Role of Complement in the Onset of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive degenerative disease of the central retina and the leading cause of severe loss of central vision in people over age 50. Patients gradually lose central visual acuity, compromising their ability to read, write, drive, and recognize faces, all of which greatly impact daily life activities. Quality of life is significantly affected in these patients, and there are worse levels of depression as a result. AMD is a complex, multifactorial disease in which age and genetics, as well as environmental factors, all play a role in its development and progression. The mechanism by which these risk factors interact and converge towards AMD are not fully understood, and therefore, drug discovery is challenging, with no successful therapeutic attempt to prevent the development of this disease. In this review, we describe the pathophysiology of AMD and review the role of complement, which is a major risk factor in the development of AMD.

Ophthalmic anterior segment metastasis masquerading as uveitis.

Ocular malignancies are rare, with many cancers of the eye being the result of metastases, the most common of which result from primary tumours of breast, lung and gastrointestinal tract. Diagnosis is often made at a late stage in the disease course, leading to poorer outcomes. Disease-directed therapy in the presence of ocular metastases varies based on the primary tumour and patient performance status but generally involves systemic treatment, either with chemotherapy or involved-field radiation. We herein present an interesting case of ocular malignancy with neuroendocrine small cell features of pulmonary origin in a patient with no prior oncological history. Meticulous ophthalmic examination led to the diagnosis of small cell lung carcinoma with anterior segment metastasis. The patient underwent six cycles of systemic chemotherapy with a favourable response, resulting in improvement in vision and regression of the ocular lesion.

Short chain fatty acids inhibit endotoxin-induced uveitis and inflammatory responses of retinal astrocytes.

Short chain fatty acids (SCFAs) are produced by gut microbiota as fermentation products of digestion-resistant oligosaccharides and fibers. Their primary roles are functioning as major energy sources for colon cells and assisting in gut homeostasis by immunomodulation. Recent evidence suggests that they affect various organs both at cellular and molecular levels, and regulate functions in distance sites including gene expression, cell proliferation, cell differentiation, apoptosis and inflammation. In this study, we examined whether SCFAs are present in the mouse eye and whether SCFAs affect inflammatory responses of the eye and retinal astrocytes (RACs). We observed that intra-peritoneal injected SCFAs were detected in the eye and reduced intraocular inflammation induced by lipopolysaccharide (LPS). Moreover, SCFAs displayed two disparate effects on LPS-stimulated RACs - namely, cytokine and chemokine production was reduced, but the ability to activate T cells was enhanced. Our results support the existence of gut-eye cross talk and suggest that SCFAs can cross the blood-eye-barrier via the systemic circulation. If applied at high concentrations, SCFAs may reduce inflammation and impact cellular functions in the intraocular milieu.

Metabolic rescue of cone photoreceptors in retinitis pigmentosa.

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. It is a leading cause of visual disability, with an incidence of ~1 in 7000 persons. Although most RP is nonsyndromic, 20%-30% of patients with RP also have an associated nonocular condition. The gene mutations responsible for RP occur overwhelmingly in rod photoreceptors. Visual loss frequently begins with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors. Although the visual disability from rod dysfunction is significant, it is the subsequent loss of central vision later in life due to cone degeneration that is catastrophic. Until recently, the reason for cone dysfunction in RP was unknown. However, it is now recognized that cones degenerate, losing outer segment (OS) synthesis and inner segment (IS) disassembly because of glucose starvation following rod demise. Rod OS phagocytosis by the apical microvilli of retinal pigment epithelium is necessary to transport glucose from the choriocapillaris to the subretinal space. Although cones lose OS with the onset of rod degeneration in RP, regardless of the gene mutation in rods, cone nuclei remain viable for years (i.e. enter cone dormancy) so that therapies aimed at reversing glucose starvation can prevent and/or recover cone function and central vision.

Gene therapy for retinitis pigmentosa.

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RP) is the most common cause of RP in North America. There is no proven cure for the disease, and multiple approaches are being studied. Gene therapy is an evolving field in medicine and ophthalmology. In this review, we will go over the basic concept of gene therapy and the different types of gene therapy that are currently being studied to treat this disease.

Zeb1 promotes corneal neovascularization by regulation of vascular endothelial cell proliferation.

Angiogenesis is required for tissue repair; but abnormal angiogenesis or neovascularization (NV) causes diseases in the eye. The avascular status in the cornea is a prerequisite for corneal clarity and thought to be maintained by the equilibrium between proangiogenic and antiangiogenic factors that controls proliferation and migration of vascular endothelial cells (ECs) sprouting from the pericorneal plexus. VEGF is the most important intrinsic factor for angiogenesis; anti-VEGF therapies are available for treating ocular NV. However, the effectiveness of the therapies is limited because of VEGF-independent mechanism(s). We show that Zeb1 is an important factor promoting vascular EC proliferation and corneal NV; and a couple of small molecule inhibitors can evict Ctbp from the Zeb1-Ctbp complex, thereby reducing EC Zeb1 expression, proliferation, and corneal NV. We conclude that Zeb1-regulation of angiogenesis is independent of Vegf and that the ZEB1-CtBP inhibitors can be of potential therapeutic significance in treating corneal NV.

