Emerging therapies for the treatment of neovascular age related macular degeneration

Numerous drugs that show promise in the treatment of neovascular age related macular degeneration are currently being evaluated in early clinical trials. Some of these drugs target the vascular endothelial growth factor pathway while others act on different targets along the angiogenesis cascade. The mechanism of action of these novel therapeutics and the results of early clinical trials will be discussed along with a review of angiogenesis.     

Transpupillary thermotherapy for choroidal neovascular membrane in age related macular degeneration

PURPOSE: To evaluate the efficacy of transpupillary thermotherapy (TTT) in choroidal neovasularisation (CNVM) secondary to age related macular degeneration (AMD). MATERIAL AND METHODS: Retrospective, non-randomized study of 28 eyes of 28 patients with subfoveal CNVM (classic, occult or mixed) secondary to AMD. RESULTS: Fifteen patients (53.57%) maintained their pre-treatment vision, 2 (7.14%) patients showed improvement of more than 2 lines and 11 (39.28%) patients showed deterioration of vision by >2 lines. Angiographic and clinical regression of CNVM was noted in 19 patients (67.8%) on an average follow up of 15.32 +/- 3.31 months. CONCLUSION: TTT leads to stabilisation of vision in 60% of treated eyes with CNVM due to AMD.     

Bevacizumab and neovascular age related macular degeneration: pathogenesis and treatment

The pathogenesis of neovascular age related macular degeneration (AMD) is multifactorial including inflammation and angiogenesis leading to choroidal neovascularization (CNV). Therapy against vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular AMD. Intravitreal off-label use of bevacizumab proved to be safe. This literature review was conducted to study improvement in visual acuity, change in central retinal thickness (CRT), safety, pharmacodynamics, and possible resistance to intravitreal bevacizumab over a one-year period in eyes with neovascular AMD. We reviewed articles between 1997 and January 2010 that included at least 30 patients with AMD who received intravitreal bevacizumab monotherapy for at least 1 year. The mean number of letters gained, decrease in CRT, and number of injections were 8 letters, 125.3 μm, and 4.3 injections, respectively. Further, randomized prospective clinical trials are needed to determine the efficacy and safety of intravitreal bevacizumab in the treatment of neovascular AMD.     

Cost utility of photodynamic therapy for predominantly classic neovascular age related macular degeneration

BACKGROUND/AIM: Age related macular degeneration (AMD) is the leading cause of severe vision impairment and blindness in older people throughout the developed world and currently affects around 420 000 UK citizens. Choroidal neovascularisation (CNV) is treatable with photodynamic therapy (PDT) but is expensive at over pound 1200 per treatment. The aim of this study was to assess the cost utility of PDT for better eye, predominantly classic, subfoveal choroidal neovascular lesions secondary to AMD. METHODS: Cost utility analysis (CUA) was conducted to estimate the cost effectiveness of PDT for scenarios involving reasonable (6/12) and poor (6/60) visual acuity. The models incorporated data from the Treatment of Age-related Macular Degeneration with PDT (TAP) Study and patient based utilities. The incremental CUA was based on decision analytical models, comparing treatment to a placebo comparator. Extensive one way sensitivity analysis of parameters was conducted to determine the robustness of the model. A discount rate of 6% was used for costs and quality adjusted life years (QALY). RESULTS: Model 1: in people with reasonable initial visual acuity, the cost utility of treating applicable neovascular AMD lesions was pound 31 607 per QALY saved, with a sensitivity analysis range from pound 25 285 to pound 37 928. Model 2: in people with poor initial visual acuity, the cost utility was pound 63 214 per QALY saved, with a sensitivity analysis range from pound 54 183 to pound 75 856. CONCLUSIONS: PDT treatment is the only available treatment for some forms of neovascular ("wet") AMD. Under these assumptions, PDT can be considered moderately cost effective for those with reasonable visual acuity but less cost effective for those with initial poor visual acuity. These findings have implications for ophthalmic practice and healthcare planning.     

