John I. Loewenstein

Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: Phase II study results

PURPOSE There is evidence to suggest that anti-vascular endothelial growth factor (anti-VEGF) therapy may be useful in treating ocular neovascularization. A phase IA single intravitreal injection study of anti-VEGF therapy for patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) revealed a good safety profile. We performed a phase II multiple injection study of anti-VEGF therapy with and without photodynamic therapy for patients with subfoveal CNV secondary to AMD to determine the safety profile of multiple injection therapy. DESIGN A phase II multiple-dose safety study. PARTICIPANTS/METHODS Twenty-one patients were treated with intravitreal injection with and without photodynamic therapy. MAIN OUTCOME MEASURES Clinical evidence of toxicity and complications. RESULTS No drug-related serious adverse events were revealed. Ophthalmic evaluation revealed that 87.5% of patients who received the anti-VEGF aptamer alone showed stabilized or improved vision 3 months after treatment and that 25% of eyes demonstrated a 3 line or greater improvement in vision on the Early Treatment of Diabetic Retinopathy Study chart during this period. A 60% 3 line gain at 3 months was noted in patients who received both the anti-VEGF aptamer and photodynamic therapy. CONCLUSIONS Anti-VEGF therapy is a promising treatment for various forms of ocular neovascularization, including AMD. Multiple intravitreal injections of the anti-VEGF aptamer were well tolerated in this phase II study. Further clinical trials are necessary to demonstrate the efficacy and long-term safety of anti-VEGF therapy for AMD.

In-vivo three-dimensional imaging of neovascular age related macular degeneration using optical frequency domain imaging at 1050 nm

PURPOSE To assess the application of optical frequency domain imaging (OFDI) at 1050 nm for the detection of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) and its response to treatment. Three patients presenting with blurred vision and exudative AMD were imaged before and after anti-VEGF treatment with ranibizumab. METHODS The patients were imaged with OFDI, a swept-source-based, high-speed optical coherence tomography (OCT) system developed at the Wellman Center for Photomedicine. A center wavelength of 1050 nm was used that has been demonstrated to provide better imaging of the deeper structures of the retina below the RPE, such as the choroidal vasculature. Three-dimensional data sets were acquired in 2 to 4 seconds. RESULTS En face images were compiled from cross-sectional OFDI data and correlated with color fundus photography (CF) and fluorescein angiograms (FAs). Cross-sectional images were coregistered with CF and FA to obtain depth-resolved information about CNV, CNV volume, retinal thickness, subretinal fluid volume and height of neurosensory detachment before and after treatment with ranibizumab. A band of reduced reflectivity below the RPE was identified in all three subjects that corresponded to areas of confirmed and suspected occult CNV on FA. After treatment, this band was reduced in volume in all patients. CONCLUSIONS High-speed 3-D OFDI at 1050 nm is a promising technology for imaging the retina and choroid in neovascular AMD. The developed system at 1050 nm provides good contrast for occult (type 1) CNV and may have advantages compared with time domain and current state of the art spectral domain OCT systems (SD-OCT) at 850 nm.

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment

Importance Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. Objective We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. Design Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). Results Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. Conclusions High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Diagnostic Testing and Disease Monitoring in Birdshot Chorioretinopathy

Birdshot chorioretinopathy (BSCR) is a rare form of posterior uveitis in which hypopigmented choroidal lesions are scattered throughout the posterior pole. In order to avoid the poor natural history of BSCR, many practitioners would argue that it is critical to diagnose and carefully monitor the often subtle activity of this disease; BSCR can progress insidiously in a white and painless eye, and treatment algorithms based on visual acuity, vitreous inflammation, and retinal vascular leakage of fluorescein alone have been ineffective. This article reviews the various modalities that can be used to diagnose and monitor BSCR, including the clinical and ophthalmoscopic features, diagnostic criteria, electroretinography (ERG- full field, multifocal, and pattern), fluorescein angiography (FA), indocyanine green (ICG) angiography, optical coherence tomography (OCT), fundus autofluorescence (AF), visual fields, HLA A29 testing, and other laboratory testing. HLA-A29 testing can be useful in diagnostically borderline cases, but a positive test is not as useful as one might think in cases where the clinical suspicion for BSCR is low. Out of all the testing modalities, the ERG has been studied most extensively in its relationship to successful treatment. The key parameter is the 30 Hz flicker implicit time, which is abnormal in 70% of patients at baseline. A normal implicit time is correlated with the chance that a patient can be successfully tapered from systemic immunomodulatory therapy without recurrence. Alternatively, some practitioners use ICG angiography or visual field testing for adjunctive monitoring. OCT is used most commonly to follow macular edema. While there is no consensus on how to best monitor disease activity, our institution uses serial ERGs as an adjunct to the normal exam.