COMPARISON OF 2D AND 3D VIDEO DISPLAYS FOR TEACHING VITREORETINAL SURGERY.

PURPOSE: To compare medical students' learning uptake and understanding of vitreoretinal surgeries by watching either 2D or 3D video recordings. METHODS: Three vitreoretinal procedures (tractional retinal detachment, exposed scleral buckle removal, and four-point scleral fixation of an intraocular lens [TSS]) were recorded simultaneously with a conventional recorder for two-dimensional viewing and a VERION 3D HD system using Sony HVO-1000MD for three-dimensional viewing. Two videos of each surgery, one 2D and the other 3D, were edited to have the same content side by side. One hundred UMass medical students randomly assigned to a 2D group or 3D, then watched corresponding videos on a MacBook. All groups wore BiAL Red-blue 3D glasses and were appropriately randomized. Students filled out questionnaires about surgical steps or anatomical relationships of the pathologies or tissues, and their answers were compared. RESULTS: There was no significant difference in comprehension between the two groups for the extraocular scleral buckle procedure. However, for the intraocular TSS and tractional retinal detachment videos, the 3D group performed better than 2D (P < 0.05) on anatomy comprehension questions. CONCLUSION: Three-dimensional videos may have value in teaching intraocular ophthalmic surgeries. Surgical procedure steps and basic ocular anatomy may have to be reviewed to ensure maximal teaching efficacy.

Choroidal hyperreflective foci in Stargardt disease shown by spectral-domain optical coherence tomography imaging: correlation with disease severity.

IMPORTANCE: The presence of choroidal hyperreflective foci in Stargardt disease is, to our knowledge, a potentially new finding. Evaluation of these foci may aid in better understanding of the disease process. OBJECTIVES: To report the presence of choroidal hyperreflective foci in spectral-domain optical coherence tomography (SD-OCT) images from eyes with Stargardt disease and investigate the relationship between the number of hyperreflective foci and disease severity. DESIGN, SETTING, AND PARTICIPANTS: Twenty-six eyes of 13 patients with a clinical diagnosis of Stargardt disease were evaluated in a retrospective case series. Patient data were collected between January 1, 2009, and August 31, 2014. MAIN OUTCOMES AND MEASURES: The number of choroidal hyperreflective foci in Stargardt disease as well as correlation with visual acuity, central macular thickness (CMT), and disease duration were the main outcomes. A total of 707 macular SD-OCT scans of 13 patients with Stargardt disease were reviewed and evaluated for the presence and number of retinal/choroidal hyperreflective foci, central macular thickness, visual acuity, and disease duration. Enhanced depth imaging with OCT (EDI-OCT) scans available for 2 patients were compared with SD-OCT scans. A PubMed/Google search was performed to identify SD-OCT images in Stargardt disease; these findings were reviewed for the presence of choroidal hyperreflective foci. RESULTS: The mean (SD) numbers of hyperreflective foci in each retinal/choroidal layer in decreasing frequency were as follows: Bruch membrane/retinal pigment epithelial (RPE) complex, 78.22 (24.39); choriocapillaris, 25.77 (17.57); Sattler layer, 18.59 (12.89); outer retina, 16.64 (6.96); inner retina, 0.95 (1.58); and Haller layer, 0.73 (0.87). The number of hyperreflective foci in the Bruch membrane/RPE complex increased exponentially with decreasing CMT (R2 = 0.99; P = .008). The number of hyperreflective foci in the Bruch membrane/RPE complex, choriocapillaris, and Sattler layer increased proportionally with decreasing visual acuity (R2 = 0.97, R2 = 0.95, and R2 = 0.99, respectively; and P = .007, P = .006, and P = .008, respectively). Direct correlation existed between the number of hyperreflective foci in the choriocapillaris and the Sattler layer and disease duration (R2 = 0.98 and R2 = 0.99, respectively; and P = .006 and P =.009, respectively). In the 10 studies on Stargardt disease, choroidal hyperreflective foci were present in 51 of 54 SD-OCT images (94%). CONCLUSIONS AND RELEVANCE: Based on the findings of the present study, choroidal hyperreflective foci in Stargardt disease, prominent at the Bruch membrane/RPE complex, choriocapillaris, and Sattler layer, correlate with disease severity in terms of retinal atrophy, decline in vision, and disease duration. Further studies are necessary to assess whether these findings are unique to Stargardt disease.

Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome.

The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.

