Karl G. Csaky

Clinical Classification of Age-related Macular Degeneration

OBJECTIVE To develop a clinical classification system for age-related macular degeneration (AMD). DESIGN Evidence-based investigation, using a modified Delphi process. PARTICIPANTS Twenty-six AMD experts, 1 neuro-ophthalmologist, 2 committee chairmen, and 1 methodologist. METHODS Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions. MAIN OUTCOME MEASURES Delphi review of the 9-item set of statements resulting from the meeting. RESULTS Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 μm), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group. CONCLUSIONS The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD. Incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care.

The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration

This study examined the association between the sequence variation/expression of CX3CR1, a chemokine receptor, and age‐related macular degeneration (AMD). Peripheral blood from 85 AMD patients and 105 subjects without AMD (controls), as well as ocular tissue from 40 pathological sections with AMD and two normal eye sections, were screened for V249I and T280M, two single nucleotide polymorphisms (SNPs) in CX3CR1. An increased prevalence, with the highest odds ratio of 3.57, of the I249 and M280 carriers was found among the AMD cases as compared with the controls. When comparing CX3CR1 expression in the archived eye sections, CX3CR1 transcripts were not detectable in the maculae of AMD eyes bearing T/M280; however, transcripts were detected in the maculae of normal eyes bearing T/T280 or T/M280 as well as in the AMD maculae bearing T/T280. Furthermore, lower CX3CR1 protein expression was observed in the maculae of AMD eyes bearing T/M280 compared with the controls bearing T/T280. The I249 and M280 alleles result in a lowered number of receptor binding sites and a decreased ligand affinity. Our data suggest that a decrease, caused by sequence variation and/or lower CX3CR1 expression, in CX3CR1‐induced cellular activities could contribute to AMD development.

Ophthalmic Drug Delivery Systems for the Treatment of Retinal Diseases: Basic Research to Clinical Applications

The basic science part of this article focuses on the anatomic barriers to the five major modes of ocular drug delivery: intraocular, periocular, hybrid, topical, and systemic. The second half is a review of the clinical and regulatory components of translational science.

Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium.

The National Eye Institute (NEI) of the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) held an open symposium on November 28–29, 2006, in Washington, DC, where representatives from both federal agencies, the Center for Medicare and Medicaid Services (CMS), university scientists and clinicians, and others conferred on endpoints and clinical trial strategies for evaluating new treatments for age-related macular degeneration (AMD), diabetic retinopathy, and other retinal disorders. The symposium was organized as a forum for discussion by the Association for Research in Vision and Ophthalmology (ARVO). Cohosts of the symposium were Janice M. Soreth, MD, Director of the Division of Anti-infective and Ophthalmology Products of the FDA’s Center for Drug Evaluation and Research (CDER), and Karl G. Csaky, MD, PhD, NEI Senior Investigator. The symposium evolved from a series of meetings between members of the eye and vision research community and CDER. The research community is looking to the FDA for information that will help with obtaining timely approval of new products arising from ophthalmic clinical research. The National Alliance for Eye and Vision Research (NAEVR) was the host of the initial meetings. NAEVR is a nonprofit advocacy organization working on behalf of professional, consumer, and industry organizations involved in eye and vision research. Stephen J. Ryan, MD, NAEVR Board President and President of the Doheny Eye Institute of the University of Southern California, in his keynote speech to symposium attendees, noted that the need for more efficient and cost-effective clinical trials “. . . is especially important in ophthalmology where new technologies are enabling better quantitative measurements of outcomes, which subsequently expedites the translation of clinical trials into improved practice patterns.” The format of the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium was a roundtable discussion moderated by Dr. Csaky. Presenters and discussants sat before an auditorium of approximately 250 observers. Audience members, mainly from industry, federal agencies, academia, and vision advocacy groups, had the opportunity to submit questions to the symposium organizers before the discussion. In essence, the symposium addressed developing standards for clinical trials in ophthalmology and focused largely on the type and duration of clinical trials or postsurveillance studies in addition to the clinical importance of the endpoints used in vision research clinical trials. The discussion consisted of five sections for which speakers and discussants addressed questions they had received in advance. The five sections were as follows:

Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma A New Cause of Uveitis

Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4) is an important costimultory receptor expressed on activated T cells. CTLA-4 blockade using a monoclonal antibody (mAb) in conjunction with tumor vaccines has improved tumor responses in animal models and enhanced numerous models of T cell-associated autoimmune diseases. Two patients with stage IV metastatic melanoma vaccinated with the gp 100 melanocyte/melanoma differentiation antigen either before or during anti-CTLA-4 mAb therapy developed uveitis. This is the first report of autoimmune disease involving the eye in patients treated with anti-CTLA-4 mAb. This suggests that CTLA-4 is an important regulatory molecule for maintenance of tolerance to melanosomal antigens and prevention of uveitis.

Aqueous humor and plasma vascular endothelial growth factor in uveitis-associated cystoid macular edema.