Prospective evaluation of aflibercept in pigment epithelial detachments secondary to neovascular age related macular degeneration

ObjectiveTo assess the efficacy of intravitreal aflibercept in treating visual loss and structural changes in patients with pigment epithelial detachments (PED) secondary to neovascular age-related macular degeneration (nAMD).MethodsProspective, exploratory, open-label study (ClinicalTrials.gov Identifier: NCT02142296). Participants with PED secondary to nAMD were enrolled and received intravitreal aflibercept injection on a monthly basis for 3 months, followed by injections on a bimonthly basis for another 9 months. Best-corrected visual acuity (BCVA), ophthalmic examinations, optical coherence tomography (OCT) imaging, and fluorescein angiography were performed based on a predetermined schedule.ResultsThirty-six participants (37 eyes) were enrolled. At the end of study, 74.3% eyes demonstrated PED height reduction of 25% or more and 34.3% demonstrated complete resolution. The average reduction in retinal thickness was 128.4 μm. Participant eyes who had at least a 25% reduction in PED height at month 4 were labelled as “responders” (73.0%, n = 27), and those who had less than 25% reduction in PED height were labelled as “partial-responders” (27.0%, n = 10). Responders demonstrated more significant reduction in PED height than partial-responders (p <0.0001). The average gain in BCVA was 10.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Responders demonstrated more gain in BCVA than partial-responders (p = 0.0018). Among the responders, 57.7% demonstrated disease recurrences with increase in PED height during bimonthly dosing.ConclusionsIntravitreal aflibercept injection for patients with PEDs secondary to nAMD has high response rate with few adverse events. Responders demonstrated BCVA gains, as well as structural improvements. However, high recurrence rate was found on bimonthly maintenance dosing.     

Cultivation of retinal pigment epithelial cells from human choroidal neovascular membranes in age related macular degeneration

A method is described for cultivating retinal pigment epithelial cells from choroidal neovascular membrane (CNV) specimens that were surgically removed in patients with age-related macular degeneration (AMD). CNV specimens of 43 patients were available for cultivation. They were incubated in supplemented DMEM/Ham's F12 cell culture medium on microporous semipermeable filter membranes. Thirty-four specimens gave rise to cell cultures, 28 of which could be subcultivated for up to 15 passages. The membrane type as classified by fluorescence angiography was compared with cellular growth in vitro. Immunocytochemistry revealed a uniform expression of cytokeratin 18 and vimentin, while factor 8, glial fibrillary acidic protein and alpha smooth muscle actin were absent in all 21 cultures stained. The expression of RPE markers cellular retinaldehyde binding protein (CRALBP) and RPE65 was detected by RT-PCR in all cultures tested. An epithelial character of the cultures was supported by the presence of apical microvilli as determined by electron microscopical studies. Therefore, the cell cultures from CNV in AMD bear characteristics of retinal pigment epithelial cells. For the first time, this cell culture system holds the potential to study human RPE cells in the context of neovascular AMD in vitro.     

Morphopathological study in age related macular degeneration

The aim of this paper is to study the morphopathological changes manifested in age-related macular degeneration. MATERIAL AND METHOD: The researched histopathological material consisted in two eye balls enucleated because of irreversible eye diseases from aged persons suffering from age-related macular degeneration. The method applied for processing the material was inclusion in paraffin, followed by usual coloration with hematoxylin-eosin. RESULTS AND CONCLUSIONS: The established changes (hard drusen, soft drusen, calcified drusen, changes of Bruch's membrane, subretinal neovascularization, serous retinal pigment epithelial detachment, disciform degeneration) prove the importance of Bruch's membrane in the pathogenesis of age-related macular degeneration.     

Metabolic physiology in age related macular degeneration

Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and?convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization.     

New aspects in age related macular degeneration

Being the leading cause of blindness in modern world Age Related Macular Degeneration has beneficiated in the last decade of important progress in diagnosis, classification and the discovery of diverse factors who contribute to the etiology of this disease. Treatments have arised who can postpone the irreversible evolution of the disease and thus preserve vision. Recent findings have identified predisposing genetic factors and also inflamatory and imunological parameters that can be modified trough a good and adequate prevention and therapy This articole reviews new aspects of patology of Age Related Macular Degeneration like the role of complement in maintaining inflamation and the role of oxidative stress on different structures of the retina.     