Photodynamic Therapy and Intravitreal Bevacizumab with Versus without Triamcinolone for Neovascular Age-related Macular Degeneration; a Randomized Clinical Trial.

PURPOSE: To compare the outcomes of photodynamic therapy (PDT) combined with intravitreal bevacizumab (IVB) with versus without intravitreal triamcinolone (IVT) in neovascular age-related macular degeneration (AMD). METHODS: Eighty-four eyes with active CNV secondary to AMD with no prior treatment were enrolled and followed for 1-year. Eligible eyes were randomly assigned to either PDT/IVB or PDT/IVB/IVT. The main outcome measure was change in best-corrected visual acuity (BCVA). RESULTS: Mean patient age was 71 ± 9 years. BCVA changes from baseline were statistically significant in both study arms at all follow-up intervals, however no significant difference was observed between the two groups regarding BCVA changes at week 12 (95% CI:-0.11-0.12 LogMAR) and other time points (all P > 0.6). Mixed model analysis revealed a significant effect from age (P < 0.001), pigment epithelial detachment (P = 0.009) and baseline BCVA (P < 0.001) on visual improvement. Significant central macular thickness (CMT) reduction occurred at all-time points as compared to baseline in both groups which was comparable between the study arms. There was no significant difference between the study arms in terms of retreatment rate (P = 0.1) and survival to the first repeat IVB injection (P = 0.065). CONCLUSION: Additional low-dose IVT to a PDT/IVB regimen for neovascular AMD provided no beneficial effects in terms BCVA or CMT, yet demonstrated a trend toward extending the injection-free period.

Missense mutation outside the forkhead domain of FOXL2 causes a severe form of BPES type II.

PURPOSE: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a developmental disease characterized by a complex eyelid malformation associated or not with premature ovarian failure (POF). BPES is essentially an autosomal dominant disease, due to mutations in the forkhead box L2 (FOXL2) gene, encoding a forkhead transcription factor. More than one hundred unique FOXL2 mutations have been described in BPES in different populations, many of which are missense mutations in the forkhead domain. Here, we report on a very severe form of BPES resulting from a missense mutation outside the forkhead domain. METHODS: A clinical and molecular genetic investigation was performed in affected and unaffected members of an Iranian family with BPES. The FOXL2 coding region was sequenced in an index case. Targeted mutation testing was performed in 8 family members. RESULTS: We have identified a heterozygous FOXL2 missense mutation c.650C→G (p.Ser217Cys) co-segregating with disease in members of a three-generation family with BPES type II. Only few missense mutations have been reported outside the forkhead domain so far. They were all found in mild BPES, in line with in vitro studies demonstrating mostly normal localization and normal or increased transactivation properties of the mutant proteins. Unlike previous studies, affected members of the family studied here showed a severe BPES phenotype, with bilateral amblyopia due to uncorrected ptosis. CONCLUSIONS: This is the first study demonstrating a severe BPES phenotype resulting from a FOXL2 missense mutation outside the forkhead domain, expanding our knowledge about the phenotypic consequences of missense mutations outside the forkhead domain in BPES.

Intravitreal bevacizumab vs. sham treatment in acute branch retinal vein occlusion with macular edema: results at 3 months (Report 1).

BACKGROUND: The goal of this work is to compare the visual and anatomical (central macular thickness; CMT) outcomes of intravitreal bevacizumab (IVB) injections relative to sham treatment in eyes with acute (less than 3 months in duration) branch retinal vein occlusion (BRVO). METHODS: In a double-masked randomized clinical trial (RCT), patients with acute BRVO were randomly assigned to one of two treatment groups: IVB (two injections of 1.25 mg IVB 6 weeks apart) or sham treatment. Primary outcome measures included changes in best-corrected visual acuity (BCVA) and CMT in optical coherence tomography (OCT) during follow-up (FU) examinations. Any complications secondary to injections were considered secondary outcomes. FU results after 6 and 12 weeks are reported. RESULTS: Eighty-one eyes (43 OD) of 81 patients (47 females) were enrolled in the study. Forty-two patients were enrolled in the IVB group, and 39 patients were enrolled in the sham group. Visual acuity and CMT improved in the IVB group after week 6 (two Snellen lines and 262 µm, respectively) and week 12 (three Snellen lines and 287 µm, respectively). After week 6, visual improvements in the IVB group were significantly increased relative to that of the sham group. However, visual improvements at week 12 were not significantly different between the two groups (1.5 Snellen lines visual improvement in the sham group at week 12). CONCLUSIONS: In acute BRVO, two IVB injections resulted in significant improvement of vision and CMT at 6 weeks relative to the sham group. However, the visual improvements in the IVB group were not significantly different from those in the sham group at 12 weeks. IVB injections accelerate an initial improvement of visual acuity but do not have any significant effects on vision after 12 weeks.

