Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. The cause of AMD is complex and many risk factors have been implicated including age, family history ...(genetics), diet, smoking, and other environmental risk factors. Over the past decade, studies has found that inflammation play a large role in the pathogenesis of age-related macular degeneration (AMD). In fact, the main genetic changes (polymorphism) associated with AMD were found to be genes that regulate inflammation, most notably complement Factor H. This review ties together many studies done over the past decade to give us new insight into the role inflammation plays in the development of AMD.
Therapeutic retinal laser photocoagulation can damage the neurosensory retina and cause iatrogenic visual impairment. Subthreshold micropulse photocoagulation may decrease this risk by selective ...tissue treatment. The aim of this study was to compare subthreshold 810-nm diode micropulse laser and subthreshold 532-nm micropulse laser on the retina by histologic examination and differential protein expression.
Fourteen Dutch-belted rabbits received subthreshold 810-nm diode micropulse laser photocoagulation in their right eye and subthreshold 532-nm micropulse laser photocoagulation in their left eye. Histology and immunohistochemical detection of stromal cell-derived factor-1 (SDF-1), β-actin, vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), and insulin-like growth factor 1 (IGF-1) were analyzed 12 hours, 3 days, 14 days, and 28 days post-laser photocoagulation.
Histologically, all time points produced a similar degree of retinal disruption in both wavelengths. Immunohistochemically, SDF-1 expression was greatest at the 12-hour time point and decreased thereafter. SDF-1, VEGF, and β-actin up-regulation was detected at early time points in both the 810- and 532-nm micropulse laser-treated animals.
Subthreshold micropulse retinal laser photocoagulation caused equivalent histologic changes from both 532- and 810-nm diode lasers. Differential protein expression was not evident between the different laser conditions.
To evaluate the morphologic changes in the macula of subjects with repaired macula-off retinal detachment (RD) using high-resolution Fourier-domain optical coherence tomography (FD OCT) and to ...perform functional correlation in a subset of patients using microperimetry (MP-1).
Prospective observational case series.
Seventeen eyes from 17 subjects who had undergone anatomically successful repair for macula-off, rhegmatogenous RD at least 3 months earlier and without visually significant maculopathy on funduscopy.
FD OCT with axial and transverse resolution of 4.5 mum and 10 to 15 mum, respectively, was used to obtain rapid serial B-scans of the macula, which were compared with that from Stratus OCT. The FD OCT B-scans were used to create a 3-dimensional volume, from which en face C-scans were created. Among 11 patients, MP-1 was performed to correlate morphologic changes with visual function.
Stratus OCT scans, FD OCT scans, and MP-1 data.
Stratus OCT and FD OCT images of the macula were obtained 3 to 30 months (mean 7 months) postoperatively in all eyes. Although Stratus OCT revealed photoreceptor disruption in 2 eyes (12%), FD OCT showed photoreceptor disruption in 13 eyes (76%). This difference was statistically significant (P<0.001, chi(2)). Both imaging modalities revealed persistent subretinal fluid in 2 eyes (12%) and lamellar hole in 1 eye. Among 7 subjects who had reliable MP-1 data, areas of abnormal function corresponded to areas of photoreceptor layer disruptions or persistent subretinal fluid in 5 subjects (71%); one subject had normal FD OCT and MP-1.
Photoreceptor disruption after macula-off RD repair is a common abnormality in the macula that is detected better with FD OCT than Stratus OCT. A good correlation between MP-1 abnormality and presence of photoreceptor disruption or subretinal fluid on FD OCT demonstrates that these anatomic abnormalities contribute to decreased visual function after successful repair.
To use ultra-high-resolution optical coherence tomography (OCT) subclinical anatomic alterations to explain suboptimum vision despite pseudophakic cystoid macula edema (CME) resolution.
University of ...California-Davis, Sacramento, California, USA.
Case study.
This study comprised patients who had cataract phacoemulsification surgery. Cases of resolved postoperative CME (diagnosed postoperatively by 1 month and resolved by 1 year) were included. Exclusion criteria included any other cause for decreased vision or compounding factors. Patients with a history of resolved pseudophakic CME were imaged using a purpose-built ultra-high-resolution OCT system with 4.5 μm axial resolution and an acquisition speed of 9 frames/sec (1000 A-scans/frame). The corrected distance visual acuity (CDVA) was determined by Early Treatment Diabetic Retinopathy Study standards. Statistical analysis was by the unpaired t test. A P value less than 0.05 was considered significant.
The review identified 56 patients with a pseudophakic CME diagnosis at least 1 month postoperatively. Fifteen eyes (26.8%) had less than 20/20 CDVA despite resolution of CME; 7 participated. Four patients with 20/20 CDVA after resolution of pseudophakic CME participated. Eyes with reduced CDVA after macula edema showed ultra-high-resolution OCT evidence of blurring of outer segments of photoreceptors, while controls showed normal outer retina morphology (P<.05).
Persistent anatomic alteration of photoreceptors visualized by ultra-high-resolution OCT correlated with reduced CDVA in patients with pseudophakic CME compared with patients who had 20/20 CDVA after macula edema. This anatomic alteration in outer photoreceptor morphology is a plausible explanation for the reduced CDVA in this disease.
No author has a financial or proprietary interest in any material or method mentioned.
Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing ...geographic atrophy (GA) progression.
Parallel-group, multicenter, randomized phase II clinical trial.
Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye.
We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months.
The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit.
Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year;
= 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (
= 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (
= 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin.
The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)-grade human bone-marrow-derived CD34(+) cells in NOD-SCID (nonobese diabetic-severe combined ...immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy.
Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 × 10(4) CD34(+) cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning.
Immunohistochemical staining 4 months after injection showed detectable CD34(+) cells in the retinal vasculature. ERG at 8 months after CD34(+) cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34(+) cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells.
Intravitreal administration of GMP-grade human bone-marrow-derived CD34(+) cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy.
To evaluate the effect of intravitreal ciliary neurotrophic factor (CNTF) implant on mean macular thickness (MMT) in eyes with retinitis pigmentosa using high-resolution Fourier domain optical ...coherence tomography imaging.
A cohort of 8 patients (CNTF-3: n = 5; CNTF-4: n = 3) enrolled in Neurotech sponsored Phase 2 clinical trial underwent Fourier domain optical coherence tomography imaging. A ≥3% change in MMT from baseline or fellow eye was considered as a measurable change.
Two patients enrolled in the CNTF-3 study received low-dose implant. At 18 months, a change in MMT from -4.47 μm to 6 μm from baseline was noted. Six patients received high-dose implant (CNTF-3: n = 3; CNTF-4: n = 3). In CNTF-3 group, 1 eye showed an increase in MMT by 19.25 μm (+7.6%) from baseline at 18 months. In CNTF-4 group, 1 eye had an increase in MMT of 27.08 μm (+11%) from baseline at 30 months; second eye had increase in MMT of 31.36 μm (+12%) from contralateral eye. Amongst these 3 responsive high-dose implant eyes, overall thickening of the retina could not be attributed to any specific retinal layer.
A heterogeneous dose-dependent response on MMT was noted in eyes treated using intravitreal CNTF implant for retinitis pigmentosa. We recommend corroboration of our findings with Neurotech sponsored clinical trial results.
To determine the level of epithelial membrane protein-2 (EMP2) expression in preretinal membranes from surgical patients with proliferative vitreoretinopathy (PVR) or epiretinal membranes (ERMs). ...EMP2, an integrin regulator, is expressed in the retinal pigment epithelium and understanding EMP2 expression in human retinal disease may help determine whether EMP2 is a potential therapeutic target.
Preretinal membranes were collected during surgical vitrectomies after obtaining consents. The membranes were fixed, processed, sectioned, and protein expression of EMP2 was evaluated by immunohistochemistry. The staining intensity (SI) and percentage of positive cells (PP) in membranes were compared by masked observers. Membranes were categorized by their cause and type including inflammatory and traumatic.
All of the membranes stained positive for EMP2. Proliferative vitreoretinopathy-induced membranes (all causes) showed greater expression of EMP2 than ERMs with higher SI (1.81 vs. 1.38; P = 0.07) and PP (2.08 vs. 1.54; P = 0.09). However all the PVR subgroups had similar levels of EMP2 expression without statistically significant differences by Kruskal-Wallis test. Inflammatory PVR had higher expression of EMP2 than ERMs (SI of 2.58 vs. 1.38); however, this was not statistically significant. No correlation was found between duration of PVR membrane and EMP2 expression. EMP2 was detected by RT-PCR in all samples (n = 6) tested.
All studied ERMs and PVR membranes express EMP2. Levels of EMP2 trended higher in all PVR subgroups than in ERMs, especially in inflammatory and traumatic PVR. Future studies are needed to determine the role of EMP2 in the pathogenesis and treatment of various retinal conditions including PVR.
Docetaxel (Taxotere) is an anticancer agent used to treat a wide range of malignancies including breast, lung, and prostate cancer. In this report, we describe a patient with bilateral vision loss ...due to cystoid macular edema (CME) associated with docetaxel therapy. This report documents for the first time the optical coherence tomography (OCT) findings of CME despite the lack of leakage with flourescein angiography and its association with the Fluid Retention Syndrome (FRS). Successful management of CME with oral acetazolamide is also discussed.
VEGF production by RPE cells has been shown to be important in regulating aberrant angiogenesis in the retina, which is responsible for multiple types of ocular pathology. EMP2 is highly expressed in ...the RPE and has been shown to regulate FAK activation, which is implicated in VEGF expression in other cell lines. The purpose of this study was to determine whether EMP2 regulates VEGF expression in the RPE cell line, ARPE-19.
ARPE-19 cells were engineered to overexpress EMP2. EMP2 siRNA was used to decrease EMP2 expression. The small molecule inhibitor PP2 was used to inhibit FAK activation. VEGF levels were measured by Western blot and ELISA. Functional differences in secreted VEGF were assayed using HUVEC migration.
VEGF expression levels correlated with levels of EMP2. An increase of VEGF by 150% was observed in EMP2 overexpressing cells as compared with ARPE-19 cells. Concordantly, EMP2 knockdown resulted in a 57% decrease in VEGF expression. HUVEC migration (P = 0.01) and vessel tube formation (P < 0.01) were significantly increased when exposed to cell culture supernatants from EMP2 overexpressing cells.
This study establishes a novel connection between EMP2 and VEGF and may reflect either a direct effect through the tetraspan web or an indirect change through FAK activation. This connection is functionally significant. In addition to the direct use of anti-VEGF antibodies, modulation of EMP2 with impact on VEGF is potentially a distinct therapeutic target for the treatment of neovascularization associated with retinal diseases that involve pathologic angiogenesis.
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