Management of neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) is becoming an increasing socio-medical problem as the proportion of the aged population is continuously increasing. However, new insights in the pathogenesis of the disease offer the opportunity to develop targeted therapies that attack the disease process more successfully than ever. This review article will focus on summarizing the actual options in the management of neovascular AMD and provide a short overview about recent therapeutic options in clinical and preclinical evaluation. The recent development of anti-VEGF substances for use in clinical routine has markedly improved the prognosis of patients with neovascular AMD. Intravitreal treatment with substances targeting all isotypes of vascular endothelial growth factor (VEGF), for the first time in the history of AMD treatments, results in a significant increase in visual acuity in patients with neovascular AMD. Overall, anti-angiogenic approaches provide vision maintenance in over 90% and substantial improvement in 25-40% of patients. The combination with occlusive therapies like photodynamic therapy (PDT) potentially offers a reduction of re-treatment frequency and long-term maintenance of the treatment benefit. Further developments interacting with various steps in the angiogenic cascade are under clinical or preclinical evaluation and may soon become available. Nevertheless, the growing number of novel therapeutic options will have to provide proof of concept in randomized controlled clinical trials, a major challenge in view of the rapidly evolving field. For those therapies, which are already in clinical use, reasonable diagnostic tools for follow-up need to be developed, as the burden of continuous clinical monitoring of all patients and all indications is significant for patients and doctors. Ultimately, economic issues will be the limiting factor for the clinical availability of different treatment options.     

Review of genetics in age related macular degeneration

Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in industrialized countries. AMD is a complex disease caused by the combination of genetic predisposition and environmental factors. The prevalence of AMD increases with age. The adverse effect of smoking is well established. Genetic predisposition has been demonstrated by familial aggregation studies and twin studies. Using genome linkage scan and association studies, multiple potentially causative genes have been identified. The chromosomes most commonly implicated are 1q25-31 and 10q26. In particular, variants in the gene for the complement factor H (CFH) and the genes PLEKHA1/LOC387715/HTRA1, Factor B (BF) and complement component 2 (C2) have been implicated as major risk or protective factors for the development of AMD. There have been some advances in the treatment of this condition; however, a complete cure remains remote but hopeful. Understanding the causative environmental and genetic interactions will facilitate the development of future preventive methods and treatments.     

Effect of age related macular degeneration on the Eger macular stressometer photostress recovery time

AIM: To assess the repeatability of Eger macular stressometer (EMS) measures of photostress recovery and determine their association with other measures of visual function. METHODS: EMS photostress recovery time was measured in 90 patients with bilateral exudative age related macular degeneration (AMD), 19 with bilateral atrophic AMD and 47 with both forms of the condition (mean age 79 (SD 13) years). Measurements were made on two occasions separated by 1 year. Intrasession repeatability was assessed by repeating the measures after a 10 minute recovery period at the first visit. Distance visual acuity was measured with a logMAR chart, near visual acuity with a MNRead chart at 25 cm, contrast sensitivity with a Pelli-Robson chart, and the presence of central visual disturbance assessed with an Amsler grid. A questionnaire was used to assess self reported difficulties with glare recovery. RESULTS: The average EMS recovery time was 11.0 (SD 8.9) seconds, decreasing by 1.6 (5.2) seconds on repeated measurement (p<0.05). EMS photostress recovery was not correlated with visual function measures or subjective difficulties with lights (p>0.05). EMS photostress recovery time did not predict those whose vision decreased over the following year compared with those among whom it remained stable. CONCLUSIONS: The EMS test is not a useful tool in determining the severity or progression of AMD.     

Impact of age related macular degeneration on quality of life

AIMS: To describe the impact of age related macular degeneration (AMD) on quality of life and explore the association with vision, health, and demographic variables. METHODS: Adult participants diagnosed with AMD and with impaired vision (visual acuity <6/12) were assessed with the Impact of Vision Impairment (IVI) questionnaire. Participants rated the extent that vision restricted participation in activities affecting quality of life and completed the Short Form General Health Survey (SF-12) and a sociodemographic questionnaire. RESULTS: The mean age of the 106 participants (66% female) was 83.6 years (range 64-98). One quarter had mild vision impairment, (VA<6/12-6/18) and 75% had moderate or severely impaired vision. Participants reported from at least "a little" concern on 23 of the 32 IVI items including reading, emotional health, mobility, and participation in relevant activities. Those with mild and moderate vision impairment were similarly affected but significantly different from those with severe vision loss (p<0.05). Distance vision was associated with IVI scores but not age, sex, or duration of vision loss. CONCLUSION: AMD affects many quality of life related activities and not just those related to reading. Referral to low vision care services should be considered for people with mild vision loss and worse.