadaver Bruch's membrane, determined the incubation time needed to form a monolayer and to exhibit apical microvilli and tight junctions, and assessed the production of basement membrane. Freshly enucleated (less than 48 hours old) human eyes were cut through the pars plana, and the anterior segment, vitreous, and retina were removed. The native retinal pigment epithelium was debrided with a surgical sponge. Bruch's membrane and choroid at the macula were trephined with a 7.0 mm diameter trephine and then incubated with 1/2 ml of Dulbecco's modified Eagle's medium +15% fetal calf serum+basic fibroblast growth factor (1 ng ml-1), and fetal human retinal pigment epithelium at a concentration of 242,000 cells ml-1. Specimens were incubated for 1, 4, 6, 8, 12, or 24 hours. The specimens were fixed in half strength Karnovsky's fixative, processed, and analysed with scanning and transmission electron microscopy. The retinal pigment epithelium covered the debrided macular specimens to different degrees at different incubation times. After 1 hour, the cells started to attach and flatten (median percent coverage: 78%). The extent of Bruch's membrane coverage by fetal retinal pigment epithelium varied greatly between specimens. After 4-6 hours, the cells covered the entire debrided surface in a monolayer (median percent coverage: 97.2% at 4 hours, 99.8% at 6 hours). Tight junctions were observed, and the cells had few apical microvilli. The lateral cell borders were obliquely oriented with respect to Bruch's membrane, and the nuclei were elongated, exhibited prominent nucleoli, and were oriented parallel to Bruch's membrane. After 6-8 hours, cells started to become hexagonal (median percent coverage at 8 hours: 99.97%). Cells attached to the inner collagenous layer tended to be flatter than cells attached to residual native basement membrane. At 12 and 24 hours, expression of hexagonal shape, tight junctions, and apical microvilli were observed more frequently (median percent coverage: 99.87% at 12 and 100% at 24 hours). No newly formed basement membrane was observed at these time points. In separate experiments comparing attachment in the presence and absence of native RPE basement membrane, the presence of native retinal pigment epithelial basement membrane promoted the early attachment of the cells and more rapid expression of normal morphology. This in vitro system provides a reproducible way to study the adherence of retinal pigment epithelium to normal and diseased human Bruch's membrane. more...

Subretinal hemorrhage can arise from the retinal and/or choroidal circulation. Significant subretinal hemorrhage occurs in several conditions, but most commonly is associated with age-related macular degeneration, presumed ocular histoplasmosis, high myopia, retinal arterial macroaneurysm, and trauma. Released toxins, outer retinal shear forces, and a diffusion barrier created by subretinal hemorrhage all contribute to photoreceptor damage and visual loss. The use of tissue plasminogen activator and improvements in surgical instrumentation have facilitated surgical drainage and have made it a useful option in the management of selected cases. Mechanisms of subretinal hemorrhage formation, underlying etiologies, diagnostic evaluation, and the histopathology of damage are summarized. Published surgical series are reviewed and surgical advances are summarized. The value of surgically removing subretinal hemorrhages to improve visual outcome remains unestablished, because definitive studies have not been performed. Guidelines for selecting candidates for surgical intervention are proposed. more...

Background: Diagnosis and treatment of ocular large cell lymphoma may lessen visual loss and prolong life. Although reports in the literature have described retinal infiltrates in eyes with large cell lymphoma, they have focused on the more prominent vitreous and subretinal pigment epithelial findings. Eyes with retinal infiltrates and hemorrhagic retinal necrosis are usually believed to harbor a microbial infection. The authors describe 5 patients, aged 57 to 85 years, with ocular lymphoma in whom the most prominent initial findings were in the retina. Method: Patients presented with findings suggestive of an infectious retinal necrosis. When the initial therapy failed, investigators performed a vitreous biopsy. Two patients had a concomitant retinal biopsy. Radiation therapy was given to four patients. Results: All five patients had vitreous cells. Three patients had prominent perivascular exudate. Four patients had grayish-white retinal infiltrates, and three patients had associated retinal hemorrhage. Three patients had subretinal small white spots. An edematous thickened retina developed in three patients, and hemorrhagic retinal necrosis developed in three patients. The initial diagnosis was believed to be acute retinal necrosis (ARN) in three patients, toxoplasmosis in one patient, and frosted branch angiitis in one patient. Vitreous biopsy was positive in two patients but negative in three patients. In two of these three patients, the diagnosis was established by retinal biopsy. Conclusion: Ocular lymphoma should be considered in the differential diagnosis of retinal vasculitis or necrotizing retinitis in a middle-aged or older patient. Retinal biopsy may be helpful in establishing the diagnosis. more...

We treated two patients with annular epiretinal membranes that produced unusual macular morphologic characteristics. Contracture of the membranes caused herniation of macular tissue through a hole in the center of the membrane. The membranes were removed surgically, and ultrastructural analysis disclosed cells with properties resembling myofibroblasts and apparent new vitreous collagen. Contracture of the cellular components probably produced tangential traction on the retina, which caused prolapse of the retinal tissue through a central defect in the membrane. more...

PURPOSE: To report the successful treatment of choroidal detachment in a patient with nanophthalmos and to report histopathologic findings in this patient’s sclera. METHODS: Choroidal detachment, secondary angle closure, and nanophthalmos were diagnosed using biomicroscopy, indirect ophthalmoscopy, and echography. Full-thickness sclerectomies in four quadrants were made on the right eye. Sclerae from these sclerectomies were studied ultrastructurally. RESULTS: Best-corrected visual acuity improved to RE, 20/60 from 20/100 preoperatively; the anterior chamber deepened, and the choroidal detachment resolved. Histopathologic studies of each of the three scleral layers disclosed abnormal collagen fibrils that were frayed, split, and contained lightly stained cores. CONCLUSION: New findings include the identification of collagen with lightly stained centers and identification of differences in collagen morphology in different areas of the sclera in a nanophthalmic eye. more...