Ocular manifestations of transconjunctival heroin abuse: a case report of an unusual route of substance abuse.

PURPOSE: The purpose of this study was to present a patient with atypical corneoconjunctival lesions as a result of transconjunctival heroin abuse. METHODS: The authors conducted a prospective 8-month follow up of a 16-year-old girl who presented with bilateral atypical corneoconjunctival lesions. RESULTS: After a period of close observation, running diagnostic tests, and conservative treatment, the nature of the disease was suspected. Further discussion with the patient's family and her final confession revealed that she was using heroin through the conjunctiva. CONCLUSION: Substance abuse should be considered in the list of differential diagnoses in patients with an unusual presentation of ocular disease.

Fundus autofluorescence changes in two cases of Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder characterized by the triad of intellectual disability, spastic diplegia or tetraplegia, and congenital ichthyosis with associated ocular features, which include macular glistening dots. Herein, two cases of SLS are presented and their fundus autofluorescence changes, which have not been reported so far, are described.

Intravitreal Bevacizumab versus Combined Bevacizumab and Triamcinolone Acetonide for Neovascular Age-Related Macular Degeneration.

PURPOSE: To compare the short-term outcomes of intravitreal bevacizumab (IVB) with the combination of IVB and intravitreal triamcinolone acetonide (IVB/IVT) for treatment of neovascular age-related macular degeneration (AMD). METHODS: This randomized clinical trial was performed on 92 eyes of 90 patients with subfoveal and juxtafoveal choroidal neovascularization (CNV) secondary to AMD. The eyes were randomly assigned to receive IVB 1.25 mg alone (53 eyes) or in combination with IVT 2 mg (39 eyes). Best-corrected visual acuity (BCVA) and fundus autofluorescence were assessed, and fluorescein angiography (FA) and optical coherence tomography (OCT) were performed at baseline and repeated 6 weeks after treatment. RESULTS: Mean age was 70.6±8.7 (range 50-89) years and 57.7% of the patients were male. BCVA improved from 1.03±0.40 to 0.93±0.38 logMAR (P=0.001) in the IVB group and from 1.08±0.33 to 0.91±0.38 logMAR (P=0.008) in the IVB/IVT group. There was a trend toward greater visual improvement with combined therapy (P=0.06). BCVA improvement was greater in eyes with +1 versus those with +2 (P=0.049) and +3 (P<0.001) fundus autofluorescence at baseline. Mean decrease in central macular thickness was 113±115 µm (P<0.001) in the IVB group versus 53.96±125 µm (P=0.008) in the IVB/IVT group with no intergroup difference (P=0.38). FA showed decreased leakage in 57.4%, increased leakage in 12.8% and no change in 29.8% of patients in the IVB group. Corresponding figures were 60.0%, 5.7% and 34.3% in the IVB/IVT group (P=0.556). CONCLUSION: Addition of triamcinolone acetonide to bevacizumab for treatment of neovascular AMD does not seem to significantly increase its short-term efficacy. More severe fundus autofluorescence appears to be predictive of poorer response to treatment.

Prophylaxis of acute posttraumatic bacterial endophthalmitis: a multicenter, randomized clinical trial of intraocular antibiotic injection, report 2.

OBJECTIVE: To evaluate the efficacy of intraocular gentamicin sulfate and clindamycin in the prevention of acute posttraumatic bacterial endophthalmitis following penetrating eye injuries. METHOD: We conducted a multicenter, randomized, double-masked controlled trial of 346 eyes with penetrating eye injury. Following primary repair, eyes were randomized to intracameral or intravitreal injection of 40 microg of gentamicin sulfate and 45 microg of clindamycin (cases) vs balanced salt solution (controls). MAIN OUTCOME MEASURE: Occurrence of endophthalmitis within 2 weeks. RESULTS: Endophthalmitis occurred in 8 (2.3%) of 167 eyes in the control group and only in 1 (0.3%) of 179 eyes in the case group (P = .04; odds ratio, 8.93 [95% confidence interval, 1.11-71.43]). In eyes with an intraocular foreign body, endophthalmitis developed in 7 of 25 control eyes and in none of 27 eyes receiving antibiotics. However, in eyes without an intraocular foreign body, endophthalmitis developed in 1 of 142 eyes and 1 of 152 eyes in the 2 groups, respectively (P value for interaction = .04). Intravitreal injection was superior to intracameral injection in preventing endophthalmitis (P value for interaction = .01). Vitreous culture results were positive in 6 (67%) of 9 eyes with endophthalmitis. CONCLUSION: Intraocular gentamicin and clindamycin are effective in the prevention of acute posttraumatic bacterial endophthalmitis in eyes with retained intraocular foreign body. APPLICATION TO CLINICAL PRACTICE: Prophylaxis of traumatic endophthalmitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00398658.