Vogt-Koyanagi-Harada Syndrome with Focal Neurologic Signs

The Vogt-Koyanagi-Harada syndrome includes inflammation of the uveal tract, retina, and meninges. Integumentary and auditory signs are common. Neurologic involvement has been reported. We studied two patients who manifested many of the varied clinical signs of Vogt-Koyanagi-Harada syndrome, but who also showed focal neurologic involvement, including acute transverse myelitis and ciliary ganglionitis. Both patients responded well to corticosteroid therapy. The findings in these patients and the results of previous studies suggest that Vogt-Koyanagi-Harada syndrome is a cell-mediated autoimmune disorder in which a component of myelin acts as an inciting antigen.

Leber Congenital Amaurosis: Disease, Genetics and Therapy

Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that was first described almost 150 years ago. LCA still remains an important cause of blindness with about 20% of children in schools for the blind being affected by it. LCA has genetic heterogeneity and the study of this disease is elucidating the genetics and molecular interactions involved in the development of the retina. This paper reviews the clinical history of the disease since it was first described. We further discuss the differential diagnosis of the disease and the difficulties encountered in making the diagnosis. We also review the genetics of the disease and the role of future therapies.

Multifocal electroretinographic abnormalities in ethambutol-induced visual loss.

Two patients who developed decreased visual acuity after several months of ethambutol treatment for Mycobacterium avium-intracellulare infection had bitemporal visual field defects that suggested optic chiasm damage. Multifocal electroretinography (mfERG) disclosed markedly low-amplitude responses at fixation and in the regions corresponding to the visual field defects. These results suggested that the visual dysfunction might be entirely attributable to retinal rather than optic nerve toxicity. These are the first reported patients to show mfERG abnormalities that correspond to bitemporal visual field defects and add to the growing evidence that ethambutol damages the retina.

Extraction of a Chronically Implanted, Microfabricated, Subretinal Electrode Array

Purpose: To assess the feasibility of extraction of a chronically implanted subretinal electrode array. Methods: Inactive, polyimide strips (10 mm × 1.5 mm × 15 μm) were surgically implanted into the subretinal space of 8 rabbits using a mostly ab externo approach. Pre- and postoperative clinical examinations, electroretinography and in some cases optical coherence tomography were performed to follow the course of the eyes. Two months after implantation, the polyimide strips were extracted from 5 eyes; 2 animals kept the implants and served as controls. All animals were then sacrificed and eyes enucleated for histological examination. Results: All 8 surgeries yielded successful placement of the arrays into the subretinal space. All 5 extraction surgeries were performed without obvious complications. Clinical examinations and electroretinography did not reveal any significant abnormalities. The histological examinations showed alterations from normal anatomy in all animals; the anatomical changes in the explanted animals were relatively mild and confined to the area of the surgery. Conclusions: Successful extraction of electrode arrays from the subretinal space of rabbits can be reliably performed 2 months after implantation, which is beyond the time period when postoperative scarring would be most intense.

Endophthalmitis associated with intravitreal injections.

With the advent of antivascular endothelial growth factor (VEGF) agents such as pegaptanib and ranibizumab, we have entered a new era of pharmacotherapy delivered through frequent intravitreal injections in a large patient population. With this paradigm change in the treatment of age-related macular degeneration (ARMD) comes the added risk of endophthalmitis. Although the incidence of endophthalmitis seems relatively low, the potential consequences can be devastating. The application of intravitreal drug delivery is quite broad, and thus, information on its safety in various settings has been widely reported in the context of clinical trials or case series. However, it is often difficult to assess the true prevalence of endophthalmitis associated with intravitreal injections on the basis of historical data, and even harder to apply these data to new drugs and populations. This monograph will briefly review endophthalmitis occurrence and outcome in previously reviewed indications for intravitreal injections; focusing primarily on more recent advances involving intravitreal delivery of agents, such as triamcinolone, pegaptanib, and ranibizumab. Current practices of intravitreal injection to minimize the occurrence of endophthalmitis will also be discussed.

Development of an Epiretinal Electronic Visual Prosthesis

Diseases of the retina and optic nerve are common causes of irreversible blind- ness. Given the lack of effective treatments, several laboratories are utilizing micro- electronic technology to develop either a cortical or retinal prosthesis. Each strategy offers certain advantages, but both face numerous and formidable challenges. Conse- quently, a clinically useful device of either type is still conceptual. The technological means to build prostheses are available but the ultimate obstacle is the integration of the technology with the brain. This review primarily focuses on our efforts to develop a retinal prosthesis. In particular we address the two problems that we believe to be most challenging: 1) need to demonstrate that retinal stimulation can produce “useful” vision in a blind patient, and 2) need to demonstrate long-term biocomopatibility of an implanted device in an animal.