To review the fields of nanotechnology and nanomedicine as they relate to the development of treatments for vision-threatening disorders.Perspective following literature review.Analysis of relevant publications in the peer-reviewed scientific literature.Nanotechnology involves the creation and use of materials and devices at the size scale of intracellular structures and molecules and involves systems and constructs on the order of100 nm. The aim of nanomedicine is the comprehensive monitoring, control, construction, repair, defense, and improvement of human biological systems at the molecular level, using engineered nanodevices and nanostructures, operating massively in parallel at the single cell level, ultimately to achieve medical benefit. The earliest impact of nanomedicine is likely to involve the areas of biopharmaceuticals (eg, drug delivery, drug discovery), implantable materials (eg, tissue regeneration scaffolds, bioresorbable materials), implantable devices (eg, intraocular pressure monitors, glaucoma drainage valves), and diagnostic tools (eg, genetic testing, imaging, intraocular pressure monitoring). Nanotechnology will bring about the development of regenerative medicine (ie, replacement and improvement of cells, tissues, and organs), ultrahigh-resolution in vivo imaging, microsensors and feedback devices, and artificial vision. "Regenerative nanomedicine," a new subfield of nanomedicine, uses nanoparticles containing gene transcription factors and other modulating molecules that allow for the reprogramming of cells in vivo.Nanotechnology already has been applied to the measurement and treatment of different disease states in ophthalmology (including early- and late-stage disease), and many additional innovations will occur during the next century. more...

Muscarinic cholinergic receptors build up on the proximal side of a ligature placed on the rat sciatic and vagus nerves. These receptors appear to be flowing down the axons of at least a portion of the nerve fibers present in sciatic and vagus nerves. Most of the anterograde flowing muscarinic binding sites are displaceable with 10−4 M carbachol indicating that many are high affinity agonist binding sites. These receptors can also be localized in the ganglionic nerve cell bodies in the dorsal root ganglia which contribute fibers to the sciatic nerve. We hypothesize that muscarinic cholinergic receptors are synthesized in the ganglion cell bodies and transported distally in sensory nerve axons in the sciatic nerve. more...

The distribution of high vs. low affinity muscarinic agonist binding sites has been determined using quantitative techniques of receptor autoradiography. The low affinity agonist sites predominate in many regions of the forebrain including the cerebral cortex, striatum, hippocampus, amygdala and thalamus. The high affinity agonist sites predominate in the brainstem and represent exclusively the type of muscarinic cholinergic receptor normally present in the principal nucleus of the trigeminal nerve, facial nerve nucleus, hypoglossal nerve nucleus, and in the ventral horn of the spinal cord. The regional localization of these subpopulations provides valuable information for future studies which seek to determine the functional importance of subtypes of muscarinic agonist binding sites. more...

We have localized the distribution of [3H]forskolin and [3H]phorbol dibutyrate binding sites autoradiographically in the rat, monkey, and human retina. In the rat and monkey retina, forskolin binding was enriched in the inner plexiform layer, in the inner and outer segments of the photoreceptors, and in the retinal pigment epithelium. In the human retina, forskolin binding sites were uniformly distributed and higher in density. Forskolin binding was also detected over the ciliary body, the ciliary epithelium, and the iris sphincter. The distribution of phorbol ester binding sites was similar in the rat, monkey, and human retina. The inner plexiform layer contained the highest density followed by the inner nuclear and outer plexiform layers, and the ganglion cell layer. In the rat, phorbol ester binding was present in the iris, the ciliary body, and the ciliary epithelium. The monkey and human ciliary body also contained a low density of phorbol ester binding sites. more...

Posterior capsule opacification following extracapsular cataract extraction is a manifestation of proliferation of anterior lens epithelium onto the posterior capsule. In addition to Elschnig pearl formation, vision is decreased in two ways. Multiple layers of proliferated epithelium produce a frank opacity. Also, the lens cells show myofibroblastic differentiation and their contraction produces numerous tiny wrinkles in the posterior capsule resulting in visual distortion. Because the cells that proliferate are anterior lens epithelial cells and because proliferation begins at the site of apposition of anterior capsular flap and the posterior capsule, a wide anterior capsulectomy should help reduce the risk of and delay the onset of visual loss from this complication of extracapsular surgery. Polishing the posterior capsule at the time of surgery will not help in this regard unless there is a complicated cataract with pre-existing posterior migration of lens epithelium. The presence of a potential cleavage plane between the proliferating epithelium and the posterior capsule provides a therapeutic alternative to surgical or laser discission. more...

An unusual, isolated case of the Rieger anomaly coincident with a multitude of dental, craniofacial, and systemic anomalies is described. Significant dental findings were severe enamel hypoplasia, conical and misshapen teeth, hypodontia, and impactions. Craniofacial disorders were underdevelopment of the maxilla, mandible, and anterior and posterior cranial bases, low-set ears, and a wide nasal bridge. Reported for the first time is the association of this genetic disorder with bilateral microcondyles and bilateral choanal atresia. Embryologic disturbance of the neural crest ectoderm is suspected. The patient also manifested anal atresia, scoliosis, kyphosis, and short stature. A discussion distinguishing this case report from the Rieger syndrome is presented. In addition, the possibility that the patient exhibited a previously unreported syndrome is also considered, and the term Short-F-R-A-M-E is proposed to name this new syndrome. more...