David G. Telander

Inflammation and Age-Related Macular Degeneration (AMD)

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.

High-resolution Fourier-Domain Optical Coherence Tomography and Microperimetric Findings After Macula-off Retinal Detachment Repair

OBJECTIVE 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). DESIGN Prospective observational case series. PARTICIPANTS 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. METHODS 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. MAIN OUTCOME MEASURES Stratus OCT scans, FD OCT scans, and MP-1 data. RESULTS 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. CONCLUSIONS 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.

High resolution Fourier-domain optical coherence tomography of retinal angiomatous proliferation.

Purpose: To study the anatomic details of retinal angiomatous proliferation (RAP) in patients with age-related macular degeneration (AMD) using high-resolution Fourier-domain optical coherence tomography (Fd-OCT) and its three-dimensional reconstructions. Methods: A Fd-OCT instrument was used to image five patients clinically diagnosed with RAP. A series of 100 raster-scanned B-scans centered over the macula was registered and rendered as a three-dimensional volume. These retinal structures were analyzed for anatomic details of the RAP lesions. Results: The RAP lesion could be identified within the retina on Fd-OCT in all five cases. Fd-OCT images of the first four cases revealed areas of intraretinal neovascularization (IRN) in the deep retina adjacent to a pigment epithelial detachment (PED). There was neovascular proliferation anteriorly and posteriorly through a break in the retinal pigment epithelium (RPE). In three of the four cases, Bruch membrane remained intact. There was no identifiable choroidal neovascularization (CNV). The fifth case had both subretinal and sub-RPE neovascular membranes without a PED. Conclusion: Fd-OCT provides unprecedented in vivo detail of the anatomy of RAP lesions that nearly resembles histologic specimens. This study suggests that the initial neovascular process in RAP can originate either within the retina or in the sub-RPE space.

Cystoid Macular Edema with Docetaxel Chemotherapy and the Fluid Retention Syndrome

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.

Long-Term Effects of Intravitreal Injection of GMP-Grade Bone-Marrow–Derived CD34+ Cells in NOD-SCID Mice with Acute Ischemia-Reperfusion Injury

PURPOSE 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. METHOD 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. RESULTS 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. CONCLUSIONS 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.

The Comparative Histologic Effects of Subthreshold 532- and 810-nm Diode Micropulse Laser on the Retina

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

High-Resolution Fourier-Domain Optical Coherence Tomography of Choroidal Neovascular Membranes Associated with Age-Related Macular Degeneration

PURPOSE To investigate the use of high-resolution Fourier-domain optical coherence tomography (Fd-OCT) to image choroidal neovascular membranes (CNVMs) associated with exudative age-related macular degeneration (eAMD). METHODS An Fd-OCT instrument with axial resolution of 4 to 4.5 microm and transverse resolution of 10 to 15 microm was used to image 21 eyes (19 subjects) with newly diagnosed eAMD. A raster series of 100 B-scans separated by 60 microm was used to study the growth pattern of CNVM and associated morphologic changes. CNVM size was determined using 250 to 300 serial virtual C-scans of reconstructed three-dimensional macular volume. RESULTS A highly reflective subretinal and/or subretinal pigment epithelial (RPE) lesion that co-localized with the CNVM seen on fluorescein angiography was detected in all eyes by Fd-OCT. Although a combined subretinal and sub-RPE growth pattern of various degrees was noted in 15 (71%) eyes, a statistically significant difference in the distribution of growth pattern was noted when classic CNVM was compared with occult CNVM (chi(2) = 10.4, df = 2, P < 0.005). Classic lesions had >90% subretinal growth pattern, whereas occult lesions had a more variable growth pattern. Angiographic CNVM size correlated with size on Fd-OCT but correlation was better for classic CNVM (classic, r = 0.99, P < 0.0001; nonclassic, r = 0.78, P < 0.001). CONCLUSIONS Fd-OCT is a promising potential alternative modality to visualize CNVM with AMD. Angiographic lesion size and type correlated with growth pattern and size of CNVM on Fd-OCT, with correlation being stronger for classic lesions.

Epithelial membrane protein-2 (EMP2) and experimental proliferative vitreoretinopathy (PVR).

Purpose: Proliferative vitreoretinopathy (PVR) is believed to result in part from de-differentiation of retinal pigment epithelium (RPE) with cellular migration in the vitreous cavity, membrane formation, and contraction in an aberrant wound-healing strategy. In an in vitro collagen-gel contraction assay, epithelial membrane protein 2 (EMP2) controls contraction through activation of focal adhesion kinase (FAK) in a RPE cell line (ARPE-19). The purpose of this study was to investigate how blocking or altering the level of EMP2 expression changed clinical PVR in an in vivo model. Methods: Using the ARPE-19 cell line, the levels of EMP2 modulated through stable transfections of an EMP2 overexpressing construct, EMP2 ribozyme, or vector alone. These transfected cell lines were used in a rabbit model of PVR. The severity of PVR was classified by two masked observers. An EMP2 blocking antibody was also used to decrease functional EMP2 in the PVR model. Immunohistochemistry was used to evaluate EMP2 expression in vivo. Results: The transfectants with lower levels of EMP2 had significantly less PVR severity than the degree of PVR induced by wild-type cells (p = 0.05). Also, the transfectants with a low-level of EMP2 expression showed a strong trend of less PVR severity than the high-levels EMP2 transfectants (p = 0.06). Blocking EMP2 with a specific polyclonal antibody significantly decreased the level of PVR severity (p = 0.02). PVR membranes were found to be positive for EMP2 expression. Conclusions: These in vivo studies support a direct correlation between EMP2 expression and severity of PVR. These results validate the potential for controlling RPE biology through a change in EMP2 expression, and provide a potential therapeutic target for this disease.

Improving visual outcomes by preserving outer retina morphology in eyes with resolved pseudophakic cystoid macular edema

Purpose To use ultra‐high‐resolution optical coherence tomography (OCT) subclinical anatomic alterations to explain suboptimum vision despite pseudophakic cystoid macula edema (CME) resolution. Setting University of California–Davis, Sacramento, California, USA. Design Case study. Methods 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 &mgr;m 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. Results 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). Conclusions 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. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Macular edema in the era of spectral-domain optical coherence tomography

The development of spectral-domain optical coherence tomography (OCT) allows for the highest commercially available resolution of in vivo retinal anatomic details to date. The ability to see the macula with ever increasing detail is dramatically improving our understanding of the pathogenesis of retinal disease. However, the only prospective study that partially evaluated spectral-domain OCT versus time-domain OCT failed to show any clinical benefit of increased OCT resolution. Clinical outcomes, eg, best-corrected visual acuity, central macular thickness and number of injections, with “newer” OCT technologies remain an unproven advantage.