PURPOSE To determine the association between cystoid macular edema and vascular endothelial growth factor concentration in the aqueous humor and plasma of uveitis patients. METHODS Cross-sectional study. Vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay in the aqueous humor of 20 uveitis patients (9 with and 11 without cystoid macular edema), and in the plasma of 40 uveitis patients (20 with and 20 without cystoid macular edema) and 20 healthy volunteers. RESULTS Mean aqueous humor vascular endothelial growth factor concentrations for uveitis patients with and without cystoid macular edema were 152.3 and 109.5 pg/ml, respectively, P =.044. Mean plasma vascular endothelial growth factor concentrations in uveitis patients with and without cystoid macular edema and in healthy volunteers were 32.2, 29.6, and 55.0 pg/ml, respectively. Uveitis patients had lower plasma vascular endothelial growth factor levels than did healthy volunteers, P =.0002. CONCLUSION In uveitis patients, vascular endothelial growth factor concentration is increased in the aqueous humor of eyes with cystoid macular edema. It may be useful to investigate vascular endothelial growth factor antagonists as a treatment for uveitis-associated cystoid macular edema.

The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy: The early treatment diabetic retinopathy follow-up study

OBJECTIVES To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. DESIGN Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. METHODS Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). MAIN OUTCOME MEASURES The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. RESULTS Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. CONCLUSIONS As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high.

Clinical Biochemical and Pathologic Correlations in Bietti's Crystalline Dystrophy

We examined three affected members of a Chinese-American family with Biettis crystalline retinopathy. The clinical characteristics of a 24-year-old proband are contrasted to the clinical findings of her grandmother, for whom we have 26 years of follow-up data. Lymphocytes and fibroblasts from a skin biopsy of the grandmother contained crystalline lysosomal material, which supports the diagnosis. Biochemical studies of the crystalline lysosomal material failed to identify the stored compounds but did not show them to be cholesterol or cholesterol ester. Finally, histopathologic studies performed for this condition demonstrated advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts.

Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy.

PURPOSE To investigate the clinical features associated with immune recovery in human immunodeficiency virus (HIV)-infected patients with cytomegalovirus retinitis who are taking highly active antiretroviral therapy. METHODS Sixteen patients were evaluated prospectively at the National Eye Institute, Bethesda, Maryland. Evaluation included a medical history and a complete ophthalmologic examination. The examination included best-corrected visual acuity score measured by means of logarithmic charts, slit-lamp biomicroscopy, dilated retinal examination, retinal photography, and fluorescein angiography. Immune-recovery uveitis was defined as the ocular inflammation associated with clinical immune recovery in patients taking potent antiretroviral regimens. The ophthalmic characteristics of immune-recovery uveitis were identified, and their effect on visual acuity was statistically analyzed. RESULTS The mean CD4+ T-lymphocyte count for the 16 patients taking highly active antiretroviral therapy at the time of evaluation was 393 cells/microl (range, 97-1,338 cells/microl). Immune-recovery uveitis was characterized by vitreitis and optic disk and macular edema. Clinically important complications of immune-recovery uveitis included cataract and epiretinal membrane formation. The visual acuity scores were significantly worse in the 23 eyes with cytomegalovirus retinitis (mean, 67.2 letters, 20/50) than in the nine eyes without cytomegalovirus retinitis (mean, 89.8 letters, 20/16) (P <.001). Regression analysis showed that a lower visual acuity score was associated with the presence of moderate to severe macular edema on fluorescein angiography and vitreous haze (P < or =. 001). CONCLUSIONS Immune-recovery uveitis is an important cause of visual morbidity in HIV-infected patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Although immune recovery associated with highly active antiretroviral therapy has allowed some patients to discontinue specific anticytomegalovirus therapy, the rejuvenated immune response can be associated with sight-threatening inflammation.

Safety Implications of Vascular Endothelial Growth Factor Blockade for Subjects Receiving Intravitreal Anti–Vascular Endothelial Growth Factor Therapies

PURPOSE To evaluate potential safety risks associated with nonspecific inhibition of vascular endothelial growth factor (VEGF). DESIGN A perspective, reviewing the current literature. METHODS Herein, we discuss the systemic safety of VEGF-targeted therapies, address safety issues for VEGF-targeted therapies in neovascular age-related macular degeneration, and propose the consideration of methods for identifying low rate systemic safety signals from patients treated with these agents. RESULTS Several prospective, randomized clinical trials have demonstrated that intravitreal anti-VEGF therapies generally are well tolerated. However, within these trials, there is some circumstantial evidence that links systemic VEGF inhibition to systemic adverse events, particularly systemic thromboembolic events. Because all of the intravitreal anti-VEGF agents have been associated with detectable levels in the systemic circulation, there is a scientific rationale for the occurrence of potential systemic adverse events. However, if safety issues are present, they occur at very low rates and may go undetected in controlled clinical trials of premarketed drugs. CONCLUSIONS We propose that highly sensitive methodologies be put into place for identifying low rate safety signals, including postmarketing clinical trials, chart reviews, electronic medical records, and various national and international registries and databases, to evaluate the systemic safety of antiangiogenic agents in ocular diseases such as neovascular age-related macular degeneration.